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Therapeutic Modalities for Musculoskeletal Injuries
by Craig R. Denegar, Ethan Saliba and Susan Saliba
384 Pages
Therapeutic Modalities for Musculoskeletal Injuries, Fourth Edition With Online Video, offers comprehensive coverage of evidence-based therapies for rehabilitation of musculoskeletal injuries. The information aligns with the Board of Certification’s Role Delineation Study/Practice Analysis, Sixth Edition, and the Commission on Accreditation of Athletic Training Education’s Athletic Training Education Competencies, Fifth Edition, and is a vital resource for students preparing for examinations as well as professionals in the field who wish to stay informed of the latest research.
Therapeutic Modalities for Musculoskeletal Injuries, Fourth Edition, applies evidence-based research and clinical experiences of top practitioners in the field to optimize the care of musculoskeletal injuries and provides students and practitioners with solid fundamentals in development of rehabilitation programs. The content of this fourth edition has been significantly updated and revitalized to include all modalities that coincide with BOC requirements and offers the latest in contemporary science in the field. Further updates include the following:
• New online video that corresponds to modalities discussed throughout the text, directly demonstrating how to apply techniques to individual patients
• A new chapter on mechanobiology that provides new understanding of the effects of movement and activity on cell function
• A new chapter on the application of exercise as a stimulus for tissue repair
• Additional information on the principles and clinical applications of cold, heat, electrotherapy, laser, and ultrasound
• Updated and revamped case studies and guided scenarios that apply all modalities found throughout the book to real-world situations
The content of the book is organized in parts to logically address therapeutic interventions for musculoskeletal injuries. Part I explains the core concepts of therapy, specifically in terms of clinical practice, and part II addresses the physiology of the acute response to tissue damage, tissue repair, and pain. Part III examines electrical modalities for pain management, provides an introduction to neuromuscular control, and addresses the use of biofeedback and neuromuscular stimulation to restore neuromuscular control in rehabilitation. Parts IV and V delve into a critical evaluation of therapeutic applications of cold, superficial heat, ultrasound, electromagnetic fields, and low-power laser therapy. Part VI examines foundational concepts of mechanobiology and explains how and why exercise and mechanical forces are essential to musculoskeletal tissue repair. Part VII brings all of the concepts from the text together through a series of case studies and guided scenarios, which allow students to apply fundamentals to real-world situations.
Therapeutic Modalities for Musculoskeletal Injuries, Fourth Edition With Online Video, contains many learning features to assist comprehension, including chapter objectives, key terms and a glossary, sidebars with clinical application of current concepts, and chapter summaries. Additionally, access to 21 online videos of applying modalities in clinical practice will help students better understand concepts from the text. For instructors, a robust set of ancillaries is provided, including a fully updated tesst package and instructor guide, as well as a newly added presentation package plus image bank to assist with lecture preparation.
Therapeutic Modalities for Musculoskeletal Injuries, Fourth Edition, explains how to apply each therapy and addresses why and when a therapeutic intervention can improve the outcome of care. Students and professionals alike will develop stronger decision-making skills when determining the safest and most effective use of each treatment method.
Part I: Principles of Therapeutic Modalities and Rehabilitation
Chapter 1. Fundamentals of Therapeutic Modalities
Chapter 2. Psychological Aspects of Injury and Rehabilitation
Chapter 3. Evidence-Based Application of Therapeutic Modalities
Part II: Physiology of Pain and Injury
Chapter 4. Tissue Healing
Chapter 5. Pain and Pain Relief
Chapter 6. Clinical Management of Pain
Part III: Electrical Modalities and Nerve Stimulation
Chapter 7. Principles of Electrical Modalities
Chapter 8. Clinical Application of Electrical Stimulation for Pain
Chapter 9. Arthrogenic Muscle Inhibition and Clinical Applications of Electrical Stimulation and Biofeedback
Part IV: Cold and Superficial Heat Therapies
Chapter 10. Principles of Cold and Superficial Heat
Chapter 11. Clinical Applications of Cold and Superficial Heat
Part V: Ultrasound, Electromagnetic Fields, and Laser Therapies
Chapter 12. Principles of Ultrasound and Diathermy
Chapter 13. Clinical Application of Ultrasound and Diathermy
Chapter 14. Principles of Low-Level Laser Therapy
Chapter 15. Clinical Application of Low-Level Laser Therapy
Part VI: Mechanobiology, Exercise, and Manual Therapies
Chapter 16. Mechanobiology
Chapter 17. Applications of Exercise and Manual Therapy to Promote Repair
Chapter 18. Mechanical Energy and Manual Therapies
Part VII: Putting it All Together
Chapter 19. Case Scenarios
Craig R. Denegar, PhD, PT, ATC, FNATA, is a professor in the department of kinesiology and director of the doctor of physical therapy program at the University of Connecticut. He has more than 30 years of experience as an athletic trainer and physical therapist and has extensive clinical practice experience related to persistent orthopedic pain.
Denegar is a member of the National Athletic Trainers’ Association (NATA) and the American Physical Therapy Association. He is editor in chief of the Journal of Athletic Training and serves on the editorial boards of the Journal of Sport Rehabilitation, Journal of Strength and Conditioning Research, and Open Access Journal of Sport Medicine. He is the former vice chair of free communications on the NATA Research and Education Foundation’s Research Committee and was the 2003 recipient of the William G. Clancy Medal for Distinguished Athletic Training Research and the 2004 Distinguished Merit Award from the Pennsylvania Athletic Trainers’ Society. Denegar was elected a fellow of the NATA in 2011 and recognized as a Most Distinguished Athletic Trainer by the NATA in 2014.
Ethan Saliba, PhD, ATC, PT, has been teaching therapeutic modalities at the University of Virginia at Charlottesville for over 25 years. He is the head athletic trainer and associate athletics director for sports medicine, and he oversees 25 varsity sports. Saliba is a certified athletic trainer, licensed physical therapist, and sport-certified specialist who has written extensively on various aspects of athletic injuries and rehabilitation. Saliba was honored as the NATA Head Athletic Trainer of the Year in 2007.
Susan Foreman Saliba, PhD, ATC, PT, is an associate professor in the Curry School of Education at the University of Virginia at Charlottesville. She has over 20 years of clinical experience and taught therapeutic modalities during that time. Susan is a member of both the NATA and the American Physical Therapy Association (APTA) and has served on the NATA Educational Executive Committee and the Free Communications Committee of the NATA Research and Education Foundation. She is conducting research on the clinical application of therapeutic modalities.
About the Contributors
Michael Joseph, PhD, PT, is an assistant professor in the department of kinesiology physical therapy program at the University of Connecticut. Joseph has more than 15 years of clinical experience as a physical therapist specializing in sports medicine and is a consultant for many professional and collegiate teams. He is a member of the American Physical Therapy Association and is on the editorial board of the Journal of Strength and Conditioning Research and the World Journal of Orthopedics. Joseph teaches clinical and musculoskeletal pathology, mechanobiology, and musculoskeletal evaluation and treatment. His focus of research is the adaptation of connective tissue to physiological loading.
Kavin Tsang, PhD, ATC, is an associate professor in the department of kinesiology at California State University at Fullerton. He is an active member of the National Athletic Trainers’ Association (NATA) and an athletic trainer certified by the Board of Certification. His clinical experiences encompass physical therapy clinics, high school athletics, collegiate intramural programs, and intercolleegiate athletics. He has been teaching therapeutic modalities in various athletic training education curricula for over 14 years. Tsang serves on the NATA Research and Education Foundation (NATA REF) Board of Directors, NATA REF Free Communications Committee, NATA Convention Program Committee, and FWATA Education Program Committee. He is also chair of the Far West Athletic Trainers’ Association (FWATA) Research and Grants Committee.
"The book meets the needs of everyone from new students to long-time professionals by clearly explaining each concept in both basic terms and in-depth detail… The inclusion of manual therapies, mechanical energy, and exercise as modalities is vital as these are emerging concepts in the healthcare and injury management fields. This book compares well with other books on therapeutic modalities, and is the most complete resource."
--Doody’s Book Review
Using Ultrasound as a Therapeutic Modality
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions.
Ultrasound
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions. Different frequencies of ultrasound are used for each application. The ultrasound units used in the practice of athletic training and physical therapy emit sound energy at frequencies between 800 kHz (800,000 Hz) and 3 MHz (3,000,000 Hz). Modern high-quality ultrasound units allow the clinician to select the treatment frequency. Typically a clinician can choose frequencies near 1 MHz and 3.3 MHz. Some units are also adjustable to 2 MHz (figure 12.1). The importance of frequency and the applications of ultrasound at various frequencies will be discussed in detail. Initially, it is important to understand that therapeutic ultrasound uses acoustic energy, delivered at very specific high frequencies.
Modern combination ultrasound, laser, and electrotherapy device.
Ultrasound machines use electrical current to create a mechanical vibration in a crystalline material housed in the "head" of the unit. Vibration of the crystalline material produces a wave of acoustic energy (ultrasound) (figure 12.2). The crystalline material in modern ultrasound devices is synthetic, although natural crystals were once used. The sound energy emitted from the ultrasound head travels through tissues and is absorbed.
Components of an ultrasound unit.
Ultrasound technology is now used extensively for diagnostic imaging. Ultrasound in the range of 3.5 MHz to 15 MHz is used to image organs of the abdomen and thorax as well as musculoskeletal tissues (Whittaker et al. 2007). Ultrasound is also routinely used for prenatal examination. Through ultrasound, some correctable birth defects can be identified, and the sex of the fetus can also be determined.
In musculoskeletal care, ultrasound can be used to detect muscle strains, ligament sprains, and degenerative changes in tendon. The sound energy used for imaging differs in frequency and pulse characteristics from that used for therapeutic purposes.
Beam Nonuniformity Ratio and Effective Radiating
Two terms describe the size and quality of an ultrasound crystal found in therapeutic ultrasound devices. Effective radiating area (ERA) is the area that receives at least 5% of the peak sound energy. This is essentially the size of the area to which sound energy is conducted when the head of the ultrasound unit contacts the skin. The ERA is somewhat smaller than the surface area of the sound head.
The beam of sound energy emitted from a crystal is not uniform but rather is characterized by areas of high intensity and lower intensity (figure 12.3). Beam nonuniformity ratio (BNR)is the ratio of the average intensity of the ultrasound beam across the ERA divided by the peak intensity of the ultrasound beam; the lower the BNR, the more uniform the intensity of the sound wave.
Beam scan of a crystal with a beam nonuniformity ratio (BNR) of 2.32, (a) top view and (b) side view. When tested on 40 subjects, the ultrasound transducer housing this crystal produced a very comfortable treatment at 1.5 to 2.0 watts per cm2 (W/cm2). Beam scan of a crystal with a BNR of 7.75, (c) top view. When this was tested on 40 subjects, the ultrasound transducer housing the crystal produced an uncomfortable treatment at 1.5 W/cm2 and was not tolerated at 2.0 W/cm2.
Courtesy of Brigham Young University Sports Injury Research Center.
A low BNR minimizes the risk of developing "hot spots" and allows the clinician to deliver higher doses of ultrasound without causing pain and discomfort. The BNR must be listed by the manufacturer on all units. Ideally, the BNR would be 1; however, this is impossible, and the acceptable range is between 2 and 6.
Unfortunately, BNR and ERA may not adequately define how an ultrasound unit will function. Holcomb and Joyce (2003) reported significant differences in the change in tissue temperature between two ultrasound units with a BNR of 3.7 and 2.3 and an ERA of 4.9 and 4.6 cm, respectively. These authors speculated that the area of peak intensity or peak area of the maximum beam nonuniformity ratio (PAMBNR) as described by Draper (1999) might explain why two ultrasound units differ in performance. Certainly a small spike of peak amplitude as illustrated in figure 12.4 will deliver less energy and therefore have less thermal effect than that provided by a larger area of peak amplitude. Johns, Straub, and Howard (2007) and Straub, Johns, and Howard (2008) reported considerable variability in ERA and special average intensity in 3 and 1 MHz ultrasound units, respectively, from different manufacturers. Differences between reported and actual ERA values were identified for all but one manufacturer when 3 MHz sound heads were evaluated (Johns, Straub, and Howard 2007). Demchak, Straub, and Johns (2007) noted differences in the rate but not peak heating of the calf muscles using three different 1 MHz ultrasound transducers. Johns et al. (2007), however, have reported greater heating with 1 MHz sound heads with more concentrated energy fields. The issue of equipment performance across parameters requires further study. Variability in the characteristics of the acoustic energy field may yield differing treatment effects and perhaps pose a risk of adverse events. Frye et al. (2007) reported blistering of the anterior shin after ultrasound to the calf muscles in laboratory experiments employing common clinical treatment parameters.
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The area of peak intensity, (a) small and (b) larger, may affect the performance of ultrasound devices.
Conducting Media
Air is a poor conductor of ultrasound energy. To maximize delivery of sound energy to the tissues, a conducting medium must be used. Several substances have been used to conduct ultrasound, including ultrasound gel, gel pads, mineral oil, lotions, and water. The amount of sound energy conducted varies substantially between conducting media. Commercial ultrasound gel (Draper 1996; Draper et al. 1993; Klucinec et al. 2000) and gel pads (Klucinec et al. 2000; Klucinec 1996) (figure 12.5) are superior conducting media. Water is not as good a conducting medium (Draper 1996; Draper et al. 1993; Klucinec et al. 2000; Klucinec 1996; Forrest and Rosen 1989, 1992), attenuating as much as 65% of the sound energy (Klucinec et al. 2000).
Ultrasound gel and gel pads.
Rubley et al. (2008) reported smaller differences (approximately 15%) in Achilles tendon tissue heating when comparing gel and degassed water as conducting media. Differences in research methods and ultrasound equipment may explain the estimated magnitude of differences between conducting media. Collectively, however, the research suggests that ultrasound gel is the conducting medium of choice for clinical administration of therapeutic ultrasound. The conducting capacities of most gels and creams have not been established. However, some have been shown to be very poor conductors of sound energy (Cameron and Monroe 1992; Draper 1996; Draper et al. 1993; Forrest and Rosen 1989, 1992; Klucinec 1996; Klucinec et al. 2000). When applying ultrasound, use gels and gel pads known to be effective conductors.
Parameters of Treatment with Ultrasound
As with electrotherapy, you can alter the treatment parameters of ultrasound depending on the desired effect. Fortunately, the number of adjustable parameters is smaller. You can control the amplitude of the sound waves and therefore the amount of sound energy being emitted from the sound head. The sound energy emitted by the crystal is measured in watts (W). The dose of sound energy delivered is based on the amount of energy being emitted divided by the radiating area of the crystal measured in square centimeters (cm2). Thus, ultrasound dose is measured in W/cm2. You can also adjust the duty cycle, duration of treatment, and frequency.
Duty cycle refers to the process of interrupting delivery of the sound wave so that periods of sound wave emission are interspersed with periods of interruption. Figure 12.6 depicts pulsed and continuous ultrasound.
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(a) In pulsed ultrasound, energy is generated only during the "on" time. Duty cycle is determined by the ratio of "on" time to pulse, in this case 50%. (b) Continuous ultrasound is shown.
Often you can select between several duty cycles. Duty cycle is calculated by dividing the time during which sound is delivered by the total time the sound head is applied. For example, if ultrasound is transmitted for 150 ms out of every second of treatment, then the duty cycle is 150/1,000, or 15%. When the emission of sound energy is not interrupted, the duty cycle equals 100%, and the ultrasound is referred to as continuous ultrasound.
Much has been learned about the treatment duration needed to elevate tissue temperatures. An interaction among the frequency, dose, and treatment duration has also been found. Some recipes for duration and intensities of ultrasound treatments used in the past do not increase tissue temperature sufficiently.
The frequency of the sound waves affects the depth at which the greatest amount of ultrasound energy is absorbed, as well as the time required to increase tissue temperature. Ultrasound units typically allow for treatment with more than one frequency, but older units had a single fixed frequency of 1 MHz. Treatments with higher frequencies are usually more appropriate for musculoskeletal injuries.
Sound Energy Absorption in Tissues
The amount of acoustic energy absorbed by tissues is influenced by many factors. The tissue characteristics, as well as the frequency, dose (W/cm2), duty cycle, and duration of treatment with ultrasound affect the amount of acoustic energy absorbed. When continuous ultrasound is delivered, the greater the energy absorption, the greater the tissue heating. Tissues with greater protein density have a higher rate of absorption, whereas tissues with a higher water content have lower absorption rates. Thus, tendon, ligament, and muscle tissue absorb more sound energy than skin and adipose tissue. Superficial bones and nerves absorb the most energy.
Ultrasound at a higher frequency (3 MHz) is absorbed more rapidly than that at a lower frequency (1 MHz) (figure 12.7). Therefore, ultrasound at higher frequencies affects tissues that are more superficial, whereas at a lower frequency less energy is absorbed superficially and more is available to penetrate into tissues. Thus, if the goal of treatment is to heat the capsular tissue at a joint such as the elbow with ultrasound, a 3 MHz frequency is appropriate. Temperature increases of up to 8°C have been reported with 3 MHz ultrasound at 1 W/cm2 in 4 min in superficial tissues such as the patellar tendon (Chan et al. 1998). If the target tissue is deep tissue, a lower frequency (1 MHz) is necessary; 10 min of continuous 1 MHz ultrasound at 2.0 W/cm2 will elevate temperature about 4°C at a depth of 2.5 cm (Draper, Castel, and Castel 1995). There is likely considerable overlap in tissue heating between 1 and 3 MHz ultrasound, as heating of tissues at 2.5 cm depths with 3 MHz ultrasound has been reported (Hayes et al. 2004). The interactions between ultrasound parameters and thermal response are discussed further shortly.
A great depth of heating is achieved with 1 MHz. The specific depth of heating is device dependent, and the values provided represent a range rather than specific limits of thermal responses.
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Mechanobiology in the Musculoskeletal System
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis.
Mechanobiology in Tendon
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis. Tendon is relatively avascular and therefore relies largely on autocrine and paracrine responses for tissue remodeling, repair, and adaptation. In addition to tenocytes, progenitor cells exist in tendon, and they are extremely mechanosensitive. Inappropriate mechanical load pushes these progenitors toward alternate phenotypes (chondrocytes, adipocytes, osteocytes), which results in the pathologic changes characteristic of tendinosis. Tendinosis is a common histologic finding in overuse tendon injuries that is characterized by noninflammatory degenerative changes of the ECM and aberrant cellular responses.
Tendon attaches muscle to bone, transmitting forces to the skeleton and resulting in joint stabilization and movement. As a result, tendons are subjected to high mechanical loads that predispose them to injury. Tendon's reaction to overuse injury has been described as a failed healing response (Maffulli, Sharma, and Luscombe 2004) due to the ineffective and insufficient inflammatory response generated after injury.
Tendon pathology may be classified as either tendonitis: inflammation, pain, and swelling of the peritenon; tendinosis: degeneration of the ECM and absence of inflammation upon histologic examination; or tendinopathy. Tendinopathy is the contemporary clinical term for tendon overuse injuries, as it does not imply an active inflammatory process, which is often the case.
While the etiologic factors of tendinopathy are not fully understood, a failure in the mechanobiologic response of the tenocyte has been implicated. Tendon structure, composition, and mechanical properties are modified in response to altered mechanical loading conditions. Disruption in the mechanobiologic response of the tenocyte creates a vicious cycle of suboptimal ECM production, in turn leading to further changes in mechanical signals transmitted to the tenocyte and propagating degenerative tissue production throughout the tendon (figure 16.8). Many hypothesize that mechanical overload initiates a degenerative signaling cascade that leads to tendinopathy, while some believe tendinopathy is a result of focal disruption of ECM and accompanying mechanobiologic understimulation of locally adherent tenocytes and progenitor cells.
Pathologic changes in tendinopathy. (a) Collagen organization: H&E. (b) Increased proteoglycan.
Reprinted, by permission, from M. Joseph et al., 2009, "Histological and molecular analysis of the biceps tendon long head post-tenotomy," The Journal of Orthopedic Research 27:1379-1385.
Signaling cascades leading to tendinosis probably result from understimulation of FACs and downstream MAPK-mediated events. The activation of stress-activated protein kinase (SAPK), a member of the MAPK family, is associated with matrix-degrading enzyme production. As mentioned, load affects progenitor cell survival and differentiation. Tendon progenitor cells exposed to 4% strain assume tenocyte function and express collagen type I. However, loads of 8% resulted in the expression of markers for bone, fat, and cartilage differentiation. The presence of these cells and their functional products is destructive to tendon ECM and health (Wang et al. 2007).
An alternative paradigm for the pathophysiology of tendinopathy is emerging and involves tenocyte-produced neuropeptides. Chemical messengers thought to be confined to neurons are produced in abundance in tendinopathic tissue. Substance P and its receptor (neurokinin-1 receptor [NK-1 R]), glutamate (Scott, Alfredson, and Forsgren 2008), acetylcholine (ACTH), and catecholamines are produced by local tendon fibroblasts. Tenocytes produce these neurochemicals in response to mechanical load. Substance P increases cellular proliferation in culture, which corresponds with observations of hypercellularity in early tendinosis. Pain in tendinopathic tissue has been traced to neurovascular ingrowth containing substance P positive nerve fibers, and the ablation of these fibers often results in relief. The NK-1 R is a G-protein coupled receptor that is responsive to mechanical signals. There is likely cross talk between integrin-linked kinase production resulting from integrin stimulation and cross-activation of the G-protein via ILK activation (see figure 16.5). Substance P signals through the MAPK cascade and results in gene expression.
Tendon cell networks communicate throughout the tissue via cytoplasmic extensions and cell junction zones. A signal that is sent in one area propagates through these channels, effecting a tissue-wide response. Intercellular connectivity is achieved through gap junctions, where connexins are the principal protein. In healthy tendon, tenocytes are arranged longitudinally between collagen fibers. Connexins 32 and 34 form communications between longitudinally arranged tenocytes, whereas connexin 43 links cells in all directions (Ragsdale, Phelps, and Luby-Phelps 1997).
Mechanobiology in Articular Cartilage
Articular cartilage is the major load-bearing tissue in synovial joints. Cartilage is unique in that it is avascular, aneural, alymphatic, and sparsely populated with cells. The cartilage cell (chondrocyte) is responsible for the remodeling of cartilage ECM, and it does so in response to mechanical force. Cartilage in relatively unloaded areas such as the medial patellar facet is softer and less resilient. Articular cartilage responds favorably to pulsatile doses of load, while static loading results in up-regulation of a host of inflammatory cytokines, matrix-degrading enzymes, and degeneration.
Chondrocytes are extremely responsive to compressive loads, as their location and function would indicate. A pericellular matrix composed of collagen VI and proteoglycan surrounds the chondrocyte and is an independent unit of force transduction. The pericellular matrix is analogous to the basal lamina in skeletal muscle, bridging the gap between cell membrane and ECM.
Membrane stretch - activated ion channels exist, are proximate to integrins, and likely have overlapping downstream signaling cascades. Stimulation of the integrin α5β1 pathway results in the production of aggrecan, the predominant proteoglycan in cartilage, along with the down-regulation of MMP3, the predominant degrading enzyme of PG. Higher levels of aggrecan and collagen II production are associated with dynamic compressive force, whereas static forces result in MMP production and ECM destruction. Chondrocytes from arthritic cartilage are unresponsive to mechanical stimulation, indicating cellular dysfunction and mechanoinsensitivity in osteoarthritis (Raizman 2010).
Inappropriate mechanical loading is the primary risk factor for the development of osteoarthritis (OA) (figure 16.9). OA is characterized by a loss of tissue homeostasis and the prevalence of catabolism. Molecular components of mechanotransduction in chondrocytes consist of integrin activation and downstream MAPK signaling, as well as stress-activated calcium channel signaling. The α5β1 integrin binds pericellular matrix fibronectin and associates with calcium channels in the surrounding cell membrane. In response to mechanical stimuli, integrin and calcium signaling pathways converge on MAPK cascade, where Ca2+ regulation of integrin activity through Src occurs (Raizman et al. 2010).
Damaged articular cartilage. Large defect in the medial femoral condyle.
The Cbp/p300-interacting transactivator 2 (CITED2) is a transcription regulator that is thought to balance catabolic and anticatabolic cascades and is thus centrally implicated in the pathogenesis of OA (Leong et al. 2011). CITED2 binds with and modulates a host of transcription factors. The ability to activate anabolic pathways and to inhibit inflammatory and catabolic pathways in response to mechanical signals suggests a central role in mechanical regulation. CITED2 is downstream of MAPK. Moderate-intensity intermittent loads activate CITED2, whereas high-intensity loads do not (Leong et al. 2011). Increased CITED2 expression correlates with the production of collagen II, maintenance of ECM, and suppression of MMPs. Integrin and associated receptors, downstream MAPK, and CITED2 represent a loading-specific pathway that has direct effects on tissue. Thus, loading of cartilage is essential to tissue health while overload leads to degeneration and OA. Exercise can play an important role in the treatment of OA, but excessive loading may accelerate the disease process.
In summary, the chondrocyte is dependent upon mechanical signals for survival. The aneural, avascular nature of articular cartilage accounts for its susceptibility to damage. Enhanced maintenance and repair of articular cartilage is possible through mechanobiologic manipulation. Chondrocyte preference for dynamic, pulsatile delivery of force will continue to be explored both in exercise prescription and modality delivery.
Mechanobiology in Bone
Metabolic demands on the skeleton are managed largely through calciotropic hormones, but the ability of the skeleton to adapt to its loading environment is essential for bone health. Wolff's law first proposed skeletal change in response to functional demands. We now understand that it is the cells of the skeleton - the osteoblasts, osteocytes, and osteoclasts - that remodel bone in response to stress. An example of bone's sensitivity to mechanical demand is demonstrated in cortical bone of the dominant arm in elite tennis players, which can be up to 35% thicker than the cortical bone of the non-dominant arm. Rapid bone loss during periods of immobility and in microgravity exemplifies the homeostatic necessity of mechanotransduction.
Bone is certainly not as deformable as connective tissue, at least elastically. Bone can experience up to 0.3% strain, much less than ligament or tendon (5% - 20%). Bone experiences a wide variety of mechanical stimuli that produce slight deformation in the bone tissue, pressure in the intramedullary cavity and within the cortices, transient pressure waves, and fluid shear forces through the canaliculi.
Osteoblasts at the surface of bone respond to deformation of the cell membrane from strain experienced on the surface of the bone from imposed forces. Osteocytes located deeper in the bone tissue respond to shear stress of fluid flow through the canaliculi (figure 16.10). An externally applied load forces fluid out of regions of high compressive strains. This fluid returns when the load is removed. This results in bone cell exposure to an oscillating fluid flow. The osteocyte population, through its interconnectedness via gap junctions, comprises a three-dimensional sensing systemin which amplification of mechanical signals propagates throughout the tissue.
Structure and lacuna canalicular network of bone.
As in tendon, integrins are important conductors of mechanical signals in bone cells (Salter, Robb, and Wright 1997). In bone, the β subunit of the integrin extracellular domain mediates binding to matrix components. Prominent matrix ligands for integrin in bone include collagen I and III and fibronectin. The formation of FAC in response to integrin activation is critical to cell adhesion, survival, and production. Mechanical signals activate the MAPK cascade, leading to down-regulation of RANK ligand (RANKL) expression and the formation of osteoclasts.
Strain, shear, and pressure result in the mobilization of intracellular calcium. This rapid increase in intracellular calcium concentration appears to occur due to phospholipase-C activity and IP3 signaling, which results in the release of calcium from intracellular stores (calcium-mediated calcium release).
Summary
Musculoskeletal cells are exposed to forces transmitted through tissue. Mechanotransduction pathways modulate diverse cellular functions. Physiologic effects result from intracellular signaling of membrane receptors and ion channels. The integrin receptor, bound to the tissue and stimulated by stress, can coactivate cytokine receptors and ion channels, resulting in a coordinated cell response. The musculoskeletal system provides a link to the physical environment. The encompassing nature of mechanical signaling likely represents the primary means by which adaptation to force exposure occurs. For clinicians this is exciting, as much of what we do involves modulating force through exercise and physical interventions. The obvious hurdle in fully accessing this tool is the difficulty of quantifying in vivo human forces, both those that result in injury and those produced by specific mechanical interventions. Future research and technology will be essential for identifying optimal mechanical interventions and their specific prescription. This chapter outlines the biology underpinning mechanical intervention. Harnessing the power of mechanotransduction is our most powerful tool for affecting musculoskeletal health and adaptation.
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Case Scenario: Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries.
Case Scenario 1
Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries. A neurological screen was normal, and concussion assessment and diagnostic imaging were negative. She complains of pain (6 on a scale of 10 with walking and standing) and muscle spasm in her neck and upper back, and intermittent headaches made worse with prolonged sitting and exercise and relieved by oral over-the-counter medication and lying down. She states at times she gets pain that radiates down her right arm.
She states that she is married and has no children. She works as a college tennis coach and director of the campus tennis center. Her medical history is unremarkable other than having sustained a right sprained ankle in high school and having wisdom teeth removed.
On presentation she denies lightheadedness, concentration and memory deficits, tinnitus or vision disturbances, and a history of neck injuries. On examination, the patient's head is slightly tilted to the left side. The patient has limited active and passive rotation and side-bending to the right side and painful end-range extension. She has tenderness to palpation along the right cervical paraspinal muscles. Upper quarter scan for sensory, strength, and reflex deficits is normal. Physical examination reveals restricted left side-glide at C5-C6, and the patient is evaluated as suffering from a flexed, left rotated, and side-bent facet with soft tissue pain and muscle spasm.
The patient complains that she has difficulty raising her right arm overhead and that her neck and upper back pain increase with prolonged sitting, driving, and lifting and carrying.
The forces involved in motor vehicle accidents can cause catastrophic injuries. The whiplash mechanism of injury may result in fracture, sprain, and muscle strain. The medical history, history of the current condition, and medical and physical examinations conducted in this case provide assurance that serious structural damage has been avoided. A thorough examination and evaluation of all pertinent information is needed before proceeding with a rehabilitation plan of care, especially in conditions involving the spine.
The first step in developing a rehabilitation plan of care is the development of a problem list. It is usually best to build a problem list around the impairments, functional limitations, and participation restrictions identified in the evaluation of the case. From the problem list, mutually agreeable short-term goals can be developed and a goal-directed application of therapeutic modalities, manual therapy, and exercise developed.
What are the problems identified in this case?
Impairments
- Pain
- Loss of cervical range of motion
- Headache
Functional limitations
- Reaching overhead and prolonged sitting/driving
Participation restrictions
- Unable to play tennis or coach effectively due to pain and loss of motion
- Has difficulty with management responsibilities due to poor tolerance of sitting
The clinician has several options to recommend for the problems listed. Pain and muscle spasm could be treated with periodic cold or superficial heat. TENS could be used as needed for the same purposes.
What would you do?
A decision on the treatment needs to be based on any contraindications for an intervention, the current condition, the patient's preferences, the clinician's experiences, and existing clinical research. After ruling out contraindications to the treatment options and conferring with the patient about the ability to control pain with oral medications, it is decided to treat her with massage to decrease pain and muscle spasm before performing joint mobilization to restore range of motion. The patient states that a hot shower is soothing and that she has access to superficial heat. She demonstrates a substantial increase in cervical range of motion after the initial treatment. She is instructed in active range of motion exercises and agrees with a plan of 20 to 30 min of superficial heating as needed for relief of pain and spasm and a four-times-per-day regimen of active range of motion, which is also to be performed after heat application. Over two subsequent visits she reports the resolution of pain at rest other than mild aching and stiffness upon rising, and she demonstrates full cervical range of motion. Postural and functional exercises are introduced to increase tolerance to daily activities and return to coaching. Three and a half weeks after her accident she is able to work a normal day, drive, and play tennis for up to an hour without limitations. She is discharged to continue with a postural and tennis function exercise program.
