Skip to main content

Advertisement

Log in

Biologics in Achilles tendon healing and repair: a review

  • Biological Adjuvants in Orthopedic Surgery (J Dines and D Grande, Section Editors)
  • Published:
Current Reviews in Musculoskeletal Medicine Aims and scope Submit manuscript

Abstract

Injuries of the Achilles tendon are relatively common with potentially devastating outcomes. Healing Achilles tendons form a fibrovascular scar resulting in a tendon which may be mechanically weaker than the native tendon. The resulting strength deficit causes a high risk for reinjury and other complications. Treatments using biologics aim to restore the normal properties of the native tendon and reduce the risk of rerupture and maximize tendon function. The purpose of this review was to summarize the current findings of various therapies using biologics in an attempt to improve the prognosis of Achilles tendon ruptures and tendinopathies. A PubMed search was performed using specific search terms. The search was open for original manuscripts and review papers limited to publication within the last 10 years. From these searches, papers were included in the review if they investigated the effects of biological augmentation on Achilles tendon repair or healing. Platelet-rich plasma may assist in the healing process of Achilles tendon ruptures, while the evidence to support its use in the treatment of chronic Achilles tendinopathies remains insufficient. The use of growth factors such as hepatocyte growth factor, recombinant human platelet-derived growth factor-BB, interleukin-6, and transforming growth factor beta as well as several bone morphogenetic proteins have shown promising results for Achilles tendon repair. In vitro and preclinical studies have indicated the potential effectiveness of bone marrow aspirate as well. Stem cells also have positive effects on Achilles tendon healing, particularly during the early phases. Polyhydroxyalkanoates (PHA), decellularized tendon tissue, and porcine small intestinal submucosa (SIS) are biomaterials which have shown promising results as scaffolds used in Achilles tendon repair. The application of biological augmentation techniques in Achilles tendon repair appears promising; however, several techniques require further investigation to evaluate their clinical application.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Adams Jr SB et al. Stem cell-bearing suture improves Achilles tendon healing in a rat model. Foot Ankle Int. 2014;35(3):293–9.

    Article  PubMed  Google Scholar 

  2. Andersen MB et al. Interleukin-6: a growth factor stimulating collagen synthesis in human tendon. J Appl Physiol (1985). 2011;110(6):1549–54.

    Article  CAS  Google Scholar 

  3. Aspenberg P. Stimulation of tendon repair: mechanical loading, GDFs and platelets. A mini-review. Int Orthop. 2007;31(6):783–9.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Aspenberg P, Virchenko O. Platelet concentrate injection improves Achilles tendon repair in rats. Acta Orthop Scand. 2004;75(1):93–9.

    Article  PubMed  Google Scholar 

  5. Barber FA et al. A biomechanical study of Achilles tendon repair augmentation using GraftJacket matrix. Foot Ankle Int. 2008;29(3):329–33.

    Article  PubMed  Google Scholar 

  6. Beattie AJ et al. Chemoattraction of progenitor cells by remodeling extracellular matrix scaffolds. Tissue Eng Part A. 2009;15(5):1119–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Bolt P et al. BMP-14 gene therapy increases tendon tensile strength in a rat model of Achilles tendon injury. J Bone Joint Surg Am. 2007;89(6):1315–20.

    Article  PubMed  Google Scholar 

  8. Broese M et al. Seeding a human tendon matrix with bone marrow aspirates compared to previously isolated hBMSCs—an in vitro study. Technol Health Care. 2011;19(6):469–79.

    PubMed  Google Scholar 

  9. Chen JL et al. Efficacy of hESC-MSCs in knitted silk-collagen scaffold for tendon tissue engineering and their roles. Biomaterials. 2010;31(36):9438–51.

    Article  CAS  PubMed  Google Scholar 

  10. Chen L et al. Autologous platelet-rich clot releasate stimulates proliferation and inhibits differentiation of adult rat tendon stem cells towards nontenocyte lineages. J Int Med Res. 2012;40(4):1399–409.

    Article  CAS  PubMed  Google Scholar 

  11. Chong AK et al. Bone marrow-derived mesenchymal stem cells influence early tendon-healing in a rabbit Achilles tendon model. J Bone Joint Surg Am. 2007;89(1):74–81.

    Article  PubMed  Google Scholar 

  12. Cui Q et al. HGF inhibits TGF-beta1-induced myofibroblast differentiation and ECM deposition via MMP-2 in Achilles tendon in rat. Eur J Appl Physiol. 2011;111(7):1457–63.

    Article  CAS  PubMed  Google Scholar 

  13. Cummings SH et al. Effect of recombinant human platelet-derived growth factor-BB-coated sutures on Achilles tendon healing in a rat model: a histological and biomechanical study. J Tissue Eng. 2012;3(1):2041731412453577.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Daher RJ et al. Tendon repair augmented with a novel circulating stem cell population. Int J Clin Exp Med. 2011;4(3):214–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Dallaudiere B et al. Efficacy of intra-tendinous injection of platelet-rich plasma in treating tendinosis: comprehensive assessment of a rat model. Eur Radiol. 2013;23(10):2830–7.

    Article  PubMed  Google Scholar 

  16. de Jonge S et al. One-year follow-up of platelet-rich plasma treatment in chronic Achilles tendinopathy: a double-blind randomized placebo-controlled trial. Am J Sports Med. 2011;39(8):1623–9.

