Response of the Injured Tendon to Growth Factors in the Presence or Absence of the Paratenon.

BACKGROUND: The paratenon is important for Achilles tendon healing. There is much interest in the use of exogenous growth factors (GFs) as potential agents for accelerating the healing of damaged Achilles tendons. PURPOSE/HYPOTHESIS: The present study used a rat model to study the responses of the injured Achilles tendon to GFs in the presence or absence of the paratenon. The hypothesis was that responses of the injured tendon to GFs would be lower in the absence of a paratenon. STUDY DESIGN: Controlled laboratory study. METHODS: A 4-mm defect was created in the right Achilles tendon of 60 skeletally mature rats, which were treated with a validated combination of GFs (bFGF, BMP-12, and TGF-ß1). Animals were randomly assigned to the intact paratenon (IP) group or resected paratenon (RP) group. Healing was studied anatomically, mechanically, and histologically after 1, 2, and 4 weeks. RESULTS: IP tendons showed improved healing compared with RP tendons. IP tendons were significantly stronger (32.2 N and 48.9 N, respectively) than RP tendons (20.1 N and 31.1 N, respectively) after 1 and 2 weeks. IP tendons did not elongate as much as RP tendons and had greater cross-sectional areas (18.0 mm2, 14.4 mm2, and 16.4 mm2, respectively) after 1, 2, and 4 weeks compared with RP tendons (10.5 mm2, 8.4 mm2, and 11.9 mm2, respectively). On histology, earlier collagen deposition and parallel orientation of fibrils were found for IP tendons. CONCLUSION: The paratenon is essential for efficient Achilles tendon healing. Healing with GFs in this Achilles tendon defect model was superior in the presence of the paratenon. CLINICAL RELEVANCE: Biological approaches to tendon engineering using GFs are in vogue and have been shown to improve healing of the rat Achilles tendon, most likely by inducing progenitor cells located within the paratenon. Clinically, resection or incision of the paratenon has been proposed for wound closure. Our data demonstrate the fundamental importance of the paratenon, which therefore should be preserved during Achilles tendon repair, especially if augmented with products such as platelet-rich plasma or autologous conditioned serum that are rich in GFs.

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.

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

PURPOSE: Tendon 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. METHODS: For 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. RESULTS: Tendon 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. CONCLUSION: Strong 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 EVIDENCE: II.

Effect of BMP-12, TGF-ß1 and autologous conditioned serum on growth factor expression in Achilles tendon healing.

PURPOSE: Achilles tendon ruptures are devastating and recover slowly and incompletely. There is a great demand for biomolecular therapies to improve recovery, yet little is understood about growth factors in a healing tendon. Here, the role of growth factors during tendon healing in a rat model and their reaction to single and multiple growth factor treatment are explored. METHODS: Rat tendons were transected surgically and resutured. The expression of bFGF, BMP-12, VEGF and TGF-ß1 was assessed by immunohistochemical analysis one to 8 weeks after surgery. Paracrine effects of TGF-ß1 or BMP-12 added by adenoviral transfer, as well as the effect of autologous conditioned serum (ACS) on growth factor expression, were evaluated. RESULTS: bFGF, BMP-12 and VEGF expression was highest 1 week after transection. bFGF and BMP-12 declined during the remaining period whereas VEGF expression persisted. TGF-ß1 expression dramatically increased after 8 weeks. ACS treatment increased bFGF (P = 0.007) and BMP-12 (P = 0.004) expression significantly after 8 weeks. Also overall expression of bFGF, BMP-12 and TGF-ß1 regardless of time point was significantly greater than controls with ACS treatment (P < 0.05). Both BMP-12 and TGF-ß1 treatments had no significant effect. No effect was observed in VEGF with any treatment. CONCLUSION: bFGF, BMP-12, VEGF and TGF-ß1 are differentially expressed during tendon healing. Additional BMP-12 or TGF-ß1 has no significant influence, whereas ACS generally increases expression of all factors except VEGF. Staged application of multiple growth factors may be the most promising biomolecular treatment.