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Orthopaedic Knowledge Update 7
Koval, KJ (ed): Orthopaedic Knowledge Update 7. Rosemont, IL. American Academy of Orthopaedic Surgeons. 2002 Ch. 1, pp. 3-18.
Kurt P. Spindler, MD, Rick W. Wright, MD
Chapter 1: Soft-Tissue Physiology and Repair
Meniscus
Structure and Function
The meniscus is a fibrocartilaginous semicircular "cushion" in a joint. Its function and structure are interdependent at both the macroscopic and microscopic levels. The primary functions of the meniscus are load transmission, shock absorption, and lubrication of the articular surfaces. The normal meniscus is stabilized by its peripheral attachments, especially the anterior and posterior horn along with the meniscal-femoral and meniscal-tibial attachments. There is relatively more motion in the lateral meniscus, which is more circular, than the medial meniscus, which is more C-shaped, partly because of the popliteal hiatus in the posterolateral corner, which does not provide peripheral attachment to the femur and the tibia in this location. The meniscus' vascular supply is from the medial and lateral geniculate arteries. It is this vascular supply with reference to the peripheral versus central location of the meniscus that determines the meniscus' potential for healing and is the predominant reason for excision versus repair. Approximately 10% to 25% of the meniscus (on the periphery or closer to the capsule) has a vascular supply and is considered the "red" zone. The inner central two thirds is avascular and is considered the "white" zone. There is a relatively increased blood supply present at the attachments of the anterior and posterior horns. Previous studies have demonstrated that tears in the red zone or vascular zone will heal whereas tears in the central avascular zone do not heal.
The meniscus is composed of an extracellular matrix, which is a complex, three-dimensional (3-D), interlocking array of ordered collagen fibers with proteoglycan and water, which is responsible for its load-bearing properties. The cells are composed of meniscal fibrochondrocytes with at least two separate populations spatially separated. By dry weight 75% is collagen, 8% to 13% is noncollagenous protein, and 1% is hexosamine. The principal collagen type is more than 90% type I, with the remainder being small amounts of type II, III, V, and VI. The load-bearing role of the meniscus is determined by the collagen fiber ultrastructure¾large collagen fiber bundles predominant in a circumferential orientation and radial collagen bundles run from the periphery toward the center (Fig. 1). There is no organization to the collagen bundles on the superior femoral surface or inferior tibial surface. The meniscus is a viscoelastic structure where the rate of creep depends on the rate of fluid exudation from the tissue and the equilibrium deformation is dependent on the collagen proteoglycan solid matrix and the applied load to this structure.
During normal knee motion, the menisci more closely follow the tibia than the femur. In flexionextension the lateral meniscus shows greater total anterior-posterior excursion than the medial meniscus. For posterior displacement only the lateral meniscus and medial meniscus are equal. As the knee flexes, the menisci move posteriorly; as the knee extends, the menisci move more anteriorly. The role of the meniscus in maintaining stability in the knee is as follows: it is not a primary stabilizer for anterior-posterior displacement but in an anterior cruciate ligament (ACL)-deficient knee the posterior horns resist anterior displacement. The lateral and medial menisci also may have a proprioceptive role in positional control in alignment. By their relative motion, the menisci position themselves for their primary role in load transmission where they are found to transmit 50% of the compressive load in the ranges of 0° to 90°. The more flexion that is achieved in the knee, the greater the contribution of the meniscus to the transmission of load across the femoral-tibial surface. Total medial meniscectomy has been shown to decrease the contact area 50% to 75%, resulting in supraphysiologic loads for a given surface area on the articular cartilage; hence, the subsequent acceleration of degenerative changes. In partial meniscectomy, the remaining rim of the meniscus transmits load; however, if the circumferential collagen fibers of the meniscus have been disrupted (these maintain hoop stresses), it functions similar to total meniscectomy.
Physiologic Responses
The meniscus responds to normal physiologic stresses including immobilization and exercise, the effects of age, and ligamentous injury and reconstruction. During a 12-week period of immobilization, the collagen content of the lateral meniscus has been shown to decrease. However, knee motion, even without weight bearing, can prevent collagen loss in the lateral meniscus. As a result of advancing age, a normal degenerative process occurs within the meniscal tissue and its response to physiologic stress becomes limited due to declining cellularity, decreased noncollagenous proteins and proteoglycans, and an increase in degradative proteases. An increase in calcium pyrophosphate crystal levels, as well as a rise in horizontal cleavage planes and tears within the meniscus, occur with age. Finally, in patients up to 30 years old, the percentage of collagen within the meniscus has been shown to increase.
Remodeling and Regeneration
Remodeling of the meniscus is the accretion of new tissue from an extrinsic source. In a study on partial meniscectomy in canines, some remodeling was found to have occurred in two thirds of the subjects. Regeneration of the meniscus has been demonstrated in animals. In a rabbit model studied after total meniscectomy, the meniscus will regenerate (if the vascular synovial tissue is exposed); however, if a synovectomy is performed, regeneration does not occur. In the canine model, 83% of the meniscus will show evidence of regrowth or regeneration. In humans, predictable degenerative changes after extensive partial and complete meniscectomy will occur and point to the fact that any regeneration is most likely clinically insignificant.
Tears and Repairs
The natural history of meniscal tears varies with respect to its vascular supply. Traumatic tears in the peripheral vascular zone have the capability for healing, while tears within the central avascular region do not. Stabilization of tears in the peripheral vascular region lead to a high percentage of healing. Investigators have tried to promote healing in the avascular region with the use of a fibrin clot, fibrin glue, endothelial cell growth factor, vascular access channels, and synovial pedicle flaps. The exact role of soluble extrinsic mediators from the blood that may modulate healing as well as cytokines such as platelet-derived growth factor (PDGF), transforming growth factor-beta, endothelial cell growth factor, and fibroblast growth factor are currently being actively investigated. PDGF has been shown in vitro to increase the proliferation of meniscal cells. In the intra-articular environment, a naturally-occurring fibrin clot from surgical bleeding might be rendered ineffective by synovial fluid dissolution. Recombinant growth factors combined with collagen-based biologic scaffolds are under investigation to promote healing within the avascular region of the meniscus. Stable tears that are either partial thickness (not extending through both the femoral and tibial surface of the meniscus) and complete longitudinal tears smaller than 7 mm are considered stable, especially in the setting of an ACL tear and reconstruction, and can be left alone. Complete, unstable tears that are larger than 10 mm warrant treatment whether the decision is repair or excision. Repair rates have clearly been shown to be adversely affected by the presence of an ACL deficiency, with a decreased healing rate and increased incidence of re-tears. Therefore, in order to preserve the meniscal repair, an ACL reconstruction is indicated. Other important factors to consider are the type of tear, whether there is a degenerative component to the tear with multiple cleavage planes within the central body of the meniscus, and whether multiple tears are present. Both outside-in and inside-out techniques have had excellent success rates in short- and long-term reports with prevention of radiographic changes of osteoarthritis.