    Article  PubMed  Google Scholar 

  17. Dhillon MS et al. Orthobiologics and platelet rich plasma. Indian J Orthop. 2014;48(1):1–9.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Dines JS et al. The effect of growth differentiation factor-5-coated sutures on tendon repair in a rat model. J Shoulder Elbow Surg. 2007;16(5 Suppl):S215–221.

    Article  PubMed  Google Scholar 

  19. Farnebo S et al. Decellularized tendon-bone composite grafts for extremity reconstruction: an experimental study. Plast Reconstr Surg. 2014;133(1):79–89.

    Article  CAS  PubMed  Google Scholar 

  20. Ferrero G et al. Ultrasound-guided injection of platelet-rich plasma in chronic Achilles and patellar tendinopathy. J Ultrasound. 2012;15(4):260–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Filardo G et al. Nonoperative biological treatment approach for partial Achilles tendon lesion. Orthopedics. 2010;33(2):120–3.

    Article  PubMed  Google Scholar 

  22. Fortier LA et al. The role of growth factors in cartilage repair. Clin Orthop Relat Res. 2011;469(10):2706–15.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Gaweda K et al. Treatment of Achilles tendinopathy with platelet-rich plasma. Int J Sports Med. 2010;31(8):577–83.

    Article  CAS  PubMed  Google Scholar 

  24. Gilbert TW et al. Degradation and remodeling of small intestinal submucosa in canine Achilles tendon repair. J Bone Joint Surg Am. 2007;89(3):621–30.

    Article  PubMed  Google Scholar 

  25. Gott M et al. Tendon phenotype should dictate tissue engineering modality in tendon repair: a review. Discov Med. 2011;12(62):75–84.

    PubMed  Google Scholar 

  26. Guerquin MJ et al. Transcription factor EGR1 directs tendon differentiation and promotes tendon repair. J Clin Invest. 2013;123(8):3564–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Harris NL et al. The effect of platelet-rich plasma on normal soft tissues in the rabbit. J Bone Joint Surg Am. 2012;94(9):786–93.

    Article  PubMed  Google Scholar 

  28. Heisterbach PE et al. Effect of BMP-12, TGF-beta1 and autologous conditioned serum on growth factor expression in Achilles tendon healing. Knee Surg Sports Traumatol Arthrosc. 2012;20(10):1907–14.

    Article  PubMed  Google Scholar 

  29. Hou Y et al. Effects of transforming growth factor-beta1 and vascular endothelial growth factor 165 gene transfer on Achilles tendon healing. Matrix Biol. 2009;28(6):324–35.

    Article  CAS  PubMed  Google Scholar 

  30. Hou Y et al. The roles of TGF-beta1 gene transfer on collagen formation during Achilles tendon healing. Biochem Biophys Res Commun. 2009;383(2):235–9.

    Article  CAS  PubMed  Google Scholar 

  31. Huang TF et al. Mesenchymal stem cells from a hypoxic culture improve and engraft Achilles tendon repair. Am J Sports Med. 2013;41(5):1117–25.

    Article  PubMed  Google Scholar 

  32. Jelinsky SA et al. Treatment with rhBMP12 or rhBMP13 increase the rate and the quality of rat Achilles tendon repair. J Orthop Res. 2011;29(10):1604–12.

    Article  CAS  PubMed  Google Scholar 

  33. Ju YJ et al. Synovial mesenchymal stem cells accelerate early remodeling of tendon-bone healing. Cell Tissue Res. 2008;332(3):469–78.

    Article  PubMed  Google Scholar 

  34. Juncosa-Melvin N et al. Effects of cell-to-collagen ratio in stem cell-seeded constructs for Achilles tendon repair. Tissue Eng. 2006;12(4):681–9.

    Article  CAS  PubMed  Google Scholar 

  35. Kashiwagi K et al. Effects of transforming growth factor-beta 1 on the early stages of healing of the Achilles tendon in a rat model. Scand J Plast Reconstr Surg Hand Surg. 2004;38(4):193–7.

    Article  PubMed  Google Scholar 

  36. Kaux JF et al. Effects of platelet-rich plasma (PRP) on the healing of Achilles tendons of rats. Wound Repair Regen. 2012;20(5):748–56.

    Article  PubMed  Google Scholar 

  37. Keller TC et al. Growth/differentiation factor-5 modulates the synthesis and expression of extracellular matrix and cell-adhesion-related molecules of rat Achilles tendon fibroblasts. Connect Tissue Res. 2011;52(4):353–64.

    Article  CAS  PubMed  Google Scholar 

  38. Kessler MW et al. Enhancement of Achilles tendon repair mediated by matrix metalloproteinase inhibition via systemic administration of doxycycline. J Orthop Res. 2014;32(4):500–6.

    Article  CAS  PubMed  Google Scholar 

  39. Kim HJ et al. The role of transforming growth factor-beta and bone morphogenetic protein with fibrin glue in healing of bone-tendon junction injury. Connect Tissue Res. 2007;48(6):309–15.

    Article  CAS  PubMed  Google Scholar 

  40. Konerding MA et al. Impact of combinatory growth factor application on rabbit Achilles tendon injury with operative versus conservative treatment: a pilot study. