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

  • Sports Medicine
  • Published:
Knee Surgery, Sports Traumatology, Arthroscopy Aims and scope

Abstract

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.

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References

  1. Abrahamsson SO, Lohmander S (1996) Differential effects of insulin-like growth factor-I on matrix and DNA synthesis in various regions and types of rabbit tendons. J Orthop Res 14:370–376

    Article  CAS  PubMed  Google Scholar 

  2. Awad HA, Butler DL, Boivin GP, Smith FN, Malaviya P, Huibregtse B, Caplan AI (1999) Autologous mesenchymal stem cell-mediated repair of tendon. Tissue Eng 5:267–277

    Article  CAS  PubMed  Google Scholar 

  3. Batten ML, Hansen JC, Dahners LE (1996) Influence of dosage and timing of application of platelet-derived growth factor on early healing of the rat medial collateral ligament. J Orthop Res 14:736–741

    Article  CAS  PubMed  Google Scholar 

  4. Bidder M, Towler DA, Gelberman RH, Boyer MI (2000) Expression of mRNA for vascular endothelial growth factor at the repair site of healing canine flexor tendon. J Orthop Res 18:247–252

    Article  CAS  PubMed  Google Scholar 

  5. Bosch G, van Schie HT, de Groot MW, Cadby JA, van de Lest CH, Barneveld A, van Weeren PR (2010) Effects of platelet-rich plasma on the quality of repair of mechanically induced core lesions in equine superficial digital flexor tendons: a placebo-controlled experimental study. J Orthop Res 28:211–217

    CAS  PubMed  Google Scholar 

  6. Brent AE, Schweitzer R, Tabin CJ (2003) A somitic compartment of tendon progenitors. Cell 113:235–248

    Article  CAS  PubMed  Google Scholar 

  7. Cao Y, Liu Y, Liu W, Shan Q, Buonocore SD, Cui L (2002) Bridging tendon defects using autologous tenocyte engineered tendon in a hen model. Plast Reconstr Surg 110:1280–1289

    Article  PubMed  Google Scholar 

  8. Chan BP, Chan KM, Maffulli N, Webb S, Lee KK (1997) Effect of basic fibroblast growth factor. An in vitro study of tendon healing. Clin Orthop Relat Res 342:239–247

    Article  PubMed  Google Scholar 

  9. Chan BP, Fu SC, Qin L, Rolf C, Chan KM (2006) Supplementation-time dependence of growth factors in promoting tendon healing. Clin Orthop Relat Res 448:240–247

    Article  CAS  PubMed  Google Scholar 

  10. Chang J, Most D, Stelnicki E, Siebert JW, Longaker MT, Hui K, Lineaweaver WC (1997) Gene expression of transforming growth factor beta-1 in rabbit zone II flexor tendon wound healing: evidence for dual mechanisms of repair. Plast Reconstr Surg 100:937–944

    Article  CAS  PubMed  Google Scholar 

  11. Chang J, Most D, Thunder R, Mehrara B, Longaker MT, Lineaweaver WC (1998) Molecular studies in flexor tendon wound healing: the role of basic fibroblast growth factor gene expression. J Hand Surg Am 23:1052–1058

    Article  CAS  PubMed  Google Scholar 

  12. Chang J, Thunder R, Most D, Longaker MT, Lineaweaver WC (2000) Studies in flexor tendon wound healing: neutralizing antibody to TGF-beta1 increases postoperative range of motion. Plast Reconstr Surg 105:148–155

    Article  CAS  PubMed  Google Scholar 

  13. Dohan Ehrenfest DM, Rasmusson L, Albrektsson T (2009) Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF). Trends Biotechnol 27:158–167

    Article  CAS  PubMed  Google Scholar 

  14. Erlacher L, McCartney J, Piek E, ten Dijke P, Yanagishita M, Oppermann H, Luyten FP (1998) Cartilage-derived morphogenetic proteins and osteogenic protein-1 differentially regulate osteogenesis. J Bone Miner Res 13:383–392

    Article  CAS  PubMed  Google Scholar 

  15. Forslund C, Aspenberg P (2003) Improved healing of transected rabbit Achilles tendon after a single injection of cartilage-derived morphogenetic protein-2. Am J Sports Med 31:555–559

    PubMed  Google Scholar 

  16. Goldfarb CA, Harwood F, Silva MJ, Gelberman RH, Amiel D, Boyer MI (2001) The effect of variations in applied rehabilitation force on collagen concentration and maturation at the intrasynovial flexor tendon repair site. J Hand Surg Am 26:841–846

    Article  CAS  PubMed  Google Scholar 

  17. Grotendorst GR (1988) Growth factors as regulators of wound repair. Int J Tissue React 10:337–344

    CAS  PubMed  Google Scholar 

  18. Heisterbach PE, Todorov A, Flückiger R, Evans CH, Majewski M (2012) Effect of BMP-12, TGF-β1 and autologous conditioned serum on growth factor expression in Achilles tendon healing. Knee Surg Sports Traumatol Arthrosc 20:1907–1914

    Article  PubMed  Google Scholar 

  19. He Q, Li Q, Chen B, Wang Z (2002) Repair of flexor tendon defects of rabbit with tissue engineering method. Chin J Traumatol 5:200–208

    PubMed  Google Scholar 

  20. Hogan MV, Bagayoko N, James R, Starnes T, Katz A, Chhabra AB (2011) Tissue engineering solutions for tendon repair. J Am Acad Orthop Surg 19:134–142

    PubMed  Google Scholar 

  21. Ide J, Kikukawa K, Hirose J, Iyama K, Sakamoto H, Mizuta H (2009) The effects of fibroblast growth factor-2 on rotator cuff reconstruction with acellular dermal matrix grafts. Arthroscopy 25:608–616

    Article  PubMed  Google Scholar 

  22. Ingraham JM, Weber RA, Childs EW (2011) Intrinsic tendon healing requires the recycling of tendon collagen fibril segments. J Hand Surg Eur 36:154–155

    Article  CAS  Google Scholar 

  23. Joshi SM, Mastrangelo AN, Magarian EM, Fleming BC, Murray MM (2009) Collagen-platelet composite enhances biomechanical and histologic healing of the porcine anterior cruciate ligament. Am J Sports Med 37:2401–2410

    Article  PubMed Central  PubMed  Google Scholar 

  24. Klein MB, Yalamanchi N, Pham H, Longaker MT, Chang J (2002) Flexor tendon healing in vitro: effects of TGF-beta on tendon cell collagen production. J Hand Surg Am 27:615–620

    Article  PubMed  Google Scholar 

  25. Kovacevic D, Rodeo SA (2008) Biological augmentation of rotator cuff tendon repair. Clin Orthop Relat Res 466:622–633

    Article  PubMed Central  PubMed  Google Scholar 

  26. Lou J, Tu Y, Burns M, Silva MJ, Manske P (2001) BMP-12 gene transfer augmentation of lacerated tendon repair. J Orthop Res 19:1199–1202

    Article  CAS  PubMed  Google Scholar 

  27. Maeda E, Shelton JC, Bader DL, Lee DA (2009) Differential regulation of gene expression in isolated tendon fascicles exposed to cyclic tensile strain in vitro. J Appl Physiol 106:506–512

    Article  CAS  PubMed  Google Scholar 

  28. Majewski M, Betz O, Ochsner PE, Liu F, Porter RM, Evans CH (2008) Ex vivo adenoviral transfer of bone morphogenetic protein 12 (BMP-12) cDNA improves Achilles tendon healing in a rat model. Gene Ther 15:1139–1146

    Article  CAS  PubMed  Google Scholar 

  29. Majewski M, Schaeren S, Kohlhaas U, Ochsner PE (2008) Postoperative rehabilitation after percutaneous Achilles tendon repair: early functional therapy versus cast immobilization. Disabil Rehabil 30:1726–1732

    Article  CAS  PubMed  Google Scholar 

  30. Majewski M, Ochsner PE, Liu F, Flückiger R, Evans CH (2009) Accelerated healing of the rat Achilles tendon in response to autologous conditioned serum. Am J Sports Med 37:2117–2125

    Article  PubMed  Google Scholar 

  31. Majewski M, Porter RM, Betz OB, Betz VM, Clahsen H, Flückiger R, Evans CH (2012) Improvement of tendon repair using muscle grafts transduced with TGF-β1 cDNA. Eur Cell Mater 23:94–101 Discussion 101–102

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Manning CN, Schwartz AG, Liu W, Xie J, Havlioglu N, Sakiyama-Elbert SE, Silva MJ, Xia Y, Gelberman RH, Thomopoulos S (2013) Controlled delivery of mesenchymal stem cells and growth factors using a nanofiber scaffold for tendon repair. Acta Biomater 9:6905–6914

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Murray DH, Kubiak EN, Jazrawi LM, Araghi A, Kummer F, Loebenberg MI, Zuckerman JD (2007) The effect of cartilage-derived morphogenetic protein 2 on initial healing of a rotator cuff defect in a rat model. J Shoulder Elbow Surg 16:251–254

    Article  PubMed  Google Scholar 

  34. Nixon AJ, Dahlgren LA, Haupt JL, Yeager AE, Ward DL (2008) Effect of adipose-derived nucleated cell fractions on tendon repair in horses with collagenase-induced tendinitis. Am J Vet Res 69:928–937

    Article  CAS  PubMed  Google Scholar 

  35. Oliva F, Via AG, Maffulli N (2011) Role of growth factors in rotator cuff healing. Sports Med Arthrosc 19:218–226

    Article  PubMed  Google Scholar 

  36. Pelinkovic D, Lee JY, Engelhardt M, Rodosky M, Cummins J, Fu FH, Huard J (2003) Muscle cell-mediated gene delivery to the rotator cuff. Tissue Eng 9:143–151