Meniscal Replacement: Prosthetics and Allografts
Meniscal replacements have used biocompatible prostheses or allografts and bioabsorbable collagen scaffolds. A synthetic prosthetic meniscal replacement has been investigated extensively in animal models. Teflon, Dacron, and carbon fiber have been used in animal models and have failed to duplicate or prevent degenerative changes in the short term. Furthermore, there is a potential for wear debris particles to cause inflammation of the synovial cavity. For these reasons a permanent meniscal prosthesis is not currently available.
Factors to be considered when using allograft menisci are antigenicity, preservation with or without secondary sterilization, and the ability of the graft to remodel into a living meniscus. While animal models have had little immunologic reaction, the antigenicity of human tissue also appears minimal. Cryopreservation is the only technique in which living donor meniscal fibrochondrocytes can survive, with viability at 10% to 40%. However, in animal models, fresh allografts, cryopreserved allografts, and deep frozen allografts all have similar results. Host-cell repopulation proceeds from superficial to the central core of the meniscus. Sterilization methods including ethylene oxide, glutaraldehyde, or gamma radiation can adversely affect graft function. In summary, animal models show reliable peripheral capsule healing and normal gross macroscopic appearance. However, an increased proteoglycan content as well as an increased water content are seen at 6 months, consistent with early degenerative changes. This raises the question about long-term allograft function.
Human allograft meniscal transplantation trials are difficult to interpret due to multiple confounding variables including additional intra-articular procedures. It appears, however, that the allografts can heal at the periphery and, if properly sized and matched, appear to remain viable in the synovial cavity. The long-term function will clearly depend on the incorporation of living fibrochondrocytes, proper size matching of these meniscal transplants, and secure bony fixation so hoop stresses can be generated and transmitted across the femoral-tibial articular surfaces.
Articular Cartilage
Structure and Function
The principal function of articular cartilage is to provide load transmission via a relatively frictionless articulation surface. This function is dependent on the specific composition and organization of the extracellular matrix that is maintained by the chondrocytes. Articular cartilage is a highly organized viscoelastic material. Articular cartilage is both aneural and devoid of blood and lymphatic vessels. The dense extracellular matrix protects the chondrocytes from immunologic recognition, and that factor along with the lack of blood and lymphatic vessels make articular cartilage an immunoprivileged site. The chondrocytes that populate the extracellular matrix depend on the flux of fluid into and out of the extracellular matrix for their metabolic requirements. The chondrocytes are believed to respond to the mechanical environment by sensing alterations in the pericellular environment. They are metabolically active and maintain the surrounding extracellular matrix. Furthermore, they clearly respond to cytokines present within the synovial fluid.
The extracellular matrix consists of water, proteoglycans, and collagen. Water makes up the majority (approximately 65% to 80%) of wet weight. Ninety-five percent of the collagen is type II with much smaller amounts of other collagens including types IV, VI, IX, X, and XI. The exact functions of these other collagens are unknown, but they are believed to be important in matrix attachment and stabilization and diameter of collagen fibrils. The collagen forms a 3-D network that encases proteoglycan molecules, predominantly keratan sulfate and chondroitin sulfate. Proteoglycan molecules are negatively charged and along with cations attract water. The high water content with the collagen-proteoglycan solid matrix is responsible for its mechanical properties. The rate of deformation or compression of articular cartilage is highly dependent on the rate of exudation of water from the matrix. The limit to deformation is dependent on the structural integrity of the collagen framework.
The ebb and flow of synovial fluid, water, and nutrients into and out of the articular surface is vital for maintenance of normal chondrocyte metabolism and the integrity of the extracellular matrix. Therefore, active joint motion and application of a physiologic load is required for maintenance of a healthy articular surface. The exact correlation between the minimum and maximum rate of loading and amount of compression necessary to maintain the articular surface is unknown. However, supraphysiologic stresses that occur after the total loss of the meniscus (which decreases contact area by over 50%) result in early degenerative changes. Furthermore, ligamentous insufficiency such as ACL tears with resultant altered joint mechanics after ACL reconstruction also may place supraphysiologic forces on articular cartilage that predispose to early degenerative changes. Finally, genetic differences and/or anatomic alignment may predispose to degenerative changes.
The normal thickness of the articular cartilage correlates with the surface pressure. The higher the peak pressures, the thicker the articular surface, with the area underneath the patella being the thickest in the human body. The basic structural anatomy of the articular cartilage can be divided into four distinct zones, superficial, middle, deep, and calcified, as shown in Figure 2. These layers differ in collagen orientation, cellular morphology, and biomechanically. The collagen orientation changes from parallel to the surface in the superficial layer to a more random, less densely packed array in the middle zone. In the deep and calcified zones the collagen bundles are perpendicular to the joint surface and subchondral bone. The largest collagen fibrils are in the deep zone, which has the highest concentration of proteoglycans and lowest concentration of water. The chondrocytes are arranged in a manner similar to that of the collagen fibrils. In the deepest calcified zone, small, low-volume chondrocytes are randomly arranged. This transitions to a columnar arrangement of spherical cells in the deep zone to a more random array of cells in the middle zone, and finally, to a flat, parallel array of chondrocytes in the superficial zone. The tidemark is a thin basophilic line seen at light microscopy sections of decalcified articular cartilage that corresponds to the boundary between the calcified and uncalcified cartilage.
Injury and Repair
Injuries to the articular surface can be divided into acute and subacute (gradual). Acute injury types include blunt trauma, shear, and thermal (including electrocautery as well as laser). Subacute or gradual types occur as a result of mechanical overload secondary to meniscal loss and/or ligamentous instability, aging, and potentially exercise. Mechanical trauma (blunt, twisting, or impact loading) to the articular cartilage leads to three basic types of tissue damage. Type 1 is the destruction or alteration of the macromolecule framework (that is, loss of matrix or macromolecules, or cell injury without evidence of disruption). Type 2 is the disruption of the articular cartilage alone (chondral fractures or fissuring). Type 3 is disruption of the articular cartilage with penetration into the subchondral bone (for example, an osteochondral fracture). The healing potentials of these lesions are significantly different because the articular cartilage is avascular. Because types 1 and 2 do not penetrate the subchondral bone, there exists an extremely poor to nonexistent potential for healing because an inflammatory component is not elicited and the chondrocytes have limited ability to initiate a repair process. In contrast, type 3 injuries produce an inflammatory response with a fibrin clot and exposure of mesenchymal undifferentiated cells that populate this fibrin clot and produce a reparative tissue. However, this tissue consists primarily of type I collagen and does not have the biomechanical properties of normal articular cartilage. This fibrocartilage is prone to early degenerative changes.
