Martin Majewski

Biologics for tendon repair

Tendon injuries are common and present a clinical challenge to orthopedic surgery mainly because these injuries often respond poorly to treatment and require prolonged rehabilitation. Therapeutic options used to repair ruptured tendons have consisted of suture, autografts, allografts, and synthetic prostheses. To date, none of these alternatives has provided a successful long-term solution, and often the restored tendons do not recover their complete strength and functionality. Unfortunately, our understanding of tendon biology lags far behind that of other musculoskeletal tissues, thus impeding the development of new treatment options for tendon conditions. Hence, in this review, after introducing the clinical significance of tendon diseases and the present understanding of tendon biology, we describe and critically assess the current strategies for enhancing tendon repair by biological means. These consist mainly of applying growth factors, stem cells, natural biomaterials and genes, alone or in combination, to the site of tendon damage. A deeper understanding of how tendon tissue and cells operate, combined with practical applications of modern molecular and cellular tools could provide the long awaited breakthrough in designing effective tendon-specific therapeutics and overall improvement of tendon disease management.

Ex vivo adenoviral transfer of bone morphogenetic protein 12 (BMP-12) cDNA improves Achilles tendon healing in a rat model.

The aim of our study was to evaluate the histological and biomechanical effects of BMP-12 gene transfer on the healing of rat Achilles tendons using a new approach employing a genetically modified muscle flap. Biopsies of autologous skeletal muscle were transduced with a type-five, first-generation adenovirus carrying the human BMP-12 cDNA (Ad.BMP-12) and surgically implanted around experimentally transected Achilles tendons in a rat model. The effect of gene transfer on healing was evaluated by mechanical and histological testing after 1, 2, 4 and 8 weeks. One week after surgery, the maximum failure load of the healing tendons was significantly increased in the BMP-12 group, compared with the controls, and the tendon stiffness was significantly higher at 1, 2 and 4 weeks. Moreover, the size of the rupture callus was increased in the presence of BMP-12 and there was evidence of accelerated remodeling of the lesion in response to BMP-12. Histological examination showed a much more organized and homogeneous pattern of collagen fibers at all time points in lesions treated with the BMP-12 cDNA muscle graft. Both single fibrils and the collagen fibers had a greater diameter, with a higher degree of collagen crimp than the collagen of the control groups. This was confirmed by sirius red staining in conjunction with polarized light microscopy, which showed a higher shift of small yellow-green fibers to strong yellow-orange fibers after 2, 4 and 8 weeks in the presence of BMP-12 cDNA. There was also an earlier shift from fibroblasts to fibrocytes within the healing tendon, with less fat cells present in the tendons of the BMP-12 group compared with the controls. Treatment with BMP-12 cDNA-transduced muscle grafts thus produced a promising acceleration and improvement of tendon healing, particularly influencing early tissue regeneration, leading to quicker recovery and improved biomechanical properties of the Achilles tendon. Further development of this approach could have clinical applications.

Midterm and Long-term Results After Arthroscopic Suture Repair of Isolated, Longitudinal, Vertical Meniscal Tears in Stable Knees

Background The long-term outcome of meniscal suture repair has not been firmly established. Purpose To compare the midterm and long-term functional and radiographic outcome of meniscal suture repairs with the natural history of the uninjured knees of each of a cohort of patients. Study Design Cohort study; Level of evidence, 3. Methods Eighty-eight patients with an isolated, longitudinal, vertical tear of one of the menisci within a stable knee were arthroscopically treated with a meniscal suture repair. No patient had a previous surgery, and no additional chondral lesion was present. The opposite knee of each patient was uninjured. Both knees of each patient were examined clinically and radiographically in a retrospective follow-up 5 to 17 years (mean, 10 years) after meniscal repair. Results Three patients with postoperative complications and 21 patients whose menisci had to be removed because of rerupture were excluded from further evaluation for purposes of this study. The remaining 64 patients reached a mean Tegner activity level of 6 points (range, 3-10 points) and achieved a mean Lysholm score of 94 points (range, 26-100 points). Osteoarthritis was found in 46 of the injured knees, compared with 27 of the uninjured knees (P = .004). However, 42 of the patients had no difference in the grade of osteoarthritis between the injured knee and the uninjured knee, 19 had a difference of 1 grade, 2 had a difference of 2 grades, and 1 had a difference of 3 grades. Conclusion Arthroscopic meniscal repair for isolated longitudinal meniscal injuries in stable knees yields favorable functional results, but its effects on the risk of secondary osteoarthritis are not clear.

