The cellular and molecular mechanisms underpinning tissue repair and its failure to heal are still poorly understood, and current therapies are limited. Poor wound healing after trauma, surgery, acute illness, or chronic disease conditions affects millions of people worldwide each year and is the consequence of poorly regulated elements of the healthy tissue repair response, including inflammation, angiogenesis, matrix deposition, and cell recruitment. Failure of one or several of these cellular processes is generally linked to an underlying clinical condition, such as vascular disease, diabetes, or aging, which are all frequently associated with healing pathologies. The search for clinical strategies that might improve the body’s natural repair mechanisms will need to be based on a thorough understanding of the basic biology of repair and regeneration. In this review, we highlight emerging concepts in tissue regeneration and repair, and provide some perspectives on how to translate current knowledge into viable clinical approaches for treating patients with wound-healing pathologies.

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Wound repair and regeneration: Mechanisms, signaling, and translation

Articular cartilage is the highly specialized connective tissue of diarthrodial joints. Its principal function is to provide a smooth, lubricated surface for articulation and to facilitate the transmission of loads with a low frictional coefficient (Figure 1). Articular cartilage is devoid of blood vessels, lymphatics, and nerves and is subject to a harsh biomechanical environment. Most important, articular cartilage has a limited capacity for intrinsic healing and repair. In this regard, the preservation and health of articular cartilage are paramount to joint health.



Figure 1.

Gross photograph of healthy articular cartilage in an adult human knee.



Injury to articular cartilage is recognized as a cause of significant musculoskeletal morbidity. The unique and complex structure of articular cartilage makes treatment and repair or restoration of the defects challenging for the patient, the surgeon, and the physical therapist. The preservation of articular cartilage is highly dependent on maintaining its organized architecture.

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The basic science of articular cartilage: structure, composition, and function

A committee of international knee experts created the International Knee Documentation Committee Subjective Knee Form, which is a knee-specific, rather than a disease-specific, measure of symptoms, function, and sports activity. The purpose of this study was to evaluate the reliability and validity of the new International Knee Documentation Committee Subjective Knee Form. To provide evidence for reliability and validity, we administered the final version of the form, along with the Short Form-36, to 533 patients with a variety of knee problems. Analyses were performed to determine reliability, validity, and differential item function related to age, sex, and diagnosis. Factor analysis revealed a single dominant component, making it reasonable to combine all questions into a single score. Internal consistency and test-retest reliability were 0.92 and 0.95, respectively. Based on test-retest reliability, the value for a true change in the score was 9.0 points. The International Knee Documentation Committee Subjective Knee Form score was related to concurrent measures of physical function (r = 0.47 to 0.66) but not to emotional function (r = 0.16 to 0.26). Analysis of differential item function indicated that the questions functioned similarly for men versus women, young versus old, and for those with different diagnoses. In conclusion, the International Knee Documentation Committee Subjective Knee Form is a reliable and valid knee-specific measure of symptoms, function, and sports activity that is appropriate for patients with a wide variety of knee problems. Use of this instrument will permit comparisons of outcome across groups with different knee problems.

Development and Validation of the International Knee Documentation Committee Subjective Knee Form

This study examined the mechanisms of anterior cruciate ligament (ACL) injury In the first part of the study, using a comprehensive, standardized questionnaire, 89 athletes (100 knees) were interviewed about the events surrounding their ACL injury A noncontact mechanism was reported in 71 (72%) knees and a contact injury in 28 (28%) knees; one patient was unsure if there was any contact Most of the injuries were sustained at footstrike with the knee close to full extension Noncontact mechanisms were classified as sudden deceleration prior to a change of direction or landing motion, while contact injuries occurred as a result of valgus collapse of the knee Hamstring flexibility parameters revealed a statistically higher level of laxity in the injured athletes compared with a matched group of 28 controls In the second part of the study, videotapes of 27 separate ACL disruptions were reviewed and confirmed that most noncontact injuries occur with the knee close to extension during a sharp deceleration or landing maneuver Because the knee is in a position to allow the extensor mechanism to strain the ACL and maximum, eccentric muscle force conditions usually apply, the quadriceps may play an important role in ACL disruption Passive protection of the ACL by the hamstring muscles may be reduced in patients with above-average flexibility

Mechanisms of anterior cruciate ligament injury.