Classification
No uniform classification system exists to define the natural history of articular cartilage lesions as well as results of treatment. Table 1 lists current classification systems. All classification systems prior to that of Noyes in 1989 were developed for patellofemoral pathology. The Noyes system uses diameter estimates based on probe widths and includes osteochondritis dissecans and articular cartilage fractures. The Dougados system acknowledges the importance of the scale diagram drawn by surgeons but grade III exposed bone was considered unique to this system versus all others. The Curl system modified the Outerbridge classification system but its shortcoming was that it did not define size of lesion. Because there is no single agreed-upon classification system that reproducibly defines depth and size of articular cartilage lesions, natural history and treatment investigations are hindered.
Treatment
Treatment of full-thickness cartilage defects has included (1) débridement, (2) abrasion arthroplasty or microfracture, (3) autologous chondrocyte cell transplantation, (4) periosteum or perichondrium transplantation, (5) mosaicplasty (single or multiple autograft osteochondral transfer) and (6) fresh allograft osteochondral transfer. Evaluation of these treatments requires validated outcome measures and adequate follow-up. Furthermore, treatment needs to control for confounding variables, such as ACL reconstruction, meniscus surgery (excision, repair, replacement), and osteotomy, which clearly have been shown to improve outcomes. These shortcomings have led the International Cartilage Repair Society to develop comprehensive documentation and classification to include the following factors: (1) etiology, (2) defect thickness, (3) size of lesion (cm2), (4) degree of containment, (5) location(s), (6) ligament integrity, (7) meniscus integrity, (8) alignment (normal, varus, valgus), (9) previous management, (10) radiologic assessment, (11) assessment by MRI (fat suppression techniques), and (12) general medical, systemic, or family history issues. With the understanding of significant confounding variables such as ACL reconstruction, as well as the clear scientific value of general and disease-specific validated outcome forms, future studies should at a minimum be prospective, use validated outcome for pretreatment and posttreatment, and stratify for major confounding variables.
Muscle
Structure and Function
The primary role of skeletal muscle is locomotion. The myotendinous junction is the most common site of injury (such as delayed muscle soreness, strains, and traumatic tears or avulsion). The length of muscle fibers may make them susceptible to injuries, especially those fibers that cross two joints. For example, the hamstring, gastrocnemius, and long head of the biceps most frequently undergo strains and/or partial tears.
Understanding muscle physiology requires knowledge of the microscopic and macroscopic anatomy including the motor unit, muscle fiber bundles, individual muscle fibers, myofibrils within fibers, and the contractile unit of the myofibril, the sarcomere (Fig. 3). Muscle contracts in response to input via nerve fibers through the neuromuscular junction (motor end plate) to all the muscle fibers innervated by that nerve fiber. These contractions are "all or none" and these fibers are scattered throughout the muscle. Therefore, the force of contraction is dependent on percentage of motor units firing. In general, smaller muscles (ocular, hand) required for fine motor control have smaller motor units (less muscle fibers per nerve fiber) as compared with larger muscles (hamstrings and gastric), which have much larger motor units. An early component of increase in strength from resistance training is neuromuscular adaptation, which includes firing a higher percentage of motor units.
The characteristics of muscle contraction depend on the type of contraction and muscle fiber types. The types of contraction include isometric (fixed load, no joint motion), concentric (moving a load as joint moves with muscle shortening), eccentric (controlling a load as the joint moves with muscle lengthening), and isokinetic (load varies at constant joint velocity). There are three basic muscle fiber types¾type I, type IIA, and type IIB (Table 2). Types I and II are determined by speed of contraction. Type I is slow-twitch and type II is fast-twitch. Type II is further divided by major mode of energy utilization with type IIB being primarily anaerobic. Conversely, type IIA is intermediate between type I and type IIB in both aerobic and anaerobic capacity. Postural muscles and primary movers are type I, and muscles associated with power generation are type II. Most muscles have both types I and II fibers.
Response to Immobilization, Exercise, and Resistance Training
Mammalian skeletal muscle is capable of responding to functional loads such as those caused by disuse, immobilization, and exercise. Muscle quickly adapts to a spectrum of disuse by rapidly losing contractile strength and mass. The profound reduction in strength and mass with bed rest or microgravity is reversible relatively quickly. During immobilization the position of muscle is significant as the muscle positioned in a lengthened position undergoes less reduction in mass versus that in a neutral or shortened state.
The type of exercise, such as aerobic or endurance training (running, biking, swimming, or cross-country skiing) versus resistance training (weight lifting) determines the specific adaptive response. Low loads characterize endurance training with high repetitions requiring oxidative metabolism by muscle. This stimulates mitochondria biogenesis and increased capillary density and results in increased Vo2max and improved fatigue resistance. At a cellular or muscle fiber level, alterations result in mRNA stability, increased protein synthesis, and greater density of mitochondria per muscle cell. It is now known that mitochondrial biogenesis may be initiated by a single episode of exercise.
Injury and Repair
The role of stretching before exercise to prevent muscle injuries has been debated. In a randomized trial of preexercise stretching during warm-up in 1,538 Army recruits during 12 weeks of training, there were no clinically meaningful reductions in risk of exerciserelated injuries. Significant factors predictive of injury were fitness and age.
Microscopic muscle injury is characterized by delayed muscle soreness that occurs throughout the muscle fiber as a result of overzealous eccentric activity for which the muscle has not had prior conditioning. Pain typically occurs 12 to 48 hours after activity. These ultrastructural changes to muscle cells are reversible during repair. Clinically apparent muscle strains are partial disruptions usually localized to the myotendinous junction in response to powerful eccentric contractions. The repair process includes inflammatory reaction followed by fibrosis. Clinically the most common sites for injury are hamstrings and gastrocnemius (especially medial head)¾both of these muscles cross two joints. Recent studies have focused on pharmacologic ways to promote repair and clinical recovery using anabolic steroids, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), ultrasound, and hyperbaric oxygen. In a rat model with muscle contusion injury, an anabolic steroid (nandrolone decanoate, 20 mg/kg), a corticosteroid (methylprednisolone acetate, 25 mg/kg) and a control group were compared. Healing (measured by active contractile tension and histology) in the corticosteroid group showed earlier improvement at day 2, but was weaker than the control group by day 7, and the muscle was degenerated at day 14. At day 14 the anabolic steroid group was significantly stronger in twitch. Naproxen (500 mg twice daily for 48 hours) was administered in the presence of delayed onset muscle soreness in a prospective randomized, double-blind trial in moderately trained men. The NSAID did not alter serum creatine kinase, muscle force deficit at 24 hours, visual analog scale pain, and immunohistochemical inflammatory cells. However, at 48 hours, naproxen significantly increased voluntary knee extension torque.
The effect of pulsed ultrasound on regeneration was investigated after a contusion injury. Though satellite cell proliferation was increased in myoregeneration there were no overall morphologic manifestations of muscle regeneration. Two studies investigated the effect of hyperbaric oxygen on muscle injury models. In a prospective randomized, double-blind study of delayed muscle soreness in 66 untrained men (18 to 35 years of age) there was a significant increase in recovery of eccentric quadriceps torque at 96 hours, but no change in visual analog scale pain at any time. In a rabbit model of acute muscle stretch, a group treated with hyperbaric oxygen demonstrated a significant reduction in functional deficit (ankle isometric torque) versus a control group. Morphologic investigation confirmed more complete healing in the treatment group than in the control group.