This case illustrates some of the complexities of developing a plan of care. There is not a single correct approach to meeting the needs of many patients. The first mandate is to do no harm. The clinician and patient must then decide which problems are most concerning, discuss the options, and agree on a plan. Once short-term goals are achieved, the intervention progresses. Modalities used to relieve pain and muscle spasm are replaced by exercises aimed at addressing functional limitations and participation restrictions.
Learn more about Therapeutic Modalities for Musculoskeletal Injuries, Fourth Edition With Online Video.
Using Ultrasound as a Therapeutic Modality
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions.
Ultrasound
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions. Different frequencies of ultrasound are used for each application. The ultrasound units used in the practice of athletic training and physical therapy emit sound energy at frequencies between 800 kHz (800,000 Hz) and 3 MHz (3,000,000 Hz). Modern high-quality ultrasound units allow the clinician to select the treatment frequency. Typically a clinician can choose frequencies near 1 MHz and 3.3 MHz. Some units are also adjustable to 2 MHz (figure 12.1). The importance of frequency and the applications of ultrasound at various frequencies will be discussed in detail. Initially, it is important to understand that therapeutic ultrasound uses acoustic energy, delivered at very specific high frequencies.
Modern combination ultrasound, laser, and electrotherapy device.
Ultrasound machines use electrical current to create a mechanical vibration in a crystalline material housed in the "head" of the unit. Vibration of the crystalline material produces a wave of acoustic energy (ultrasound) (figure 12.2). The crystalline material in modern ultrasound devices is synthetic, although natural crystals were once used. The sound energy emitted from the ultrasound head travels through tissues and is absorbed.
Components of an ultrasound unit.
Ultrasound technology is now used extensively for diagnostic imaging. Ultrasound in the range of 3.5 MHz to 15 MHz is used to image organs of the abdomen and thorax as well as musculoskeletal tissues (Whittaker et al. 2007). Ultrasound is also routinely used for prenatal examination. Through ultrasound, some correctable birth defects can be identified, and the sex of the fetus can also be determined.
In musculoskeletal care, ultrasound can be used to detect muscle strains, ligament sprains, and degenerative changes in tendon. The sound energy used for imaging differs in frequency and pulse characteristics from that used for therapeutic purposes.
Beam Nonuniformity Ratio and Effective Radiating
Two terms describe the size and quality of an ultrasound crystal found in therapeutic ultrasound devices. Effective radiating area (ERA) is the area that receives at least 5% of the peak sound energy. This is essentially the size of the area to which sound energy is conducted when the head of the ultrasound unit contacts the skin. The ERA is somewhat smaller than the surface area of the sound head.
The beam of sound energy emitted from a crystal is not uniform but rather is characterized by areas of high intensity and lower intensity (figure 12.3). Beam nonuniformity ratio (BNR)is the ratio of the average intensity of the ultrasound beam across the ERA divided by the peak intensity of the ultrasound beam; the lower the BNR, the more uniform the intensity of the sound wave.
Beam scan of a crystal with a beam nonuniformity ratio (BNR) of 2.32, (a) top view and (b) side view. When tested on 40 subjects, the ultrasound transducer housing this crystal produced a very comfortable treatment at 1.5 to 2.0 watts per cm2 (W/cm2). Beam scan of a crystal with a BNR of 7.75, (c) top view. When this was tested on 40 subjects, the ultrasound transducer housing the crystal produced an uncomfortable treatment at 1.5 W/cm2 and was not tolerated at 2.0 W/cm2.
Courtesy of Brigham Young University Sports Injury Research Center.
A low BNR minimizes the risk of developing "hot spots" and allows the clinician to deliver higher doses of ultrasound without causing pain and discomfort. The BNR must be listed by the manufacturer on all units. Ideally, the BNR would be 1; however, this is impossible, and the acceptable range is between 2 and 6.
Unfortunately, BNR and ERA may not adequately define how an ultrasound unit will function. Holcomb and Joyce (2003) reported significant differences in the change in tissue temperature between two ultrasound units with a BNR of 3.7 and 2.3 and an ERA of 4.9 and 4.6 cm, respectively. These authors speculated that the area of peak intensity or peak area of the maximum beam nonuniformity ratio (PAMBNR) as described by Draper (1999) might explain why two ultrasound units differ in performance. Certainly a small spike of peak amplitude as illustrated in figure 12.4 will deliver less energy and therefore have less thermal effect than that provided by a larger area of peak amplitude. Johns, Straub, and Howard (2007) and Straub, Johns, and Howard (2008) reported considerable variability in ERA and special average intensity in 3 and 1 MHz ultrasound units, respectively, from different manufacturers. Differences between reported and actual ERA values were identified for all but one manufacturer when 3 MHz sound heads were evaluated (Johns, Straub, and Howard 2007). Demchak, Straub, and Johns (2007) noted differences in the rate but not peak heating of the calf muscles using three different 1 MHz ultrasound transducers. Johns et al. (2007), however, have reported greater heating with 1 MHz sound heads with more concentrated energy fields. The issue of equipment performance across parameters requires further study. Variability in the characteristics of the acoustic energy field may yield differing treatment effects and perhaps pose a risk of adverse events. Frye et al. (2007) reported blistering of the anterior shin after ultrasound to the calf muscles in laboratory experiments employing common clinical treatment parameters.
| |
The area of peak intensity, (a) small and (b) larger, may affect the performance of ultrasound devices.
Conducting Media
Air is a poor conductor of ultrasound energy. To maximize delivery of sound energy to the tissues, a conducting medium must be used. Several substances have been used to conduct ultrasound, including ultrasound gel, gel pads, mineral oil, lotions, and water. The amount of sound energy conducted varies substantially between conducting media. Commercial ultrasound gel (Draper 1996; Draper et al. 1993; Klucinec et al. 2000) and gel pads (Klucinec et al. 2000; Klucinec 1996) (figure 12.5) are superior conducting media. Water is not as good a conducting medium (Draper 1996; Draper et al. 1993; Klucinec et al. 2000; Klucinec 1996; Forrest and Rosen 1989, 1992), attenuating as much as 65% of the sound energy (Klucinec et al. 2000).
Ultrasound gel and gel pads.
Rubley et al. (2008) reported smaller differences (approximately 15%) in Achilles tendon tissue heating when comparing gel and degassed water as conducting media. Differences in research methods and ultrasound equipment may explain the estimated magnitude of differences between conducting media. Collectively, however, the research suggests that ultrasound gel is the conducting medium of choice for clinical administration of therapeutic ultrasound. The conducting capacities of most gels and creams have not been established. However, some have been shown to be very poor conductors of sound energy (Cameron and Monroe 1992; Draper 1996; Draper et al. 1993; Forrest and Rosen 1989, 1992; Klucinec 1996; Klucinec et al. 2000). When applying ultrasound, use gels and gel pads known to be effective conductors.
Parameters of Treatment with Ultrasound
As with electrotherapy, you can alter the treatment parameters of ultrasound depending on the desired effect. Fortunately, the number of adjustable parameters is smaller. You can control the amplitude of the sound waves and therefore the amount of sound energy being emitted from the sound head. The sound energy emitted by the crystal is measured in watts (W). The dose of sound energy delivered is based on the amount of energy being emitted divided by the radiating area of the crystal measured in square centimeters (cm2). Thus, ultrasound dose is measured in W/cm2. You can also adjust the duty cycle, duration of treatment, and frequency.
Duty cycle refers to the process of interrupting delivery of the sound wave so that periods of sound wave emission are interspersed with periods of interruption. Figure 12.6 depicts pulsed and continuous ultrasound.
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(a) In pulsed ultrasound, energy is generated only during the "on" time. Duty cycle is determined by the ratio of "on" time to pulse, in this case 50%. (b) Continuous ultrasound is shown.
Often you can select between several duty cycles. Duty cycle is calculated by dividing the time during which sound is delivered by the total time the sound head is applied. For example, if ultrasound is transmitted for 150 ms out of every second of treatment, then the duty cycle is 150/1,000, or 15%. When the emission of sound energy is not interrupted, the duty cycle equals 100%, and the ultrasound is referred to as continuous ultrasound.
Much has been learned about the treatment duration needed to elevate tissue temperatures. An interaction among the frequency, dose, and treatment duration has also been found. Some recipes for duration and intensities of ultrasound treatments used in the past do not increase tissue temperature sufficiently.
The frequency of the sound waves affects the depth at which the greatest amount of ultrasound energy is absorbed, as well as the time required to increase tissue temperature. Ultrasound units typically allow for treatment with more than one frequency, but older units had a single fixed frequency of 1 MHz. Treatments with higher frequencies are usually more appropriate for musculoskeletal injuries.
Sound Energy Absorption in Tissues
The amount of acoustic energy absorbed by tissues is influenced by many factors. The tissue characteristics, as well as the frequency, dose (W/cm2), duty cycle, and duration of treatment with ultrasound affect the amount of acoustic energy absorbed. When continuous ultrasound is delivered, the greater the energy absorption, the greater the tissue heating. Tissues with greater protein density have a higher rate of absorption, whereas tissues with a higher water content have lower absorption rates. Thus, tendon, ligament, and muscle tissue absorb more sound energy than skin and adipose tissue. Superficial bones and nerves absorb the most energy.
Ultrasound at a higher frequency (3 MHz) is absorbed more rapidly than that at a lower frequency (1 MHz) (figure 12.7). Therefore, ultrasound at higher frequencies affects tissues that are more superficial, whereas at a lower frequency less energy is absorbed superficially and more is available to penetrate into tissues. Thus, if the goal of treatment is to heat the capsular tissue at a joint such as the elbow with ultrasound, a 3 MHz frequency is appropriate. Temperature increases of up to 8°C have been reported with 3 MHz ultrasound at 1 W/cm2 in 4 min in superficial tissues such as the patellar tendon (Chan et al. 1998). If the target tissue is deep tissue, a lower frequency (1 MHz) is necessary; 10 min of continuous 1 MHz ultrasound at 2.0 W/cm2 will elevate temperature about 4°C at a depth of 2.5 cm (Draper, Castel, and Castel 1995). There is likely considerable overlap in tissue heating between 1 and 3 MHz ultrasound, as heating of tissues at 2.5 cm depths with 3 MHz ultrasound has been reported (Hayes et al. 2004). The interactions between ultrasound parameters and thermal response are discussed further shortly.
A great depth of heating is achieved with 1 MHz. The specific depth of heating is device dependent, and the values provided represent a range rather than specific limits of thermal responses.
Learn more about Therapeutic Modalities for Musculoskeletal Injuries, Fourth Edition With Online Video.
Mechanobiology in the Musculoskeletal System
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis.
Mechanobiology in Tendon
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis. Tendon is relatively avascular and therefore relies largely on autocrine and paracrine responses for tissue remodeling, repair, and adaptation. In addition to tenocytes, progenitor cells exist in tendon, and they are extremely mechanosensitive. Inappropriate mechanical load pushes these progenitors toward alternate phenotypes (chondrocytes, adipocytes, osteocytes), which results in the pathologic changes characteristic of tendinosis. Tendinosis is a common histologic finding in overuse tendon injuries that is characterized by noninflammatory degenerative changes of the ECM and aberrant cellular responses.
Tendon attaches muscle to bone, transmitting forces to the skeleton and resulting in joint stabilization and movement. As a result, tendons are subjected to high mechanical loads that predispose them to injury. Tendon's reaction to overuse injury has been described as a failed healing response (Maffulli, Sharma, and Luscombe 2004) due to the ineffective and insufficient inflammatory response generated after injury.
Tendon pathology may be classified as either tendonitis: inflammation, pain, and swelling of the peritenon; tendinosis: degeneration of the ECM and absence of inflammation upon histologic examination; or tendinopathy. Tendinopathy is the contemporary clinical term for tendon overuse injuries, as it does not imply an active inflammatory process, which is often the case.
While the etiologic factors of tendinopathy are not fully understood, a failure in the mechanobiologic response of the tenocyte has been implicated. Tendon structure, composition, and mechanical properties are modified in response to altered mechanical loading conditions. Disruption in the mechanobiologic response of the tenocyte creates a vicious cycle of suboptimal ECM production, in turn leading to further changes in mechanical signals transmitted to the tenocyte and propagating degenerative tissue production throughout the tendon (figure 16.8). Many hypothesize that mechanical overload initiates a degenerative signaling cascade that leads to tendinopathy, while some believe tendinopathy is a result of focal disruption of ECM and accompanying mechanobiologic understimulation of locally adherent tenocytes and progenitor cells.
Pathologic changes in tendinopathy. (a) Collagen organization: H&E. (b) Increased proteoglycan.
Reprinted, by permission, from M. Joseph et al., 2009, "Histological and molecular analysis of the biceps tendon long head post-tenotomy," The Journal of Orthopedic Research 27:1379-1385.
Signaling cascades leading to tendinosis probably result from understimulation of FACs and downstream MAPK-mediated events. The activation of stress-activated protein kinase (SAPK), a member of the MAPK family, is associated with matrix-degrading enzyme production. As mentioned, load affects progenitor cell survival and differentiation. Tendon progenitor cells exposed to 4% strain assume tenocyte function and express collagen type I. However, loads of 8% resulted in the expression of markers for bone, fat, and cartilage differentiation. The presence of these cells and their functional products is destructive to tendon ECM and health (Wang et al. 2007).
An alternative paradigm for the pathophysiology of tendinopathy is emerging and involves tenocyte-produced neuropeptides. Chemical messengers thought to be confined to neurons are produced in abundance in tendinopathic tissue. Substance P and its receptor (neurokinin-1 receptor [NK-1 R]), glutamate (Scott, Alfredson, and Forsgren 2008), acetylcholine (ACTH), and catecholamines are produced by local tendon fibroblasts. Tenocytes produce these neurochemicals in response to mechanical load. Substance P increases cellular proliferation in culture, which corresponds with observations of hypercellularity in early tendinosis. Pain in tendinopathic tissue has been traced to neurovascular ingrowth containing substance P positive nerve fibers, and the ablation of these fibers often results in relief. The NK-1 R is a G-protein coupled receptor that is responsive to mechanical signals. There is likely cross talk between integrin-linked kinase production resulting from integrin stimulation and cross-activation of the G-protein via ILK activation (see figure 16.5). Substance P signals through the MAPK cascade and results in gene expression.
Tendon cell networks communicate throughout the tissue via cytoplasmic extensions and cell junction zones. A signal that is sent in one area propagates through these channels, effecting a tissue-wide response. Intercellular connectivity is achieved through gap junctions, where connexins are the principal protein. In healthy tendon, tenocytes are arranged longitudinally between collagen fibers. Connexins 32 and 34 form communications between longitudinally arranged tenocytes, whereas connexin 43 links cells in all directions (Ragsdale, Phelps, and Luby-Phelps 1997).
Mechanobiology in Articular Cartilage
Articular cartilage is the major load-bearing tissue in synovial joints. Cartilage is unique in that it is avascular, aneural, alymphatic, and sparsely populated with cells. The cartilage cell (chondrocyte) is responsible for the remodeling of cartilage ECM, and it does so in response to mechanical force. Cartilage in relatively unloaded areas such as the medial patellar facet is softer and less resilient. Articular cartilage responds favorably to pulsatile doses of load, while static loading results in up-regulation of a host of inflammatory cytokines, matrix-degrading enzymes, and degeneration.
Chondrocytes are extremely responsive to compressive loads, as their location and function would indicate. A pericellular matrix composed of collagen VI and proteoglycan surrounds the chondrocyte and is an independent unit of force transduction. The pericellular matrix is analogous to the basal lamina in skeletal muscle, bridging the gap between cell membrane and ECM.
Membrane stretch - activated ion channels exist, are proximate to integrins, and likely have overlapping downstream signaling cascades. Stimulation of the integrin α5β1 pathway results in the production of aggrecan, the predominant proteoglycan in cartilage, along with the down-regulation of MMP3, the predominant degrading enzyme of PG. Higher levels of aggrecan and collagen II production are associated with dynamic compressive force, whereas static forces result in MMP production and ECM destruction. Chondrocytes from arthritic cartilage are unresponsive to mechanical stimulation, indicating cellular dysfunction and mechanoinsensitivity in osteoarthritis (Raizman 2010).
Inappropriate mechanical loading is the primary risk factor for the development of osteoarthritis (OA) (figure 16.9). OA is characterized by a loss of tissue homeostasis and the prevalence of catabolism. Molecular components of mechanotransduction in chondrocytes consist of integrin activation and downstream MAPK signaling, as well as stress-activated calcium channel signaling. The α5β1 integrin binds pericellular matrix fibronectin and associates with calcium channels in the surrounding cell membrane. In response to mechanical stimuli, integrin and calcium signaling pathways converge on MAPK cascade, where Ca2+ regulation of integrin activity through Src occurs (Raizman et al. 2010).
Damaged articular cartilage. Large defect in the medial femoral condyle.
The Cbp/p300-interacting transactivator 2 (CITED2) is a transcription regulator that is thought to balance catabolic and anticatabolic cascades and is thus centrally implicated in the pathogenesis of OA (Leong et al. 2011). CITED2 binds with and modulates a host of transcription factors. The ability to activate anabolic pathways and to inhibit inflammatory and catabolic pathways in response to mechanical signals suggests a central role in mechanical regulation. CITED2 is downstream of MAPK. Moderate-intensity intermittent loads activate CITED2, whereas high-intensity loads do not (Leong et al. 2011). Increased CITED2 expression correlates with the production of collagen II, maintenance of ECM, and suppression of MMPs. Integrin and associated receptors, downstream MAPK, and CITED2 represent a loading-specific pathway that has direct effects on tissue. Thus, loading of cartilage is essential to tissue health while overload leads to degeneration and OA. Exercise can play an important role in the treatment of OA, but excessive loading may accelerate the disease process.
In summary, the chondrocyte is dependent upon mechanical signals for survival. The aneural, avascular nature of articular cartilage accounts for its susceptibility to damage. Enhanced maintenance and repair of articular cartilage is possible through mechanobiologic manipulation. Chondrocyte preference for dynamic, pulsatile delivery of force will continue to be explored both in exercise prescription and modality delivery.
Mechanobiology in Bone
Metabolic demands on the skeleton are managed largely through calciotropic hormones, but the ability of the skeleton to adapt to its loading environment is essential for bone health. Wolff's law first proposed skeletal change in response to functional demands. We now understand that it is the cells of the skeleton - the osteoblasts, osteocytes, and osteoclasts - that remodel bone in response to stress. An example of bone's sensitivity to mechanical demand is demonstrated in cortical bone of the dominant arm in elite tennis players, which can be up to 35% thicker than the cortical bone of the non-dominant arm. Rapid bone loss during periods of immobility and in microgravity exemplifies the homeostatic necessity of mechanotransduction.
Bone is certainly not as deformable as connective tissue, at least elastically. Bone can experience up to 0.3% strain, much less than ligament or tendon (5% - 20%). Bone experiences a wide variety of mechanical stimuli that produce slight deformation in the bone tissue, pressure in the intramedullary cavity and within the cortices, transient pressure waves, and fluid shear forces through the canaliculi.
Osteoblasts at the surface of bone respond to deformation of the cell membrane from strain experienced on the surface of the bone from imposed forces. Osteocytes located deeper in the bone tissue respond to shear stress of fluid flow through the canaliculi (figure 16.10). An externally applied load forces fluid out of regions of high compressive strains. This fluid returns when the load is removed. This results in bone cell exposure to an oscillating fluid flow. The osteocyte population, through its interconnectedness via gap junctions, comprises a three-dimensional sensing systemin which amplification of mechanical signals propagates throughout the tissue.
Structure and lacuna canalicular network of bone.
As in tendon, integrins are important conductors of mechanical signals in bone cells (Salter, Robb, and Wright 1997). In bone, the β subunit of the integrin extracellular domain mediates binding to matrix components. Prominent matrix ligands for integrin in bone include collagen I and III and fibronectin. The formation of FAC in response to integrin activation is critical to cell adhesion, survival, and production. Mechanical signals activate the MAPK cascade, leading to down-regulation of RANK ligand (RANKL) expression and the formation of osteoclasts.
Strain, shear, and pressure result in the mobilization of intracellular calcium. This rapid increase in intracellular calcium concentration appears to occur due to phospholipase-C activity and IP3 signaling, which results in the release of calcium from intracellular stores (calcium-mediated calcium release).
Summary
Musculoskeletal cells are exposed to forces transmitted through tissue. Mechanotransduction pathways modulate diverse cellular functions. Physiologic effects result from intracellular signaling of membrane receptors and ion channels. The integrin receptor, bound to the tissue and stimulated by stress, can coactivate cytokine receptors and ion channels, resulting in a coordinated cell response. The musculoskeletal system provides a link to the physical environment. The encompassing nature of mechanical signaling likely represents the primary means by which adaptation to force exposure occurs. For clinicians this is exciting, as much of what we do involves modulating force through exercise and physical interventions. The obvious hurdle in fully accessing this tool is the difficulty of quantifying in vivo human forces, both those that result in injury and those produced by specific mechanical interventions. Future research and technology will be essential for identifying optimal mechanical interventions and their specific prescription. This chapter outlines the biology underpinning mechanical intervention. Harnessing the power of mechanotransduction is our most powerful tool for affecting musculoskeletal health and adaptation.
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Case Scenario: Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries.
Case Scenario 1
Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries. A neurological screen was normal, and concussion assessment and diagnostic imaging were negative. She complains of pain (6 on a scale of 10 with walking and standing) and muscle spasm in her neck and upper back, and intermittent headaches made worse with prolonged sitting and exercise and relieved by oral over-the-counter medication and lying down. She states at times she gets pain that radiates down her right arm.
She states that she is married and has no children. She works as a college tennis coach and director of the campus tennis center. Her medical history is unremarkable other than having sustained a right sprained ankle in high school and having wisdom teeth removed.
On presentation she denies lightheadedness, concentration and memory deficits, tinnitus or vision disturbances, and a history of neck injuries. On examination, the patient's head is slightly tilted to the left side. The patient has limited active and passive rotation and side-bending to the right side and painful end-range extension. She has tenderness to palpation along the right cervical paraspinal muscles. Upper quarter scan for sensory, strength, and reflex deficits is normal. Physical examination reveals restricted left side-glide at C5-C6, and the patient is evaluated as suffering from a flexed, left rotated, and side-bent facet with soft tissue pain and muscle spasm.
The patient complains that she has difficulty raising her right arm overhead and that her neck and upper back pain increase with prolonged sitting, driving, and lifting and carrying.
The forces involved in motor vehicle accidents can cause catastrophic injuries. The whiplash mechanism of injury may result in fracture, sprain, and muscle strain. The medical history, history of the current condition, and medical and physical examinations conducted in this case provide assurance that serious structural damage has been avoided. A thorough examination and evaluation of all pertinent information is needed before proceeding with a rehabilitation plan of care, especially in conditions involving the spine.
The first step in developing a rehabilitation plan of care is the development of a problem list. It is usually best to build a problem list around the impairments, functional limitations, and participation restrictions identified in the evaluation of the case. From the problem list, mutually agreeable short-term goals can be developed and a goal-directed application of therapeutic modalities, manual therapy, and exercise developed.
What are the problems identified in this case?
Impairments
- Pain
- Loss of cervical range of motion
- Headache
Functional limitations
- Reaching overhead and prolonged sitting/driving
Participation restrictions
- Unable to play tennis or coach effectively due to pain and loss of motion
- Has difficulty with management responsibilities due to poor tolerance of sitting
The clinician has several options to recommend for the problems listed. Pain and muscle spasm could be treated with periodic cold or superficial heat. TENS could be used as needed for the same purposes.
What would you do?
A decision on the treatment needs to be based on any contraindications for an intervention, the current condition, the patient's preferences, the clinician's experiences, and existing clinical research. After ruling out contraindications to the treatment options and conferring with the patient about the ability to control pain with oral medications, it is decided to treat her with massage to decrease pain and muscle spasm before performing joint mobilization to restore range of motion. The patient states that a hot shower is soothing and that she has access to superficial heat. She demonstrates a substantial increase in cervical range of motion after the initial treatment. She is instructed in active range of motion exercises and agrees with a plan of 20 to 30 min of superficial heating as needed for relief of pain and spasm and a four-times-per-day regimen of active range of motion, which is also to be performed after heat application. Over two subsequent visits she reports the resolution of pain at rest other than mild aching and stiffness upon rising, and she demonstrates full cervical range of motion. Postural and functional exercises are introduced to increase tolerance to daily activities and return to coaching. Three and a half weeks after her accident she is able to work a normal day, drive, and play tennis for up to an hour without limitations. She is discharged to continue with a postural and tennis function exercise program.
This case illustrates some of the complexities of developing a plan of care. There is not a single correct approach to meeting the needs of many patients. The first mandate is to do no harm. The clinician and patient must then decide which problems are most concerning, discuss the options, and agree on a plan. Once short-term goals are achieved, the intervention progresses. Modalities used to relieve pain and muscle spasm are replaced by exercises aimed at addressing functional limitations and participation restrictions.
Learn more about Therapeutic Modalities for Musculoskeletal Injuries, Fourth Edition With Online Video.
Using Ultrasound as a Therapeutic Modality
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions.
Ultrasound
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions. Different frequencies of ultrasound are used for each application. The ultrasound units used in the practice of athletic training and physical therapy emit sound energy at frequencies between 800 kHz (800,000 Hz) and 3 MHz (3,000,000 Hz). Modern high-quality ultrasound units allow the clinician to select the treatment frequency. Typically a clinician can choose frequencies near 1 MHz and 3.3 MHz. Some units are also adjustable to 2 MHz (figure 12.1). The importance of frequency and the applications of ultrasound at various frequencies will be discussed in detail. Initially, it is important to understand that therapeutic ultrasound uses acoustic energy, delivered at very specific high frequencies.
Modern combination ultrasound, laser, and electrotherapy device.
Ultrasound machines use electrical current to create a mechanical vibration in a crystalline material housed in the "head" of the unit. Vibration of the crystalline material produces a wave of acoustic energy (ultrasound) (figure 12.2). The crystalline material in modern ultrasound devices is synthetic, although natural crystals were once used. The sound energy emitted from the ultrasound head travels through tissues and is absorbed.
Components of an ultrasound unit.
Ultrasound technology is now used extensively for diagnostic imaging. Ultrasound in the range of 3.5 MHz to 15 MHz is used to image organs of the abdomen and thorax as well as musculoskeletal tissues (Whittaker et al. 2007). Ultrasound is also routinely used for prenatal examination. Through ultrasound, some correctable birth defects can be identified, and the sex of the fetus can also be determined.
In musculoskeletal care, ultrasound can be used to detect muscle strains, ligament sprains, and degenerative changes in tendon. The sound energy used for imaging differs in frequency and pulse characteristics from that used for therapeutic purposes.
Beam Nonuniformity Ratio and Effective Radiating
Two terms describe the size and quality of an ultrasound crystal found in therapeutic ultrasound devices. Effective radiating area (ERA) is the area that receives at least 5% of the peak sound energy. This is essentially the size of the area to which sound energy is conducted when the head of the ultrasound unit contacts the skin. The ERA is somewhat smaller than the surface area of the sound head.
The beam of sound energy emitted from a crystal is not uniform but rather is characterized by areas of high intensity and lower intensity (figure 12.3). Beam nonuniformity ratio (BNR)is the ratio of the average intensity of the ultrasound beam across the ERA divided by the peak intensity of the ultrasound beam; the lower the BNR, the more uniform the intensity of the sound wave.
Beam scan of a crystal with a beam nonuniformity ratio (BNR) of 2.32, (a) top view and (b) side view. When tested on 40 subjects, the ultrasound transducer housing this crystal produced a very comfortable treatment at 1.5 to 2.0 watts per cm2 (W/cm2). Beam scan of a crystal with a BNR of 7.75, (c) top view. When this was tested on 40 subjects, the ultrasound transducer housing the crystal produced an uncomfortable treatment at 1.5 W/cm2 and was not tolerated at 2.0 W/cm2.
Courtesy of Brigham Young University Sports Injury Research Center.
A low BNR minimizes the risk of developing "hot spots" and allows the clinician to deliver higher doses of ultrasound without causing pain and discomfort. The BNR must be listed by the manufacturer on all units. Ideally, the BNR would be 1; however, this is impossible, and the acceptable range is between 2 and 6.
Unfortunately, BNR and ERA may not adequately define how an ultrasound unit will function. Holcomb and Joyce (2003) reported significant differences in the change in tissue temperature between two ultrasound units with a BNR of 3.7 and 2.3 and an ERA of 4.9 and 4.6 cm, respectively. These authors speculated that the area of peak intensity or peak area of the maximum beam nonuniformity ratio (PAMBNR) as described by Draper (1999) might explain why two ultrasound units differ in performance. Certainly a small spike of peak amplitude as illustrated in figure 12.4 will deliver less energy and therefore have less thermal effect than that provided by a larger area of peak amplitude. Johns, Straub, and Howard (2007) and Straub, Johns, and Howard (2008) reported considerable variability in ERA and special average intensity in 3 and 1 MHz ultrasound units, respectively, from different manufacturers. Differences between reported and actual ERA values were identified for all but one manufacturer when 3 MHz sound heads were evaluated (Johns, Straub, and Howard 2007). Demchak, Straub, and Johns (2007) noted differences in the rate but not peak heating of the calf muscles using three different 1 MHz ultrasound transducers. Johns et al. (2007), however, have reported greater heating with 1 MHz sound heads with more concentrated energy fields. The issue of equipment performance across parameters requires further study. Variability in the characteristics of the acoustic energy field may yield differing treatment effects and perhaps pose a risk of adverse events. Frye et al. (2007) reported blistering of the anterior shin after ultrasound to the calf muscles in laboratory experiments employing common clinical treatment parameters.
| |
The area of peak intensity, (a) small and (b) larger, may affect the performance of ultrasound devices.
Conducting Media
Air is a poor conductor of ultrasound energy. To maximize delivery of sound energy to the tissues, a conducting medium must be used. Several substances have been used to conduct ultrasound, including ultrasound gel, gel pads, mineral oil, lotions, and water. The amount of sound energy conducted varies substantially between conducting media. Commercial ultrasound gel (Draper 1996; Draper et al. 1993; Klucinec et al. 2000) and gel pads (Klucinec et al. 2000; Klucinec 1996) (figure 12.5) are superior conducting media. Water is not as good a conducting medium (Draper 1996; Draper et al. 1993; Klucinec et al. 2000; Klucinec 1996; Forrest and Rosen 1989, 1992), attenuating as much as 65% of the sound energy (Klucinec et al. 2000).
Ultrasound gel and gel pads.
Rubley et al. (2008) reported smaller differences (approximately 15%) in Achilles tendon tissue heating when comparing gel and degassed water as conducting media. Differences in research methods and ultrasound equipment may explain the estimated magnitude of differences between conducting media. Collectively, however, the research suggests that ultrasound gel is the conducting medium of choice for clinical administration of therapeutic ultrasound. The conducting capacities of most gels and creams have not been established. However, some have been shown to be very poor conductors of sound energy (Cameron and Monroe 1992; Draper 1996; Draper et al. 1993; Forrest and Rosen 1989, 1992; Klucinec 1996; Klucinec et al. 2000). When applying ultrasound, use gels and gel pads known to be effective conductors.