Avoiding Sural Nerve Injuries During Percutaneous Achilles Tendon Repair

Background Sural nerve injury is a reported risk during percutaneous repair of the Achilles tendon. Hypothesis Exposure of the sural nerve during percutaneous repair can minimize the risk of nerve injury. Study Design Case control study; Level of evidence, 3. Methods The authors retrospectively examined the results of 84 patients who were treated for acute Achilles tendon rupture at 2 different hospitals. Both hospitals used the same percutaneous repair technique, except that the sural nerve was exposed in the 38 patients (mean age, 38 years; range, 23-68 years) of one hospital; the nerve was not exposed in the 46 patients (mean age, 42 years; range, 24-71 years) of the other hospital (the nonexposure group). Results All patients recovered and returned to work after 44 days (range, 5-202 days). All patients returned to their previous sports levels within 1 year. On the 100-point Hannover Achilles Tendon Score, the mean score was 81 points (range, 44-100 points). The overall incidence of sural nerve related complications was 18%. All sural nerve lesions occurred in the nonexposure group. In the total study population, there were 3 cases of deep vein thrombosis, 1 rerupture, and 1 case of infection. Conclusion Sural nerve injuries can be minimized during surgery by carefully placing the stab incisions to expose the nerve so as to avoid it during repair. If the sural nerve is exposed, percutaneous repair of the ruptured Achilles tendon is a safe and reliable method of treating Achilles tendon ruptures.

Accelerated Healing of the Rat Achilles Tendon in Response to Autologous Conditioned Serum

Background Despite advances in the treatment of ruptured Achilles tendon, imperfections of endogenous repair often leave patients symptomatic. Local administration of autologous conditioned serum (ACS) in patients with inflammatory, degenerative conditions has shown beneficial effects. Purpose Because ACS also contains growth factors that should accelerate tendon healing, we studied the effect of ACS on the healing of transected rat Achilles tendon. Study Design Controlled laboratory study. Methods In preliminary in vitro experiments, rat tendons were incubated with ACS and the effect on the expression of Col1A1 and Col3A1 was assessed by real-time quantitative polymerase chain reaction. To test its effect in vivo, the Achilles tendons of 80 Sprague Dawley rats were transected and sutured back together. Ten rats from each group (ACS group, n = 40; control group, n = 40) were euthanized at 1, 2, 4, and 8 weeks postoperatively for biomechanical (n = 7) and histologic (n = 3) testing. Lysyl oxidase activity was assayed by a flurometric assay. The organization of repair tissue was assessed histologically with hematoxylin and eosin- and with Sirius red-stained sections, and with immunohistochemistry. Results Tendons exposed to ACS in vitro showed a greatly enhanced expression of the Col1A1 gene. The ACS-treated tendons were thicker, had more type I collagen, and an accelerated recovery of tendon stiffness and histologic maturity of the repair tissue. However, there were no differences in the maximum load to failure between groups up to week 8, perhaps because lysyl oxidase activities were unchanged. Conclusion and Clinical Relevance Overall, our study demonstrates that treatment with ACS has the potential to improve Achilles tendon healing and should be considered as a treatment modality in man. However, as strength was not shown to be increased within the parameters of this study, the clinical importance of the observed changes in humans still needs to be defined.

Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering

PurposeTendon injuries vary from acute rupture to chronic tendinopathy. For an optimal treatment of either condition, a profound knowledge is essential. Therefore, this article shall give an overview of physiology, biology, and pathology of tendon healing and state of the art in tendon bioengineering.MethodsFor a preferably comprehensive survey, the current literature listed in PubMed and published in English peer-reviewed journals (March 2013) was systematically reviewed for tendon healing and tendon bioengineering including cytokine modulation, autologous sources of growth factors, biomaterials, gene therapy, and cell-based therapy. No differentiation was made between clinical and preclinical in vitro investigations.ResultsTendon healing happens in certain stadiums of inflammation, formation, and remodelling. An additional process of “collagen recycling” close to the healing site has been described recently. With increasing comprehension of physiology and pathology of tendon healing, several promising approaches in tendon bioengineering using growth factors, biomaterials, gene therapy, or cell-based therapy are described. However, only some of these are already used routinely in clinics.ConclusionStrong and resistant tendons are crucial for a healthy musculoskeletal system. The new approaches in tendon bioengineering are promising to aid physiological tendon healing and thus resulting in a stronger and more resistant tendon after injury. The growing knowledge in this field will need to be further taken into clinical studies so that especially those patients with prolonged courses, revision surgery, or chronic tendinopathy and high-demanding patients, i.e., professional athletes would benefit.Level of evidenceII.

Measurement of knee joint gaps without bone resection: "physiologic" extension and flexion gaps in total knee arthroplasty are asymmetric and unequal and anterior and posterior cruciate ligament resections produce different gap changes

General agreement is that flexion and extension gaps should be equal and symmetrical in total knee arthroplasty (TKA) procedures. However, comparisons using a standard TKA approach to normal knee joints that have not undergone bone resection are currently unavailable. Since bony preparation can influence capsule and ligament tension, our purpose was to perform measurements without this influence. Ten normal cadaveric knees were assessed using a standard medial parapatellar TKA approach with patellar subluxation. Gap measurements were carried out twice each alternating 100 and 200 N per compartment using a prototypical force‐determining ligament balancer without the need for bony resection. Initial measurements were performed in extension, followed by 90° of flexion. The ACL was then resected, and finally the PCL was resected, and measurements were carried out in an analogous fashion. In general, the lateral compartment could be stretched further than the medial compartment, and the corresponding flexion gap values were significantly larger. ACL resection predominantly increased extension gaps, while PCL resection increased flexion gaps. Distraction force of 100 N per compartment appeared adequate; increasing to 200 N did not improve the results.

Anterior Knee Laxity Increases Gapping of Posterior Horn Medial Meniscal Tears

Background Meniscal tears often occur in association with anterior cruciate ligament (ACL) lesions or in chronically lax knees. It is also known that meniscal repairs are less likely to heal in ACL-deficient knees. Purpose To test the effect of different knee joint motion and loading conditions on the gapping behavior of longitudinal posterior horn meniscal tears in stable and ACL-deficient knee joints. Study Design Controlled laboratory study. Methods Longitudinal tears of 3 cm were set in the posterior horn of the medial menisci in 10 human cadaveric joints. The medial plateau of the knees was replaced by a transparent replica, and an arthroscope was placed underneath to observe the gapping phenomenon of the meniscal tears. The maximum gap width occurring during flexion-extension under various motion and loading situations was registered in intact and ACL-deficient joints before and after meniscal repair with FasT-Fix suture anchors. Results Longitudinal meniscal tears gapped significantly wider after ACL transection under 30-N axial joint load (P < .05). Increasing the axial load to 200 N or applying external moments to the knee did not lead to further alterations in the gap size. Gapping was significantly reduced after meniscal repair (P < .01). However, after meniscal repair, gapping under 30-N and 200-N axial joint load was still increased significantly after ACL transection compared with the ACL-intact state (P < .05). Conclusion Anterior knee laxity increases gapping across both unrepaired and repaired vertical peripheral medial meniscal posterior horn tears. Clinical Relevance Repairing such meniscal tears without reconstructing the ACL may affect meniscus healing rates or increase the risk of retears. Moderate rehabilitation regimens can be recommended, allowing at least for partial weightbearing and knee motion from extension to 120° of flexion in a stable knee. However, caution should be recommended if meniscal repair is performed in a knee joint with persistent anterior laxity due to ACL deficiency.