Muscle lacerations remain a difficult problem clinically because of the paucity of investigations on recovery of function. A mouse model of gastrocnemius laceration studied surgical repair versus short period of immobilization (5 days) on healing, with the repair group showing significant increased recovery of tetanus strength 1 month after injury (81% control repair versus 18% control immobilized). Histologic and immunohistochemical evaluation revealed improved healing with suture repair as evidenced by higher regenerating myofibers, less development of a deep scar, and a more fibrotic scar. The role of cytokines (basic fibroblastic growth factor, insulin-like growth factor, and nerve growth factors) or gene therapy in improving muscle regeneration and repair is currently under investigation.
Ligament
Structure and Function
Ligaments are dense regular connective tissues that consist of short wide bands of tough fibrous tissue, which provide bone-to-bone connections. These tissues have been studied extensively because of their importance in work and sports injuries. Much of the research involving ligaments has focused on the knee. Water is the primary component of ligaments, comprising 60% to 80% of their weight. Collagen is the predominant dry weight component at 70%¾type I collagen is the most common type in normal ligament at 90%. Type III collagen, among others, makes up the remaining 10%. Type III collagen is found more commonly in injured ligaments. Elastin makes up 1% of the dry weight except in spine ligaments, where it is found at a higher rate. Elastin allows the ligament to return to its normal length by storing energy during loading. Fibroblasts are found between the rows of collagen fibers; these cellular components of ligaments produce the extracellular matrix. Ligaments exhibit a more interwoven structure than tendons because of their more variable direction of loading. The fibrous structure of ligament collagen is similar to that found in other tissues containing collagen with a polypeptide chain and triple helix formation. Cross-links are crucial to ligament function because they add significant strength to the structure. The extracellular matrix also contains proteoglycans, which store water and affect viscoelastic properties of the structure. Groups of fibers organized as bands or bundles make up the ultrastructure of ligaments. Studies of the ACL demonstrate that separate bands tighten and loosen based on their location and the flexion angle of the knee.
The transition from ligament to bone at its insertion site is complex. Two types of insertion sites are found: direct and indirect, with direct being more common. An example of a direct insertion is the femoral attachment of the medial collateral ligament (MCL). In direct insertions, the collagen deep fibers attach at right angles to the bone through four distinct zones over a distance of 1 mm. Collagen with extracellular matrix and fibroblasts makes up zone 1. Zone 2 is fibrocartilage with cellular changes. Mineralized fibrocartilage is found in zone 3. Zones 2 and 3 are separated by the tidemark or mineralization front. The abrupt transition to bone distinguishes zone 4. In indirect insertions, the superficial layer connects directly to the periosteum while the deep layer anchors to bone by Sharpey fibers (direct-connection collagen of tendon into bone). An example of an indirect insertion is the tibial insertion of the MCL.
Histologic studies have revealed a uniform microvascularity throughout the ligament. This vascular supply originates from the ligament insertions and epiligamentous tissue. The vascular supply is critical in supplying nutritional support for the processes of matrix synthesis and repair. Histologic studies of human and animal ligaments have demonstrated specialized nerve endings in ligaments. The ACL and MCL had been demonstrated to have a nerve supply, which provides proprioceptive pain responses.
The biomechanical properties of ligaments are related to structural and mechanical properties. The structural properties characterize the behavior of the overall bone-ligament-bone complex (load-elongation relationship) and are influenced by the mechanical properties and ligament geometry as well as the insertion site characteristics (Figs. 4 and 5). The mechanical properties of the ligament under tensile loading (stress-strain relationship) are affected by collagen composition and fiber orientation. The structural properties of the ligament complex can be measured by tensile testing and the subsequent load elongation curve. Like the load elongation curve obtained in tendon testing, two regions are noted in the ligament load elongation curve. A low-stiffness region called the toe region is followed by a more linear region with higher stiffness. The nonlinear response is caused by collagen fiber crimp and a lack of uniformity of the individual fiber recruitment. During initial testing, large elongation is noted with small force because of the straightening of the crimp. After the initial crimp is released, larger forces are required to elongate the fibers. Following elongation of the fibers, the ultimate load of the bone-ligament-bone complex is reached and failure occurs. The curve slope can end abruptly or gradually. A gradual failure represents failure of small individual fibers prior to complete ligament disruption. The mechanical properties can also be obtained from the same load elongation curve. The stress-strain curve will demonstrate the modulus of elasticity, tensile strength, ultimate strain, and strain energy density. The ACL and MCL have been extensively studied because of their frequency of injury. The mechanical properties of the ACL and MCL differ significantly. The elastic modulus for the MCL is twice that of the ACL. The MCL has more dense fiber bundles with less crimp than the ACL. The MCL also has more collagen fibers per unit area than the ACL. Fibril diameter in the MCL is on average higher than that seen in the ACL. It is believed that this factor contributes to a higher resistance to elongation.
Factors Affecting Ligament Properties
An increased prevalence of ACL injury is noted in females. Anatomic features such as intercondylar notch size and shape, femoral or tibial geometry, or pelvic width have been suggested as contributing factors. Gender differences in muscle response to sport-specific activities, such as cutting, jumping, and landing, have also been proposed. Gender differences in ligament properties at the molecular level also may influence these rates. Estrogen's effect on fibroblast proliferation and collagen synthesis has been studied in vitro. Physiologic levels of 17-ß estradiol reduce collagen synthesis by more than 40% in isolated ligament cells as compared with controls, and resulted in a significant decrease in proliferation. Reverse transcriptase polymerase estrogen and progesterone receptor expression has been identified in the ACL of humans and rabbits. Ovariectomized rabbits were used to study estrogen's effect on ACL load to failure. Half of the rabbits were given supplemental estrogen and were noted to have a significantly reduced load to failure as compared with controls, who received no estrogen.
Skeletal maturity and age have been demonstrated to affect ligament mechanical and structural properties. Young donors (age 22 to 35 years) demonstrate a significant increase in ligament stiffness and ultimate load. In vitro studies using fibroblast cultures from MCL specimens of physically immature, mature, and senescent rabbits demonstrated declining collagen synthesis with age.
Structural and mechanical properties of ligaments are changed by immobilization. In a study involving rats, the cruciate ligaments demonstrated a 25% decrease in load-to-failure after 4 weeks of immobilization. In a study of the MCL in rabbits, the bone-ligament-bone complex was noted to demonstrate an ultimate load-to-failure decrease of 66% as compared with the opposite nonimmobilized control. The energy absorbed at failure decreased to 16% of the opposite limb. The structural property decrease is caused by a combination of changes. The MCL-tibial insertion demonstrates marked disruption of the deep fiber bone insertions with osteoclastic subperiosteal bone resorption. A slow reversal of these effects is noted with remobilization with the ultimate load and energy absorbed to failure reaching 80% to 90% of control at 1 year. Evaluation of the new bone formation at the ligament insertion site reveals that return to normal is slow. The mechanical properties of the MCL returned to normal after 9 weeks of remobilization. The properties of the bone-ligament-bone complex are also affected by exercise but to a much lesser extent than by immobilization.