Parameters of Treatment with Ultrasound
As with electrotherapy, you can alter the treatment parameters of ultrasound depending on the desired effect. Fortunately, the number of adjustable parameters is smaller. You can control the amplitude of the sound waves and therefore the amount of sound energy being emitted from the sound head. The sound energy emitted by the crystal is measured in watts (W). The dose of sound energy delivered is based on the amount of energy being emitted divided by the radiating area of the crystal measured in square centimeters (cm2). Thus, ultrasound dose is measured in W/cm2. You can also adjust the duty cycle, duration of treatment, and frequency.
Duty cycle refers to the process of interrupting delivery of the sound wave so that periods of sound wave emission are interspersed with periods of interruption. Figure 12.6 depicts pulsed and continuous ultrasound.
| |
(a) In pulsed ultrasound, energy is generated only during the "on" time. Duty cycle is determined by the ratio of "on" time to pulse, in this case 50%. (b) Continuous ultrasound is shown.
Often you can select between several duty cycles. Duty cycle is calculated by dividing the time during which sound is delivered by the total time the sound head is applied. For example, if ultrasound is transmitted for 150 ms out of every second of treatment, then the duty cycle is 150/1,000, or 15%. When the emission of sound energy is not interrupted, the duty cycle equals 100%, and the ultrasound is referred to as continuous ultrasound.
Much has been learned about the treatment duration needed to elevate tissue temperatures. An interaction among the frequency, dose, and treatment duration has also been found. Some recipes for duration and intensities of ultrasound treatments used in the past do not increase tissue temperature sufficiently.
The frequency of the sound waves affects the depth at which the greatest amount of ultrasound energy is absorbed, as well as the time required to increase tissue temperature. Ultrasound units typically allow for treatment with more than one frequency, but older units had a single fixed frequency of 1 MHz. Treatments with higher frequencies are usually more appropriate for musculoskeletal injuries.
Sound Energy Absorption in Tissues
The amount of acoustic energy absorbed by tissues is influenced by many factors. The tissue characteristics, as well as the frequency, dose (W/cm2), duty cycle, and duration of treatment with ultrasound affect the amount of acoustic energy absorbed. When continuous ultrasound is delivered, the greater the energy absorption, the greater the tissue heating. Tissues with greater protein density have a higher rate of absorption, whereas tissues with a higher water content have lower absorption rates. Thus, tendon, ligament, and muscle tissue absorb more sound energy than skin and adipose tissue. Superficial bones and nerves absorb the most energy.
Ultrasound at a higher frequency (3 MHz) is absorbed more rapidly than that at a lower frequency (1 MHz) (figure 12.7). Therefore, ultrasound at higher frequencies affects tissues that are more superficial, whereas at a lower frequency less energy is absorbed superficially and more is available to penetrate into tissues. Thus, if the goal of treatment is to heat the capsular tissue at a joint such as the elbow with ultrasound, a 3 MHz frequency is appropriate. Temperature increases of up to 8°C have been reported with 3 MHz ultrasound at 1 W/cm2 in 4 min in superficial tissues such as the patellar tendon (Chan et al. 1998). If the target tissue is deep tissue, a lower frequency (1 MHz) is necessary; 10 min of continuous 1 MHz ultrasound at 2.0 W/cm2 will elevate temperature about 4°C at a depth of 2.5 cm (Draper, Castel, and Castel 1995). There is likely considerable overlap in tissue heating between 1 and 3 MHz ultrasound, as heating of tissues at 2.5 cm depths with 3 MHz ultrasound has been reported (Hayes et al. 2004). The interactions between ultrasound parameters and thermal response are discussed further shortly.
A great depth of heating is achieved with 1 MHz. The specific depth of heating is device dependent, and the values provided represent a range rather than specific limits of thermal responses.
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Mechanobiology in the Musculoskeletal System
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis.
Mechanobiology in Tendon
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis. Tendon is relatively avascular and therefore relies largely on autocrine and paracrine responses for tissue remodeling, repair, and adaptation. In addition to tenocytes, progenitor cells exist in tendon, and they are extremely mechanosensitive. Inappropriate mechanical load pushes these progenitors toward alternate phenotypes (chondrocytes, adipocytes, osteocytes), which results in the pathologic changes characteristic of tendinosis. Tendinosis is a common histologic finding in overuse tendon injuries that is characterized by noninflammatory degenerative changes of the ECM and aberrant cellular responses.
Tendon attaches muscle to bone, transmitting forces to the skeleton and resulting in joint stabilization and movement. As a result, tendons are subjected to high mechanical loads that predispose them to injury. Tendon's reaction to overuse injury has been described as a failed healing response (Maffulli, Sharma, and Luscombe 2004) due to the ineffective and insufficient inflammatory response generated after injury.
Tendon pathology may be classified as either tendonitis: inflammation, pain, and swelling of the peritenon; tendinosis: degeneration of the ECM and absence of inflammation upon histologic examination; or tendinopathy. Tendinopathy is the contemporary clinical term for tendon overuse injuries, as it does not imply an active inflammatory process, which is often the case.
While the etiologic factors of tendinopathy are not fully understood, a failure in the mechanobiologic response of the tenocyte has been implicated. Tendon structure, composition, and mechanical properties are modified in response to altered mechanical loading conditions. Disruption in the mechanobiologic response of the tenocyte creates a vicious cycle of suboptimal ECM production, in turn leading to further changes in mechanical signals transmitted to the tenocyte and propagating degenerative tissue production throughout the tendon (figure 16.8). Many hypothesize that mechanical overload initiates a degenerative signaling cascade that leads to tendinopathy, while some believe tendinopathy is a result of focal disruption of ECM and accompanying mechanobiologic understimulation of locally adherent tenocytes and progenitor cells.
Pathologic changes in tendinopathy. (a) Collagen organization: H&E. (b) Increased proteoglycan.
Reprinted, by permission, from M. Joseph et al., 2009, "Histological and molecular analysis of the biceps tendon long head post-tenotomy," The Journal of Orthopedic Research 27:1379-1385.
Signaling cascades leading to tendinosis probably result from understimulation of FACs and downstream MAPK-mediated events. The activation of stress-activated protein kinase (SAPK), a member of the MAPK family, is associated with matrix-degrading enzyme production. As mentioned, load affects progenitor cell survival and differentiation. Tendon progenitor cells exposed to 4% strain assume tenocyte function and express collagen type I. However, loads of 8% resulted in the expression of markers for bone, fat, and cartilage differentiation. The presence of these cells and their functional products is destructive to tendon ECM and health (Wang et al. 2007).
An alternative paradigm for the pathophysiology of tendinopathy is emerging and involves tenocyte-produced neuropeptides. Chemical messengers thought to be confined to neurons are produced in abundance in tendinopathic tissue. Substance P and its receptor (neurokinin-1 receptor [NK-1 R]), glutamate (Scott, Alfredson, and Forsgren 2008), acetylcholine (ACTH), and catecholamines are produced by local tendon fibroblasts. Tenocytes produce these neurochemicals in response to mechanical load. Substance P increases cellular proliferation in culture, which corresponds with observations of hypercellularity in early tendinosis. Pain in tendinopathic tissue has been traced to neurovascular ingrowth containing substance P positive nerve fibers, and the ablation of these fibers often results in relief. The NK-1 R is a G-protein coupled receptor that is responsive to mechanical signals. There is likely cross talk between integrin-linked kinase production resulting from integrin stimulation and cross-activation of the G-protein via ILK activation (see figure 16.5). Substance P signals through the MAPK cascade and results in gene expression.
Tendon cell networks communicate throughout the tissue via cytoplasmic extensions and cell junction zones. A signal that is sent in one area propagates through these channels, effecting a tissue-wide response. Intercellular connectivity is achieved through gap junctions, where connexins are the principal protein. In healthy tendon, tenocytes are arranged longitudinally between collagen fibers. Connexins 32 and 34 form communications between longitudinally arranged tenocytes, whereas connexin 43 links cells in all directions (Ragsdale, Phelps, and Luby-Phelps 1997).
Mechanobiology in Articular Cartilage
Articular cartilage is the major load-bearing tissue in synovial joints. Cartilage is unique in that it is avascular, aneural, alymphatic, and sparsely populated with cells. The cartilage cell (chondrocyte) is responsible for the remodeling of cartilage ECM, and it does so in response to mechanical force. Cartilage in relatively unloaded areas such as the medial patellar facet is softer and less resilient. Articular cartilage responds favorably to pulsatile doses of load, while static loading results in up-regulation of a host of inflammatory cytokines, matrix-degrading enzymes, and degeneration.
Chondrocytes are extremely responsive to compressive loads, as their location and function would indicate. A pericellular matrix composed of collagen VI and proteoglycan surrounds the chondrocyte and is an independent unit of force transduction. The pericellular matrix is analogous to the basal lamina in skeletal muscle, bridging the gap between cell membrane and ECM.
Membrane stretch - activated ion channels exist, are proximate to integrins, and likely have overlapping downstream signaling cascades. Stimulation of the integrin α5β1 pathway results in the production of aggrecan, the predominant proteoglycan in cartilage, along with the down-regulation of MMP3, the predominant degrading enzyme of PG. Higher levels of aggrecan and collagen II production are associated with dynamic compressive force, whereas static forces result in MMP production and ECM destruction. Chondrocytes from arthritic cartilage are unresponsive to mechanical stimulation, indicating cellular dysfunction and mechanoinsensitivity in osteoarthritis (Raizman 2010).
Inappropriate mechanical loading is the primary risk factor for the development of osteoarthritis (OA) (figure 16.9). OA is characterized by a loss of tissue homeostasis and the prevalence of catabolism. Molecular components of mechanotransduction in chondrocytes consist of integrin activation and downstream MAPK signaling, as well as stress-activated calcium channel signaling. The α5β1 integrin binds pericellular matrix fibronectin and associates with calcium channels in the surrounding cell membrane. In response to mechanical stimuli, integrin and calcium signaling pathways converge on MAPK cascade, where Ca2+ regulation of integrin activity through Src occurs (Raizman et al. 2010).
Damaged articular cartilage. Large defect in the medial femoral condyle.
The Cbp/p300-interacting transactivator 2 (CITED2) is a transcription regulator that is thought to balance catabolic and anticatabolic cascades and is thus centrally implicated in the pathogenesis of OA (Leong et al. 2011). CITED2 binds with and modulates a host of transcription factors. The ability to activate anabolic pathways and to inhibit inflammatory and catabolic pathways in response to mechanical signals suggests a central role in mechanical regulation. CITED2 is downstream of MAPK. Moderate-intensity intermittent loads activate CITED2, whereas high-intensity loads do not (Leong et al. 2011). Increased CITED2 expression correlates with the production of collagen II, maintenance of ECM, and suppression of MMPs. Integrin and associated receptors, downstream MAPK, and CITED2 represent a loading-specific pathway that has direct effects on tissue. Thus, loading of cartilage is essential to tissue health while overload leads to degeneration and OA. Exercise can play an important role in the treatment of OA, but excessive loading may accelerate the disease process.
In summary, the chondrocyte is dependent upon mechanical signals for survival. The aneural, avascular nature of articular cartilage accounts for its susceptibility to damage. Enhanced maintenance and repair of articular cartilage is possible through mechanobiologic manipulation. Chondrocyte preference for dynamic, pulsatile delivery of force will continue to be explored both in exercise prescription and modality delivery.
Mechanobiology in Bone
Metabolic demands on the skeleton are managed largely through calciotropic hormones, but the ability of the skeleton to adapt to its loading environment is essential for bone health. Wolff's law first proposed skeletal change in response to functional demands. We now understand that it is the cells of the skeleton - the osteoblasts, osteocytes, and osteoclasts - that remodel bone in response to stress. An example of bone's sensitivity to mechanical demand is demonstrated in cortical bone of the dominant arm in elite tennis players, which can be up to 35% thicker than the cortical bone of the non-dominant arm. Rapid bone loss during periods of immobility and in microgravity exemplifies the homeostatic necessity of mechanotransduction.
Bone is certainly not as deformable as connective tissue, at least elastically. Bone can experience up to 0.3% strain, much less than ligament or tendon (5% - 20%). Bone experiences a wide variety of mechanical stimuli that produce slight deformation in the bone tissue, pressure in the intramedullary cavity and within the cortices, transient pressure waves, and fluid shear forces through the canaliculi.
Osteoblasts at the surface of bone respond to deformation of the cell membrane from strain experienced on the surface of the bone from imposed forces. Osteocytes located deeper in the bone tissue respond to shear stress of fluid flow through the canaliculi (figure 16.10). An externally applied load forces fluid out of regions of high compressive strains. This fluid returns when the load is removed. This results in bone cell exposure to an oscillating fluid flow. The osteocyte population, through its interconnectedness via gap junctions, comprises a three-dimensional sensing systemin which amplification of mechanical signals propagates throughout the tissue.
Structure and lacuna canalicular network of bone.
As in tendon, integrins are important conductors of mechanical signals in bone cells (Salter, Robb, and Wright 1997). In bone, the β subunit of the integrin extracellular domain mediates binding to matrix components. Prominent matrix ligands for integrin in bone include collagen I and III and fibronectin. The formation of FAC in response to integrin activation is critical to cell adhesion, survival, and production. Mechanical signals activate the MAPK cascade, leading to down-regulation of RANK ligand (RANKL) expression and the formation of osteoclasts.
Strain, shear, and pressure result in the mobilization of intracellular calcium. This rapid increase in intracellular calcium concentration appears to occur due to phospholipase-C activity and IP3 signaling, which results in the release of calcium from intracellular stores (calcium-mediated calcium release).
Summary
Musculoskeletal cells are exposed to forces transmitted through tissue. Mechanotransduction pathways modulate diverse cellular functions. Physiologic effects result from intracellular signaling of membrane receptors and ion channels. The integrin receptor, bound to the tissue and stimulated by stress, can coactivate cytokine receptors and ion channels, resulting in a coordinated cell response. The musculoskeletal system provides a link to the physical environment. The encompassing nature of mechanical signaling likely represents the primary means by which adaptation to force exposure occurs. For clinicians this is exciting, as much of what we do involves modulating force through exercise and physical interventions. The obvious hurdle in fully accessing this tool is the difficulty of quantifying in vivo human forces, both those that result in injury and those produced by specific mechanical interventions. Future research and technology will be essential for identifying optimal mechanical interventions and their specific prescription. This chapter outlines the biology underpinning mechanical intervention. Harnessing the power of mechanotransduction is our most powerful tool for affecting musculoskeletal health and adaptation.
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Case Scenario: Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries.
Case Scenario 1
Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries. A neurological screen was normal, and concussion assessment and diagnostic imaging were negative. She complains of pain (6 on a scale of 10 with walking and standing) and muscle spasm in her neck and upper back, and intermittent headaches made worse with prolonged sitting and exercise and relieved by oral over-the-counter medication and lying down. She states at times she gets pain that radiates down her right arm.
She states that she is married and has no children. She works as a college tennis coach and director of the campus tennis center. Her medical history is unremarkable other than having sustained a right sprained ankle in high school and having wisdom teeth removed.
On presentation she denies lightheadedness, concentration and memory deficits, tinnitus or vision disturbances, and a history of neck injuries. On examination, the patient's head is slightly tilted to the left side. The patient has limited active and passive rotation and side-bending to the right side and painful end-range extension. She has tenderness to palpation along the right cervical paraspinal muscles. Upper quarter scan for sensory, strength, and reflex deficits is normal. Physical examination reveals restricted left side-glide at C5-C6, and the patient is evaluated as suffering from a flexed, left rotated, and side-bent facet with soft tissue pain and muscle spasm.
The patient complains that she has difficulty raising her right arm overhead and that her neck and upper back pain increase with prolonged sitting, driving, and lifting and carrying.
The forces involved in motor vehicle accidents can cause catastrophic injuries. The whiplash mechanism of injury may result in fracture, sprain, and muscle strain. The medical history, history of the current condition, and medical and physical examinations conducted in this case provide assurance that serious structural damage has been avoided. A thorough examination and evaluation of all pertinent information is needed before proceeding with a rehabilitation plan of care, especially in conditions involving the spine.
The first step in developing a rehabilitation plan of care is the development of a problem list. It is usually best to build a problem list around the impairments, functional limitations, and participation restrictions identified in the evaluation of the case. From the problem list, mutually agreeable short-term goals can be developed and a goal-directed application of therapeutic modalities, manual therapy, and exercise developed.
What are the problems identified in this case?
Impairments
- Pain
- Loss of cervical range of motion
- Headache
Functional limitations
- Reaching overhead and prolonged sitting/driving
Participation restrictions
- Unable to play tennis or coach effectively due to pain and loss of motion
- Has difficulty with management responsibilities due to poor tolerance of sitting
The clinician has several options to recommend for the problems listed. Pain and muscle spasm could be treated with periodic cold or superficial heat. TENS could be used as needed for the same purposes.
What would you do?
A decision on the treatment needs to be based on any contraindications for an intervention, the current condition, the patient's preferences, the clinician's experiences, and existing clinical research. After ruling out contraindications to the treatment options and conferring with the patient about the ability to control pain with oral medications, it is decided to treat her with massage to decrease pain and muscle spasm before performing joint mobilization to restore range of motion. The patient states that a hot shower is soothing and that she has access to superficial heat. She demonstrates a substantial increase in cervical range of motion after the initial treatment. She is instructed in active range of motion exercises and agrees with a plan of 20 to 30 min of superficial heating as needed for relief of pain and spasm and a four-times-per-day regimen of active range of motion, which is also to be performed after heat application. Over two subsequent visits she reports the resolution of pain at rest other than mild aching and stiffness upon rising, and she demonstrates full cervical range of motion. Postural and functional exercises are introduced to increase tolerance to daily activities and return to coaching. Three and a half weeks after her accident she is able to work a normal day, drive, and play tennis for up to an hour without limitations. She is discharged to continue with a postural and tennis function exercise program.
This case illustrates some of the complexities of developing a plan of care. There is not a single correct approach to meeting the needs of many patients. The first mandate is to do no harm. The clinician and patient must then decide which problems are most concerning, discuss the options, and agree on a plan. Once short-term goals are achieved, the intervention progresses. Modalities used to relieve pain and muscle spasm are replaced by exercises aimed at addressing functional limitations and participation restrictions.
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Using Ultrasound as a Therapeutic Modality
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions.
Ultrasound
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions. Different frequencies of ultrasound are used for each application. The ultrasound units used in the practice of athletic training and physical therapy emit sound energy at frequencies between 800 kHz (800,000 Hz) and 3 MHz (3,000,000 Hz). Modern high-quality ultrasound units allow the clinician to select the treatment frequency. Typically a clinician can choose frequencies near 1 MHz and 3.3 MHz. Some units are also adjustable to 2 MHz (figure 12.1). The importance of frequency and the applications of ultrasound at various frequencies will be discussed in detail. Initially, it is important to understand that therapeutic ultrasound uses acoustic energy, delivered at very specific high frequencies.
Modern combination ultrasound, laser, and electrotherapy device.
Ultrasound machines use electrical current to create a mechanical vibration in a crystalline material housed in the "head" of the unit. Vibration of the crystalline material produces a wave of acoustic energy (ultrasound) (figure 12.2). The crystalline material in modern ultrasound devices is synthetic, although natural crystals were once used. The sound energy emitted from the ultrasound head travels through tissues and is absorbed.
Components of an ultrasound unit.
Ultrasound technology is now used extensively for diagnostic imaging. Ultrasound in the range of 3.5 MHz to 15 MHz is used to image organs of the abdomen and thorax as well as musculoskeletal tissues (Whittaker et al. 2007). Ultrasound is also routinely used for prenatal examination. Through ultrasound, some correctable birth defects can be identified, and the sex of the fetus can also be determined.
In musculoskeletal care, ultrasound can be used to detect muscle strains, ligament sprains, and degenerative changes in tendon. The sound energy used for imaging differs in frequency and pulse characteristics from that used for therapeutic purposes.
Beam Nonuniformity Ratio and Effective Radiating
Two terms describe the size and quality of an ultrasound crystal found in therapeutic ultrasound devices. Effective radiating area (ERA) is the area that receives at least 5% of the peak sound energy. This is essentially the size of the area to which sound energy is conducted when the head of the ultrasound unit contacts the skin. The ERA is somewhat smaller than the surface area of the sound head.
The beam of sound energy emitted from a crystal is not uniform but rather is characterized by areas of high intensity and lower intensity (figure 12.3). Beam nonuniformity ratio (BNR)is the ratio of the average intensity of the ultrasound beam across the ERA divided by the peak intensity of the ultrasound beam; the lower the BNR, the more uniform the intensity of the sound wave.
Beam scan of a crystal with a beam nonuniformity ratio (BNR) of 2.32, (a) top view and (b) side view. When tested on 40 subjects, the ultrasound transducer housing this crystal produced a very comfortable treatment at 1.5 to 2.0 watts per cm2 (W/cm2). Beam scan of a crystal with a BNR of 7.75, (c) top view. When this was tested on 40 subjects, the ultrasound transducer housing the crystal produced an uncomfortable treatment at 1.5 W/cm2 and was not tolerated at 2.0 W/cm2.
Courtesy of Brigham Young University Sports Injury Research Center.
A low BNR minimizes the risk of developing "hot spots" and allows the clinician to deliver higher doses of ultrasound without causing pain and discomfort. The BNR must be listed by the manufacturer on all units. Ideally, the BNR would be 1; however, this is impossible, and the acceptable range is between 2 and 6.
Unfortunately, BNR and ERA may not adequately define how an ultrasound unit will function. Holcomb and Joyce (2003) reported significant differences in the change in tissue temperature between two ultrasound units with a BNR of 3.7 and 2.3 and an ERA of 4.9 and 4.6 cm, respectively. These authors speculated that the area of peak intensity or peak area of the maximum beam nonuniformity ratio (PAMBNR) as described by Draper (1999) might explain why two ultrasound units differ in performance. Certainly a small spike of peak amplitude as illustrated in figure 12.4 will deliver less energy and therefore have less thermal effect than that provided by a larger area of peak amplitude. Johns, Straub, and Howard (2007) and Straub, Johns, and Howard (2008) reported considerable variability in ERA and special average intensity in 3 and 1 MHz ultrasound units, respectively, from different manufacturers. Differences between reported and actual ERA values were identified for all but one manufacturer when 3 MHz sound heads were evaluated (Johns, Straub, and Howard 2007). Demchak, Straub, and Johns (2007) noted differences in the rate but not peak heating of the calf muscles using three different 1 MHz ultrasound transducers. Johns et al. (2007), however, have reported greater heating with 1 MHz sound heads with more concentrated energy fields. The issue of equipment performance across parameters requires further study. Variability in the characteristics of the acoustic energy field may yield differing treatment effects and perhaps pose a risk of adverse events. Frye et al. (2007) reported blistering of the anterior shin after ultrasound to the calf muscles in laboratory experiments employing common clinical treatment parameters.
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The area of peak intensity, (a) small and (b) larger, may affect the performance of ultrasound devices.
Conducting Media
Air is a poor conductor of ultrasound energy. To maximize delivery of sound energy to the tissues, a conducting medium must be used. Several substances have been used to conduct ultrasound, including ultrasound gel, gel pads, mineral oil, lotions, and water. The amount of sound energy conducted varies substantially between conducting media. Commercial ultrasound gel (Draper 1996; Draper et al. 1993; Klucinec et al. 2000) and gel pads (Klucinec et al. 2000; Klucinec 1996) (figure 12.5) are superior conducting media. Water is not as good a conducting medium (Draper 1996; Draper et al. 1993; Klucinec et al. 2000; Klucinec 1996; Forrest and Rosen 1989, 1992), attenuating as much as 65% of the sound energy (Klucinec et al. 2000).
Ultrasound gel and gel pads.
Rubley et al. (2008) reported smaller differences (approximately 15%) in Achilles tendon tissue heating when comparing gel and degassed water as conducting media. Differences in research methods and ultrasound equipment may explain the estimated magnitude of differences between conducting media. Collectively, however, the research suggests that ultrasound gel is the conducting medium of choice for clinical administration of therapeutic ultrasound. The conducting capacities of most gels and creams have not been established. However, some have been shown to be very poor conductors of sound energy (Cameron and Monroe 1992; Draper 1996; Draper et al. 1993; Forrest and Rosen 1989, 1992; Klucinec 1996; Klucinec et al. 2000). When applying ultrasound, use gels and gel pads known to be effective conductors.
Parameters of Treatment with Ultrasound
As with electrotherapy, you can alter the treatment parameters of ultrasound depending on the desired effect. Fortunately, the number of adjustable parameters is smaller. You can control the amplitude of the sound waves and therefore the amount of sound energy being emitted from the sound head. The sound energy emitted by the crystal is measured in watts (W). The dose of sound energy delivered is based on the amount of energy being emitted divided by the radiating area of the crystal measured in square centimeters (cm2). Thus, ultrasound dose is measured in W/cm2. You can also adjust the duty cycle, duration of treatment, and frequency.
Duty cycle refers to the process of interrupting delivery of the sound wave so that periods of sound wave emission are interspersed with periods of interruption. Figure 12.6 depicts pulsed and continuous ultrasound.
| |
(a) In pulsed ultrasound, energy is generated only during the "on" time. Duty cycle is determined by the ratio of "on" time to pulse, in this case 50%. (b) Continuous ultrasound is shown.
Often you can select between several duty cycles. Duty cycle is calculated by dividing the time during which sound is delivered by the total time the sound head is applied. For example, if ultrasound is transmitted for 150 ms out of every second of treatment, then the duty cycle is 150/1,000, or 15%. When the emission of sound energy is not interrupted, the duty cycle equals 100%, and the ultrasound is referred to as continuous ultrasound.
Much has been learned about the treatment duration needed to elevate tissue temperatures. An interaction among the frequency, dose, and treatment duration has also been found. Some recipes for duration and intensities of ultrasound treatments used in the past do not increase tissue temperature sufficiently.
The frequency of the sound waves affects the depth at which the greatest amount of ultrasound energy is absorbed, as well as the time required to increase tissue temperature. Ultrasound units typically allow for treatment with more than one frequency, but older units had a single fixed frequency of 1 MHz. Treatments with higher frequencies are usually more appropriate for musculoskeletal injuries.
Sound Energy Absorption in Tissues
The amount of acoustic energy absorbed by tissues is influenced by many factors. The tissue characteristics, as well as the frequency, dose (W/cm2), duty cycle, and duration of treatment with ultrasound affect the amount of acoustic energy absorbed. When continuous ultrasound is delivered, the greater the energy absorption, the greater the tissue heating. Tissues with greater protein density have a higher rate of absorption, whereas tissues with a higher water content have lower absorption rates. Thus, tendon, ligament, and muscle tissue absorb more sound energy than skin and adipose tissue. Superficial bones and nerves absorb the most energy.
Ultrasound at a higher frequency (3 MHz) is absorbed more rapidly than that at a lower frequency (1 MHz) (figure 12.7). Therefore, ultrasound at higher frequencies affects tissues that are more superficial, whereas at a lower frequency less energy is absorbed superficially and more is available to penetrate into tissues. Thus, if the goal of treatment is to heat the capsular tissue at a joint such as the elbow with ultrasound, a 3 MHz frequency is appropriate. Temperature increases of up to 8°C have been reported with 3 MHz ultrasound at 1 W/cm2 in 4 min in superficial tissues such as the patellar tendon (Chan et al. 1998). If the target tissue is deep tissue, a lower frequency (1 MHz) is necessary; 10 min of continuous 1 MHz ultrasound at 2.0 W/cm2 will elevate temperature about 4°C at a depth of 2.5 cm (Draper, Castel, and Castel 1995). There is likely considerable overlap in tissue heating between 1 and 3 MHz ultrasound, as heating of tissues at 2.5 cm depths with 3 MHz ultrasound has been reported (Hayes et al. 2004). The interactions between ultrasound parameters and thermal response are discussed further shortly.
A great depth of heating is achieved with 1 MHz. The specific depth of heating is device dependent, and the values provided represent a range rather than specific limits of thermal responses.
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Mechanobiology in the Musculoskeletal System
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis.
Mechanobiology in Tendon
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis. Tendon is relatively avascular and therefore relies largely on autocrine and paracrine responses for tissue remodeling, repair, and adaptation. In addition to tenocytes, progenitor cells exist in tendon, and they are extremely mechanosensitive. Inappropriate mechanical load pushes these progenitors toward alternate phenotypes (chondrocytes, adipocytes, osteocytes), which results in the pathologic changes characteristic of tendinosis. Tendinosis is a common histologic finding in overuse tendon injuries that is characterized by noninflammatory degenerative changes of the ECM and aberrant cellular responses.
Tendon attaches muscle to bone, transmitting forces to the skeleton and resulting in joint stabilization and movement. As a result, tendons are subjected to high mechanical loads that predispose them to injury. Tendon's reaction to overuse injury has been described as a failed healing response (Maffulli, Sharma, and Luscombe 2004) due to the ineffective and insufficient inflammatory response generated after injury.
Tendon pathology may be classified as either tendonitis: inflammation, pain, and swelling of the peritenon; tendinosis: degeneration of the ECM and absence of inflammation upon histologic examination; or tendinopathy. Tendinopathy is the contemporary clinical term for tendon overuse injuries, as it does not imply an active inflammatory process, which is often the case.
While the etiologic factors of tendinopathy are not fully understood, a failure in the mechanobiologic response of the tenocyte has been implicated. Tendon structure, composition, and mechanical properties are modified in response to altered mechanical loading conditions. Disruption in the mechanobiologic response of the tenocyte creates a vicious cycle of suboptimal ECM production, in turn leading to further changes in mechanical signals transmitted to the tenocyte and propagating degenerative tissue production throughout the tendon (figure 16.8). Many hypothesize that mechanical overload initiates a degenerative signaling cascade that leads to tendinopathy, while some believe tendinopathy is a result of focal disruption of ECM and accompanying mechanobiologic understimulation of locally adherent tenocytes and progenitor cells.
Pathologic changes in tendinopathy. (a) Collagen organization: H&E. (b) Increased proteoglycan.
Reprinted, by permission, from M. Joseph et al., 2009, "Histological and molecular analysis of the biceps tendon long head post-tenotomy," The Journal of Orthopedic Research 27:1379-1385.
Signaling cascades leading to tendinosis probably result from understimulation of FACs and downstream MAPK-mediated events. The activation of stress-activated protein kinase (SAPK), a member of the MAPK family, is associated with matrix-degrading enzyme production. As mentioned, load affects progenitor cell survival and differentiation. Tendon progenitor cells exposed to 4% strain assume tenocyte function and express collagen type I. However, loads of 8% resulted in the expression of markers for bone, fat, and cartilage differentiation. The presence of these cells and their functional products is destructive to tendon ECM and health (Wang et al. 2007).
An alternative paradigm for the pathophysiology of tendinopathy is emerging and involves tenocyte-produced neuropeptides. Chemical messengers thought to be confined to neurons are produced in abundance in tendinopathic tissue. Substance P and its receptor (neurokinin-1 receptor [NK-1 R]), glutamate (Scott, Alfredson, and Forsgren 2008), acetylcholine (ACTH), and catecholamines are produced by local tendon fibroblasts. Tenocytes produce these neurochemicals in response to mechanical load. Substance P increases cellular proliferation in culture, which corresponds with observations of hypercellularity in early tendinosis. Pain in tendinopathic tissue has been traced to neurovascular ingrowth containing substance P positive nerve fibers, and the ablation of these fibers often results in relief. The NK-1 R is a G-protein coupled receptor that is responsive to mechanical signals. There is likely cross talk between integrin-linked kinase production resulting from integrin stimulation and cross-activation of the G-protein via ILK activation (see figure 16.5). Substance P signals through the MAPK cascade and results in gene expression.