A specific pattern of injury to the superior labrum of the shoulder was identified arthroscopically in twenty-seven patients included in a retrospective review of more than 700 shoulder arthroscopies performed at our institution. The injury of the superior labrum begins posteriorly and extends anteriorly, stopping before or at the mid-glenoid notch and including the "anchor" of the biceps tendon to the labrum. We have labeled this injury a "SLAP lesion" (Superior Labrum Anterior and Posterior). There were 23 males and four females with an average age of 37.5 years. Time from injury to surgery averaged 29.3 months. The most common mechanism of injury was a compression force to the shoulder, usually as the result of a fall onto an outstretched arm, with the shoulder positioned in abduction and slight forward flexion at the time of the impact. The most common clinical complaints were pain, greater with overhead activity, and a painful "catching" or "popping" in the shoulder. No imaging test accurately defined the superior labral pathology preoperatively. We divided the superior labrum pathology into four distinct types. Treatment was performed arthroscopically based on the type of SLAP lesion noted at the time of surgery. The SLAP lesion, which has not been previously described, can be diagnosed only arthroscopically and may be treated successfully by arthroscopic techniques alone in many patients.

SLAP lesions of the shoulder

Our study evaluated tendon-to-bone healing in a dog model. Twenty adult mongrel dogs had a transplantation of the long digital extensor tendon into a 4.8-millimeter drill-hole in the proximal tibial metaphysis. Four dogs were killed at each of five time-periods (two, four, eight, twelve, and twenty-six weeks after the transplantation), and the histological and biomechanical characteristics of the tendon-bone interface were evaluated. Serial histological analysis revealed progressive reestablishment of collagen-fiber continuity between the bone and the tendon. A layer of cellular, fibrous tissue was noted between the tendon and the bone, along the length of the bone tunnel; this layer progressively matured and reorganized during the healing process. The collagen fibers that attached the tendon to the bone resembled Sharpey fibers. High-resolution radiographs showed remodeling of the trabecular bone that surrounded the tendon. At the two, four, and eight-week time-periods, all specimens had failed by pull-out of the tendon from the bone tunnel. The strength of the interface was noted to have significantly and progressively increased between the second and the twelfth week after the transplantation. At the twelve and twenty-six-week time-periods, all specimens had failed by pull-out of the tendon from the clamp or by mid-substance rupture of the tendon. The progressive increase in strength was correlated with the degree of bone ingrowth, mineralization, and maturation of the healing tissue, noted histologically.

Tendon-healing in a bone tunnel: a biomechanical and histological study in the dog.

We used an in vitro knee-testing apparatus to measure anterior-posterior displacement of the tibia on the femur and the accompanying tibial rotation in response to an applied anterior-posterior force. Testing was performed on nine intact knees, on five knees after medial meniscectomy, on three knees after isolated section of the anterior cruciate ligament, and on eight knees after both excision of the medial meniscus and section of the anterior cruciate ligament. The induced anterior-posterior displacement and the coupled rotation were unaffected by meniscectomy. Isolated section of the anterior cruciate ligament allowed a significant (p less than 0.05) increase in anterior displacement but had no effect on posterior displacement. The coupled internal rotation associated with anterior displacement was lost after section of the anterior cruciate ligament. Excision of the medial meniscus and section of the anterior cruciate ligament allowed significantly (p less than 0.05) greater increases in anterior displacement than those already increased by isolated section of the anterior cruciate ligament.

The effect of medial meniscectomy on anterior-posterior motion of the knee.

Injury to the posterolateral structures of the knee, including the popliteus tendon and arcuate complex, frequently results in poorly understood patterns of instability. To evaluate the static function of these tissues, we used a mechanical testing apparatus that allowed five degrees of freedom to test seventeen specimens from human cadavera at angles of flexion that ranged from zero to 90 degrees. Selective section of the lateral collateral ligament, popliteus-arcuate (deep) ligament complex, anterior cruciate ligament, and posterior cruciate ligament was performed. At all angles of flexion, the lateral collateral ligament and deep ligament complex functioned together as the principal structures preventing varus rotation and external rotation of the tibia, while the posterior cruciate ligament was the principal structure preventing posterior translation. However, at angles of flexion of 30 degrees or less, the amount of posterior translation after section of only the lateral collateral ligament and the deep structures was similar to that noted after isolated section of the posterior cruciate ligament. Isolated section of the posterior cruciate ligament did not affect varus or external rotation of the tibia at any position of flexion of the knee. When the posterior cruciate ligament was sectioned after the lateral collateral ligament and deep ligament complex had been cut, a large increase in posterior translation and varus rotation resulted at all angles of flexion. In addition, at angles of flexion of more than 30 degrees, external rotation of the tibia also increased. The application of internal tibial torque resulted in no increase in tibial rotation after isolated section of the anterior cruciate ligament or combined section of the lateral collateral ligament and deep ligament complex. However, combined section of all three structures increased internal rotation at 30 and 60 degrees of flexion. The increases in external rotation that were produced by section of the lateral collateral ligament and deep ligament complex were not changed by the addition of the section of the anterior cruciate ligament.

The Role of the Posterolateral and Cruciate Ligaments in the Stability of the Human Knee. A Biomechanical Study

We tested the anterior-posterior motion of nine normal cadaver knees in zero to 90 degrees of flexion using a specially designed apparatus. This apparatus applied a dynamic anterior-posterior force to each knee and measured the resulting tibial displacement, rotation, and torque. In the intact knee, an anterior force produced an internal tibial torque and internal tibial rotation, while a posterior force produced an external torque and external rotation. Anterior-posterior displacement increased by 30 per cent when the tibia was allowed to rotate freely about its neutral rotation position. Isolated section of the anterior cruciate ligament produced more than double the amount of anterior displacement without affecting posterior displacement. Isolated section of the posterior cruciate ligament produced almost triple the amount of posterior displacement without affecting anterior displacement. After cutting either the anterior or the posterior cruciate ligament, the resulting internal or external secondary tibial rotation disappeared. It appears, therefore, that the anterior and posterior cruciate ligaments are the primary restraints to motion in the anterior and posterior directions as well as the causes of internal and external tibial rotation during anterior and posterior motion.

An in vitro biomechanical evaluation of anterior-posterior motion of the knee. Tibial displacement, rotation, and torque.

Articular cartilage, a connective tissue that provides resistance to compressive forces during joint movements, has not been examined in detail by conventional Fourier transform infrared (FTIR) spectroscopy, microspectroscopy (FTIRM), or imaging (FTIRI). The current study reports FTIRM and FTIRI analyses of normal bovine cartilage and identifies the specific molecular components of cartilage that contribute to its IR spectrum. FTIRM data acquired through the superficial, middle, and deep zones of thin sections of bovine articular cartilage showed a variation in intensities of the absorbance bands that arise from the primary nonaqueous components of cartilage, collagen, and proteoglycan (primarily aggrecan) and thus reflected the differences in quantity of these specific components. The spectra of mixtures of model compounds, which had varying proportions of type II collagen and aggrecan, were analyzed to identify spectral markers that could be used to quantitatively analyze these components in cartilage. Collagen and aggrecan were then imaged by FTIRI based on markers found in the model compounds. Polarization experiments were also performed to determine the spatial distribution of the collagen orientation in the different zones of cartilage. This study provides a framework in which complex pathological changes in this heterogeneous tissue can be assessed by IR microscopic imaging.

Peter A. Torzilli

Papers

Tendon-healing in a bone tunnel: a biomechanical and histological study in the dog.

The effect of medial meniscectomy on anterior-posterior motion of the knee.

The Role of the Posterolateral and Cruciate Ligaments in the Stability of the Human Knee. A Biomechanical Study

An in vitro biomechanical evaluation of anterior-posterior motion of the knee. Tibial displacement, rotation, and torque.

FTIR microscopic imaging of collagen and proteoglycan in bovine cartilage.