Injury and Repair
The healing process of extra-articular ligaments is similar to wound repair in other structures. The ligaments heal by a scar repair process. This process, while a continuum, can be divided into four phases based on biologic events. Phase 1, the inflammatory phase, is marked by hematoma formation and occurs during the first 3 days. Platelets, inflammatory cells, and erythrocytes aggregate at the site of the injury. Cytokines are released and induce angiogenesis and the formation of granulation tissue. Fibroblasts (from the neighboring tissue and the systemic circulation) proliferate near the end of this phase. Early scar formation occurs, composed primarily of type III collagen. During phase 2, cell proliferation matrix deposition occur. During this time, the fibrin clot organizes and the ligament injury gap is filled with a vascular granulation tissue. Type I collagen synthesis dominates in both the scar area and the adjacent normal ligament. Phases 3 and 4 occur over weeks to months and represent remodeling and maturation of the scar. The cellularity and vascularity at the scar site gradually decrease. The type I and type III collagen ratios begin to approach normal levels. An increase in collagen density occurs and then plateaus. Despite this plateau, the tensile strength gradually increases as a result of matrix changes involving collagen reorganization and cross-linking. Even with this reorganization, the strength of the injured ligament never reaches that of the uninjured ligament. The tensile strength of the healed ligament correlates with the concentration of large-diameter type I collagen fibrils and pyridinoline cross-links. Small-diameter collagen fibrils and decreased cross-link density dominate ligament scarring.
The MCL and other extra-articular ligaments have an intrinsic healing response, which has not been observed in intra-articular ligaments such as the ACL. This difference in healing has been extensively studied and may be a result of a variety of biologic factors. Intra-articular ligaments have a limited blood supply compared with extra-articular ligaments, and the environment inside the joint may not permit the inflammatory phase of healing. Based on this lack of healing response, graft reconstruction of the ACL remains the recommended choice of treatment.
The effect of injury size on healing of the MCL was demonstrated in a rabbit study. An 8-mm gap injury or a 4-mm Z-plasty injury was created. Both injuries healed with histologically similar tissue when evaluated at 40, 78, or 100 weeks. Mechanically, there were significantly decreased structural properties at all intervals. This study suggests there are long-term structural weaknesses in large gap injuries. Collagen fibril diameter has been demonstrated to be similar in healing and grafted ligaments with a predominance of small-diameter fibrils (probably newly synthesized collagen). An in vitro study using rabbit MCL tissue incubated in collagenase for 3 and 6 days demonstrated mean fibril diameter values resembling 40-week scar values. This study demonstrates that collagenase may alter the fibril diameter, and therefore the small fibrils found in healing ligaments and reconstruction grafts may represent the enzymatically reduced endogenous fibrils. Collagen fibril diameter has been studied in a long-term model of the MCL. A consistent pattern of small-diameter fibrils is noted at 40 weeks in the rabbit MCL injury model. An increased number of large-diameter fibrils are noted at 78 and 104 weeks, but 90% of the fibrils are still of small diameter. No rabbits demonstrated the fibril pattern seen in uninjured ligaments. The proteoglycan network is significantly altered in healing ligaments. In the normal ligament, decorin is the most common proteoglycan, representing 80% of the total. In the healing ligament, biglycan is predominant and decorin is barely detected. The proteoglycan-rich matrix accumulates in the injury gap by 3 weeks postinjury and is present for up to 2 years. The increased level of biglycan may interfere with normal collagen remodeling, preventing a return to normal ligamentous tissue.
The effect of ibuprofen on healing of MCL injuries in rabbits has been studied. A 14-day course of ibuprofen did not affect load-to-failure of healing MCL injuries tested at 14 and 28 days as compared with untreated controls. Some evidence exists that hyperbaric oxygen treatment may improve MCL healing. A study using a rat model demonstrated a significant increase in load-to-failure at 6 weeks in rats treated with hyperbaric oxygen as compared with untreated controls.
Tendon
Structure and Function
Tendons are made up of dense regular connective tissue highly specialized to transmit high tensile loads from muscle to bone. Collagen (86% type I and 5% type III of the dry weight) is the major constituent of tendon. Three collagen chains are combined in a collagen molecule and organize into microfibrils and then fibrils. Proteoglycans and glycoproteins with water combine with fibrils in a matrix to form fascicles. The fascicles coalesce to bundles, which are surrounded by the endotenon. The endotenon supports the vascular supply, lymphatics, and nerves. The epitenon and subsequently the paratenon surround a set of bundles and complete the structural anatomy of the tendon.
Fibroblasts align along the fibril subunits, but the tendon is relatively hypocellular. Proteoglycans, although small in concentration, provide an important function. Proteoglycans are extremely hydrophilic and influence the viscoelastic properties of tendons. Decorin is widely distributed and is thought to play a fundamental role in regulating collagen fiber formation in vivo. Decorin is speculated to prevent slippage during tendon deformation, thus increasing the tensile strength of the tendon. Compared with ligaments, deformation is less under an applied load. Thus, tendons are better able to transmit load from muscle to bone, allowing motion during contraction or to resist motion during eccentric contraction. Tendons typically transmit tensile forces but in tendons that wrap around an articular surface, compressive forces are produced. Tendons in these regions develop a more cartilaginous structure.
Tendons can be divided into two major categories: (1) those that pull in a straight line, are not enclosed in a sheath but are surrounded by the paratenon (Achilles tendon), a loose connective tissue continuous with the tendon, or (2) those that are required to bend, such as the flexor tendons of the hand, that are enclosed by a tendon sheath that directs the tendon path and acts as a pulley. Motion of this type of tendon is assisted by synovial fluid produced by the synovial membrane or epitenon. The vascular supply of these two types of tendons is quite different. Tendons within a sheath receive their vascular supply from the perimysium, the periosteal insertion, and long and short vinculae by way of the proximal mesotendon. In tendons surrounded by the paratenon the vascular supply enters from the periphery into a longitudinal system of capillaries. These tendons also receive blood supply from the perimysium and their osseous insertions.