Effect of a Simple Collagen Type I Sponge for Achilles Tendon Repair in a Rat Model

Background: Several sophisticated approaches to tendon engineering have been investigated as ways to improve tendon healing with the early formation of repair tissue with possibly a high amount of type I collagen. Besides the new formation of collagen type I, there is evidence for the natural integration of surrounding collagen type I from healthy tendon parts into the healing defect. However, the simple application of a type I collagen sponge to the healing site to increase the amount of local collagen type I has not been investigated. Hypothesis: Healing of the rat Achilles tendon can be accelerated by an additional supply of collagen type I, resulting in increased tear resistance. Study Design: Controlled laboratory study. Methods: The right Achilles tendons of 42 rats were transected. In half of the animals, a type I collagen sponge was placed into the gap. Animals were allowed to move freely in their cages to simulate early functional therapy. After 1, 2, and 4 weeks, tendon length, width, maximal load to failure, and stiffness were measured and the healing site studied histologically according to the Bonar score. Inflammation was evaluated by the appearance of macrophages and neutrophilic and eosinophilic granulocytes. Results: Defects receiving collagen sponges showed improved healing, with significantly stronger (29.5 vs 5.0 N, respectively, at 1 week; P = .00003), shorter (11.6 vs 14.5 mm, respectively, at 4 weeks; P = .005), thicker (10.0 vs 1.8 mm2, respectively, at 1 week; P = .00002), and less stiff (19.5 vs 30.5 N/mm, respectively, at 4 weeks; P = .02) tendons than control tendons. Overall, the biomechanical properties of the collagen-treated tendons appeared to be significantly closer to those of native, uninjured tendons compared with tendons in the control group. Histologically, no inflammatory reaction due to the collagen sponge was found. Conclusion: Tendon healing was accelerated by the type I collagen sponge. Moreover, the mechanical properties of collagen-treated tendons appeared to be significantly closer to those of normal, uninjured tendons compared with control tendons without collagen treatment. Clinical Relevance: As a simple type I collagen sponge seems to increase the amount of local collagen type I, the careful use of such sponges might be an option for tendon augmentation during Achilles tendon surgery.

The Role of the Paratenon in Achilles Tendon Healing: A Study in Rats

Background: The role of the paratenon in tendon healing is unknown. The present study compares healing in the presence or absence of the paratenon in an Achilles tendon defect model in rats. Hypothesis: Resection of the paratenon impairs tendon healing. Study Design: Controlled laboratory study. Methods: Sixty skeletally mature Sprague Dawley rats were randomly assigned to either a resected paratenon (RP) group or an intact paratenon (IP) group. In all animals, a 4-mm portion of the Achilles tendon was resected in the midsubstance. In the RP group, the paratenon was resected completely. In the IP group, the paratenon was opened longitudinally and closed again after the tendon defect had been created. One, 2, and 4 weeks after surgery, 7 animals per group were tested biomechanically and 3 animals per group examined histologically. Results: The recovery of mechanical strength was much more rapid in IP tendons. Tear resistance was significantly increased for IP tendons (41.3 ± 8.8 N and 47.3 ± 14.1 N, respectively) compared with RP tendons (19.3 ± 9.1 N and 33.2 ± 6.4 N, respectively) after 1 and 2 weeks. The cross-sectional area was larger in the IP group after 1 and 2 weeks (8.2 ± 2.3 mm2 and 11.3 ± 3.1 mm2 vs 5.0 ± 2.4 mm2 and 5.9 ± 2.0 mm2, respectively) compared with the RP group. Tendon stiffness was greater in the IP group after 1 week (10.4 ± 1.9 N/mm vs 4.5 ± 1.6 N/mm, respectively) compared with the RP group. In comparison, normal contralateral tendons had a maximal tear resistance of 56.6 ± 7.2 N, a cross-sectional area of 3.6 ± 0.7 mm2, and stiffness of 17.3 ± 3.8 N/mm. Hematoxylin and eosin staining revealed slightly delayed healing of RP tendons. Early collagen formation was seen in the IP group already after 1 week, whereas in the RP group, this only occurred after 2 weeks. After 4 weeks, the IP tendons showed more collagen crimp formation than the RP tendons. Conclusion: An intact paratenon promotes healing of the Achilles tendon. Clinical Relevance: Although incision or resection of the paratenon has been advocated when repairing injured or degenerative tendons, our data suggest that the integrity of the paratenon should be preserved.