Tendon cell networks communicate throughout the tissue via cytoplasmic extensions and cell junction zones. A signal that is sent in one area propagates through these channels, effecting a tissue-wide response. Intercellular connectivity is achieved through gap junctions, where connexins are the principal protein. In healthy tendon, tenocytes are arranged longitudinally between collagen fibers. Connexins 32 and 34 form communications between longitudinally arranged tenocytes, whereas connexin 43 links cells in all directions (Ragsdale, Phelps, and Luby-Phelps 1997).
Mechanobiology in Articular Cartilage
Articular cartilage is the major load-bearing tissue in synovial joints. Cartilage is unique in that it is avascular, aneural, alymphatic, and sparsely populated with cells. The cartilage cell (chondrocyte) is responsible for the remodeling of cartilage ECM, and it does so in response to mechanical force. Cartilage in relatively unloaded areas such as the medial patellar facet is softer and less resilient. Articular cartilage responds favorably to pulsatile doses of load, while static loading results in up-regulation of a host of inflammatory cytokines, matrix-degrading enzymes, and degeneration.
Chondrocytes are extremely responsive to compressive loads, as their location and function would indicate. A pericellular matrix composed of collagen VI and proteoglycan surrounds the chondrocyte and is an independent unit of force transduction. The pericellular matrix is analogous to the basal lamina in skeletal muscle, bridging the gap between cell membrane and ECM.
Membrane stretch - activated ion channels exist, are proximate to integrins, and likely have overlapping downstream signaling cascades. Stimulation of the integrin α5β1 pathway results in the production of aggrecan, the predominant proteoglycan in cartilage, along with the down-regulation of MMP3, the predominant degrading enzyme of PG. Higher levels of aggrecan and collagen II production are associated with dynamic compressive force, whereas static forces result in MMP production and ECM destruction. Chondrocytes from arthritic cartilage are unresponsive to mechanical stimulation, indicating cellular dysfunction and mechanoinsensitivity in osteoarthritis (Raizman 2010).
Inappropriate mechanical loading is the primary risk factor for the development of osteoarthritis (OA) (figure 16.9). OA is characterized by a loss of tissue homeostasis and the prevalence of catabolism. Molecular components of mechanotransduction in chondrocytes consist of integrin activation and downstream MAPK signaling, as well as stress-activated calcium channel signaling. The α5β1 integrin binds pericellular matrix fibronectin and associates with calcium channels in the surrounding cell membrane. In response to mechanical stimuli, integrin and calcium signaling pathways converge on MAPK cascade, where Ca2+ regulation of integrin activity through Src occurs (Raizman et al. 2010).
Damaged articular cartilage. Large defect in the medial femoral condyle.
The Cbp/p300-interacting transactivator 2 (CITED2) is a transcription regulator that is thought to balance catabolic and anticatabolic cascades and is thus centrally implicated in the pathogenesis of OA (Leong et al. 2011). CITED2 binds with and modulates a host of transcription factors. The ability to activate anabolic pathways and to inhibit inflammatory and catabolic pathways in response to mechanical signals suggests a central role in mechanical regulation. CITED2 is downstream of MAPK. Moderate-intensity intermittent loads activate CITED2, whereas high-intensity loads do not (Leong et al. 2011). Increased CITED2 expression correlates with the production of collagen II, maintenance of ECM, and suppression of MMPs. Integrin and associated receptors, downstream MAPK, and CITED2 represent a loading-specific pathway that has direct effects on tissue. Thus, loading of cartilage is essential to tissue health while overload leads to degeneration and OA. Exercise can play an important role in the treatment of OA, but excessive loading may accelerate the disease process.
In summary, the chondrocyte is dependent upon mechanical signals for survival. The aneural, avascular nature of articular cartilage accounts for its susceptibility to damage. Enhanced maintenance and repair of articular cartilage is possible through mechanobiologic manipulation. Chondrocyte preference for dynamic, pulsatile delivery of force will continue to be explored both in exercise prescription and modality delivery.
Mechanobiology in Bone
Metabolic demands on the skeleton are managed largely through calciotropic hormones, but the ability of the skeleton to adapt to its loading environment is essential for bone health. Wolff's law first proposed skeletal change in response to functional demands. We now understand that it is the cells of the skeleton - the osteoblasts, osteocytes, and osteoclasts - that remodel bone in response to stress. An example of bone's sensitivity to mechanical demand is demonstrated in cortical bone of the dominant arm in elite tennis players, which can be up to 35% thicker than the cortical bone of the non-dominant arm. Rapid bone loss during periods of immobility and in microgravity exemplifies the homeostatic necessity of mechanotransduction.
Bone is certainly not as deformable as connective tissue, at least elastically. Bone can experience up to 0.3% strain, much less than ligament or tendon (5% - 20%). Bone experiences a wide variety of mechanical stimuli that produce slight deformation in the bone tissue, pressure in the intramedullary cavity and within the cortices, transient pressure waves, and fluid shear forces through the canaliculi.
Osteoblasts at the surface of bone respond to deformation of the cell membrane from strain experienced on the surface of the bone from imposed forces. Osteocytes located deeper in the bone tissue respond to shear stress of fluid flow through the canaliculi (figure 16.10). An externally applied load forces fluid out of regions of high compressive strains. This fluid returns when the load is removed. This results in bone cell exposure to an oscillating fluid flow. The osteocyte population, through its interconnectedness via gap junctions, comprises a three-dimensional sensing systemin which amplification of mechanical signals propagates throughout the tissue.
Structure and lacuna canalicular network of bone.
As in tendon, integrins are important conductors of mechanical signals in bone cells (Salter, Robb, and Wright 1997). In bone, the β subunit of the integrin extracellular domain mediates binding to matrix components. Prominent matrix ligands for integrin in bone include collagen I and III and fibronectin. The formation of FAC in response to integrin activation is critical to cell adhesion, survival, and production. Mechanical signals activate the MAPK cascade, leading to down-regulation of RANK ligand (RANKL) expression and the formation of osteoclasts.
Strain, shear, and pressure result in the mobilization of intracellular calcium. This rapid increase in intracellular calcium concentration appears to occur due to phospholipase-C activity and IP3 signaling, which results in the release of calcium from intracellular stores (calcium-mediated calcium release).
Summary
Musculoskeletal cells are exposed to forces transmitted through tissue. Mechanotransduction pathways modulate diverse cellular functions. Physiologic effects result from intracellular signaling of membrane receptors and ion channels. The integrin receptor, bound to the tissue and stimulated by stress, can coactivate cytokine receptors and ion channels, resulting in a coordinated cell response. The musculoskeletal system provides a link to the physical environment. The encompassing nature of mechanical signaling likely represents the primary means by which adaptation to force exposure occurs. For clinicians this is exciting, as much of what we do involves modulating force through exercise and physical interventions. The obvious hurdle in fully accessing this tool is the difficulty of quantifying in vivo human forces, both those that result in injury and those produced by specific mechanical interventions. Future research and technology will be essential for identifying optimal mechanical interventions and their specific prescription. This chapter outlines the biology underpinning mechanical intervention. Harnessing the power of mechanotransduction is our most powerful tool for affecting musculoskeletal health and adaptation.
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Case Scenario: Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries.
Case Scenario 1
Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries. A neurological screen was normal, and concussion assessment and diagnostic imaging were negative. She complains of pain (6 on a scale of 10 with walking and standing) and muscle spasm in her neck and upper back, and intermittent headaches made worse with prolonged sitting and exercise and relieved by oral over-the-counter medication and lying down. She states at times she gets pain that radiates down her right arm.
She states that she is married and has no children. She works as a college tennis coach and director of the campus tennis center. Her medical history is unremarkable other than having sustained a right sprained ankle in high school and having wisdom teeth removed.
On presentation she denies lightheadedness, concentration and memory deficits, tinnitus or vision disturbances, and a history of neck injuries. On examination, the patient's head is slightly tilted to the left side. The patient has limited active and passive rotation and side-bending to the right side and painful end-range extension. She has tenderness to palpation along the right cervical paraspinal muscles. Upper quarter scan for sensory, strength, and reflex deficits is normal. Physical examination reveals restricted left side-glide at C5-C6, and the patient is evaluated as suffering from a flexed, left rotated, and side-bent facet with soft tissue pain and muscle spasm.
The patient complains that she has difficulty raising her right arm overhead and that her neck and upper back pain increase with prolonged sitting, driving, and lifting and carrying.
The forces involved in motor vehicle accidents can cause catastrophic injuries. The whiplash mechanism of injury may result in fracture, sprain, and muscle strain. The medical history, history of the current condition, and medical and physical examinations conducted in this case provide assurance that serious structural damage has been avoided. A thorough examination and evaluation of all pertinent information is needed before proceeding with a rehabilitation plan of care, especially in conditions involving the spine.
The first step in developing a rehabilitation plan of care is the development of a problem list. It is usually best to build a problem list around the impairments, functional limitations, and participation restrictions identified in the evaluation of the case. From the problem list, mutually agreeable short-term goals can be developed and a goal-directed application of therapeutic modalities, manual therapy, and exercise developed.
What are the problems identified in this case?
Impairments
- Pain
- Loss of cervical range of motion
- Headache
Functional limitations
- Reaching overhead and prolonged sitting/driving
Participation restrictions
- Unable to play tennis or coach effectively due to pain and loss of motion
- Has difficulty with management responsibilities due to poor tolerance of sitting
The clinician has several options to recommend for the problems listed. Pain and muscle spasm could be treated with periodic cold or superficial heat. TENS could be used as needed for the same purposes.
What would you do?
A decision on the treatment needs to be based on any contraindications for an intervention, the current condition, the patient's preferences, the clinician's experiences, and existing clinical research. After ruling out contraindications to the treatment options and conferring with the patient about the ability to control pain with oral medications, it is decided to treat her with massage to decrease pain and muscle spasm before performing joint mobilization to restore range of motion. The patient states that a hot shower is soothing and that she has access to superficial heat. She demonstrates a substantial increase in cervical range of motion after the initial treatment. She is instructed in active range of motion exercises and agrees with a plan of 20 to 30 min of superficial heating as needed for relief of pain and spasm and a four-times-per-day regimen of active range of motion, which is also to be performed after heat application. Over two subsequent visits she reports the resolution of pain at rest other than mild aching and stiffness upon rising, and she demonstrates full cervical range of motion. Postural and functional exercises are introduced to increase tolerance to daily activities and return to coaching. Three and a half weeks after her accident she is able to work a normal day, drive, and play tennis for up to an hour without limitations. She is discharged to continue with a postural and tennis function exercise program.
This case illustrates some of the complexities of developing a plan of care. There is not a single correct approach to meeting the needs of many patients. The first mandate is to do no harm. The clinician and patient must then decide which problems are most concerning, discuss the options, and agree on a plan. Once short-term goals are achieved, the intervention progresses. Modalities used to relieve pain and muscle spasm are replaced by exercises aimed at addressing functional limitations and participation restrictions.
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Using Ultrasound as a Therapeutic Modality
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions.
Ultrasound
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions. Different frequencies of ultrasound are used for each application. The ultrasound units used in the practice of athletic training and physical therapy emit sound energy at frequencies between 800 kHz (800,000 Hz) and 3 MHz (3,000,000 Hz). Modern high-quality ultrasound units allow the clinician to select the treatment frequency. Typically a clinician can choose frequencies near 1 MHz and 3.3 MHz. Some units are also adjustable to 2 MHz (figure 12.1). The importance of frequency and the applications of ultrasound at various frequencies will be discussed in detail. Initially, it is important to understand that therapeutic ultrasound uses acoustic energy, delivered at very specific high frequencies.
Modern combination ultrasound, laser, and electrotherapy device.
Ultrasound machines use electrical current to create a mechanical vibration in a crystalline material housed in the "head" of the unit. Vibration of the crystalline material produces a wave of acoustic energy (ultrasound) (figure 12.2). The crystalline material in modern ultrasound devices is synthetic, although natural crystals were once used. The sound energy emitted from the ultrasound head travels through tissues and is absorbed.
Components of an ultrasound unit.
Ultrasound technology is now used extensively for diagnostic imaging. Ultrasound in the range of 3.5 MHz to 15 MHz is used to image organs of the abdomen and thorax as well as musculoskeletal tissues (Whittaker et al. 2007). Ultrasound is also routinely used for prenatal examination. Through ultrasound, some correctable birth defects can be identified, and the sex of the fetus can also be determined.
In musculoskeletal care, ultrasound can be used to detect muscle strains, ligament sprains, and degenerative changes in tendon. The sound energy used for imaging differs in frequency and pulse characteristics from that used for therapeutic purposes.
Beam Nonuniformity Ratio and Effective Radiating
Two terms describe the size and quality of an ultrasound crystal found in therapeutic ultrasound devices. Effective radiating area (ERA) is the area that receives at least 5% of the peak sound energy. This is essentially the size of the area to which sound energy is conducted when the head of the ultrasound unit contacts the skin. The ERA is somewhat smaller than the surface area of the sound head.
The beam of sound energy emitted from a crystal is not uniform but rather is characterized by areas of high intensity and lower intensity (figure 12.3). Beam nonuniformity ratio (BNR)is the ratio of the average intensity of the ultrasound beam across the ERA divided by the peak intensity of the ultrasound beam; the lower the BNR, the more uniform the intensity of the sound wave.
Beam scan of a crystal with a beam nonuniformity ratio (BNR) of 2.32, (a) top view and (b) side view. When tested on 40 subjects, the ultrasound transducer housing this crystal produced a very comfortable treatment at 1.5 to 2.0 watts per cm2 (W/cm2). Beam scan of a crystal with a BNR of 7.75, (c) top view. When this was tested on 40 subjects, the ultrasound transducer housing the crystal produced an uncomfortable treatment at 1.5 W/cm2 and was not tolerated at 2.0 W/cm2.
Courtesy of Brigham Young University Sports Injury Research Center.
A low BNR minimizes the risk of developing "hot spots" and allows the clinician to deliver higher doses of ultrasound without causing pain and discomfort. The BNR must be listed by the manufacturer on all units. Ideally, the BNR would be 1; however, this is impossible, and the acceptable range is between 2 and 6.
Unfortunately, BNR and ERA may not adequately define how an ultrasound unit will function. Holcomb and Joyce (2003) reported significant differences in the change in tissue temperature between two ultrasound units with a BNR of 3.7 and 2.3 and an ERA of 4.9 and 4.6 cm, respectively. These authors speculated that the area of peak intensity or peak area of the maximum beam nonuniformity ratio (PAMBNR) as described by Draper (1999) might explain why two ultrasound units differ in performance. Certainly a small spike of peak amplitude as illustrated in figure 12.4 will deliver less energy and therefore have less thermal effect than that provided by a larger area of peak amplitude. Johns, Straub, and Howard (2007) and Straub, Johns, and Howard (2008) reported considerable variability in ERA and special average intensity in 3 and 1 MHz ultrasound units, respectively, from different manufacturers. Differences between reported and actual ERA values were identified for all but one manufacturer when 3 MHz sound heads were evaluated (Johns, Straub, and Howard 2007). Demchak, Straub, and Johns (2007) noted differences in the rate but not peak heating of the calf muscles using three different 1 MHz ultrasound transducers. Johns et al. (2007), however, have reported greater heating with 1 MHz sound heads with more concentrated energy fields. The issue of equipment performance across parameters requires further study. Variability in the characteristics of the acoustic energy field may yield differing treatment effects and perhaps pose a risk of adverse events. Frye et al. (2007) reported blistering of the anterior shin after ultrasound to the calf muscles in laboratory experiments employing common clinical treatment parameters.
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The area of peak intensity, (a) small and (b) larger, may affect the performance of ultrasound devices.
Conducting Media
Air is a poor conductor of ultrasound energy. To maximize delivery of sound energy to the tissues, a conducting medium must be used. Several substances have been used to conduct ultrasound, including ultrasound gel, gel pads, mineral oil, lotions, and water. The amount of sound energy conducted varies substantially between conducting media. Commercial ultrasound gel (Draper 1996; Draper et al. 1993; Klucinec et al. 2000) and gel pads (Klucinec et al. 2000; Klucinec 1996) (figure 12.5) are superior conducting media. Water is not as good a conducting medium (Draper 1996; Draper et al. 1993; Klucinec et al. 2000; Klucinec 1996; Forrest and Rosen 1989, 1992), attenuating as much as 65% of the sound energy (Klucinec et al. 2000).
Ultrasound gel and gel pads.
Rubley et al. (2008) reported smaller differences (approximately 15%) in Achilles tendon tissue heating when comparing gel and degassed water as conducting media. Differences in research methods and ultrasound equipment may explain the estimated magnitude of differences between conducting media. Collectively, however, the research suggests that ultrasound gel is the conducting medium of choice for clinical administration of therapeutic ultrasound. The conducting capacities of most gels and creams have not been established. However, some have been shown to be very poor conductors of sound energy (Cameron and Monroe 1992; Draper 1996; Draper et al. 1993; Forrest and Rosen 1989, 1992; Klucinec 1996; Klucinec et al. 2000). When applying ultrasound, use gels and gel pads known to be effective conductors.
Parameters of Treatment with Ultrasound
As with electrotherapy, you can alter the treatment parameters of ultrasound depending on the desired effect. Fortunately, the number of adjustable parameters is smaller. You can control the amplitude of the sound waves and therefore the amount of sound energy being emitted from the sound head. The sound energy emitted by the crystal is measured in watts (W). The dose of sound energy delivered is based on the amount of energy being emitted divided by the radiating area of the crystal measured in square centimeters (cm2). Thus, ultrasound dose is measured in W/cm2. You can also adjust the duty cycle, duration of treatment, and frequency.
Duty cycle refers to the process of interrupting delivery of the sound wave so that periods of sound wave emission are interspersed with periods of interruption. Figure 12.6 depicts pulsed and continuous ultrasound.
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(a) In pulsed ultrasound, energy is generated only during the "on" time. Duty cycle is determined by the ratio of "on" time to pulse, in this case 50%. (b) Continuous ultrasound is shown.
Often you can select between several duty cycles. Duty cycle is calculated by dividing the time during which sound is delivered by the total time the sound head is applied. For example, if ultrasound is transmitted for 150 ms out of every second of treatment, then the duty cycle is 150/1,000, or 15%. When the emission of sound energy is not interrupted, the duty cycle equals 100%, and the ultrasound is referred to as continuous ultrasound.
Much has been learned about the treatment duration needed to elevate tissue temperatures. An interaction among the frequency, dose, and treatment duration has also been found. Some recipes for duration and intensities of ultrasound treatments used in the past do not increase tissue temperature sufficiently.
The frequency of the sound waves affects the depth at which the greatest amount of ultrasound energy is absorbed, as well as the time required to increase tissue temperature. Ultrasound units typically allow for treatment with more than one frequency, but older units had a single fixed frequency of 1 MHz. Treatments with higher frequencies are usually more appropriate for musculoskeletal injuries.
Sound Energy Absorption in Tissues
The amount of acoustic energy absorbed by tissues is influenced by many factors. The tissue characteristics, as well as the frequency, dose (W/cm2), duty cycle, and duration of treatment with ultrasound affect the amount of acoustic energy absorbed. When continuous ultrasound is delivered, the greater the energy absorption, the greater the tissue heating. Tissues with greater protein density have a higher rate of absorption, whereas tissues with a higher water content have lower absorption rates. Thus, tendon, ligament, and muscle tissue absorb more sound energy than skin and adipose tissue. Superficial bones and nerves absorb the most energy.
Ultrasound at a higher frequency (3 MHz) is absorbed more rapidly than that at a lower frequency (1 MHz) (figure 12.7). Therefore, ultrasound at higher frequencies affects tissues that are more superficial, whereas at a lower frequency less energy is absorbed superficially and more is available to penetrate into tissues. Thus, if the goal of treatment is to heat the capsular tissue at a joint such as the elbow with ultrasound, a 3 MHz frequency is appropriate. Temperature increases of up to 8°C have been reported with 3 MHz ultrasound at 1 W/cm2 in 4 min in superficial tissues such as the patellar tendon (Chan et al. 1998). If the target tissue is deep tissue, a lower frequency (1 MHz) is necessary; 10 min of continuous 1 MHz ultrasound at 2.0 W/cm2 will elevate temperature about 4°C at a depth of 2.5 cm (Draper, Castel, and Castel 1995). There is likely considerable overlap in tissue heating between 1 and 3 MHz ultrasound, as heating of tissues at 2.5 cm depths with 3 MHz ultrasound has been reported (Hayes et al. 2004). The interactions between ultrasound parameters and thermal response are discussed further shortly.
A great depth of heating is achieved with 1 MHz. The specific depth of heating is device dependent, and the values provided represent a range rather than specific limits of thermal responses.
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Mechanobiology in the Musculoskeletal System
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis.
Mechanobiology in Tendon
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis. Tendon is relatively avascular and therefore relies largely on autocrine and paracrine responses for tissue remodeling, repair, and adaptation. In addition to tenocytes, progenitor cells exist in tendon, and they are extremely mechanosensitive. Inappropriate mechanical load pushes these progenitors toward alternate phenotypes (chondrocytes, adipocytes, osteocytes), which results in the pathologic changes characteristic of tendinosis. Tendinosis is a common histologic finding in overuse tendon injuries that is characterized by noninflammatory degenerative changes of the ECM and aberrant cellular responses.
Tendon attaches muscle to bone, transmitting forces to the skeleton and resulting in joint stabilization and movement. As a result, tendons are subjected to high mechanical loads that predispose them to injury. Tendon's reaction to overuse injury has been described as a failed healing response (Maffulli, Sharma, and Luscombe 2004) due to the ineffective and insufficient inflammatory response generated after injury.
Tendon pathology may be classified as either tendonitis: inflammation, pain, and swelling of the peritenon; tendinosis: degeneration of the ECM and absence of inflammation upon histologic examination; or tendinopathy. Tendinopathy is the contemporary clinical term for tendon overuse injuries, as it does not imply an active inflammatory process, which is often the case.
While the etiologic factors of tendinopathy are not fully understood, a failure in the mechanobiologic response of the tenocyte has been implicated. Tendon structure, composition, and mechanical properties are modified in response to altered mechanical loading conditions. Disruption in the mechanobiologic response of the tenocyte creates a vicious cycle of suboptimal ECM production, in turn leading to further changes in mechanical signals transmitted to the tenocyte and propagating degenerative tissue production throughout the tendon (figure 16.8). Many hypothesize that mechanical overload initiates a degenerative signaling cascade that leads to tendinopathy, while some believe tendinopathy is a result of focal disruption of ECM and accompanying mechanobiologic understimulation of locally adherent tenocytes and progenitor cells.
Pathologic changes in tendinopathy. (a) Collagen organization: H&E. (b) Increased proteoglycan.
Reprinted, by permission, from M. Joseph et al., 2009, "Histological and molecular analysis of the biceps tendon long head post-tenotomy," The Journal of Orthopedic Research 27:1379-1385.
Signaling cascades leading to tendinosis probably result from understimulation of FACs and downstream MAPK-mediated events. The activation of stress-activated protein kinase (SAPK), a member of the MAPK family, is associated with matrix-degrading enzyme production. As mentioned, load affects progenitor cell survival and differentiation. Tendon progenitor cells exposed to 4% strain assume tenocyte function and express collagen type I. However, loads of 8% resulted in the expression of markers for bone, fat, and cartilage differentiation. The presence of these cells and their functional products is destructive to tendon ECM and health (Wang et al. 2007).
An alternative paradigm for the pathophysiology of tendinopathy is emerging and involves tenocyte-produced neuropeptides. Chemical messengers thought to be confined to neurons are produced in abundance in tendinopathic tissue. Substance P and its receptor (neurokinin-1 receptor [NK-1 R]), glutamate (Scott, Alfredson, and Forsgren 2008), acetylcholine (ACTH), and catecholamines are produced by local tendon fibroblasts. Tenocytes produce these neurochemicals in response to mechanical load. Substance P increases cellular proliferation in culture, which corresponds with observations of hypercellularity in early tendinosis. Pain in tendinopathic tissue has been traced to neurovascular ingrowth containing substance P positive nerve fibers, and the ablation of these fibers often results in relief. The NK-1 R is a G-protein coupled receptor that is responsive to mechanical signals. There is likely cross talk between integrin-linked kinase production resulting from integrin stimulation and cross-activation of the G-protein via ILK activation (see figure 16.5). Substance P signals through the MAPK cascade and results in gene expression.
Tendon cell networks communicate throughout the tissue via cytoplasmic extensions and cell junction zones. A signal that is sent in one area propagates through these channels, effecting a tissue-wide response. Intercellular connectivity is achieved through gap junctions, where connexins are the principal protein. In healthy tendon, tenocytes are arranged longitudinally between collagen fibers. Connexins 32 and 34 form communications between longitudinally arranged tenocytes, whereas connexin 43 links cells in all directions (Ragsdale, Phelps, and Luby-Phelps 1997).
Mechanobiology in Articular Cartilage
Articular cartilage is the major load-bearing tissue in synovial joints. Cartilage is unique in that it is avascular, aneural, alymphatic, and sparsely populated with cells. The cartilage cell (chondrocyte) is responsible for the remodeling of cartilage ECM, and it does so in response to mechanical force. Cartilage in relatively unloaded areas such as the medial patellar facet is softer and less resilient. Articular cartilage responds favorably to pulsatile doses of load, while static loading results in up-regulation of a host of inflammatory cytokines, matrix-degrading enzymes, and degeneration.
Chondrocytes are extremely responsive to compressive loads, as their location and function would indicate. A pericellular matrix composed of collagen VI and proteoglycan surrounds the chondrocyte and is an independent unit of force transduction. The pericellular matrix is analogous to the basal lamina in skeletal muscle, bridging the gap between cell membrane and ECM.
Membrane stretch - activated ion channels exist, are proximate to integrins, and likely have overlapping downstream signaling cascades. Stimulation of the integrin α5β1 pathway results in the production of aggrecan, the predominant proteoglycan in cartilage, along with the down-regulation of MMP3, the predominant degrading enzyme of PG. Higher levels of aggrecan and collagen II production are associated with dynamic compressive force, whereas static forces result in MMP production and ECM destruction. Chondrocytes from arthritic cartilage are unresponsive to mechanical stimulation, indicating cellular dysfunction and mechanoinsensitivity in osteoarthritis (Raizman 2010).
Inappropriate mechanical loading is the primary risk factor for the development of osteoarthritis (OA) (figure 16.9). OA is characterized by a loss of tissue homeostasis and the prevalence of catabolism. Molecular components of mechanotransduction in chondrocytes consist of integrin activation and downstream MAPK signaling, as well as stress-activated calcium channel signaling. The α5β1 integrin binds pericellular matrix fibronectin and associates with calcium channels in the surrounding cell membrane. In response to mechanical stimuli, integrin and calcium signaling pathways converge on MAPK cascade, where Ca2+ regulation of integrin activity through Src occurs (Raizman et al. 2010).
Damaged articular cartilage. Large defect in the medial femoral condyle.
The Cbp/p300-interacting transactivator 2 (CITED2) is a transcription regulator that is thought to balance catabolic and anticatabolic cascades and is thus centrally implicated in the pathogenesis of OA (Leong et al. 2011). CITED2 binds with and modulates a host of transcription factors. The ability to activate anabolic pathways and to inhibit inflammatory and catabolic pathways in response to mechanical signals suggests a central role in mechanical regulation. CITED2 is downstream of MAPK. Moderate-intensity intermittent loads activate CITED2, whereas high-intensity loads do not (Leong et al. 2011). Increased CITED2 expression correlates with the production of collagen II, maintenance of ECM, and suppression of MMPs. Integrin and associated receptors, downstream MAPK, and CITED2 represent a loading-specific pathway that has direct effects on tissue. Thus, loading of cartilage is essential to tissue health while overload leads to degeneration and OA. Exercise can play an important role in the treatment of OA, but excessive loading may accelerate the disease process.
In summary, the chondrocyte is dependent upon mechanical signals for survival. The aneural, avascular nature of articular cartilage accounts for its susceptibility to damage. Enhanced maintenance and repair of articular cartilage is possible through mechanobiologic manipulation. Chondrocyte preference for dynamic, pulsatile delivery of force will continue to be explored both in exercise prescription and modality delivery.
Mechanobiology in Bone
Metabolic demands on the skeleton are managed largely through calciotropic hormones, but the ability of the skeleton to adapt to its loading environment is essential for bone health. Wolff's law first proposed skeletal change in response to functional demands. We now understand that it is the cells of the skeleton - the osteoblasts, osteocytes, and osteoclasts - that remodel bone in response to stress. An example of bone's sensitivity to mechanical demand is demonstrated in cortical bone of the dominant arm in elite tennis players, which can be up to 35% thicker than the cortical bone of the non-dominant arm. Rapid bone loss during periods of immobility and in microgravity exemplifies the homeostatic necessity of mechanotransduction.
Bone is certainly not as deformable as connective tissue, at least elastically. Bone can experience up to 0.3% strain, much less than ligament or tendon (5% - 20%). Bone experiences a wide variety of mechanical stimuli that produce slight deformation in the bone tissue, pressure in the intramedullary cavity and within the cortices, transient pressure waves, and fluid shear forces through the canaliculi.
Osteoblasts at the surface of bone respond to deformation of the cell membrane from strain experienced on the surface of the bone from imposed forces. Osteocytes located deeper in the bone tissue respond to shear stress of fluid flow through the canaliculi (figure 16.10). An externally applied load forces fluid out of regions of high compressive strains. This fluid returns when the load is removed. This results in bone cell exposure to an oscillating fluid flow. The osteocyte population, through its interconnectedness via gap junctions, comprises a three-dimensional sensing systemin which amplification of mechanical signals propagates throughout the tissue.
Structure and lacuna canalicular network of bone.
As in tendon, integrins are important conductors of mechanical signals in bone cells (Salter, Robb, and Wright 1997). In bone, the β subunit of the integrin extracellular domain mediates binding to matrix components. Prominent matrix ligands for integrin in bone include collagen I and III and fibronectin. The formation of FAC in response to integrin activation is critical to cell adhesion, survival, and production. Mechanical signals activate the MAPK cascade, leading to down-regulation of RANK ligand (RANKL) expression and the formation of osteoclasts.
Strain, shear, and pressure result in the mobilization of intracellular calcium. This rapid increase in intracellular calcium concentration appears to occur due to phospholipase-C activity and IP3 signaling, which results in the release of calcium from intracellular stores (calcium-mediated calcium release).
Summary
Musculoskeletal cells are exposed to forces transmitted through tissue. Mechanotransduction pathways modulate diverse cellular functions. Physiologic effects result from intracellular signaling of membrane receptors and ion channels. The integrin receptor, bound to the tissue and stimulated by stress, can coactivate cytokine receptors and ion channels, resulting in a coordinated cell response. The musculoskeletal system provides a link to the physical environment. The encompassing nature of mechanical signaling likely represents the primary means by which adaptation to force exposure occurs. For clinicians this is exciting, as much of what we do involves modulating force through exercise and physical interventions. The obvious hurdle in fully accessing this tool is the difficulty of quantifying in vivo human forces, both those that result in injury and those produced by specific mechanical interventions. Future research and technology will be essential for identifying optimal mechanical interventions and their specific prescription. This chapter outlines the biology underpinning mechanical intervention. Harnessing the power of mechanotransduction is our most powerful tool for affecting musculoskeletal health and adaptation.
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Case Scenario: Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries.
Case Scenario 1
Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries. A neurological screen was normal, and concussion assessment and diagnostic imaging were negative. She complains of pain (6 on a scale of 10 with walking and standing) and muscle spasm in her neck and upper back, and intermittent headaches made worse with prolonged sitting and exercise and relieved by oral over-the-counter medication and lying down. She states at times she gets pain that radiates down her right arm.
She states that she is married and has no children. She works as a college tennis coach and director of the campus tennis center. Her medical history is unremarkable other than having sustained a right sprained ankle in high school and having wisdom teeth removed.
On presentation she denies lightheadedness, concentration and memory deficits, tinnitus or vision disturbances, and a history of neck injuries. On examination, the patient's head is slightly tilted to the left side. The patient has limited active and passive rotation and side-bending to the right side and painful end-range extension. She has tenderness to palpation along the right cervical paraspinal muscles. Upper quarter scan for sensory, strength, and reflex deficits is normal. Physical examination reveals restricted left side-glide at C5-C6, and the patient is evaluated as suffering from a flexed, left rotated, and side-bent facet with soft tissue pain and muscle spasm.
The patient complains that she has difficulty raising her right arm overhead and that her neck and upper back pain increase with prolonged sitting, driving, and lifting and carrying.
The forces involved in motor vehicle accidents can cause catastrophic injuries. The whiplash mechanism of injury may result in fracture, sprain, and muscle strain. The medical history, history of the current condition, and medical and physical examinations conducted in this case provide assurance that serious structural damage has been avoided. A thorough examination and evaluation of all pertinent information is needed before proceeding with a rehabilitation plan of care, especially in conditions involving the spine.
The first step in developing a rehabilitation plan of care is the development of a problem list. It is usually best to build a problem list around the impairments, functional limitations, and participation restrictions identified in the evaluation of the case. From the problem list, mutually agreeable short-term goals can be developed and a goal-directed application of therapeutic modalities, manual therapy, and exercise developed.
What are the problems identified in this case?
Impairments
- Pain
- Loss of cervical range of motion
- Headache
Functional limitations
- Reaching overhead and prolonged sitting/driving
Participation restrictions
- Unable to play tennis or coach effectively due to pain and loss of motion
- Has difficulty with management responsibilities due to poor tolerance of sitting
The clinician has several options to recommend for the problems listed. Pain and muscle spasm could be treated with periodic cold or superficial heat. TENS could be used as needed for the same purposes.
What would you do?
A decision on the treatment needs to be based on any contraindications for an intervention, the current condition, the patient's preferences, the clinician's experiences, and existing clinical research. After ruling out contraindications to the treatment options and conferring with the patient about the ability to control pain with oral medications, it is decided to treat her with massage to decrease pain and muscle spasm before performing joint mobilization to restore range of motion. The patient states that a hot shower is soothing and that she has access to superficial heat. She demonstrates a substantial increase in cervical range of motion after the initial treatment. She is instructed in active range of motion exercises and agrees with a plan of 20 to 30 min of superficial heating as needed for relief of pain and spasm and a four-times-per-day regimen of active range of motion, which is also to be performed after heat application. Over two subsequent visits she reports the resolution of pain at rest other than mild aching and stiffness upon rising, and she demonstrates full cervical range of motion. Postural and functional exercises are introduced to increase tolerance to daily activities and return to coaching. Three and a half weeks after her accident she is able to work a normal day, drive, and play tennis for up to an hour without limitations. She is discharged to continue with a postural and tennis function exercise program.
This case illustrates some of the complexities of developing a plan of care. There is not a single correct approach to meeting the needs of many patients. The first mandate is to do no harm. The clinician and patient must then decide which problems are most concerning, discuss the options, and agree on a plan. Once short-term goals are achieved, the intervention progresses. Modalities used to relieve pain and muscle spasm are replaced by exercises aimed at addressing functional limitations and participation restrictions.
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Using Ultrasound as a Therapeutic Modality
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions.
Ultrasound
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions. Different frequencies of ultrasound are used for each application. The ultrasound units used in the practice of athletic training and physical therapy emit sound energy at frequencies between 800 kHz (800,000 Hz) and 3 MHz (3,000,000 Hz). Modern high-quality ultrasound units allow the clinician to select the treatment frequency. Typically a clinician can choose frequencies near 1 MHz and 3.3 MHz. Some units are also adjustable to 2 MHz (figure 12.1). The importance of frequency and the applications of ultrasound at various frequencies will be discussed in detail. Initially, it is important to understand that therapeutic ultrasound uses acoustic energy, delivered at very specific high frequencies.
Modern combination ultrasound, laser, and electrotherapy device.
Ultrasound machines use electrical current to create a mechanical vibration in a crystalline material housed in the "head" of the unit. Vibration of the crystalline material produces a wave of acoustic energy (ultrasound) (figure 12.2). The crystalline material in modern ultrasound devices is synthetic, although natural crystals were once used. The sound energy emitted from the ultrasound head travels through tissues and is absorbed.
Components of an ultrasound unit.
Ultrasound technology is now used extensively for diagnostic imaging. Ultrasound in the range of 3.5 MHz to 15 MHz is used to image organs of the abdomen and thorax as well as musculoskeletal tissues (Whittaker et al. 2007). Ultrasound is also routinely used for prenatal examination. Through ultrasound, some correctable birth defects can be identified, and the sex of the fetus can also be determined.
In musculoskeletal care, ultrasound can be used to detect muscle strains, ligament sprains, and degenerative changes in tendon. The sound energy used for imaging differs in frequency and pulse characteristics from that used for therapeutic purposes.
Beam Nonuniformity Ratio and Effective Radiating
Two terms describe the size and quality of an ultrasound crystal found in therapeutic ultrasound devices. Effective radiating area (ERA) is the area that receives at least 5% of the peak sound energy. This is essentially the size of the area to which sound energy is conducted when the head of the ultrasound unit contacts the skin. The ERA is somewhat smaller than the surface area of the sound head.
The beam of sound energy emitted from a crystal is not uniform but rather is characterized by areas of high intensity and lower intensity (figure 12.3). Beam nonuniformity ratio (BNR)is the ratio of the average intensity of the ultrasound beam across the ERA divided by the peak intensity of the ultrasound beam; the lower the BNR, the more uniform the intensity of the sound wave.
Beam scan of a crystal with a beam nonuniformity ratio (BNR) of 2.32, (a) top view and (b) side view. When tested on 40 subjects, the ultrasound transducer housing this crystal produced a very comfortable treatment at 1.5 to 2.0 watts per cm2 (W/cm2). Beam scan of a crystal with a BNR of 7.75, (c) top view. When this was tested on 40 subjects, the ultrasound transducer housing the crystal produced an uncomfortable treatment at 1.5 W/cm2 and was not tolerated at 2.0 W/cm2.
Courtesy of Brigham Young University Sports Injury Research Center.
A low BNR minimizes the risk of developing "hot spots" and allows the clinician to deliver higher doses of ultrasound without causing pain and discomfort. The BNR must be listed by the manufacturer on all units. Ideally, the BNR would be 1; however, this is impossible, and the acceptable range is between 2 and 6.
Unfortunately, BNR and ERA may not adequately define how an ultrasound unit will function. Holcomb and Joyce (2003) reported significant differences in the change in tissue temperature between two ultrasound units with a BNR of 3.7 and 2.3 and an ERA of 4.9 and 4.6 cm, respectively. These authors speculated that the area of peak intensity or peak area of the maximum beam nonuniformity ratio (PAMBNR) as described by Draper (1999) might explain why two ultrasound units differ in performance. Certainly a small spike of peak amplitude as illustrated in figure 12.4 will deliver less energy and therefore have less thermal effect than that provided by a larger area of peak amplitude. Johns, Straub, and Howard (2007) and Straub, Johns, and Howard (2008) reported considerable variability in ERA and special average intensity in 3 and 1 MHz ultrasound units, respectively, from different manufacturers. Differences between reported and actual ERA values were identified for all but one manufacturer when 3 MHz sound heads were evaluated (Johns, Straub, and Howard 2007). Demchak, Straub, and Johns (2007) noted differences in the rate but not peak heating of the calf muscles using three different 1 MHz ultrasound transducers. Johns et al. (2007), however, have reported greater heating with 1 MHz sound heads with more concentrated energy fields. The issue of equipment performance across parameters requires further study. Variability in the characteristics of the acoustic energy field may yield differing treatment effects and perhaps pose a risk of adverse events. Frye et al. (2007) reported blistering of the anterior shin after ultrasound to the calf muscles in laboratory experiments employing common clinical treatment parameters.
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The area of peak intensity, (a) small and (b) larger, may affect the performance of ultrasound devices.
Conducting Media
Air is a poor conductor of ultrasound energy. To maximize delivery of sound energy to the tissues, a conducting medium must be used. Several substances have been used to conduct ultrasound, including ultrasound gel, gel pads, mineral oil, lotions, and water. The amount of sound energy conducted varies substantially between conducting media. Commercial ultrasound gel (Draper 1996; Draper et al. 1993; Klucinec et al. 2000) and gel pads (Klucinec et al. 2000; Klucinec 1996) (figure 12.5) are superior conducting media. Water is not as good a conducting medium (Draper 1996; Draper et al. 1993; Klucinec et al. 2000; Klucinec 1996; Forrest and Rosen 1989, 1992), attenuating as much as 65% of the sound energy (Klucinec et al. 2000).
Ultrasound gel and gel pads.
Rubley et al. (2008) reported smaller differences (approximately 15%) in Achilles tendon tissue heating when comparing gel and degassed water as conducting media. Differences in research methods and ultrasound equipment may explain the estimated magnitude of differences between conducting media. Collectively, however, the research suggests that ultrasound gel is the conducting medium of choice for clinical administration of therapeutic ultrasound. The conducting capacities of most gels and creams have not been established. However, some have been shown to be very poor conductors of sound energy (Cameron and Monroe 1992; Draper 1996; Draper et al. 1993; Forrest and Rosen 1989, 1992; Klucinec 1996; Klucinec et al. 2000). When applying ultrasound, use gels and gel pads known to be effective conductors.
Parameters of Treatment with Ultrasound
As with electrotherapy, you can alter the treatment parameters of ultrasound depending on the desired effect. Fortunately, the number of adjustable parameters is smaller. You can control the amplitude of the sound waves and therefore the amount of sound energy being emitted from the sound head. The sound energy emitted by the crystal is measured in watts (W). The dose of sound energy delivered is based on the amount of energy being emitted divided by the radiating area of the crystal measured in square centimeters (cm2). Thus, ultrasound dose is measured in W/cm2. You can also adjust the duty cycle, duration of treatment, and frequency.
Duty cycle refers to the process of interrupting delivery of the sound wave so that periods of sound wave emission are interspersed with periods of interruption. Figure 12.6 depicts pulsed and continuous ultrasound.
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(a) In pulsed ultrasound, energy is generated only during the "on" time. Duty cycle is determined by the ratio of "on" time to pulse, in this case 50%. (b) Continuous ultrasound is shown.
Often you can select between several duty cycles. Duty cycle is calculated by dividing the time during which sound is delivered by the total time the sound head is applied. For example, if ultrasound is transmitted for 150 ms out of every second of treatment, then the duty cycle is 150/1,000, or 15%. When the emission of sound energy is not interrupted, the duty cycle equals 100%, and the ultrasound is referred to as continuous ultrasound.
Much has been learned about the treatment duration needed to elevate tissue temperatures. An interaction among the frequency, dose, and treatment duration has also been found. Some recipes for duration and intensities of ultrasound treatments used in the past do not increase tissue temperature sufficiently.
The frequency of the sound waves affects the depth at which the greatest amount of ultrasound energy is absorbed, as well as the time required to increase tissue temperature. Ultrasound units typically allow for treatment with more than one frequency, but older units had a single fixed frequency of 1 MHz. Treatments with higher frequencies are usually more appropriate for musculoskeletal injuries.
Sound Energy Absorption in Tissues
The amount of acoustic energy absorbed by tissues is influenced by many factors. The tissue characteristics, as well as the frequency, dose (W/cm2), duty cycle, and duration of treatment with ultrasound affect the amount of acoustic energy absorbed. When continuous ultrasound is delivered, the greater the energy absorption, the greater the tissue heating. Tissues with greater protein density have a higher rate of absorption, whereas tissues with a higher water content have lower absorption rates. Thus, tendon, ligament, and muscle tissue absorb more sound energy than skin and adipose tissue. Superficial bones and nerves absorb the most energy.
Ultrasound at a higher frequency (3 MHz) is absorbed more rapidly than that at a lower frequency (1 MHz) (figure 12.7). Therefore, ultrasound at higher frequencies affects tissues that are more superficial, whereas at a lower frequency less energy is absorbed superficially and more is available to penetrate into tissues. Thus, if the goal of treatment is to heat the capsular tissue at a joint such as the elbow with ultrasound, a 3 MHz frequency is appropriate. Temperature increases of up to 8°C have been reported with 3 MHz ultrasound at 1 W/cm2 in 4 min in superficial tissues such as the patellar tendon (Chan et al. 1998). If the target tissue is deep tissue, a lower frequency (1 MHz) is necessary; 10 min of continuous 1 MHz ultrasound at 2.0 W/cm2 will elevate temperature about 4°C at a depth of 2.5 cm (Draper, Castel, and Castel 1995). There is likely considerable overlap in tissue heating between 1 and 3 MHz ultrasound, as heating of tissues at 2.5 cm depths with 3 MHz ultrasound has been reported (Hayes et al. 2004). The interactions between ultrasound parameters and thermal response are discussed further shortly.
A great depth of heating is achieved with 1 MHz. The specific depth of heating is device dependent, and the values provided represent a range rather than specific limits of thermal responses.
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Mechanobiology in the Musculoskeletal System
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis.
Mechanobiology in Tendon
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis. Tendon is relatively avascular and therefore relies largely on autocrine and paracrine responses for tissue remodeling, repair, and adaptation. In addition to tenocytes, progenitor cells exist in tendon, and they are extremely mechanosensitive. Inappropriate mechanical load pushes these progenitors toward alternate phenotypes (chondrocytes, adipocytes, osteocytes), which results in the pathologic changes characteristic of tendinosis. Tendinosis is a common histologic finding in overuse tendon injuries that is characterized by noninflammatory degenerative changes of the ECM and aberrant cellular responses.
Tendon attaches muscle to bone, transmitting forces to the skeleton and resulting in joint stabilization and movement. As a result, tendons are subjected to high mechanical loads that predispose them to injury. Tendon's reaction to overuse injury has been described as a failed healing response (Maffulli, Sharma, and Luscombe 2004) due to the ineffective and insufficient inflammatory response generated after injury.
Tendon pathology may be classified as either tendonitis: inflammation, pain, and swelling of the peritenon; tendinosis: degeneration of the ECM and absence of inflammation upon histologic examination; or tendinopathy. Tendinopathy is the contemporary clinical term for tendon overuse injuries, as it does not imply an active inflammatory process, which is often the case.
While the etiologic factors of tendinopathy are not fully understood, a failure in the mechanobiologic response of the tenocyte has been implicated. Tendon structure, composition, and mechanical properties are modified in response to altered mechanical loading conditions. Disruption in the mechanobiologic response of the tenocyte creates a vicious cycle of suboptimal ECM production, in turn leading to further changes in mechanical signals transmitted to the tenocyte and propagating degenerative tissue production throughout the tendon (figure 16.8). Many hypothesize that mechanical overload initiates a degenerative signaling cascade that leads to tendinopathy, while some believe tendinopathy is a result of focal disruption of ECM and accompanying mechanobiologic understimulation of locally adherent tenocytes and progenitor cells.
Pathologic changes in tendinopathy. (a) Collagen organization: H&E. (b) Increased proteoglycan.
Reprinted, by permission, from M. Joseph et al., 2009, "Histological and molecular analysis of the biceps tendon long head post-tenotomy," The Journal of Orthopedic Research 27:1379-1385.
Signaling cascades leading to tendinosis probably result from understimulation of FACs and downstream MAPK-mediated events. The activation of stress-activated protein kinase (SAPK), a member of the MAPK family, is associated with matrix-degrading enzyme production. As mentioned, load affects progenitor cell survival and differentiation. Tendon progenitor cells exposed to 4% strain assume tenocyte function and express collagen type I. However, loads of 8% resulted in the expression of markers for bone, fat, and cartilage differentiation. The presence of these cells and their functional products is destructive to tendon ECM and health (Wang et al. 2007).
An alternative paradigm for the pathophysiology of tendinopathy is emerging and involves tenocyte-produced neuropeptides. Chemical messengers thought to be confined to neurons are produced in abundance in tendinopathic tissue. Substance P and its receptor (neurokinin-1 receptor [NK-1 R]), glutamate (Scott, Alfredson, and Forsgren 2008), acetylcholine (ACTH), and catecholamines are produced by local tendon fibroblasts. Tenocytes produce these neurochemicals in response to mechanical load. Substance P increases cellular proliferation in culture, which corresponds with observations of hypercellularity in early tendinosis. Pain in tendinopathic tissue has been traced to neurovascular ingrowth containing substance P positive nerve fibers, and the ablation of these fibers often results in relief. The NK-1 R is a G-protein coupled receptor that is responsive to mechanical signals. There is likely cross talk between integrin-linked kinase production resulting from integrin stimulation and cross-activation of the G-protein via ILK activation (see figure 16.5). Substance P signals through the MAPK cascade and results in gene expression.
Tendon cell networks communicate throughout the tissue via cytoplasmic extensions and cell junction zones. A signal that is sent in one area propagates through these channels, effecting a tissue-wide response. Intercellular connectivity is achieved through gap junctions, where connexins are the principal protein. In healthy tendon, tenocytes are arranged longitudinally between collagen fibers. Connexins 32 and 34 form communications between longitudinally arranged tenocytes, whereas connexin 43 links cells in all directions (Ragsdale, Phelps, and Luby-Phelps 1997).
Mechanobiology in Articular Cartilage
Articular cartilage is the major load-bearing tissue in synovial joints. Cartilage is unique in that it is avascular, aneural, alymphatic, and sparsely populated with cells. The cartilage cell (chondrocyte) is responsible for the remodeling of cartilage ECM, and it does so in response to mechanical force. Cartilage in relatively unloaded areas such as the medial patellar facet is softer and less resilient. Articular cartilage responds favorably to pulsatile doses of load, while static loading results in up-regulation of a host of inflammatory cytokines, matrix-degrading enzymes, and degeneration.
Chondrocytes are extremely responsive to compressive loads, as their location and function would indicate. A pericellular matrix composed of collagen VI and proteoglycan surrounds the chondrocyte and is an independent unit of force transduction. The pericellular matrix is analogous to the basal lamina in skeletal muscle, bridging the gap between cell membrane and ECM.
Membrane stretch - activated ion channels exist, are proximate to integrins, and likely have overlapping downstream signaling cascades. Stimulation of the integrin α5β1 pathway results in the production of aggrecan, the predominant proteoglycan in cartilage, along with the down-regulation of MMP3, the predominant degrading enzyme of PG. Higher levels of aggrecan and collagen II production are associated with dynamic compressive force, whereas static forces result in MMP production and ECM destruction. Chondrocytes from arthritic cartilage are unresponsive to mechanical stimulation, indicating cellular dysfunction and mechanoinsensitivity in osteoarthritis (Raizman 2010).
Inappropriate mechanical loading is the primary risk factor for the development of osteoarthritis (OA) (figure 16.9). OA is characterized by a loss of tissue homeostasis and the prevalence of catabolism. Molecular components of mechanotransduction in chondrocytes consist of integrin activation and downstream MAPK signaling, as well as stress-activated calcium channel signaling. The α5β1 integrin binds pericellular matrix fibronectin and associates with calcium channels in the surrounding cell membrane. In response to mechanical stimuli, integrin and calcium signaling pathways converge on MAPK cascade, where Ca2+ regulation of integrin activity through Src occurs (Raizman et al. 2010).
Damaged articular cartilage. Large defect in the medial femoral condyle.
The Cbp/p300-interacting transactivator 2 (CITED2) is a transcription regulator that is thought to balance catabolic and anticatabolic cascades and is thus centrally implicated in the pathogenesis of OA (Leong et al. 2011). CITED2 binds with and modulates a host of transcription factors. The ability to activate anabolic pathways and to inhibit inflammatory and catabolic pathways in response to mechanical signals suggests a central role in mechanical regulation. CITED2 is downstream of MAPK. Moderate-intensity intermittent loads activate CITED2, whereas high-intensity loads do not (Leong et al. 2011). Increased CITED2 expression correlates with the production of collagen II, maintenance of ECM, and suppression of MMPs. Integrin and associated receptors, downstream MAPK, and CITED2 represent a loading-specific pathway that has direct effects on tissue. Thus, loading of cartilage is essential to tissue health while overload leads to degeneration and OA. Exercise can play an important role in the treatment of OA, but excessive loading may accelerate the disease process.
In summary, the chondrocyte is dependent upon mechanical signals for survival. The aneural, avascular nature of articular cartilage accounts for its susceptibility to damage. Enhanced maintenance and repair of articular cartilage is possible through mechanobiologic manipulation. Chondrocyte preference for dynamic, pulsatile delivery of force will continue to be explored both in exercise prescription and modality delivery.
Mechanobiology in Bone
Metabolic demands on the skeleton are managed largely through calciotropic hormones, but the ability of the skeleton to adapt to its loading environment is essential for bone health. Wolff's law first proposed skeletal change in response to functional demands. We now understand that it is the cells of the skeleton - the osteoblasts, osteocytes, and osteoclasts - that remodel bone in response to stress. An example of bone's sensitivity to mechanical demand is demonstrated in cortical bone of the dominant arm in elite tennis players, which can be up to 35% thicker than the cortical bone of the non-dominant arm. Rapid bone loss during periods of immobility and in microgravity exemplifies the homeostatic necessity of mechanotransduction.
Bone is certainly not as deformable as connective tissue, at least elastically. Bone can experience up to 0.3% strain, much less than ligament or tendon (5% - 20%). Bone experiences a wide variety of mechanical stimuli that produce slight deformation in the bone tissue, pressure in the intramedullary cavity and within the cortices, transient pressure waves, and fluid shear forces through the canaliculi.
Osteoblasts at the surface of bone respond to deformation of the cell membrane from strain experienced on the surface of the bone from imposed forces. Osteocytes located deeper in the bone tissue respond to shear stress of fluid flow through the canaliculi (figure 16.10). An externally applied load forces fluid out of regions of high compressive strains. This fluid returns when the load is removed. This results in bone cell exposure to an oscillating fluid flow. The osteocyte population, through its interconnectedness via gap junctions, comprises a three-dimensional sensing systemin which amplification of mechanical signals propagates throughout the tissue.
Structure and lacuna canalicular network of bone.
As in tendon, integrins are important conductors of mechanical signals in bone cells (Salter, Robb, and Wright 1997). In bone, the β subunit of the integrin extracellular domain mediates binding to matrix components. Prominent matrix ligands for integrin in bone include collagen I and III and fibronectin. The formation of FAC in response to integrin activation is critical to cell adhesion, survival, and production. Mechanical signals activate the MAPK cascade, leading to down-regulation of RANK ligand (RANKL) expression and the formation of osteoclasts.
Strain, shear, and pressure result in the mobilization of intracellular calcium. This rapid increase in intracellular calcium concentration appears to occur due to phospholipase-C activity and IP3 signaling, which results in the release of calcium from intracellular stores (calcium-mediated calcium release).
Summary
Musculoskeletal cells are exposed to forces transmitted through tissue. Mechanotransduction pathways modulate diverse cellular functions. Physiologic effects result from intracellular signaling of membrane receptors and ion channels. The integrin receptor, bound to the tissue and stimulated by stress, can coactivate cytokine receptors and ion channels, resulting in a coordinated cell response. The musculoskeletal system provides a link to the physical environment. The encompassing nature of mechanical signaling likely represents the primary means by which adaptation to force exposure occurs. For clinicians this is exciting, as much of what we do involves modulating force through exercise and physical interventions. The obvious hurdle in fully accessing this tool is the difficulty of quantifying in vivo human forces, both those that result in injury and those produced by specific mechanical interventions. Future research and technology will be essential for identifying optimal mechanical interventions and their specific prescription. This chapter outlines the biology underpinning mechanical intervention. Harnessing the power of mechanotransduction is our most powerful tool for affecting musculoskeletal health and adaptation.
Learn more about Therapeutic Modalities for Musculoskeletal Injuries, Fourth Edition With Online Video.
Case Scenario: Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries.
Case Scenario 1
Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries. A neurological screen was normal, and concussion assessment and diagnostic imaging were negative. She complains of pain (6 on a scale of 10 with walking and standing) and muscle spasm in her neck and upper back, and intermittent headaches made worse with prolonged sitting and exercise and relieved by oral over-the-counter medication and lying down. She states at times she gets pain that radiates down her right arm.
She states that she is married and has no children. She works as a college tennis coach and director of the campus tennis center. Her medical history is unremarkable other than having sustained a right sprained ankle in high school and having wisdom teeth removed.
On presentation she denies lightheadedness, concentration and memory deficits, tinnitus or vision disturbances, and a history of neck injuries. On examination, the patient's head is slightly tilted to the left side. The patient has limited active and passive rotation and side-bending to the right side and painful end-range extension. She has tenderness to palpation along the right cervical paraspinal muscles. Upper quarter scan for sensory, strength, and reflex deficits is normal. Physical examination reveals restricted left side-glide at C5-C6, and the patient is evaluated as suffering from a flexed, left rotated, and side-bent facet with soft tissue pain and muscle spasm.
The patient complains that she has difficulty raising her right arm overhead and that her neck and upper back pain increase with prolonged sitting, driving, and lifting and carrying.
The forces involved in motor vehicle accidents can cause catastrophic injuries. The whiplash mechanism of injury may result in fracture, sprain, and muscle strain. The medical history, history of the current condition, and medical and physical examinations conducted in this case provide assurance that serious structural damage has been avoided. A thorough examination and evaluation of all pertinent information is needed before proceeding with a rehabilitation plan of care, especially in conditions involving the spine.
The first step in developing a rehabilitation plan of care is the development of a problem list. It is usually best to build a problem list around the impairments, functional limitations, and participation restrictions identified in the evaluation of the case. From the problem list, mutually agreeable short-term goals can be developed and a goal-directed application of therapeutic modalities, manual therapy, and exercise developed.
What are the problems identified in this case?
Impairments
- Pain
- Loss of cervical range of motion
- Headache
Functional limitations
- Reaching overhead and prolonged sitting/driving
Participation restrictions
- Unable to play tennis or coach effectively due to pain and loss of motion
- Has difficulty with management responsibilities due to poor tolerance of sitting
The clinician has several options to recommend for the problems listed. Pain and muscle spasm could be treated with periodic cold or superficial heat. TENS could be used as needed for the same purposes.
What would you do?
A decision on the treatment needs to be based on any contraindications for an intervention, the current condition, the patient's preferences, the clinician's experiences, and existing clinical research. After ruling out contraindications to the treatment options and conferring with the patient about the ability to control pain with oral medications, it is decided to treat her with massage to decrease pain and muscle spasm before performing joint mobilization to restore range of motion. The patient states that a hot shower is soothing and that she has access to superficial heat. She demonstrates a substantial increase in cervical range of motion after the initial treatment. She is instructed in active range of motion exercises and agrees with a plan of 20 to 30 min of superficial heating as needed for relief of pain and spasm and a four-times-per-day regimen of active range of motion, which is also to be performed after heat application. Over two subsequent visits she reports the resolution of pain at rest other than mild aching and stiffness upon rising, and she demonstrates full cervical range of motion. Postural and functional exercises are introduced to increase tolerance to daily activities and return to coaching. Three and a half weeks after her accident she is able to work a normal day, drive, and play tennis for up to an hour without limitations. She is discharged to continue with a postural and tennis function exercise program.
This case illustrates some of the complexities of developing a plan of care. There is not a single correct approach to meeting the needs of many patients. The first mandate is to do no harm. The clinician and patient must then decide which problems are most concerning, discuss the options, and agree on a plan. Once short-term goals are achieved, the intervention progresses. Modalities used to relieve pain and muscle spasm are replaced by exercises aimed at addressing functional limitations and participation restrictions.
Learn more about Therapeutic Modalities for Musculoskeletal Injuries, Fourth Edition With Online Video.
Using Ultrasound as a Therapeutic Modality
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions.
Ultrasound
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions. Different frequencies of ultrasound are used for each application. The ultrasound units used in the practice of athletic training and physical therapy emit sound energy at frequencies between 800 kHz (800,000 Hz) and 3 MHz (3,000,000 Hz). Modern high-quality ultrasound units allow the clinician to select the treatment frequency. Typically a clinician can choose frequencies near 1 MHz and 3.3 MHz. Some units are also adjustable to 2 MHz (figure 12.1). The importance of frequency and the applications of ultrasound at various frequencies will be discussed in detail. Initially, it is important to understand that therapeutic ultrasound uses acoustic energy, delivered at very specific high frequencies.
Modern combination ultrasound, laser, and electrotherapy device.
Ultrasound machines use electrical current to create a mechanical vibration in a crystalline material housed in the "head" of the unit. Vibration of the crystalline material produces a wave of acoustic energy (ultrasound) (figure 12.2). The crystalline material in modern ultrasound devices is synthetic, although natural crystals were once used. The sound energy emitted from the ultrasound head travels through tissues and is absorbed.
Components of an ultrasound unit.
Ultrasound technology is now used extensively for diagnostic imaging. Ultrasound in the range of 3.5 MHz to 15 MHz is used to image organs of the abdomen and thorax as well as musculoskeletal tissues (Whittaker et al. 2007). Ultrasound is also routinely used for prenatal examination. Through ultrasound, some correctable birth defects can be identified, and the sex of the fetus can also be determined.
In musculoskeletal care, ultrasound can be used to detect muscle strains, ligament sprains, and degenerative changes in tendon. The sound energy used for imaging differs in frequency and pulse characteristics from that used for therapeutic purposes.
Beam Nonuniformity Ratio and Effective Radiating
Two terms describe the size and quality of an ultrasound crystal found in therapeutic ultrasound devices. Effective radiating area (ERA) is the area that receives at least 5% of the peak sound energy. This is essentially the size of the area to which sound energy is conducted when the head of the ultrasound unit contacts the skin. The ERA is somewhat smaller than the surface area of the sound head.
The beam of sound energy emitted from a crystal is not uniform but rather is characterized by areas of high intensity and lower intensity (figure 12.3). Beam nonuniformity ratio (BNR)is the ratio of the average intensity of the ultrasound beam across the ERA divided by the peak intensity of the ultrasound beam; the lower the BNR, the more uniform the intensity of the sound wave.
Beam scan of a crystal with a beam nonuniformity ratio (BNR) of 2.32, (a) top view and (b) side view. When tested on 40 subjects, the ultrasound transducer housing this crystal produced a very comfortable treatment at 1.5 to 2.0 watts per cm2 (W/cm2). Beam scan of a crystal with a BNR of 7.75, (c) top view. When this was tested on 40 subjects, the ultrasound transducer housing the crystal produced an uncomfortable treatment at 1.5 W/cm2 and was not tolerated at 2.0 W/cm2.
Courtesy of Brigham Young University Sports Injury Research Center.
A low BNR minimizes the risk of developing "hot spots" and allows the clinician to deliver higher doses of ultrasound without causing pain and discomfort. The BNR must be listed by the manufacturer on all units. Ideally, the BNR would be 1; however, this is impossible, and the acceptable range is between 2 and 6.