The mechanical and structural properties of tendons are critical to their ability to generate tensile force. The mechanical properties of the tendon are dependent on the structure of the collagen fibrils. The structural properties of the bone-tendon-muscle unit depend not only on the mechanical properties of the tendon but on its myotendinous junction and bony insertion. The structural properties of the bone-tendon-muscle unit are represented by a load-elongation curve similar to that of ligaments. The load-elongation curve demonstrates an initial toe region where the tendon shows initial stretch without significant force applied secondary to the straightening of the cramped fibrils and orientation of the longitudinal collagen fibers. The toe region is smaller in tendon compared to ligament because the collagen fibers are oriented in a more parallel fashion and therefore less realignment occurs during initial loading. Following the toe region is a more linear region, which represents the elastic modulus of the tendon. Tendon failure occurs abruptly or in a downward curve. The downward curve represents permanent structural changes or irreversible elongation in the tendon. Young animals, which are skeletally immature, demonstrate a more abrupt failure on the load-elongation curve than skeletally mature animals. Viscoelastic properties of tendons affect their function. In isometric contractions, the muscle-tendon unit length remains constant but elongation of the tendon occurs secondary to creep, which allows the muscle to shorten. This improves muscle function during isometric contractions. Preconditioning occurs when the initial cycles of elongation following a period of rest reveal increased energy loss. Following preconditioning, the load elongation cycle is more repeatable. This is why warm-up prior to exercise is critical for appropriate muscle-tendon-bone unit function.
Factors Affecting Tendon Properties
The anatomic location of tendons affects their mechanical and structural properties. Biomechanical and biochemical studies have revealed significant differences between flexor and extensor tendons. In adult miniature swine, the ultimate load to failure of digital flexor tendons is twice that of digital extensor tendons. In addition, on load-elongation curves, hysteresis (energy loss) is twice as large in extensor tendons as compared with flexor tendons. Biochemically the collagen content of digital flexor tendons is higher than that of extensor tendons. Age and maturation increase the difference between the types of tendons.
Exercise has been shown to impart positive effects on the mechanical and structural properties of tendons. The elastic modulus and ultimate load to failure of swine digital extensor tendons has been shown to increase following exercise. Collagen synthesis and fibril diameter both increase following exercise as demonstrated by biochemical studies. Larger fibrils demonstrate improved tensile stress properties due to increased cross-links. In a study of stress-shielded and partially stress-shielded patellar tendons, the stress-shielded tendons demonstrated significantly less tensile strength when tested at 1, 2, 3, and 6 weeks as compared with even the partially stress-shielded tendons. In an in vitro study of the stress-shielded canine digital flexor tendon, a significant decrease was noted in the elastic modulus over an 8-week period. The canine digital flexor tendon demonstrated a significant increase in tensile properties when subjected to cyclic loading, compared with in vitro tendons, which underwent no stress. Exercise has been shown to have a differential effect on different tendons suggesting that some tendons may have the ability to improve their structural properties while others work near their peak capacity. Immobilization of tendon decreases its tensile strength, stiffness, and total weight due to a decrease in cellularity, collagen organization, collagen fibril diameter, and collagen cross-links and an altered proteoglycan and water content. Remobilization results in a slow return to normal of the biochemical and biomechanical properties of the tendon. This process takes much longer than the period of immobilization and points to the need for early mobilization of tendons when possible.
A reduction in tendon vascularity and cellularity is noted with aging. The aging process also results in an increased amount of insoluble collagen, increased maturation of collagen cross-links, increased collagen fibril diameter, reduced collagen turnover, and decreased proteoglycan and water content. These changes, which may become evident by the third decade, result in a weaker, stiffer, and less compliant tendon. Additional degenerative changes in the tendon will increase the possibility of injury. Exercise may help slow these age-related changes.
Fluoroquinolones, a class of widely used antibiotics, have been associated with tendinitis. Musculoskeletal effects of these medications have a reported incidence of less than 1% and consist mainly of arthralgias and myalgias. Achilles tendon disorders are most common, including reports of sharp pain in the tendon a few hours after medication administration and reports of bilateral tendon ruptures. Investigators have studied the toxic effects of these medications. Tenocytes in the Achilles tendon demonstrated cellular degeneration. Pefloxacin administration demonstrated a decrease in proteoglycan production and oxidative damage of type I collagen in mouse Achilles tendons. In particular, there was a decrease in production of decorin, which is critical for tendon structural strength. Further studies are necessary to determine the exact nature of risk of these medications for tendon disorders.
Injury and Repair
Tendon injuries occur by one of three mechanisms. Direct trauma can result in transection of the tendon. Indirect injury is an avulsion of the tendon from its bony insertion. Indirect intrasubstance injury can result from intrinsic or extrinsic factors. Trauma frequently results in a direct injury to tendon (such as tendon lacerations in the hand). A bony avulsion can result from an overwhelming stress to the bony tendon unit (such as ring finger flexor digitorum profundus avulsion injuries). Repetitive submaximal overload or repetitive pressure against a bony surface, as seen by the supraspinatus beneath the acromion, can result in intrasubstance degeneration. Tendon healing following an injury mimics the wound repair response in other soft tissues. The four phases of healing (inflammation, proliferation, remodeling, and maturation) occur.
Rat and rabbit Achilles tendons have been used to study extrasynovial tendon healing. Following tendon injury, the gap fills with inflammatory products, blood cells, nuclear debris, and fibrin. Fibroblasts and capillary buds fill the gap between the tendon ends by proliferating from the paratenon. After 3 days, collagen synthesis can be detected. Type I collagen production is increased 15- to 22-fold. After 2 weeks, a fibrous bridge consisting of fibroblasts and collagen fibers fuses the tendon. Between 3 and 4 weeks, the collagen fibers begin to organize longitudinally in a process that continues for many months. The scar mass during the early stages of healing is much larger than the uninjured tendon, but gradually decreases in size during healing because of collagen reorganization and collagen fibril cross-linking. This process improves with appropriately applied stress.
Healing in tendons enclosed by a sheath has been a topic of research for many years. Early studies suggested that healing occurred by granulation tissue from the sheath. Recent investigations have demonstrated that tendon cells participate in the healing response. Pro-alpha-1 collagen mRNA has been demonstrated to be present in epitenon and endotenon cells in the healing flexor tendon. In healing flexor tendons, which undergo controlled passive motion, the intrinsic healing response of the epitenon is the predominant form of healing. In immobilized tendons, granulation tissue from the digital sheath and endotenon cellular proliferation dominate the healing response. During the intrinsic healing response collagen synthesis and vascular response are noted followed by collagen maturation and reorganization similar to the wound repair response seen in other tissues.
Factors Affecting Tendon Repair
Factors that affect tendon repair include suture repair type, continuous passive motion, gap formation, and load experienced by the healing tendon. Aggressive and early active motion and weight bearing have been demonstrated to increase the rate of tendon rupture and gap formation. On the other hand, early and controlled passive mobilization has been demonstrated to improve several factors involving tendon repair. Controlled passive motion improves the repair strength in the early period following repair and decreases adhesions. In the canine digital flexor tendon an eight-strand repair resulted in increased stiffness and load to failure of the repair at 3 and 6 weeks when compared with the Savage, Tajima, and Kessler types of repair. Gap formation (elongation) at the repair site of healing flexor tendons has been associated with adhesion formation and poor functional outcome. A study evaluating gap formation in the healing canine flexor tendon demonstrated a significant increase in ultimate force, repair site rigidity, and repair site strain in tendons with less than 3 mm of gap compared with tendons that have greater than 3 mm of gap. These differences were noted at both 10-day and 42-day time periods during mechanical testing and no difference was noted in the prevalence of adhesions.