    Article  CAS  PubMed  Google Scholar 

  37. Qi J, Dmochowski JM, Banes AN, Tsuzaki M, Bynum D, Patterson M, Creighton A, Gomez S, Tech K, Cederlund A, Banes AJ (2012) Differential expression and cellular localization of novel isoforms of the tendon biomarker tenomodulin. J Appl Physiol 113:861–871

    Article  CAS  PubMed  Google Scholar 

  38. Rumian AP, Draper ER, Wallace AL, Goodship AE (2009) The influence of the mechanical environment on remodelling of the patellar tendon. J Bone Joint Surg Br 91:557–564

    Article  CAS  PubMed  Google Scholar 

  39. Serhan CN, Savill J (2005) Resolution of inflammation: the beginning programs the end. Nat Immunol 6:1191–1197

    Article  CAS  PubMed  Google Scholar 

  40. Sharma P, Maffulli N (2005) The future: rehabilitation, gene therapy, optimization of healing. Foot Ankle Clin 10:383–397

    Article  PubMed  Google Scholar 

  41. Sharma P, Maffulli N (2006) Biology of tendon injury: healing, modeling and remodeling. J Musculoskelet Neuronal Interact 6:181–190

    CAS  PubMed  Google Scholar 

  42. Skutek M, van Griensven M, Zeichen J, Brauer N, Bosch U (2001) Cyclic mechanical stretching modulates secretion pattern of growth factors in human tendon fibroblasts. Eur J Appl Physiol 86:48–52

    Article  CAS  PubMed  Google Scholar 

  43. Trippel SB, Wroblewski J, Makower AM, Whelan MC, Schoenfeld D, Doctrow SR (1993) Regulation of growth-plate chondrocytes by insulin-like growth-factor I and basic fibroblast growth factor. J Bone Joint Surg Am 75:177–189

    CAS  PubMed  Google Scholar 

  44. Tsuzaki M, Brigman BE, Yamamoto J, Lawrence WT, Simmons JG, Mohapatra NK, Lund PK, Van Wyk J, Hannafin JA, Bhargava MM, Banes AJ (2000) Insulin-like growth factor-I is expressed by avian flexor tendon cells. J Orthop Res 18:546–556

    Article  CAS  PubMed  Google Scholar 

  45. Uggen JC, Dines J, Uggen CW, Mason JS, Razzano P, Dines D, Grande DA (2005) Tendon gene therapy modulates the local repair environment in the shoulder. J Am Osteopath Assoc 105:20–21

    PubMed  Google Scholar 

  46. Uysal CA, Tobita M, Hyakusoku H, Mizuno H (2012) Adipose-derived stem cells enhance primary tendon repair: biomechanical and immunohistochemical evaluation. J Plast Reconstr Aesthet Surg 65:1712–1719

    Article  PubMed  Google Scholar 

  47. de Vos RJ, Weir A, van Schie HT, Bierma-Zeinstra SM, Verhaar JA, Weinans H, Tol JL (2010) Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA 303:144–149

    Article  PubMed  Google Scholar 

  48. Wang XT, Liu PY, Tang JB (2005) Tendon healing in vitro: modification of tenocytes with exogenous vascular endothelial growth factor gene increases expression of transforming growth factor beta but minimally affects expression of collagen genes. J Hand Surg Am 30:222–229

    Article  PubMed  Google Scholar 

  49. Watts AE, Yeager AE, Kopyov OV, Nixon AJ (2011) Fetal derived embryonic-like stem cells improve healing in a large animal flexor tendonitis model. Stem Cell Res Ther 2:4

    Article  PubMed Central  PubMed  Google Scholar 

  50. Würgler-Hauri CC, Dourte LM, Baradet TC, Williams GR, Soslowsky LJ (2007) Temporal expression of 8 growth factors in tendon-to-bone healing in a rat supraspinatus model. J Shoulder Elbow Surg 16:S198–S203

    Article  PubMed Central  PubMed  Google Scholar 

  51. Young RG, Butler DL, Weber W, Caplan AI, Gordon SL, Fink DJ (1998) Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair. J Orthop Res 16:406–413

    Article  CAS  PubMed  Google Scholar 

  52. Zhang F, Liu H, Stile F, Lei MP, Pang Y, Oswald TM, Beck J, Dorsett-Martin W, Lineaweaver WC (2003) Effect of vascular endothelial growth factor on rat Achilles tendon healing. Plast Reconstr Surg 112:1613–1619

    Article  PubMed  Google Scholar 

  53. Zhang J, Wang JH (2010) Mechanobiological response of tendon stem cells: implications of tendon homeostasis and pathogenesis of tendinopathy. J Orthop Res 28:639–643

    PubMed  Google Scholar 

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Correspondence to Sebastian A. Müller.

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Müller, S.A., Todorov, A., Heisterbach, P.E. et al. Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering. Knee Surg Sports Traumatol Arthrosc 23, 2097–2105 (2015). https://doi.org/10.1007/s00167-013-2680-z

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