Unfortunately, BNR and ERA may not adequately define how an ultrasound unit will function. Holcomb and Joyce (2003) reported significant differences in the change in tissue temperature between two ultrasound units with a BNR of 3.7 and 2.3 and an ERA of 4.9 and 4.6 cm, respectively. These authors speculated that the area of peak intensity or peak area of the maximum beam nonuniformity ratio (PAMBNR) as described by Draper (1999) might explain why two ultrasound units differ in performance. Certainly a small spike of peak amplitude as illustrated in figure 12.4 will deliver less energy and therefore have less thermal effect than that provided by a larger area of peak amplitude. Johns, Straub, and Howard (2007) and Straub, Johns, and Howard (2008) reported considerable variability in ERA and special average intensity in 3 and 1 MHz ultrasound units, respectively, from different manufacturers. Differences between reported and actual ERA values were identified for all but one manufacturer when 3 MHz sound heads were evaluated (Johns, Straub, and Howard 2007). Demchak, Straub, and Johns (2007) noted differences in the rate but not peak heating of the calf muscles using three different 1 MHz ultrasound transducers. Johns et al. (2007), however, have reported greater heating with 1 MHz sound heads with more concentrated energy fields. The issue of equipment performance across parameters requires further study. Variability in the characteristics of the acoustic energy field may yield differing treatment effects and perhaps pose a risk of adverse events. Frye et al. (2007) reported blistering of the anterior shin after ultrasound to the calf muscles in laboratory experiments employing common clinical treatment parameters.
| |
The area of peak intensity, (a) small and (b) larger, may affect the performance of ultrasound devices.
Conducting Media
Air is a poor conductor of ultrasound energy. To maximize delivery of sound energy to the tissues, a conducting medium must be used. Several substances have been used to conduct ultrasound, including ultrasound gel, gel pads, mineral oil, lotions, and water. The amount of sound energy conducted varies substantially between conducting media. Commercial ultrasound gel (Draper 1996; Draper et al. 1993; Klucinec et al. 2000) and gel pads (Klucinec et al. 2000; Klucinec 1996) (figure 12.5) are superior conducting media. Water is not as good a conducting medium (Draper 1996; Draper et al. 1993; Klucinec et al. 2000; Klucinec 1996; Forrest and Rosen 1989, 1992), attenuating as much as 65% of the sound energy (Klucinec et al. 2000).
Ultrasound gel and gel pads.
Rubley et al. (2008) reported smaller differences (approximately 15%) in Achilles tendon tissue heating when comparing gel and degassed water as conducting media. Differences in research methods and ultrasound equipment may explain the estimated magnitude of differences between conducting media. Collectively, however, the research suggests that ultrasound gel is the conducting medium of choice for clinical administration of therapeutic ultrasound. The conducting capacities of most gels and creams have not been established. However, some have been shown to be very poor conductors of sound energy (Cameron and Monroe 1992; Draper 1996; Draper et al. 1993; Forrest and Rosen 1989, 1992; Klucinec 1996; Klucinec et al. 2000). When applying ultrasound, use gels and gel pads known to be effective conductors.
Parameters of Treatment with Ultrasound
As with electrotherapy, you can alter the treatment parameters of ultrasound depending on the desired effect. Fortunately, the number of adjustable parameters is smaller. You can control the amplitude of the sound waves and therefore the amount of sound energy being emitted from the sound head. The sound energy emitted by the crystal is measured in watts (W). The dose of sound energy delivered is based on the amount of energy being emitted divided by the radiating area of the crystal measured in square centimeters (cm2). Thus, ultrasound dose is measured in W/cm2. You can also adjust the duty cycle, duration of treatment, and frequency.
Duty cycle refers to the process of interrupting delivery of the sound wave so that periods of sound wave emission are interspersed with periods of interruption. Figure 12.6 depicts pulsed and continuous ultrasound.
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(a) In pulsed ultrasound, energy is generated only during the "on" time. Duty cycle is determined by the ratio of "on" time to pulse, in this case 50%. (b) Continuous ultrasound is shown.
Often you can select between several duty cycles. Duty cycle is calculated by dividing the time during which sound is delivered by the total time the sound head is applied. For example, if ultrasound is transmitted for 150 ms out of every second of treatment, then the duty cycle is 150/1,000, or 15%. When the emission of sound energy is not interrupted, the duty cycle equals 100%, and the ultrasound is referred to as continuous ultrasound.
Much has been learned about the treatment duration needed to elevate tissue temperatures. An interaction among the frequency, dose, and treatment duration has also been found. Some recipes for duration and intensities of ultrasound treatments used in the past do not increase tissue temperature sufficiently.
The frequency of the sound waves affects the depth at which the greatest amount of ultrasound energy is absorbed, as well as the time required to increase tissue temperature. Ultrasound units typically allow for treatment with more than one frequency, but older units had a single fixed frequency of 1 MHz. Treatments with higher frequencies are usually more appropriate for musculoskeletal injuries.
Sound Energy Absorption in Tissues
The amount of acoustic energy absorbed by tissues is influenced by many factors. The tissue characteristics, as well as the frequency, dose (W/cm2), duty cycle, and duration of treatment with ultrasound affect the amount of acoustic energy absorbed. When continuous ultrasound is delivered, the greater the energy absorption, the greater the tissue heating. Tissues with greater protein density have a higher rate of absorption, whereas tissues with a higher water content have lower absorption rates. Thus, tendon, ligament, and muscle tissue absorb more sound energy than skin and adipose tissue. Superficial bones and nerves absorb the most energy.
Ultrasound at a higher frequency (3 MHz) is absorbed more rapidly than that at a lower frequency (1 MHz) (figure 12.7). Therefore, ultrasound at higher frequencies affects tissues that are more superficial, whereas at a lower frequency less energy is absorbed superficially and more is available to penetrate into tissues. Thus, if the goal of treatment is to heat the capsular tissue at a joint such as the elbow with ultrasound, a 3 MHz frequency is appropriate. Temperature increases of up to 8°C have been reported with 3 MHz ultrasound at 1 W/cm2 in 4 min in superficial tissues such as the patellar tendon (Chan et al. 1998). If the target tissue is deep tissue, a lower frequency (1 MHz) is necessary; 10 min of continuous 1 MHz ultrasound at 2.0 W/cm2 will elevate temperature about 4°C at a depth of 2.5 cm (Draper, Castel, and Castel 1995). There is likely considerable overlap in tissue heating between 1 and 3 MHz ultrasound, as heating of tissues at 2.5 cm depths with 3 MHz ultrasound has been reported (Hayes et al. 2004). The interactions between ultrasound parameters and thermal response are discussed further shortly.
A great depth of heating is achieved with 1 MHz. The specific depth of heating is device dependent, and the values provided represent a range rather than specific limits of thermal responses.
Learn more about Therapeutic Modalities for Musculoskeletal Injuries, Fourth Edition With Online Video.
Mechanobiology in the Musculoskeletal System
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis.
Mechanobiology in Tendon
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis. Tendon is relatively avascular and therefore relies largely on autocrine and paracrine responses for tissue remodeling, repair, and adaptation. In addition to tenocytes, progenitor cells exist in tendon, and they are extremely mechanosensitive. Inappropriate mechanical load pushes these progenitors toward alternate phenotypes (chondrocytes, adipocytes, osteocytes), which results in the pathologic changes characteristic of tendinosis. Tendinosis is a common histologic finding in overuse tendon injuries that is characterized by noninflammatory degenerative changes of the ECM and aberrant cellular responses.
Tendon attaches muscle to bone, transmitting forces to the skeleton and resulting in joint stabilization and movement. As a result, tendons are subjected to high mechanical loads that predispose them to injury. Tendon's reaction to overuse injury has been described as a failed healing response (Maffulli, Sharma, and Luscombe 2004) due to the ineffective and insufficient inflammatory response generated after injury.
Tendon pathology may be classified as either tendonitis: inflammation, pain, and swelling of the peritenon; tendinosis: degeneration of the ECM and absence of inflammation upon histologic examination; or tendinopathy. Tendinopathy is the contemporary clinical term for tendon overuse injuries, as it does not imply an active inflammatory process, which is often the case.
While the etiologic factors of tendinopathy are not fully understood, a failure in the mechanobiologic response of the tenocyte has been implicated. Tendon structure, composition, and mechanical properties are modified in response to altered mechanical loading conditions. Disruption in the mechanobiologic response of the tenocyte creates a vicious cycle of suboptimal ECM production, in turn leading to further changes in mechanical signals transmitted to the tenocyte and propagating degenerative tissue production throughout the tendon (figure 16.8). Many hypothesize that mechanical overload initiates a degenerative signaling cascade that leads to tendinopathy, while some believe tendinopathy is a result of focal disruption of ECM and accompanying mechanobiologic understimulation of locally adherent tenocytes and progenitor cells.
Pathologic changes in tendinopathy. (a) Collagen organization: H&E. (b) Increased proteoglycan.
Reprinted, by permission, from M. Joseph et al., 2009, "Histological and molecular analysis of the biceps tendon long head post-tenotomy," The Journal of Orthopedic Research 27:1379-1385.
Signaling cascades leading to tendinosis probably result from understimulation of FACs and downstream MAPK-mediated events. The activation of stress-activated protein kinase (SAPK), a member of the MAPK family, is associated with matrix-degrading enzyme production. As mentioned, load affects progenitor cell survival and differentiation. Tendon progenitor cells exposed to 4% strain assume tenocyte function and express collagen type I. However, loads of 8% resulted in the expression of markers for bone, fat, and cartilage differentiation. The presence of these cells and their functional products is destructive to tendon ECM and health (Wang et al. 2007).
An alternative paradigm for the pathophysiology of tendinopathy is emerging and involves tenocyte-produced neuropeptides. Chemical messengers thought to be confined to neurons are produced in abundance in tendinopathic tissue. Substance P and its receptor (neurokinin-1 receptor [NK-1 R]), glutamate (Scott, Alfredson, and Forsgren 2008), acetylcholine (ACTH), and catecholamines are produced by local tendon fibroblasts. Tenocytes produce these neurochemicals in response to mechanical load. Substance P increases cellular proliferation in culture, which corresponds with observations of hypercellularity in early tendinosis. Pain in tendinopathic tissue has been traced to neurovascular ingrowth containing substance P positive nerve fibers, and the ablation of these fibers often results in relief. The NK-1 R is a G-protein coupled receptor that is responsive to mechanical signals. There is likely cross talk between integrin-linked kinase production resulting from integrin stimulation and cross-activation of the G-protein via ILK activation (see figure 16.5). Substance P signals through the MAPK cascade and results in gene expression.
Tendon cell networks communicate throughout the tissue via cytoplasmic extensions and cell junction zones. A signal that is sent in one area propagates through these channels, effecting a tissue-wide response. Intercellular connectivity is achieved through gap junctions, where connexins are the principal protein. In healthy tendon, tenocytes are arranged longitudinally between collagen fibers. Connexins 32 and 34 form communications between longitudinally arranged tenocytes, whereas connexin 43 links cells in all directions (Ragsdale, Phelps, and Luby-Phelps 1997).
Mechanobiology in Articular Cartilage
Articular cartilage is the major load-bearing tissue in synovial joints. Cartilage is unique in that it is avascular, aneural, alymphatic, and sparsely populated with cells. The cartilage cell (chondrocyte) is responsible for the remodeling of cartilage ECM, and it does so in response to mechanical force. Cartilage in relatively unloaded areas such as the medial patellar facet is softer and less resilient. Articular cartilage responds favorably to pulsatile doses of load, while static loading results in up-regulation of a host of inflammatory cytokines, matrix-degrading enzymes, and degeneration.
Chondrocytes are extremely responsive to compressive loads, as their location and function would indicate. A pericellular matrix composed of collagen VI and proteoglycan surrounds the chondrocyte and is an independent unit of force transduction. The pericellular matrix is analogous to the basal lamina in skeletal muscle, bridging the gap between cell membrane and ECM.
Membrane stretch - activated ion channels exist, are proximate to integrins, and likely have overlapping downstream signaling cascades. Stimulation of the integrin α5β1 pathway results in the production of aggrecan, the predominant proteoglycan in cartilage, along with the down-regulation of MMP3, the predominant degrading enzyme of PG. Higher levels of aggrecan and collagen II production are associated with dynamic compressive force, whereas static forces result in MMP production and ECM destruction. Chondrocytes from arthritic cartilage are unresponsive to mechanical stimulation, indicating cellular dysfunction and mechanoinsensitivity in osteoarthritis (Raizman 2010).
Inappropriate mechanical loading is the primary risk factor for the development of osteoarthritis (OA) (figure 16.9). OA is characterized by a loss of tissue homeostasis and the prevalence of catabolism. Molecular components of mechanotransduction in chondrocytes consist of integrin activation and downstream MAPK signaling, as well as stress-activated calcium channel signaling. The α5β1 integrin binds pericellular matrix fibronectin and associates with calcium channels in the surrounding cell membrane. In response to mechanical stimuli, integrin and calcium signaling pathways converge on MAPK cascade, where Ca2+ regulation of integrin activity through Src occurs (Raizman et al. 2010).
Damaged articular cartilage. Large defect in the medial femoral condyle.
The Cbp/p300-interacting transactivator 2 (CITED2) is a transcription regulator that is thought to balance catabolic and anticatabolic cascades and is thus centrally implicated in the pathogenesis of OA (Leong et al. 2011). CITED2 binds with and modulates a host of transcription factors. The ability to activate anabolic pathways and to inhibit inflammatory and catabolic pathways in response to mechanical signals suggests a central role in mechanical regulation. CITED2 is downstream of MAPK. Moderate-intensity intermittent loads activate CITED2, whereas high-intensity loads do not (Leong et al. 2011). Increased CITED2 expression correlates with the production of collagen II, maintenance of ECM, and suppression of MMPs. Integrin and associated receptors, downstream MAPK, and CITED2 represent a loading-specific pathway that has direct effects on tissue. Thus, loading of cartilage is essential to tissue health while overload leads to degeneration and OA. Exercise can play an important role in the treatment of OA, but excessive loading may accelerate the disease process.
In summary, the chondrocyte is dependent upon mechanical signals for survival. The aneural, avascular nature of articular cartilage accounts for its susceptibility to damage. Enhanced maintenance and repair of articular cartilage is possible through mechanobiologic manipulation. Chondrocyte preference for dynamic, pulsatile delivery of force will continue to be explored both in exercise prescription and modality delivery.
Mechanobiology in Bone
Metabolic demands on the skeleton are managed largely through calciotropic hormones, but the ability of the skeleton to adapt to its loading environment is essential for bone health. Wolff's law first proposed skeletal change in response to functional demands. We now understand that it is the cells of the skeleton - the osteoblasts, osteocytes, and osteoclasts - that remodel bone in response to stress. An example of bone's sensitivity to mechanical demand is demonstrated in cortical bone of the dominant arm in elite tennis players, which can be up to 35% thicker than the cortical bone of the non-dominant arm. Rapid bone loss during periods of immobility and in microgravity exemplifies the homeostatic necessity of mechanotransduction.
Bone is certainly not as deformable as connective tissue, at least elastically. Bone can experience up to 0.3% strain, much less than ligament or tendon (5% - 20%). Bone experiences a wide variety of mechanical stimuli that produce slight deformation in the bone tissue, pressure in the intramedullary cavity and within the cortices, transient pressure waves, and fluid shear forces through the canaliculi.
Osteoblasts at the surface of bone respond to deformation of the cell membrane from strain experienced on the surface of the bone from imposed forces. Osteocytes located deeper in the bone tissue respond to shear stress of fluid flow through the canaliculi (figure 16.10). An externally applied load forces fluid out of regions of high compressive strains. This fluid returns when the load is removed. This results in bone cell exposure to an oscillating fluid flow. The osteocyte population, through its interconnectedness via gap junctions, comprises a three-dimensional sensing systemin which amplification of mechanical signals propagates throughout the tissue.
Structure and lacuna canalicular network of bone.
As in tendon, integrins are important conductors of mechanical signals in bone cells (Salter, Robb, and Wright 1997). In bone, the β subunit of the integrin extracellular domain mediates binding to matrix components. Prominent matrix ligands for integrin in bone include collagen I and III and fibronectin. The formation of FAC in response to integrin activation is critical to cell adhesion, survival, and production. Mechanical signals activate the MAPK cascade, leading to down-regulation of RANK ligand (RANKL) expression and the formation of osteoclasts.
Strain, shear, and pressure result in the mobilization of intracellular calcium. This rapid increase in intracellular calcium concentration appears to occur due to phospholipase-C activity and IP3 signaling, which results in the release of calcium from intracellular stores (calcium-mediated calcium release).
Summary
Musculoskeletal cells are exposed to forces transmitted through tissue. Mechanotransduction pathways modulate diverse cellular functions. Physiologic effects result from intracellular signaling of membrane receptors and ion channels. The integrin receptor, bound to the tissue and stimulated by stress, can coactivate cytokine receptors and ion channels, resulting in a coordinated cell response. The musculoskeletal system provides a link to the physical environment. The encompassing nature of mechanical signaling likely represents the primary means by which adaptation to force exposure occurs. For clinicians this is exciting, as much of what we do involves modulating force through exercise and physical interventions. The obvious hurdle in fully accessing this tool is the difficulty of quantifying in vivo human forces, both those that result in injury and those produced by specific mechanical interventions. Future research and technology will be essential for identifying optimal mechanical interventions and their specific prescription. This chapter outlines the biology underpinning mechanical intervention. Harnessing the power of mechanotransduction is our most powerful tool for affecting musculoskeletal health and adaptation.
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Case Scenario: Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries.
Case Scenario 1
Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries. A neurological screen was normal, and concussion assessment and diagnostic imaging were negative. She complains of pain (6 on a scale of 10 with walking and standing) and muscle spasm in her neck and upper back, and intermittent headaches made worse with prolonged sitting and exercise and relieved by oral over-the-counter medication and lying down. She states at times she gets pain that radiates down her right arm.
She states that she is married and has no children. She works as a college tennis coach and director of the campus tennis center. Her medical history is unremarkable other than having sustained a right sprained ankle in high school and having wisdom teeth removed.
On presentation she denies lightheadedness, concentration and memory deficits, tinnitus or vision disturbances, and a history of neck injuries. On examination, the patient's head is slightly tilted to the left side. The patient has limited active and passive rotation and side-bending to the right side and painful end-range extension. She has tenderness to palpation along the right cervical paraspinal muscles. Upper quarter scan for sensory, strength, and reflex deficits is normal. Physical examination reveals restricted left side-glide at C5-C6, and the patient is evaluated as suffering from a flexed, left rotated, and side-bent facet with soft tissue pain and muscle spasm.
The patient complains that she has difficulty raising her right arm overhead and that her neck and upper back pain increase with prolonged sitting, driving, and lifting and carrying.
The forces involved in motor vehicle accidents can cause catastrophic injuries. The whiplash mechanism of injury may result in fracture, sprain, and muscle strain. The medical history, history of the current condition, and medical and physical examinations conducted in this case provide assurance that serious structural damage has been avoided. A thorough examination and evaluation of all pertinent information is needed before proceeding with a rehabilitation plan of care, especially in conditions involving the spine.
The first step in developing a rehabilitation plan of care is the development of a problem list. It is usually best to build a problem list around the impairments, functional limitations, and participation restrictions identified in the evaluation of the case. From the problem list, mutually agreeable short-term goals can be developed and a goal-directed application of therapeutic modalities, manual therapy, and exercise developed.
What are the problems identified in this case?
Impairments
- Pain
- Loss of cervical range of motion
- Headache
Functional limitations
- Reaching overhead and prolonged sitting/driving
Participation restrictions
- Unable to play tennis or coach effectively due to pain and loss of motion
- Has difficulty with management responsibilities due to poor tolerance of sitting
The clinician has several options to recommend for the problems listed. Pain and muscle spasm could be treated with periodic cold or superficial heat. TENS could be used as needed for the same purposes.
What would you do?
A decision on the treatment needs to be based on any contraindications for an intervention, the current condition, the patient's preferences, the clinician's experiences, and existing clinical research. After ruling out contraindications to the treatment options and conferring with the patient about the ability to control pain with oral medications, it is decided to treat her with massage to decrease pain and muscle spasm before performing joint mobilization to restore range of motion. The patient states that a hot shower is soothing and that she has access to superficial heat. She demonstrates a substantial increase in cervical range of motion after the initial treatment. She is instructed in active range of motion exercises and agrees with a plan of 20 to 30 min of superficial heating as needed for relief of pain and spasm and a four-times-per-day regimen of active range of motion, which is also to be performed after heat application. Over two subsequent visits she reports the resolution of pain at rest other than mild aching and stiffness upon rising, and she demonstrates full cervical range of motion. Postural and functional exercises are introduced to increase tolerance to daily activities and return to coaching. Three and a half weeks after her accident she is able to work a normal day, drive, and play tennis for up to an hour without limitations. She is discharged to continue with a postural and tennis function exercise program.
This case illustrates some of the complexities of developing a plan of care. There is not a single correct approach to meeting the needs of many patients. The first mandate is to do no harm. The clinician and patient must then decide which problems are most concerning, discuss the options, and agree on a plan. Once short-term goals are achieved, the intervention progresses. Modalities used to relieve pain and muscle spasm are replaced by exercises aimed at addressing functional limitations and participation restrictions.
Learn more about Therapeutic Modalities for Musculoskeletal Injuries, Fourth Edition With Online Video.
Using Ultrasound as a Therapeutic Modality
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions.
Ultrasound
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions. Different frequencies of ultrasound are used for each application. The ultrasound units used in the practice of athletic training and physical therapy emit sound energy at frequencies between 800 kHz (800,000 Hz) and 3 MHz (3,000,000 Hz). Modern high-quality ultrasound units allow the clinician to select the treatment frequency. Typically a clinician can choose frequencies near 1 MHz and 3.3 MHz. Some units are also adjustable to 2 MHz (figure 12.1). The importance of frequency and the applications of ultrasound at various frequencies will be discussed in detail. Initially, it is important to understand that therapeutic ultrasound uses acoustic energy, delivered at very specific high frequencies.
Modern combination ultrasound, laser, and electrotherapy device.
Ultrasound machines use electrical current to create a mechanical vibration in a crystalline material housed in the "head" of the unit. Vibration of the crystalline material produces a wave of acoustic energy (ultrasound) (figure 12.2). The crystalline material in modern ultrasound devices is synthetic, although natural crystals were once used. The sound energy emitted from the ultrasound head travels through tissues and is absorbed.
Components of an ultrasound unit.
Ultrasound technology is now used extensively for diagnostic imaging. Ultrasound in the range of 3.5 MHz to 15 MHz is used to image organs of the abdomen and thorax as well as musculoskeletal tissues (Whittaker et al. 2007). Ultrasound is also routinely used for prenatal examination. Through ultrasound, some correctable birth defects can be identified, and the sex of the fetus can also be determined.
In musculoskeletal care, ultrasound can be used to detect muscle strains, ligament sprains, and degenerative changes in tendon. The sound energy used for imaging differs in frequency and pulse characteristics from that used for therapeutic purposes.
Beam Nonuniformity Ratio and Effective Radiating
Two terms describe the size and quality of an ultrasound crystal found in therapeutic ultrasound devices. Effective radiating area (ERA) is the area that receives at least 5% of the peak sound energy. This is essentially the size of the area to which sound energy is conducted when the head of the ultrasound unit contacts the skin. The ERA is somewhat smaller than the surface area of the sound head.
The beam of sound energy emitted from a crystal is not uniform but rather is characterized by areas of high intensity and lower intensity (figure 12.3). Beam nonuniformity ratio (BNR)is the ratio of the average intensity of the ultrasound beam across the ERA divided by the peak intensity of the ultrasound beam; the lower the BNR, the more uniform the intensity of the sound wave.
Beam scan of a crystal with a beam nonuniformity ratio (BNR) of 2.32, (a) top view and (b) side view. When tested on 40 subjects, the ultrasound transducer housing this crystal produced a very comfortable treatment at 1.5 to 2.0 watts per cm2 (W/cm2). Beam scan of a crystal with a BNR of 7.75, (c) top view. When this was tested on 40 subjects, the ultrasound transducer housing the crystal produced an uncomfortable treatment at 1.5 W/cm2 and was not tolerated at 2.0 W/cm2.
Courtesy of Brigham Young University Sports Injury Research Center.
A low BNR minimizes the risk of developing "hot spots" and allows the clinician to deliver higher doses of ultrasound without causing pain and discomfort. The BNR must be listed by the manufacturer on all units. Ideally, the BNR would be 1; however, this is impossible, and the acceptable range is between 2 and 6.
Unfortunately, BNR and ERA may not adequately define how an ultrasound unit will function. Holcomb and Joyce (2003) reported significant differences in the change in tissue temperature between two ultrasound units with a BNR of 3.7 and 2.3 and an ERA of 4.9 and 4.6 cm, respectively. These authors speculated that the area of peak intensity or peak area of the maximum beam nonuniformity ratio (PAMBNR) as described by Draper (1999) might explain why two ultrasound units differ in performance. Certainly a small spike of peak amplitude as illustrated in figure 12.4 will deliver less energy and therefore have less thermal effect than that provided by a larger area of peak amplitude. Johns, Straub, and Howard (2007) and Straub, Johns, and Howard (2008) reported considerable variability in ERA and special average intensity in 3 and 1 MHz ultrasound units, respectively, from different manufacturers. Differences between reported and actual ERA values were identified for all but one manufacturer when 3 MHz sound heads were evaluated (Johns, Straub, and Howard 2007). Demchak, Straub, and Johns (2007) noted differences in the rate but not peak heating of the calf muscles using three different 1 MHz ultrasound transducers. Johns et al. (2007), however, have reported greater heating with 1 MHz sound heads with more concentrated energy fields. The issue of equipment performance across parameters requires further study. Variability in the characteristics of the acoustic energy field may yield differing treatment effects and perhaps pose a risk of adverse events. Frye et al. (2007) reported blistering of the anterior shin after ultrasound to the calf muscles in laboratory experiments employing common clinical treatment parameters.
| |
The area of peak intensity, (a) small and (b) larger, may affect the performance of ultrasound devices.
Conducting Media
Air is a poor conductor of ultrasound energy. To maximize delivery of sound energy to the tissues, a conducting medium must be used. Several substances have been used to conduct ultrasound, including ultrasound gel, gel pads, mineral oil, lotions, and water. The amount of sound energy conducted varies substantially between conducting media. Commercial ultrasound gel (Draper 1996; Draper et al. 1993; Klucinec et al. 2000) and gel pads (Klucinec et al. 2000; Klucinec 1996) (figure 12.5) are superior conducting media. Water is not as good a conducting medium (Draper 1996; Draper et al. 1993; Klucinec et al. 2000; Klucinec 1996; Forrest and Rosen 1989, 1992), attenuating as much as 65% of the sound energy (Klucinec et al. 2000).
Ultrasound gel and gel pads.
Rubley et al. (2008) reported smaller differences (approximately 15%) in Achilles tendon tissue heating when comparing gel and degassed water as conducting media. Differences in research methods and ultrasound equipment may explain the estimated magnitude of differences between conducting media. Collectively, however, the research suggests that ultrasound gel is the conducting medium of choice for clinical administration of therapeutic ultrasound. The conducting capacities of most gels and creams have not been established. However, some have been shown to be very poor conductors of sound energy (Cameron and Monroe 1992; Draper 1996; Draper et al. 1993; Forrest and Rosen 1989, 1992; Klucinec 1996; Klucinec et al. 2000). When applying ultrasound, use gels and gel pads known to be effective conductors.
Parameters of Treatment with Ultrasound
As with electrotherapy, you can alter the treatment parameters of ultrasound depending on the desired effect. Fortunately, the number of adjustable parameters is smaller. You can control the amplitude of the sound waves and therefore the amount of sound energy being emitted from the sound head. The sound energy emitted by the crystal is measured in watts (W). The dose of sound energy delivered is based on the amount of energy being emitted divided by the radiating area of the crystal measured in square centimeters (cm2). Thus, ultrasound dose is measured in W/cm2. You can also adjust the duty cycle, duration of treatment, and frequency.
Duty cycle refers to the process of interrupting delivery of the sound wave so that periods of sound wave emission are interspersed with periods of interruption. Figure 12.6 depicts pulsed and continuous ultrasound.
| |
(a) In pulsed ultrasound, energy is generated only during the "on" time. Duty cycle is determined by the ratio of "on" time to pulse, in this case 50%. (b) Continuous ultrasound is shown.
Often you can select between several duty cycles. Duty cycle is calculated by dividing the time during which sound is delivered by the total time the sound head is applied. For example, if ultrasound is transmitted for 150 ms out of every second of treatment, then the duty cycle is 150/1,000, or 15%. When the emission of sound energy is not interrupted, the duty cycle equals 100%, and the ultrasound is referred to as continuous ultrasound.
Much has been learned about the treatment duration needed to elevate tissue temperatures. An interaction among the frequency, dose, and treatment duration has also been found. Some recipes for duration and intensities of ultrasound treatments used in the past do not increase tissue temperature sufficiently.
The frequency of the sound waves affects the depth at which the greatest amount of ultrasound energy is absorbed, as well as the time required to increase tissue temperature. Ultrasound units typically allow for treatment with more than one frequency, but older units had a single fixed frequency of 1 MHz. Treatments with higher frequencies are usually more appropriate for musculoskeletal injuries.
Sound Energy Absorption in Tissues
The amount of acoustic energy absorbed by tissues is influenced by many factors. The tissue characteristics, as well as the frequency, dose (W/cm2), duty cycle, and duration of treatment with ultrasound affect the amount of acoustic energy absorbed. When continuous ultrasound is delivered, the greater the energy absorption, the greater the tissue heating. Tissues with greater protein density have a higher rate of absorption, whereas tissues with a higher water content have lower absorption rates. Thus, tendon, ligament, and muscle tissue absorb more sound energy than skin and adipose tissue. Superficial bones and nerves absorb the most energy.
Ultrasound at a higher frequency (3 MHz) is absorbed more rapidly than that at a lower frequency (1 MHz) (figure 12.7). Therefore, ultrasound at higher frequencies affects tissues that are more superficial, whereas at a lower frequency less energy is absorbed superficially and more is available to penetrate into tissues. Thus, if the goal of treatment is to heat the capsular tissue at a joint such as the elbow with ultrasound, a 3 MHz frequency is appropriate. Temperature increases of up to 8°C have been reported with 3 MHz ultrasound at 1 W/cm2 in 4 min in superficial tissues such as the patellar tendon (Chan et al. 1998). If the target tissue is deep tissue, a lower frequency (1 MHz) is necessary; 10 min of continuous 1 MHz ultrasound at 2.0 W/cm2 will elevate temperature about 4°C at a depth of 2.5 cm (Draper, Castel, and Castel 1995). There is likely considerable overlap in tissue heating between 1 and 3 MHz ultrasound, as heating of tissues at 2.5 cm depths with 3 MHz ultrasound has been reported (Hayes et al. 2004). The interactions between ultrasound parameters and thermal response are discussed further shortly.
A great depth of heating is achieved with 1 MHz. The specific depth of heating is device dependent, and the values provided represent a range rather than specific limits of thermal responses.
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Mechanobiology in the Musculoskeletal System
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis.
Mechanobiology in Tendon
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis. Tendon is relatively avascular and therefore relies largely on autocrine and paracrine responses for tissue remodeling, repair, and adaptation. In addition to tenocytes, progenitor cells exist in tendon, and they are extremely mechanosensitive. Inappropriate mechanical load pushes these progenitors toward alternate phenotypes (chondrocytes, adipocytes, osteocytes), which results in the pathologic changes characteristic of tendinosis. Tendinosis is a common histologic finding in overuse tendon injuries that is characterized by noninflammatory degenerative changes of the ECM and aberrant cellular responses.
Tendon attaches muscle to bone, transmitting forces to the skeleton and resulting in joint stabilization and movement. As a result, tendons are subjected to high mechanical loads that predispose them to injury. Tendon's reaction to overuse injury has been described as a failed healing response (Maffulli, Sharma, and Luscombe 2004) due to the ineffective and insufficient inflammatory response generated after injury.
Tendon pathology may be classified as either tendonitis: inflammation, pain, and swelling of the peritenon; tendinosis: degeneration of the ECM and absence of inflammation upon histologic examination; or tendinopathy. Tendinopathy is the contemporary clinical term for tendon overuse injuries, as it does not imply an active inflammatory process, which is often the case.
While the etiologic factors of tendinopathy are not fully understood, a failure in the mechanobiologic response of the tenocyte has been implicated. Tendon structure, composition, and mechanical properties are modified in response to altered mechanical loading conditions. Disruption in the mechanobiologic response of the tenocyte creates a vicious cycle of suboptimal ECM production, in turn leading to further changes in mechanical signals transmitted to the tenocyte and propagating degenerative tissue production throughout the tendon (figure 16.8). Many hypothesize that mechanical overload initiates a degenerative signaling cascade that leads to tendinopathy, while some believe tendinopathy is a result of focal disruption of ECM and accompanying mechanobiologic understimulation of locally adherent tenocytes and progenitor cells.
Pathologic changes in tendinopathy. (a) Collagen organization: H&E. (b) Increased proteoglycan.
Reprinted, by permission, from M. Joseph et al., 2009, "Histological and molecular analysis of the biceps tendon long head post-tenotomy," The Journal of Orthopedic Research 27:1379-1385.
Signaling cascades leading to tendinosis probably result from understimulation of FACs and downstream MAPK-mediated events. The activation of stress-activated protein kinase (SAPK), a member of the MAPK family, is associated with matrix-degrading enzyme production. As mentioned, load affects progenitor cell survival and differentiation. Tendon progenitor cells exposed to 4% strain assume tenocyte function and express collagen type I. However, loads of 8% resulted in the expression of markers for bone, fat, and cartilage differentiation. The presence of these cells and their functional products is destructive to tendon ECM and health (Wang et al. 2007).
An alternative paradigm for the pathophysiology of tendinopathy is emerging and involves tenocyte-produced neuropeptides. Chemical messengers thought to be confined to neurons are produced in abundance in tendinopathic tissue. Substance P and its receptor (neurokinin-1 receptor [NK-1 R]), glutamate (Scott, Alfredson, and Forsgren 2008), acetylcholine (ACTH), and catecholamines are produced by local tendon fibroblasts. Tenocytes produce these neurochemicals in response to mechanical load. Substance P increases cellular proliferation in culture, which corresponds with observations of hypercellularity in early tendinosis. Pain in tendinopathic tissue has been traced to neurovascular ingrowth containing substance P positive nerve fibers, and the ablation of these fibers often results in relief. The NK-1 R is a G-protein coupled receptor that is responsive to mechanical signals. There is likely cross talk between integrin-linked kinase production resulting from integrin stimulation and cross-activation of the G-protein via ILK activation (see figure 16.5). Substance P signals through the MAPK cascade and results in gene expression.
Tendon cell networks communicate throughout the tissue via cytoplasmic extensions and cell junction zones. A signal that is sent in one area propagates through these channels, effecting a tissue-wide response. Intercellular connectivity is achieved through gap junctions, where connexins are the principal protein. In healthy tendon, tenocytes are arranged longitudinally between collagen fibers. Connexins 32 and 34 form communications between longitudinally arranged tenocytes, whereas connexin 43 links cells in all directions (Ragsdale, Phelps, and Luby-Phelps 1997).
Mechanobiology in Articular Cartilage
Articular cartilage is the major load-bearing tissue in synovial joints. Cartilage is unique in that it is avascular, aneural, alymphatic, and sparsely populated with cells. The cartilage cell (chondrocyte) is responsible for the remodeling of cartilage ECM, and it does so in response to mechanical force. Cartilage in relatively unloaded areas such as the medial patellar facet is softer and less resilient. Articular cartilage responds favorably to pulsatile doses of load, while static loading results in up-regulation of a host of inflammatory cytokines, matrix-degrading enzymes, and degeneration.
Chondrocytes are extremely responsive to compressive loads, as their location and function would indicate. A pericellular matrix composed of collagen VI and proteoglycan surrounds the chondrocyte and is an independent unit of force transduction. The pericellular matrix is analogous to the basal lamina in skeletal muscle, bridging the gap between cell membrane and ECM.
Membrane stretch - activated ion channels exist, are proximate to integrins, and likely have overlapping downstream signaling cascades. Stimulation of the integrin α5β1 pathway results in the production of aggrecan, the predominant proteoglycan in cartilage, along with the down-regulation of MMP3, the predominant degrading enzyme of PG. Higher levels of aggrecan and collagen II production are associated with dynamic compressive force, whereas static forces result in MMP production and ECM destruction. Chondrocytes from arthritic cartilage are unresponsive to mechanical stimulation, indicating cellular dysfunction and mechanoinsensitivity in osteoarthritis (Raizman 2010).
Inappropriate mechanical loading is the primary risk factor for the development of osteoarthritis (OA) (figure 16.9). OA is characterized by a loss of tissue homeostasis and the prevalence of catabolism. Molecular components of mechanotransduction in chondrocytes consist of integrin activation and downstream MAPK signaling, as well as stress-activated calcium channel signaling. The α5β1 integrin binds pericellular matrix fibronectin and associates with calcium channels in the surrounding cell membrane. In response to mechanical stimuli, integrin and calcium signaling pathways converge on MAPK cascade, where Ca2+ regulation of integrin activity through Src occurs (Raizman et al. 2010).
Damaged articular cartilage. Large defect in the medial femoral condyle.
The Cbp/p300-interacting transactivator 2 (CITED2) is a transcription regulator that is thought to balance catabolic and anticatabolic cascades and is thus centrally implicated in the pathogenesis of OA (Leong et al. 2011). CITED2 binds with and modulates a host of transcription factors. The ability to activate anabolic pathways and to inhibit inflammatory and catabolic pathways in response to mechanical signals suggests a central role in mechanical regulation. CITED2 is downstream of MAPK. Moderate-intensity intermittent loads activate CITED2, whereas high-intensity loads do not (Leong et al. 2011). Increased CITED2 expression correlates with the production of collagen II, maintenance of ECM, and suppression of MMPs. Integrin and associated receptors, downstream MAPK, and CITED2 represent a loading-specific pathway that has direct effects on tissue. Thus, loading of cartilage is essential to tissue health while overload leads to degeneration and OA. Exercise can play an important role in the treatment of OA, but excessive loading may accelerate the disease process.
In summary, the chondrocyte is dependent upon mechanical signals for survival. The aneural, avascular nature of articular cartilage accounts for its susceptibility to damage. Enhanced maintenance and repair of articular cartilage is possible through mechanobiologic manipulation. Chondrocyte preference for dynamic, pulsatile delivery of force will continue to be explored both in exercise prescription and modality delivery.
Mechanobiology in Bone
Metabolic demands on the skeleton are managed largely through calciotropic hormones, but the ability of the skeleton to adapt to its loading environment is essential for bone health. Wolff's law first proposed skeletal change in response to functional demands. We now understand that it is the cells of the skeleton - the osteoblasts, osteocytes, and osteoclasts - that remodel bone in response to stress. An example of bone's sensitivity to mechanical demand is demonstrated in cortical bone of the dominant arm in elite tennis players, which can be up to 35% thicker than the cortical bone of the non-dominant arm. Rapid bone loss during periods of immobility and in microgravity exemplifies the homeostatic necessity of mechanotransduction.
Bone is certainly not as deformable as connective tissue, at least elastically. Bone can experience up to 0.3% strain, much less than ligament or tendon (5% - 20%). Bone experiences a wide variety of mechanical stimuli that produce slight deformation in the bone tissue, pressure in the intramedullary cavity and within the cortices, transient pressure waves, and fluid shear forces through the canaliculi.
Osteoblasts at the surface of bone respond to deformation of the cell membrane from strain experienced on the surface of the bone from imposed forces. Osteocytes located deeper in the bone tissue respond to shear stress of fluid flow through the canaliculi (figure 16.10). An externally applied load forces fluid out of regions of high compressive strains. This fluid returns when the load is removed. This results in bone cell exposure to an oscillating fluid flow. The osteocyte population, through its interconnectedness via gap junctions, comprises a three-dimensional sensing systemin which amplification of mechanical signals propagates throughout the tissue.
Structure and lacuna canalicular network of bone.
As in tendon, integrins are important conductors of mechanical signals in bone cells (Salter, Robb, and Wright 1997). In bone, the β subunit of the integrin extracellular domain mediates binding to matrix components. Prominent matrix ligands for integrin in bone include collagen I and III and fibronectin. The formation of FAC in response to integrin activation is critical to cell adhesion, survival, and production. Mechanical signals activate the MAPK cascade, leading to down-regulation of RANK ligand (RANKL) expression and the formation of osteoclasts.
Strain, shear, and pressure result in the mobilization of intracellular calcium. This rapid increase in intracellular calcium concentration appears to occur due to phospholipase-C activity and IP3 signaling, which results in the release of calcium from intracellular stores (calcium-mediated calcium release).
Summary
Musculoskeletal cells are exposed to forces transmitted through tissue. Mechanotransduction pathways modulate diverse cellular functions. Physiologic effects result from intracellular signaling of membrane receptors and ion channels. The integrin receptor, bound to the tissue and stimulated by stress, can coactivate cytokine receptors and ion channels, resulting in a coordinated cell response. The musculoskeletal system provides a link to the physical environment. The encompassing nature of mechanical signaling likely represents the primary means by which adaptation to force exposure occurs. For clinicians this is exciting, as much of what we do involves modulating force through exercise and physical interventions. The obvious hurdle in fully accessing this tool is the difficulty of quantifying in vivo human forces, both those that result in injury and those produced by specific mechanical interventions. Future research and technology will be essential for identifying optimal mechanical interventions and their specific prescription. This chapter outlines the biology underpinning mechanical intervention. Harnessing the power of mechanotransduction is our most powerful tool for affecting musculoskeletal health and adaptation.
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Case Scenario: Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries.
Case Scenario 1
Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries. A neurological screen was normal, and concussion assessment and diagnostic imaging were negative. She complains of pain (6 on a scale of 10 with walking and standing) and muscle spasm in her neck and upper back, and intermittent headaches made worse with prolonged sitting and exercise and relieved by oral over-the-counter medication and lying down. She states at times she gets pain that radiates down her right arm.
She states that she is married and has no children. She works as a college tennis coach and director of the campus tennis center. Her medical history is unremarkable other than having sustained a right sprained ankle in high school and having wisdom teeth removed.
On presentation she denies lightheadedness, concentration and memory deficits, tinnitus or vision disturbances, and a history of neck injuries. On examination, the patient's head is slightly tilted to the left side. The patient has limited active and passive rotation and side-bending to the right side and painful end-range extension. She has tenderness to palpation along the right cervical paraspinal muscles. Upper quarter scan for sensory, strength, and reflex deficits is normal. Physical examination reveals restricted left side-glide at C5-C6, and the patient is evaluated as suffering from a flexed, left rotated, and side-bent facet with soft tissue pain and muscle spasm.
The patient complains that she has difficulty raising her right arm overhead and that her neck and upper back pain increase with prolonged sitting, driving, and lifting and carrying.
The forces involved in motor vehicle accidents can cause catastrophic injuries. The whiplash mechanism of injury may result in fracture, sprain, and muscle strain. The medical history, history of the current condition, and medical and physical examinations conducted in this case provide assurance that serious structural damage has been avoided. A thorough examination and evaluation of all pertinent information is needed before proceeding with a rehabilitation plan of care, especially in conditions involving the spine.
The first step in developing a rehabilitation plan of care is the development of a problem list. It is usually best to build a problem list around the impairments, functional limitations, and participation restrictions identified in the evaluation of the case. From the problem list, mutually agreeable short-term goals can be developed and a goal-directed application of therapeutic modalities, manual therapy, and exercise developed.
What are the problems identified in this case?
Impairments
- Pain
- Loss of cervical range of motion
- Headache
Functional limitations
- Reaching overhead and prolonged sitting/driving
Participation restrictions
- Unable to play tennis or coach effectively due to pain and loss of motion
- Has difficulty with management responsibilities due to poor tolerance of sitting
The clinician has several options to recommend for the problems listed. Pain and muscle spasm could be treated with periodic cold or superficial heat. TENS could be used as needed for the same purposes.
What would you do?
A decision on the treatment needs to be based on any contraindications for an intervention, the current condition, the patient's preferences, the clinician's experiences, and existing clinical research. After ruling out contraindications to the treatment options and conferring with the patient about the ability to control pain with oral medications, it is decided to treat her with massage to decrease pain and muscle spasm before performing joint mobilization to restore range of motion. The patient states that a hot shower is soothing and that she has access to superficial heat. She demonstrates a substantial increase in cervical range of motion after the initial treatment. She is instructed in active range of motion exercises and agrees with a plan of 20 to 30 min of superficial heating as needed for relief of pain and spasm and a four-times-per-day regimen of active range of motion, which is also to be performed after heat application. Over two subsequent visits she reports the resolution of pain at rest other than mild aching and stiffness upon rising, and she demonstrates full cervical range of motion. Postural and functional exercises are introduced to increase tolerance to daily activities and return to coaching. Three and a half weeks after her accident she is able to work a normal day, drive, and play tennis for up to an hour without limitations. She is discharged to continue with a postural and tennis function exercise program.
This case illustrates some of the complexities of developing a plan of care. There is not a single correct approach to meeting the needs of many patients. The first mandate is to do no harm. The clinician and patient must then decide which problems are most concerning, discuss the options, and agree on a plan. Once short-term goals are achieved, the intervention progresses. Modalities used to relieve pain and muscle spasm are replaced by exercises aimed at addressing functional limitations and participation restrictions.
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Using Ultrasound as a Therapeutic Modality
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions.
Ultrasound
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions. Different frequencies of ultrasound are used for each application. The ultrasound units used in the practice of athletic training and physical therapy emit sound energy at frequencies between 800 kHz (800,000 Hz) and 3 MHz (3,000,000 Hz). Modern high-quality ultrasound units allow the clinician to select the treatment frequency. Typically a clinician can choose frequencies near 1 MHz and 3.3 MHz. Some units are also adjustable to 2 MHz (figure 12.1). The importance of frequency and the applications of ultrasound at various frequencies will be discussed in detail. Initially, it is important to understand that therapeutic ultrasound uses acoustic energy, delivered at very specific high frequencies.
Modern combination ultrasound, laser, and electrotherapy device.
Ultrasound machines use electrical current to create a mechanical vibration in a crystalline material housed in the "head" of the unit. Vibration of the crystalline material produces a wave of acoustic energy (ultrasound) (figure 12.2). The crystalline material in modern ultrasound devices is synthetic, although natural crystals were once used. The sound energy emitted from the ultrasound head travels through tissues and is absorbed.
Components of an ultrasound unit.
Ultrasound technology is now used extensively for diagnostic imaging. Ultrasound in the range of 3.5 MHz to 15 MHz is used to image organs of the abdomen and thorax as well as musculoskeletal tissues (Whittaker et al. 2007). Ultrasound is also routinely used for prenatal examination. Through ultrasound, some correctable birth defects can be identified, and the sex of the fetus can also be determined.
In musculoskeletal care, ultrasound can be used to detect muscle strains, ligament sprains, and degenerative changes in tendon. The sound energy used for imaging differs in frequency and pulse characteristics from that used for therapeutic purposes.
Beam Nonuniformity Ratio and Effective Radiating
Two terms describe the size and quality of an ultrasound crystal found in therapeutic ultrasound devices. Effective radiating area (ERA) is the area that receives at least 5% of the peak sound energy. This is essentially the size of the area to which sound energy is conducted when the head of the ultrasound unit contacts the skin. The ERA is somewhat smaller than the surface area of the sound head.
The beam of sound energy emitted from a crystal is not uniform but rather is characterized by areas of high intensity and lower intensity (figure 12.3). Beam nonuniformity ratio (BNR)is the ratio of the average intensity of the ultrasound beam across the ERA divided by the peak intensity of the ultrasound beam; the lower the BNR, the more uniform the intensity of the sound wave.
Beam scan of a crystal with a beam nonuniformity ratio (BNR) of 2.32, (a) top view and (b) side view. When tested on 40 subjects, the ultrasound transducer housing this crystal produced a very comfortable treatment at 1.5 to 2.0 watts per cm2 (W/cm2). Beam scan of a crystal with a BNR of 7.75, (c) top view. When this was tested on 40 subjects, the ultrasound transducer housing the crystal produced an uncomfortable treatment at 1.5 W/cm2 and was not tolerated at 2.0 W/cm2.
Courtesy of Brigham Young University Sports Injury Research Center.
A low BNR minimizes the risk of developing "hot spots" and allows the clinician to deliver higher doses of ultrasound without causing pain and discomfort. The BNR must be listed by the manufacturer on all units. Ideally, the BNR would be 1; however, this is impossible, and the acceptable range is between 2 and 6.
Unfortunately, BNR and ERA may not adequately define how an ultrasound unit will function. Holcomb and Joyce (2003) reported significant differences in the change in tissue temperature between two ultrasound units with a BNR of 3.7 and 2.3 and an ERA of 4.9 and 4.6 cm, respectively. These authors speculated that the area of peak intensity or peak area of the maximum beam nonuniformity ratio (PAMBNR) as described by Draper (1999) might explain why two ultrasound units differ in performance. Certainly a small spike of peak amplitude as illustrated in figure 12.4 will deliver less energy and therefore have less thermal effect than that provided by a larger area of peak amplitude. Johns, Straub, and Howard (2007) and Straub, Johns, and Howard (2008) reported considerable variability in ERA and special average intensity in 3 and 1 MHz ultrasound units, respectively, from different manufacturers. Differences between reported and actual ERA values were identified for all but one manufacturer when 3 MHz sound heads were evaluated (Johns, Straub, and Howard 2007). Demchak, Straub, and Johns (2007) noted differences in the rate but not peak heating of the calf muscles using three different 1 MHz ultrasound transducers. Johns et al. (2007), however, have reported greater heating with 1 MHz sound heads with more concentrated energy fields. The issue of equipment performance across parameters requires further study. Variability in the characteristics of the acoustic energy field may yield differing treatment effects and perhaps pose a risk of adverse events. Frye et al. (2007) reported blistering of the anterior shin after ultrasound to the calf muscles in laboratory experiments employing common clinical treatment parameters.
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The area of peak intensity, (a) small and (b) larger, may affect the performance of ultrasound devices.
Conducting Media
Air is a poor conductor of ultrasound energy. To maximize delivery of sound energy to the tissues, a conducting medium must be used. Several substances have been used to conduct ultrasound, including ultrasound gel, gel pads, mineral oil, lotions, and water. The amount of sound energy conducted varies substantially between conducting media. Commercial ultrasound gel (Draper 1996; Draper et al. 1993; Klucinec et al. 2000) and gel pads (Klucinec et al. 2000; Klucinec 1996) (figure 12.5) are superior conducting media. Water is not as good a conducting medium (Draper 1996; Draper et al. 1993; Klucinec et al. 2000; Klucinec 1996; Forrest and Rosen 1989, 1992), attenuating as much as 65% of the sound energy (Klucinec et al. 2000).
Ultrasound gel and gel pads.
Rubley et al. (2008) reported smaller differences (approximately 15%) in Achilles tendon tissue heating when comparing gel and degassed water as conducting media. Differences in research methods and ultrasound equipment may explain the estimated magnitude of differences between conducting media. Collectively, however, the research suggests that ultrasound gel is the conducting medium of choice for clinical administration of therapeutic ultrasound. The conducting capacities of most gels and creams have not been established. However, some have been shown to be very poor conductors of sound energy (Cameron and Monroe 1992; Draper 1996; Draper et al. 1993; Forrest and Rosen 1989, 1992; Klucinec 1996; Klucinec et al. 2000). When applying ultrasound, use gels and gel pads known to be effective conductors.
Parameters of Treatment with Ultrasound
As with electrotherapy, you can alter the treatment parameters of ultrasound depending on the desired effect. Fortunately, the number of adjustable parameters is smaller. You can control the amplitude of the sound waves and therefore the amount of sound energy being emitted from the sound head. The sound energy emitted by the crystal is measured in watts (W). The dose of sound energy delivered is based on the amount of energy being emitted divided by the radiating area of the crystal measured in square centimeters (cm2). Thus, ultrasound dose is measured in W/cm2. You can also adjust the duty cycle, duration of treatment, and frequency.
Duty cycle refers to the process of interrupting delivery of the sound wave so that periods of sound wave emission are interspersed with periods of interruption. Figure 12.6 depicts pulsed and continuous ultrasound.
| |
(a) In pulsed ultrasound, energy is generated only during the "on" time. Duty cycle is determined by the ratio of "on" time to pulse, in this case 50%. (b) Continuous ultrasound is shown.
Often you can select between several duty cycles. Duty cycle is calculated by dividing the time during which sound is delivered by the total time the sound head is applied. For example, if ultrasound is transmitted for 150 ms out of every second of treatment, then the duty cycle is 150/1,000, or 15%. When the emission of sound energy is not interrupted, the duty cycle equals 100%, and the ultrasound is referred to as continuous ultrasound.
Much has been learned about the treatment duration needed to elevate tissue temperatures. An interaction among the frequency, dose, and treatment duration has also been found. Some recipes for duration and intensities of ultrasound treatments used in the past do not increase tissue temperature sufficiently.
The frequency of the sound waves affects the depth at which the greatest amount of ultrasound energy is absorbed, as well as the time required to increase tissue temperature. Ultrasound units typically allow for treatment with more than one frequency, but older units had a single fixed frequency of 1 MHz. Treatments with higher frequencies are usually more appropriate for musculoskeletal injuries.
Sound Energy Absorption in Tissues
The amount of acoustic energy absorbed by tissues is influenced by many factors. The tissue characteristics, as well as the frequency, dose (W/cm2), duty cycle, and duration of treatment with ultrasound affect the amount of acoustic energy absorbed. When continuous ultrasound is delivered, the greater the energy absorption, the greater the tissue heating. Tissues with greater protein density have a higher rate of absorption, whereas tissues with a higher water content have lower absorption rates. Thus, tendon, ligament, and muscle tissue absorb more sound energy than skin and adipose tissue. Superficial bones and nerves absorb the most energy.
Ultrasound at a higher frequency (3 MHz) is absorbed more rapidly than that at a lower frequency (1 MHz) (figure 12.7). Therefore, ultrasound at higher frequencies affects tissues that are more superficial, whereas at a lower frequency less energy is absorbed superficially and more is available to penetrate into tissues. Thus, if the goal of treatment is to heat the capsular tissue at a joint such as the elbow with ultrasound, a 3 MHz frequency is appropriate. Temperature increases of up to 8°C have been reported with 3 MHz ultrasound at 1 W/cm2 in 4 min in superficial tissues such as the patellar tendon (Chan et al. 1998). If the target tissue is deep tissue, a lower frequency (1 MHz) is necessary; 10 min of continuous 1 MHz ultrasound at 2.0 W/cm2 will elevate temperature about 4°C at a depth of 2.5 cm (Draper, Castel, and Castel 1995). There is likely considerable overlap in tissue heating between 1 and 3 MHz ultrasound, as heating of tissues at 2.5 cm depths with 3 MHz ultrasound has been reported (Hayes et al. 2004). The interactions between ultrasound parameters and thermal response are discussed further shortly.
A great depth of heating is achieved with 1 MHz. The specific depth of heating is device dependent, and the values provided represent a range rather than specific limits of thermal responses.
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Mechanobiology in the Musculoskeletal System
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis.
Mechanobiology in Tendon
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis. Tendon is relatively avascular and therefore relies largely on autocrine and paracrine responses for tissue remodeling, repair, and adaptation. In addition to tenocytes, progenitor cells exist in tendon, and they are extremely mechanosensitive. Inappropriate mechanical load pushes these progenitors toward alternate phenotypes (chondrocytes, adipocytes, osteocytes), which results in the pathologic changes characteristic of tendinosis. Tendinosis is a common histologic finding in overuse tendon injuries that is characterized by noninflammatory degenerative changes of the ECM and aberrant cellular responses.
Tendon attaches muscle to bone, transmitting forces to the skeleton and resulting in joint stabilization and movement. As a result, tendons are subjected to high mechanical loads that predispose them to injury. Tendon's reaction to overuse injury has been described as a failed healing response (Maffulli, Sharma, and Luscombe 2004) due to the ineffective and insufficient inflammatory response generated after injury.
Tendon pathology may be classified as either tendonitis: inflammation, pain, and swelling of the peritenon; tendinosis: degeneration of the ECM and absence of inflammation upon histologic examination; or tendinopathy. Tendinopathy is the contemporary clinical term for tendon overuse injuries, as it does not imply an active inflammatory process, which is often the case.
While the etiologic factors of tendinopathy are not fully understood, a failure in the mechanobiologic response of the tenocyte has been implicated. Tendon structure, composition, and mechanical properties are modified in response to altered mechanical loading conditions. Disruption in the mechanobiologic response of the tenocyte creates a vicious cycle of suboptimal ECM production, in turn leading to further changes in mechanical signals transmitted to the tenocyte and propagating degenerative tissue production throughout the tendon (figure 16.8). Many hypothesize that mechanical overload initiates a degenerative signaling cascade that leads to tendinopathy, while some believe tendinopathy is a result of focal disruption of ECM and accompanying mechanobiologic understimulation of locally adherent tenocytes and progenitor cells.
Pathologic changes in tendinopathy. (a) Collagen organization: H&E. (b) Increased proteoglycan.
Reprinted, by permission, from M. Joseph et al., 2009, "Histological and molecular analysis of the biceps tendon long head post-tenotomy," The Journal of Orthopedic Research 27:1379-1385.
Signaling cascades leading to tendinosis probably result from understimulation of FACs and downstream MAPK-mediated events. The activation of stress-activated protein kinase (SAPK), a member of the MAPK family, is associated with matrix-degrading enzyme production. As mentioned, load affects progenitor cell survival and differentiation. Tendon progenitor cells exposed to 4% strain assume tenocyte function and express collagen type I. However, loads of 8% resulted in the expression of markers for bone, fat, and cartilage differentiation. The presence of these cells and their functional products is destructive to tendon ECM and health (Wang et al. 2007).
An alternative paradigm for the pathophysiology of tendinopathy is emerging and involves tenocyte-produced neuropeptides. Chemical messengers thought to be confined to neurons are produced in abundance in tendinopathic tissue. Substance P and its receptor (neurokinin-1 receptor [NK-1 R]), glutamate (Scott, Alfredson, and Forsgren 2008), acetylcholine (ACTH), and catecholamines are produced by local tendon fibroblasts. Tenocytes produce these neurochemicals in response to mechanical load. Substance P increases cellular proliferation in culture, which corresponds with observations of hypercellularity in early tendinosis. Pain in tendinopathic tissue has been traced to neurovascular ingrowth containing substance P positive nerve fibers, and the ablation of these fibers often results in relief. The NK-1 R is a G-protein coupled receptor that is responsive to mechanical signals. There is likely cross talk between integrin-linked kinase production resulting from integrin stimulation and cross-activation of the G-protein via ILK activation (see figure 16.5). Substance P signals through the MAPK cascade and results in gene expression.
Tendon cell networks communicate throughout the tissue via cytoplasmic extensions and cell junction zones. A signal that is sent in one area propagates through these channels, effecting a tissue-wide response. Intercellular connectivity is achieved through gap junctions, where connexins are the principal protein. In healthy tendon, tenocytes are arranged longitudinally between collagen fibers. Connexins 32 and 34 form communications between longitudinally arranged tenocytes, whereas connexin 43 links cells in all directions (Ragsdale, Phelps, and Luby-Phelps 1997).
Mechanobiology in Articular Cartilage
Articular cartilage is the major load-bearing tissue in synovial joints. Cartilage is unique in that it is avascular, aneural, alymphatic, and sparsely populated with cells. The cartilage cell (chondrocyte) is responsible for the remodeling of cartilage ECM, and it does so in response to mechanical force. Cartilage in relatively unloaded areas such as the medial patellar facet is softer and less resilient. Articular cartilage responds favorably to pulsatile doses of load, while static loading results in up-regulation of a host of inflammatory cytokines, matrix-degrading enzymes, and degeneration.
Chondrocytes are extremely responsive to compressive loads, as their location and function would indicate. A pericellular matrix composed of collagen VI and proteoglycan surrounds the chondrocyte and is an independent unit of force transduction. The pericellular matrix is analogous to the basal lamina in skeletal muscle, bridging the gap between cell membrane and ECM.
Membrane stretch - activated ion channels exist, are proximate to integrins, and likely have overlapping downstream signaling cascades. Stimulation of the integrin α5β1 pathway results in the production of aggrecan, the predominant proteoglycan in cartilage, along with the down-regulation of MMP3, the predominant degrading enzyme of PG. Higher levels of aggrecan and collagen II production are associated with dynamic compressive force, whereas static forces result in MMP production and ECM destruction. Chondrocytes from arthritic cartilage are unresponsive to mechanical stimulation, indicating cellular dysfunction and mechanoinsensitivity in osteoarthritis (Raizman 2010).
Inappropriate mechanical loading is the primary risk factor for the development of osteoarthritis (OA) (figure 16.9). OA is characterized by a loss of tissue homeostasis and the prevalence of catabolism. Molecular components of mechanotransduction in chondrocytes consist of integrin activation and downstream MAPK signaling, as well as stress-activated calcium channel signaling. The α5β1 integrin binds pericellular matrix fibronectin and associates with calcium channels in the surrounding cell membrane. In response to mechanical stimuli, integrin and calcium signaling pathways converge on MAPK cascade, where Ca2+ regulation of integrin activity through Src occurs (Raizman et al. 2010).
Damaged articular cartilage. Large defect in the medial femoral condyle.
The Cbp/p300-interacting transactivator 2 (CITED2) is a transcription regulator that is thought to balance catabolic and anticatabolic cascades and is thus centrally implicated in the pathogenesis of OA (Leong et al. 2011). CITED2 binds with and modulates a host of transcription factors. The ability to activate anabolic pathways and to inhibit inflammatory and catabolic pathways in response to mechanical signals suggests a central role in mechanical regulation. CITED2 is downstream of MAPK. Moderate-intensity intermittent loads activate CITED2, whereas high-intensity loads do not (Leong et al. 2011). Increased CITED2 expression correlates with the production of collagen II, maintenance of ECM, and suppression of MMPs. Integrin and associated receptors, downstream MAPK, and CITED2 represent a loading-specific pathway that has direct effects on tissue. Thus, loading of cartilage is essential to tissue health while overload leads to degeneration and OA. Exercise can play an important role in the treatment of OA, but excessive loading may accelerate the disease process.
In summary, the chondrocyte is dependent upon mechanical signals for survival. The aneural, avascular nature of articular cartilage accounts for its susceptibility to damage. Enhanced maintenance and repair of articular cartilage is possible through mechanobiologic manipulation. Chondrocyte preference for dynamic, pulsatile delivery of force will continue to be explored both in exercise prescription and modality delivery.
Mechanobiology in Bone
Metabolic demands on the skeleton are managed largely through calciotropic hormones, but the ability of the skeleton to adapt to its loading environment is essential for bone health. Wolff's law first proposed skeletal change in response to functional demands. We now understand that it is the cells of the skeleton - the osteoblasts, osteocytes, and osteoclasts - that remodel bone in response to stress. An example of bone's sensitivity to mechanical demand is demonstrated in cortical bone of the dominant arm in elite tennis players, which can be up to 35% thicker than the cortical bone of the non-dominant arm. Rapid bone loss during periods of immobility and in microgravity exemplifies the homeostatic necessity of mechanotransduction.