Novel approaches to improve tendon healing are being studied. Cytokines such as PDGF, epidermal growth factor, and insulin-like growth factor-1 have been noted to improve tendon healing. Growth and differentiation factors 5 and 6 from the bone morphogenetic protein family used in a rat Achilles tendon healing model via collagen sponges at the injury site have demonstrated increased tensile strength of the healing tendon. The appropriate type and timing of cytokine delivery to facilitate the most rapid and quality repair has yet to be determined. Mesenchymal stem cells in a collagen matrix have been delivered to a rabbit Achilles tendon injury model (1-cm tendon gap) and structural and material properties were noted to be twice those of the control tissues.
Factors Affecting Tendon-to-Bone Healing
Tendon-to-bone healing is critical for success in numerous reconstructive surgical procedures. When tendon grafts heal within a bone tunnel, a fibrovascular interface forms between the bone and tendon. Bony ingrowth is noted in this interface with the eventual development of an indirect insertion in which tendon collagen fibers are continuous with bone. In rotator cuff repair, bone ingrowth also occurs in the interface between tendon and bone. Animal models show no advantage in repairing tendon to a cancellous bone trough versus repair directly to cortical bone. Studies have demonstrated that the strength of repair correlates directly with bone ingrowth into the fibrous interface.
In a human cadaver finger model, an eight-strand-suture technique resulted in a significant improvement in tendon-bone elongation when exposed to a 20-N force. The sutures were secured to a suture anchor or a dorsally placed button. The eight-strand repair secured to a dorsal button was stronger than the four- or eight-strand repair performed with a suture anchor. Bone morphogenetic protein-2 has been used to improve the tendon graft-to-bone tunnel healing in a canine model. Biomechanical testing of this model showed higher tendon pullout strength in the cytokine-treated tendons as compared with controls. Histologic and radiologic evaluation demonstrated more extensive bone formation around the tendon and closer bone tendon apposition.
Tendon Overuse Injury
Tendon overuse injuries result from repetitive microtrauma. The patient responds early with the inflammatory cell infiltration, tissue edema, and fibrin exudation. If the overload becomes chronic, the synovial cells and fibroblasts proliferate, capillaries form, and the paratenon thickens. The process of tendinosis involves alteration to cells, collagen fibers, and matrix components. A reparative and degenerative process affects the tendon. The tensile strength of the tendon decreases and microtears develop in the tendon. As tendon fibers fail, the resulting load on the rest of the tendon increases, which places it at risk for progressive failure. This process occurs at the lateral epicondyle in tennis elbow, at the inferior insertion or the patellar tendon due to patella tendinitis, and at the Achilles tendon insertion to calcaneus with Achilles tendinitis. With tendon failure, the typical wound repair response occurs in most tendons, but is limited in others, such as the rotator cuff.
Nerve
Structure and Function
A neuron consists of four distinct regions: the axon, dendrites, presynaptic terminal, and the cell body. The cell body only contains 10% of the volume of the neuron but is the metabolic center containing the nucleus and organelles for protein and RNA synthesis. The dendrites are branches from the cell body that receive signals from other nerve cells. Each cell body contains only one axon that is responsible for the conduction of information by propagating electrical signals. The action potential is an all-or-none phenomenon initiated from the axon hillock, the region where the axon originates. Proteins are synthesized in the cell body, assembled into the appropriate macromolecules, and sent down the axon using axoplasmic transport. Presynaptic terminals are specialized regions at the end of axons, which transmit information to dendrites or cell bodies. Axons insulated by a myelin sheath (produced by Schwann cells) conduct electrical impulses using less energy at a higher frequency and at a faster speed than noninsulated axons. Myelin consists of 30% protein and 70% lipid (mainly cholesterol and phospholipid).
The nerve fiber consists of the axon and its myelin sheath. Surrounding the nerve fiber is a basement membrane and connective tissue called the endoneurium. A collection of nerve fibers forms a fascicle. The perineurium is the connective tissue that surrounds the fascicle. Several fascicles together form the peripheral nerve, which is surrounded by a connective tissue layer called the epineurium that supplies a protective framework for the fascicles. The vascular supply of peripheral nerves relies on an intrinsic and extrinsic system. The intrinsic system is a vascular plexus in the epineurium, perineurium, and endoneurium. The extrinsic system consists of regional vessels, which enter the nerve trunk at various sites running in the connective tissue that surrounds the nerve trunk. Both systems are oriented longitudinally with anastomotic connections between them. The perineurial and endoneurial plexuses make up a defined vascular unit, which can remain intact when fascicles are separated. The endoneurial plexus consists of arterioles, venules, and capillaries, which form an anastomotic network along the fascicle. The capillaries are large, nearly twice the size of muscle capillaries with functional characteristics similar to those in the central nervous system. The blood-nerve barrier is similar to the blood- brain barrier protecting and maintaining an appropriate endoneurial environment.
Nerves have biomechanical properties and although testing is difficult, demonstrate a typical stress-strain relationship. A more linear region at higher stress follows a compliant, low-strained toe region. During normal physiologic function, nerves work in the toe region of the stress-strain curve. In repair situations, the nerves may be expected to operate under more stress when the ends of nerves are reopposed to span injury gaps. This is critical, for while nerves have demonstrated ultimate strain ranging from 20% to 60%, ischemic damage is noted at strain rates as low as 15%. In clinical situations, joints and extremities are frequently immobilized to protect nerve repairs.
Injury and Repair
Peripheral nerve injuries can be divided into two broad categories: those that result in no axon discontinuity and only temporary loss of nerve conduction, and those injuries where axons are damaged to a point where axonal degeneration occurs proximal and distal to the injury. Wallerian degeneration is a result of axon discontinuity. This process occurs within hours of the injury. The myelin surrounding the axon undergoes deterioration with loss of nerve conduction. This process extends proximally from the site of injury usually to the next node of Ranvier and distally to the target organ. Schwann cells of intact nerve fibers do not usually divide, but following injury these cells undergo mitosis with a cell proliferation peak at 3 days. The Schwann cells act in phagocytosis of myelin and axonal debris. The Schwann cells maintain cytoplasmic tubes called the bands of Büngner that run beneath the nerve fiber basal lamina. These Schwann cells assist the process of regeneration by synthesis of nerve growth factor. The nerve cell body also undergoes changes following peripheral nerve injury. The focus of the nerve cell body changes to synthesis of proteins necessary for axonal repair and growth instead of the previous production of neurotransmitters. At the tip of the regenerating axon is the growth cone, which accomplishes the process of axonal regeneration. In order for regeneration to occur, the zone of injury must be crossed by the growth cone to make contact with the endoneurial tubes of the distal nerve stump. The ability to complete this process is affected by several factors including amount of nerve damage, gap, and scar formation. Regeneration is accomplished at an average of 1 mm per day in adults but may be faster in children.
Classification systems exist for nerve injuries. Neurapraxia, usually secondary to compression, results in local myelin damage, but the axon remains in continuity. Axonotmesis by definition is a loss of continuity of the axon with some preservation of the nerve connective tissue. Neurotmesis results in physiologic discontinuity of the nerve, although the nerve may not be actually transsected. In Sunderland's classification system five types of nerve injury are described. Type 1 is equivalent to neurapraxia, types 2, 3, and 4 are equivalent to axonotmesis, and type 5 is equivalent to neurotmesis. Axonotmesis, type 2, is a loss of continuity of the axons with the endoneurium, perineurium, and epineurium intact. Axonotmesis, type 3, is loss of continuity of the axons and endoneurium with the perineurium and epineurium intact. Axonotmesis, type 4, is loss of continuity of the axons, endoneurium, and perineurium, with the epineurium intact.
Historically, it was believed that nerve repair should be delayed for 3 weeks to allow for completion of wallerian degeneration; however, more recent studies have demonstrated that immediate primary repair improves results. Primary repair requires adequate soft-tissue coverage, skeletal stability with low tension on the nerve repair, and a good vascular supply. Two types of nerve repair, grouped fascicular repair and simple epineurial repair, are possible. Theoretically, grouped fascicular repair is advantageous because axon realignment can be more accurate, although this may require additional dissection resulting in increased scarring and decreased vascular supply. Prospective studies comparing grouped fascicular repair with simple epineurial repair have not demonstrated an improvement with the fascicular repair. Researchers continue to try to identify factors that will improve nerve repair and nerve regeneration at the biologic level. Growth factors have been given systemically or locally with some promising results in animal models.
When primary repair is impossible, nerve grafting is required. Autogenous grafting remains the standard approach. The sural nerve or the medial and lateral antebrachial cutaneous nerve have commonly been used. For larger nerves, multiple segments of graft may be necessary. In this setting, a group fascicular repair is attempted. The direction of the nerve graft is reversed from proximal to distal, and a tension-free repair performed. In smaller nerves, a single segment of graft may be used. Investigations of larger nerve grafts in animal models have demonstrated slower revascularization compared with that of smaller multisegment nerve grafts. Allografts would be an excellent choice if the results were equivalent to autogenous grafts. Advantages of allografts include no donor nerve sacrifice, faster surgical procedures, and the ability to store grafts in tissue banks. The main impediment to allograft use has been the immunogenic host response. A recent study demonstrated allograft repair results equivalent to autograft repair following a biologic detergent technique that removed the cellular components, which are immunogenic, without production of cell debris. Further work to improve allograft results and to develop other conduits for nerve regeneration will hopefully add other options in the future.
Annotated Bibliography
Meniscus
Stollsteimer GT, Shelton WR, Dukes A, Bomboy AL: Meniscal allograft transplantation: A 1- to 5-year follow-up of 22 patients. Arthroscopy 2000;16:343-347.
This article documents the technique of using cryopreserved meniscal allografts in 22 patients and 23 knees with an average follow-up of 40 months using the Internation Knee Documentation Committee, Lysholm, and Tegner scoring systems. The most significant finding was a clinical improvement in perioperative pain as measured by the Lysholm, and on follow-up MRI of a subset the average size of meniscus was 63% of normal. Other confounding variables or procedures performed during this study were not discussed.
Articular Cartilage
Browne JE, Branch TP: Surgical alternatives for treatment of articular cartilage lesions. J Am Acad Orthop Surg 2000;8:180-189.
This article provides a comprehensive review of treatment of articular cartilage lesions and a recommended approach. The authors state that currently there are no peer-reviewed prospective randomized controlled trials of surgical versus nonsurgical treatment for full-thickness articular cartilage defects.
Muscle
Terjung RL, Clarkson P, Eichner ER, et al: American College of Sports Medicine roundtable: The physiological and health effects of oral creatine supplementation. Med Sci Sports Exerc 2000;32:706-717.
This consensus statement by the American College of Sports Medicine summarizes the research on creatine supplementation to increase muscle strength during resistance training. Exercise performance during short periods of extremely powerful activity (for example, squats or bench press) can be enhanced, especially during repeated bouts of activity. However, creatine supplementation does not increase maximum isokinetic strength, the rate of maximal force generation, nor aerobic exercise performance. Although creatine supplementation exhibits small but significant physiologic and performance changes, these increases in performance are realized during very specific exercise conditions as outlined in the original research protocols. This suggests that the apparent high expectations for performance enhancement in sports evidenced by the extensive use of creatine supplements are inordinate.
Yan Z: Skeletal muscle adaptation and cell cycle regulation. Exerc Sport Sci Rev 2000;28:24-26.
This excellent review studies skeletal muscle adaptation to altered functional demands and its effect on the satellite cells as they are stimulated and differentiated into myofibrils. It is hypothesized that this process is of fundamental importance for adaptation of exercise because nuclei from satellite cells maintain a constant nuclear to cytoplasm ratio, and they also alter gene expression and thereby provide the mechanism by which skeletal muscle adapts to altered functional demands.
Ligament
Rodeo SA, Suzuki K, Deng XH, Wozney J, Warren RF: Use of recombinant human bone morphogenetic protein-2 to enhance tendon healing in a bone tunnel. Am J Sports Med 1999;27:476-488.
A study involving the canine long digital extensor tendon transplanted into a drill hole in the proximal tibia demonstrated that dogs treated with human bone morphogenetic protein- 2 at the tendon-bone interface resulted in improved histologic and biomechanical healing.
Slauterbeck J, Clevenger C, Lundberg W, Burchfield DM: Estrogen level alters the failure load of the rabbit anterior cruciate ligament. J Orthop Res 1999;17:405-408.
In a study involving ovariectomized rabbits, estrogen supplementation resulted in a significant decrease in the ultimate load to failure of the ACL as compared with rabbits without estrogen supplementation.
Tendon
Gelberman RH, Boyer MI, Brodt MD, Winters SC, Silva MJ: The effect of gap formation at the repair site on the strength and excursion of intrasynovial flexor tendons: An experimental study on the early stages of tendon-healing in dogs. J Bone Joint Surg Am 1999;81:975-982.
Gap formation was studied at the repair site of dog intrasynovial flexor tendons. A gap of > 3 mm did not increase the prevalence of adhesions or decrease range of motion but did decrease the strength and stiffness of the repair.
Nerve
Best TJ, Mackinnon SE, Evans PJ, Hunter D, Midha R: Peripheral nerve revascularization: Histomorphometric study of small-and large-caliber grafts. J Reconstr Microsurg 1999;15:183-190.
Small-caliber and large-caliber nerve graft revascularization was studied, with a significantly improved and faster response noted in the small-caliber graphs at 7 and 40 days following repair.
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