Bone is certainly not as deformable as connective tissue, at least elastically. Bone can experience up to 0.3% strain, much less than ligament or tendon (5% - 20%). Bone experiences a wide variety of mechanical stimuli that produce slight deformation in the bone tissue, pressure in the intramedullary cavity and within the cortices, transient pressure waves, and fluid shear forces through the canaliculi.
Osteoblasts at the surface of bone respond to deformation of the cell membrane from strain experienced on the surface of the bone from imposed forces. Osteocytes located deeper in the bone tissue respond to shear stress of fluid flow through the canaliculi (figure 16.10). An externally applied load forces fluid out of regions of high compressive strains. This fluid returns when the load is removed. This results in bone cell exposure to an oscillating fluid flow. The osteocyte population, through its interconnectedness via gap junctions, comprises a three-dimensional sensing systemin which amplification of mechanical signals propagates throughout the tissue.
Structure and lacuna canalicular network of bone.
As in tendon, integrins are important conductors of mechanical signals in bone cells (Salter, Robb, and Wright 1997). In bone, the β subunit of the integrin extracellular domain mediates binding to matrix components. Prominent matrix ligands for integrin in bone include collagen I and III and fibronectin. The formation of FAC in response to integrin activation is critical to cell adhesion, survival, and production. Mechanical signals activate the MAPK cascade, leading to down-regulation of RANK ligand (RANKL) expression and the formation of osteoclasts.
Strain, shear, and pressure result in the mobilization of intracellular calcium. This rapid increase in intracellular calcium concentration appears to occur due to phospholipase-C activity and IP3 signaling, which results in the release of calcium from intracellular stores (calcium-mediated calcium release).
Summary
Musculoskeletal cells are exposed to forces transmitted through tissue. Mechanotransduction pathways modulate diverse cellular functions. Physiologic effects result from intracellular signaling of membrane receptors and ion channels. The integrin receptor, bound to the tissue and stimulated by stress, can coactivate cytokine receptors and ion channels, resulting in a coordinated cell response. The musculoskeletal system provides a link to the physical environment. The encompassing nature of mechanical signaling likely represents the primary means by which adaptation to force exposure occurs. For clinicians this is exciting, as much of what we do involves modulating force through exercise and physical interventions. The obvious hurdle in fully accessing this tool is the difficulty of quantifying in vivo human forces, both those that result in injury and those produced by specific mechanical interventions. Future research and technology will be essential for identifying optimal mechanical interventions and their specific prescription. This chapter outlines the biology underpinning mechanical intervention. Harnessing the power of mechanotransduction is our most powerful tool for affecting musculoskeletal health and adaptation.
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Case Scenario: Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries.
Case Scenario 1
Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries. A neurological screen was normal, and concussion assessment and diagnostic imaging were negative. She complains of pain (6 on a scale of 10 with walking and standing) and muscle spasm in her neck and upper back, and intermittent headaches made worse with prolonged sitting and exercise and relieved by oral over-the-counter medication and lying down. She states at times she gets pain that radiates down her right arm.
She states that she is married and has no children. She works as a college tennis coach and director of the campus tennis center. Her medical history is unremarkable other than having sustained a right sprained ankle in high school and having wisdom teeth removed.
On presentation she denies lightheadedness, concentration and memory deficits, tinnitus or vision disturbances, and a history of neck injuries. On examination, the patient's head is slightly tilted to the left side. The patient has limited active and passive rotation and side-bending to the right side and painful end-range extension. She has tenderness to palpation along the right cervical paraspinal muscles. Upper quarter scan for sensory, strength, and reflex deficits is normal. Physical examination reveals restricted left side-glide at C5-C6, and the patient is evaluated as suffering from a flexed, left rotated, and side-bent facet with soft tissue pain and muscle spasm.
The patient complains that she has difficulty raising her right arm overhead and that her neck and upper back pain increase with prolonged sitting, driving, and lifting and carrying.
The forces involved in motor vehicle accidents can cause catastrophic injuries. The whiplash mechanism of injury may result in fracture, sprain, and muscle strain. The medical history, history of the current condition, and medical and physical examinations conducted in this case provide assurance that serious structural damage has been avoided. A thorough examination and evaluation of all pertinent information is needed before proceeding with a rehabilitation plan of care, especially in conditions involving the spine.
The first step in developing a rehabilitation plan of care is the development of a problem list. It is usually best to build a problem list around the impairments, functional limitations, and participation restrictions identified in the evaluation of the case. From the problem list, mutually agreeable short-term goals can be developed and a goal-directed application of therapeutic modalities, manual therapy, and exercise developed.
What are the problems identified in this case?
Impairments
- Pain
- Loss of cervical range of motion
- Headache
Functional limitations
- Reaching overhead and prolonged sitting/driving
Participation restrictions
- Unable to play tennis or coach effectively due to pain and loss of motion
- Has difficulty with management responsibilities due to poor tolerance of sitting
The clinician has several options to recommend for the problems listed. Pain and muscle spasm could be treated with periodic cold or superficial heat. TENS could be used as needed for the same purposes.
What would you do?
A decision on the treatment needs to be based on any contraindications for an intervention, the current condition, the patient's preferences, the clinician's experiences, and existing clinical research. After ruling out contraindications to the treatment options and conferring with the patient about the ability to control pain with oral medications, it is decided to treat her with massage to decrease pain and muscle spasm before performing joint mobilization to restore range of motion. The patient states that a hot shower is soothing and that she has access to superficial heat. She demonstrates a substantial increase in cervical range of motion after the initial treatment. She is instructed in active range of motion exercises and agrees with a plan of 20 to 30 min of superficial heating as needed for relief of pain and spasm and a four-times-per-day regimen of active range of motion, which is also to be performed after heat application. Over two subsequent visits she reports the resolution of pain at rest other than mild aching and stiffness upon rising, and she demonstrates full cervical range of motion. Postural and functional exercises are introduced to increase tolerance to daily activities and return to coaching. Three and a half weeks after her accident she is able to work a normal day, drive, and play tennis for up to an hour without limitations. She is discharged to continue with a postural and tennis function exercise program.
This case illustrates some of the complexities of developing a plan of care. There is not a single correct approach to meeting the needs of many patients. The first mandate is to do no harm. The clinician and patient must then decide which problems are most concerning, discuss the options, and agree on a plan. Once short-term goals are achieved, the intervention progresses. Modalities used to relieve pain and muscle spasm are replaced by exercises aimed at addressing functional limitations and participation restrictions.
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Using Ultrasound as a Therapeutic Modality
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions.
Ultrasound
Ultrasound differs from the modalities discussed in the previous three chapters in that it transmits energy that falls within the acoustic, rather than electromagnetic, spectrum. Ultrasound is used in medicine for imaging as well as in the treatment of musculoskeletal conditions. Different frequencies of ultrasound are used for each application. The ultrasound units used in the practice of athletic training and physical therapy emit sound energy at frequencies between 800 kHz (800,000 Hz) and 3 MHz (3,000,000 Hz). Modern high-quality ultrasound units allow the clinician to select the treatment frequency. Typically a clinician can choose frequencies near 1 MHz and 3.3 MHz. Some units are also adjustable to 2 MHz (figure 12.1). The importance of frequency and the applications of ultrasound at various frequencies will be discussed in detail. Initially, it is important to understand that therapeutic ultrasound uses acoustic energy, delivered at very specific high frequencies.
Modern combination ultrasound, laser, and electrotherapy device.
Ultrasound machines use electrical current to create a mechanical vibration in a crystalline material housed in the "head" of the unit. Vibration of the crystalline material produces a wave of acoustic energy (ultrasound) (figure 12.2). The crystalline material in modern ultrasound devices is synthetic, although natural crystals were once used. The sound energy emitted from the ultrasound head travels through tissues and is absorbed.
Components of an ultrasound unit.
Ultrasound technology is now used extensively for diagnostic imaging. Ultrasound in the range of 3.5 MHz to 15 MHz is used to image organs of the abdomen and thorax as well as musculoskeletal tissues (Whittaker et al. 2007). Ultrasound is also routinely used for prenatal examination. Through ultrasound, some correctable birth defects can be identified, and the sex of the fetus can also be determined.
In musculoskeletal care, ultrasound can be used to detect muscle strains, ligament sprains, and degenerative changes in tendon. The sound energy used for imaging differs in frequency and pulse characteristics from that used for therapeutic purposes.
Beam Nonuniformity Ratio and Effective Radiating
Two terms describe the size and quality of an ultrasound crystal found in therapeutic ultrasound devices. Effective radiating area (ERA) is the area that receives at least 5% of the peak sound energy. This is essentially the size of the area to which sound energy is conducted when the head of the ultrasound unit contacts the skin. The ERA is somewhat smaller than the surface area of the sound head.
The beam of sound energy emitted from a crystal is not uniform but rather is characterized by areas of high intensity and lower intensity (figure 12.3). Beam nonuniformity ratio (BNR)is the ratio of the average intensity of the ultrasound beam across the ERA divided by the peak intensity of the ultrasound beam; the lower the BNR, the more uniform the intensity of the sound wave.
Beam scan of a crystal with a beam nonuniformity ratio (BNR) of 2.32, (a) top view and (b) side view. When tested on 40 subjects, the ultrasound transducer housing this crystal produced a very comfortable treatment at 1.5 to 2.0 watts per cm2 (W/cm2). Beam scan of a crystal with a BNR of 7.75, (c) top view. When this was tested on 40 subjects, the ultrasound transducer housing the crystal produced an uncomfortable treatment at 1.5 W/cm2 and was not tolerated at 2.0 W/cm2.
Courtesy of Brigham Young University Sports Injury Research Center.
A low BNR minimizes the risk of developing "hot spots" and allows the clinician to deliver higher doses of ultrasound without causing pain and discomfort. The BNR must be listed by the manufacturer on all units. Ideally, the BNR would be 1; however, this is impossible, and the acceptable range is between 2 and 6.
Unfortunately, BNR and ERA may not adequately define how an ultrasound unit will function. Holcomb and Joyce (2003) reported significant differences in the change in tissue temperature between two ultrasound units with a BNR of 3.7 and 2.3 and an ERA of 4.9 and 4.6 cm, respectively. These authors speculated that the area of peak intensity or peak area of the maximum beam nonuniformity ratio (PAMBNR) as described by Draper (1999) might explain why two ultrasound units differ in performance. Certainly a small spike of peak amplitude as illustrated in figure 12.4 will deliver less energy and therefore have less thermal effect than that provided by a larger area of peak amplitude. Johns, Straub, and Howard (2007) and Straub, Johns, and Howard (2008) reported considerable variability in ERA and special average intensity in 3 and 1 MHz ultrasound units, respectively, from different manufacturers. Differences between reported and actual ERA values were identified for all but one manufacturer when 3 MHz sound heads were evaluated (Johns, Straub, and Howard 2007). Demchak, Straub, and Johns (2007) noted differences in the rate but not peak heating of the calf muscles using three different 1 MHz ultrasound transducers. Johns et al. (2007), however, have reported greater heating with 1 MHz sound heads with more concentrated energy fields. The issue of equipment performance across parameters requires further study. Variability in the characteristics of the acoustic energy field may yield differing treatment effects and perhaps pose a risk of adverse events. Frye et al. (2007) reported blistering of the anterior shin after ultrasound to the calf muscles in laboratory experiments employing common clinical treatment parameters.
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The area of peak intensity, (a) small and (b) larger, may affect the performance of ultrasound devices.
Conducting Media
Air is a poor conductor of ultrasound energy. To maximize delivery of sound energy to the tissues, a conducting medium must be used. Several substances have been used to conduct ultrasound, including ultrasound gel, gel pads, mineral oil, lotions, and water. The amount of sound energy conducted varies substantially between conducting media. Commercial ultrasound gel (Draper 1996; Draper et al. 1993; Klucinec et al. 2000) and gel pads (Klucinec et al. 2000; Klucinec 1996) (figure 12.5) are superior conducting media. Water is not as good a conducting medium (Draper 1996; Draper et al. 1993; Klucinec et al. 2000; Klucinec 1996; Forrest and Rosen 1989, 1992), attenuating as much as 65% of the sound energy (Klucinec et al. 2000).
Ultrasound gel and gel pads.
Rubley et al. (2008) reported smaller differences (approximately 15%) in Achilles tendon tissue heating when comparing gel and degassed water as conducting media. Differences in research methods and ultrasound equipment may explain the estimated magnitude of differences between conducting media. Collectively, however, the research suggests that ultrasound gel is the conducting medium of choice for clinical administration of therapeutic ultrasound. The conducting capacities of most gels and creams have not been established. However, some have been shown to be very poor conductors of sound energy (Cameron and Monroe 1992; Draper 1996; Draper et al. 1993; Forrest and Rosen 1989, 1992; Klucinec 1996; Klucinec et al. 2000). When applying ultrasound, use gels and gel pads known to be effective conductors.
Parameters of Treatment with Ultrasound
As with electrotherapy, you can alter the treatment parameters of ultrasound depending on the desired effect. Fortunately, the number of adjustable parameters is smaller. You can control the amplitude of the sound waves and therefore the amount of sound energy being emitted from the sound head. The sound energy emitted by the crystal is measured in watts (W). The dose of sound energy delivered is based on the amount of energy being emitted divided by the radiating area of the crystal measured in square centimeters (cm2). Thus, ultrasound dose is measured in W/cm2. You can also adjust the duty cycle, duration of treatment, and frequency.
Duty cycle refers to the process of interrupting delivery of the sound wave so that periods of sound wave emission are interspersed with periods of interruption. Figure 12.6 depicts pulsed and continuous ultrasound.
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(a) In pulsed ultrasound, energy is generated only during the "on" time. Duty cycle is determined by the ratio of "on" time to pulse, in this case 50%. (b) Continuous ultrasound is shown.
Often you can select between several duty cycles. Duty cycle is calculated by dividing the time during which sound is delivered by the total time the sound head is applied. For example, if ultrasound is transmitted for 150 ms out of every second of treatment, then the duty cycle is 150/1,000, or 15%. When the emission of sound energy is not interrupted, the duty cycle equals 100%, and the ultrasound is referred to as continuous ultrasound.
Much has been learned about the treatment duration needed to elevate tissue temperatures. An interaction among the frequency, dose, and treatment duration has also been found. Some recipes for duration and intensities of ultrasound treatments used in the past do not increase tissue temperature sufficiently.
The frequency of the sound waves affects the depth at which the greatest amount of ultrasound energy is absorbed, as well as the time required to increase tissue temperature. Ultrasound units typically allow for treatment with more than one frequency, but older units had a single fixed frequency of 1 MHz. Treatments with higher frequencies are usually more appropriate for musculoskeletal injuries.
Sound Energy Absorption in Tissues
The amount of acoustic energy absorbed by tissues is influenced by many factors. The tissue characteristics, as well as the frequency, dose (W/cm2), duty cycle, and duration of treatment with ultrasound affect the amount of acoustic energy absorbed. When continuous ultrasound is delivered, the greater the energy absorption, the greater the tissue heating. Tissues with greater protein density have a higher rate of absorption, whereas tissues with a higher water content have lower absorption rates. Thus, tendon, ligament, and muscle tissue absorb more sound energy than skin and adipose tissue. Superficial bones and nerves absorb the most energy.
Ultrasound at a higher frequency (3 MHz) is absorbed more rapidly than that at a lower frequency (1 MHz) (figure 12.7). Therefore, ultrasound at higher frequencies affects tissues that are more superficial, whereas at a lower frequency less energy is absorbed superficially and more is available to penetrate into tissues. Thus, if the goal of treatment is to heat the capsular tissue at a joint such as the elbow with ultrasound, a 3 MHz frequency is appropriate. Temperature increases of up to 8°C have been reported with 3 MHz ultrasound at 1 W/cm2 in 4 min in superficial tissues such as the patellar tendon (Chan et al. 1998). If the target tissue is deep tissue, a lower frequency (1 MHz) is necessary; 10 min of continuous 1 MHz ultrasound at 2.0 W/cm2 will elevate temperature about 4°C at a depth of 2.5 cm (Draper, Castel, and Castel 1995). There is likely considerable overlap in tissue heating between 1 and 3 MHz ultrasound, as heating of tissues at 2.5 cm depths with 3 MHz ultrasound has been reported (Hayes et al. 2004). The interactions between ultrasound parameters and thermal response are discussed further shortly.
A great depth of heating is achieved with 1 MHz. The specific depth of heating is device dependent, and the values provided represent a range rather than specific limits of thermal responses.
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Mechanobiology in the Musculoskeletal System
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis.
Mechanobiology in Tendon
The success of eccentric exercise for the treatment of tendinopathy is an excellent example of mechanotransduction at work. The tendon fibroblast (tenocyte) is the predominant cell found in tendon and is responsible for producing the components of the ECM and maintaining tissue homeostasis. Tendon is relatively avascular and therefore relies largely on autocrine and paracrine responses for tissue remodeling, repair, and adaptation. In addition to tenocytes, progenitor cells exist in tendon, and they are extremely mechanosensitive. Inappropriate mechanical load pushes these progenitors toward alternate phenotypes (chondrocytes, adipocytes, osteocytes), which results in the pathologic changes characteristic of tendinosis. Tendinosis is a common histologic finding in overuse tendon injuries that is characterized by noninflammatory degenerative changes of the ECM and aberrant cellular responses.
Tendon attaches muscle to bone, transmitting forces to the skeleton and resulting in joint stabilization and movement. As a result, tendons are subjected to high mechanical loads that predispose them to injury. Tendon's reaction to overuse injury has been described as a failed healing response (Maffulli, Sharma, and Luscombe 2004) due to the ineffective and insufficient inflammatory response generated after injury.
Tendon pathology may be classified as either tendonitis: inflammation, pain, and swelling of the peritenon; tendinosis: degeneration of the ECM and absence of inflammation upon histologic examination; or tendinopathy. Tendinopathy is the contemporary clinical term for tendon overuse injuries, as it does not imply an active inflammatory process, which is often the case.
While the etiologic factors of tendinopathy are not fully understood, a failure in the mechanobiologic response of the tenocyte has been implicated. Tendon structure, composition, and mechanical properties are modified in response to altered mechanical loading conditions. Disruption in the mechanobiologic response of the tenocyte creates a vicious cycle of suboptimal ECM production, in turn leading to further changes in mechanical signals transmitted to the tenocyte and propagating degenerative tissue production throughout the tendon (figure 16.8). Many hypothesize that mechanical overload initiates a degenerative signaling cascade that leads to tendinopathy, while some believe tendinopathy is a result of focal disruption of ECM and accompanying mechanobiologic understimulation of locally adherent tenocytes and progenitor cells.
Pathologic changes in tendinopathy. (a) Collagen organization: H&E. (b) Increased proteoglycan.
Reprinted, by permission, from M. Joseph et al., 2009, "Histological and molecular analysis of the biceps tendon long head post-tenotomy," The Journal of Orthopedic Research 27:1379-1385.
Signaling cascades leading to tendinosis probably result from understimulation of FACs and downstream MAPK-mediated events. The activation of stress-activated protein kinase (SAPK), a member of the MAPK family, is associated with matrix-degrading enzyme production. As mentioned, load affects progenitor cell survival and differentiation. Tendon progenitor cells exposed to 4% strain assume tenocyte function and express collagen type I. However, loads of 8% resulted in the expression of markers for bone, fat, and cartilage differentiation. The presence of these cells and their functional products is destructive to tendon ECM and health (Wang et al. 2007).
An alternative paradigm for the pathophysiology of tendinopathy is emerging and involves tenocyte-produced neuropeptides. Chemical messengers thought to be confined to neurons are produced in abundance in tendinopathic tissue. Substance P and its receptor (neurokinin-1 receptor [NK-1 R]), glutamate (Scott, Alfredson, and Forsgren 2008), acetylcholine (ACTH), and catecholamines are produced by local tendon fibroblasts. Tenocytes produce these neurochemicals in response to mechanical load. Substance P increases cellular proliferation in culture, which corresponds with observations of hypercellularity in early tendinosis. Pain in tendinopathic tissue has been traced to neurovascular ingrowth containing substance P positive nerve fibers, and the ablation of these fibers often results in relief. The NK-1 R is a G-protein coupled receptor that is responsive to mechanical signals. There is likely cross talk between integrin-linked kinase production resulting from integrin stimulation and cross-activation of the G-protein via ILK activation (see figure 16.5). Substance P signals through the MAPK cascade and results in gene expression.
Tendon cell networks communicate throughout the tissue via cytoplasmic extensions and cell junction zones. A signal that is sent in one area propagates through these channels, effecting a tissue-wide response. Intercellular connectivity is achieved through gap junctions, where connexins are the principal protein. In healthy tendon, tenocytes are arranged longitudinally between collagen fibers. Connexins 32 and 34 form communications between longitudinally arranged tenocytes, whereas connexin 43 links cells in all directions (Ragsdale, Phelps, and Luby-Phelps 1997).
Mechanobiology in Articular Cartilage
Articular cartilage is the major load-bearing tissue in synovial joints. Cartilage is unique in that it is avascular, aneural, alymphatic, and sparsely populated with cells. The cartilage cell (chondrocyte) is responsible for the remodeling of cartilage ECM, and it does so in response to mechanical force. Cartilage in relatively unloaded areas such as the medial patellar facet is softer and less resilient. Articular cartilage responds favorably to pulsatile doses of load, while static loading results in up-regulation of a host of inflammatory cytokines, matrix-degrading enzymes, and degeneration.
Chondrocytes are extremely responsive to compressive loads, as their location and function would indicate. A pericellular matrix composed of collagen VI and proteoglycan surrounds the chondrocyte and is an independent unit of force transduction. The pericellular matrix is analogous to the basal lamina in skeletal muscle, bridging the gap between cell membrane and ECM.
Membrane stretch - activated ion channels exist, are proximate to integrins, and likely have overlapping downstream signaling cascades. Stimulation of the integrin α5β1 pathway results in the production of aggrecan, the predominant proteoglycan in cartilage, along with the down-regulation of MMP3, the predominant degrading enzyme of PG. Higher levels of aggrecan and collagen II production are associated with dynamic compressive force, whereas static forces result in MMP production and ECM destruction. Chondrocytes from arthritic cartilage are unresponsive to mechanical stimulation, indicating cellular dysfunction and mechanoinsensitivity in osteoarthritis (Raizman 2010).
Inappropriate mechanical loading is the primary risk factor for the development of osteoarthritis (OA) (figure 16.9). OA is characterized by a loss of tissue homeostasis and the prevalence of catabolism. Molecular components of mechanotransduction in chondrocytes consist of integrin activation and downstream MAPK signaling, as well as stress-activated calcium channel signaling. The α5β1 integrin binds pericellular matrix fibronectin and associates with calcium channels in the surrounding cell membrane. In response to mechanical stimuli, integrin and calcium signaling pathways converge on MAPK cascade, where Ca2+ regulation of integrin activity through Src occurs (Raizman et al. 2010).
Damaged articular cartilage. Large defect in the medial femoral condyle.
The Cbp/p300-interacting transactivator 2 (CITED2) is a transcription regulator that is thought to balance catabolic and anticatabolic cascades and is thus centrally implicated in the pathogenesis of OA (Leong et al. 2011). CITED2 binds with and modulates a host of transcription factors. The ability to activate anabolic pathways and to inhibit inflammatory and catabolic pathways in response to mechanical signals suggests a central role in mechanical regulation. CITED2 is downstream of MAPK. Moderate-intensity intermittent loads activate CITED2, whereas high-intensity loads do not (Leong et al. 2011). Increased CITED2 expression correlates with the production of collagen II, maintenance of ECM, and suppression of MMPs. Integrin and associated receptors, downstream MAPK, and CITED2 represent a loading-specific pathway that has direct effects on tissue. Thus, loading of cartilage is essential to tissue health while overload leads to degeneration and OA. Exercise can play an important role in the treatment of OA, but excessive loading may accelerate the disease process.
In summary, the chondrocyte is dependent upon mechanical signals for survival. The aneural, avascular nature of articular cartilage accounts for its susceptibility to damage. Enhanced maintenance and repair of articular cartilage is possible through mechanobiologic manipulation. Chondrocyte preference for dynamic, pulsatile delivery of force will continue to be explored both in exercise prescription and modality delivery.
Mechanobiology in Bone
Metabolic demands on the skeleton are managed largely through calciotropic hormones, but the ability of the skeleton to adapt to its loading environment is essential for bone health. Wolff's law first proposed skeletal change in response to functional demands. We now understand that it is the cells of the skeleton - the osteoblasts, osteocytes, and osteoclasts - that remodel bone in response to stress. An example of bone's sensitivity to mechanical demand is demonstrated in cortical bone of the dominant arm in elite tennis players, which can be up to 35% thicker than the cortical bone of the non-dominant arm. Rapid bone loss during periods of immobility and in microgravity exemplifies the homeostatic necessity of mechanotransduction.
Bone is certainly not as deformable as connective tissue, at least elastically. Bone can experience up to 0.3% strain, much less than ligament or tendon (5% - 20%). Bone experiences a wide variety of mechanical stimuli that produce slight deformation in the bone tissue, pressure in the intramedullary cavity and within the cortices, transient pressure waves, and fluid shear forces through the canaliculi.
Osteoblasts at the surface of bone respond to deformation of the cell membrane from strain experienced on the surface of the bone from imposed forces. Osteocytes located deeper in the bone tissue respond to shear stress of fluid flow through the canaliculi (figure 16.10). An externally applied load forces fluid out of regions of high compressive strains. This fluid returns when the load is removed. This results in bone cell exposure to an oscillating fluid flow. The osteocyte population, through its interconnectedness via gap junctions, comprises a three-dimensional sensing systemin which amplification of mechanical signals propagates throughout the tissue.
Structure and lacuna canalicular network of bone.
As in tendon, integrins are important conductors of mechanical signals in bone cells (Salter, Robb, and Wright 1997). In bone, the β subunit of the integrin extracellular domain mediates binding to matrix components. Prominent matrix ligands for integrin in bone include collagen I and III and fibronectin. The formation of FAC in response to integrin activation is critical to cell adhesion, survival, and production. Mechanical signals activate the MAPK cascade, leading to down-regulation of RANK ligand (RANKL) expression and the formation of osteoclasts.
Strain, shear, and pressure result in the mobilization of intracellular calcium. This rapid increase in intracellular calcium concentration appears to occur due to phospholipase-C activity and IP3 signaling, which results in the release of calcium from intracellular stores (calcium-mediated calcium release).
Summary
Musculoskeletal cells are exposed to forces transmitted through tissue. Mechanotransduction pathways modulate diverse cellular functions. Physiologic effects result from intracellular signaling of membrane receptors and ion channels. The integrin receptor, bound to the tissue and stimulated by stress, can coactivate cytokine receptors and ion channels, resulting in a coordinated cell response. The musculoskeletal system provides a link to the physical environment. The encompassing nature of mechanical signaling likely represents the primary means by which adaptation to force exposure occurs. For clinicians this is exciting, as much of what we do involves modulating force through exercise and physical interventions. The obvious hurdle in fully accessing this tool is the difficulty of quantifying in vivo human forces, both those that result in injury and those produced by specific mechanical interventions. Future research and technology will be essential for identifying optimal mechanical interventions and their specific prescription. This chapter outlines the biology underpinning mechanical intervention. Harnessing the power of mechanotransduction is our most powerful tool for affecting musculoskeletal health and adaptation.
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Case Scenario: Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries.
Case Scenario 1
Neck Pain
A 28-year-old female tennis coach and player is referred for care, complaining of neck pain following a motor vehicle accident 6 days ago. She was at a complete stop when her car was hit from behind. She was transported to the emergency department at a local hospital. She was discharged after being evaluated for injuries. A neurological screen was normal, and concussion assessment and diagnostic imaging were negative. She complains of pain (6 on a scale of 10 with walking and standing) and muscle spasm in her neck and upper back, and intermittent headaches made worse with prolonged sitting and exercise and relieved by oral over-the-counter medication and lying down. She states at times she gets pain that radiates down her right arm.
She states that she is married and has no children. She works as a college tennis coach and director of the campus tennis center. Her medical history is unremarkable other than having sustained a right sprained ankle in high school and having wisdom teeth removed.
On presentation she denies lightheadedness, concentration and memory deficits, tinnitus or vision disturbances, and a history of neck injuries. On examination, the patient's head is slightly tilted to the left side. The patient has limited active and passive rotation and side-bending to the right side and painful end-range extension. She has tenderness to palpation along the right cervical paraspinal muscles. Upper quarter scan for sensory, strength, and reflex deficits is normal. Physical examination reveals restricted left side-glide at C5-C6, and the patient is evaluated as suffering from a flexed, left rotated, and side-bent facet with soft tissue pain and muscle spasm.
The patient complains that she has difficulty raising her right arm overhead and that her neck and upper back pain increase with prolonged sitting, driving, and lifting and carrying.
The forces involved in motor vehicle accidents can cause catastrophic injuries. The whiplash mechanism of injury may result in fracture, sprain, and muscle strain. The medical history, history of the current condition, and medical and physical examinations conducted in this case provide assurance that serious structural damage has been avoided. A thorough examination and evaluation of all pertinent information is needed before proceeding with a rehabilitation plan of care, especially in conditions involving the spine.
The first step in developing a rehabilitation plan of care is the development of a problem list. It is usually best to build a problem list around the impairments, functional limitations, and participation restrictions identified in the evaluation of the case. From the problem list, mutually agreeable short-term goals can be developed and a goal-directed application of therapeutic modalities, manual therapy, and exercise developed.
What are the problems identified in this case?
Impairments
- Pain
- Loss of cervical range of motion
- Headache
Functional limitations
- Reaching overhead and prolonged sitting/driving
Participation restrictions
- Unable to play tennis or coach effectively due to pain and loss of motion
- Has difficulty with management responsibilities due to poor tolerance of sitting
The clinician has several options to recommend for the problems listed. Pain and muscle spasm could be treated with periodic cold or superficial heat. TENS could be used as needed for the same purposes.
What would you do?
A decision on the treatment needs to be based on any contraindications for an intervention, the current condition, the patient's preferences, the clinician's experiences, and existing clinical research. After ruling out contraindications to the treatment options and conferring with the patient about the ability to control pain with oral medications, it is decided to treat her with massage to decrease pain and muscle spasm before performing joint mobilization to restore range of motion. The patient states that a hot shower is soothing and that she has access to superficial heat. She demonstrates a substantial increase in cervical range of motion after the initial treatment. She is instructed in active range of motion exercises and agrees with a plan of 20 to 30 min of superficial heating as needed for relief of pain and spasm and a four-times-per-day regimen of active range of motion, which is also to be performed after heat application. Over two subsequent visits she reports the resolution of pain at rest other than mild aching and stiffness upon rising, and she demonstrates full cervical range of motion. Postural and functional exercises are introduced to increase tolerance to daily activities and return to coaching. Three and a half weeks after her accident she is able to work a normal day, drive, and play tennis for up to an hour without limitations. She is discharged to continue with a postural and tennis function exercise program.
This case illustrates some of the complexities of developing a plan of care. There is not a single correct approach to meeting the needs of many patients. The first mandate is to do no harm. The clinician and patient must then decide which problems are most concerning, discuss the options, and agree on a plan. Once short-term goals are achieved, the intervention progresses. Modalities used to relieve pain and muscle spasm are replaced by exercises aimed at addressing functional limitations and participation restrictions.
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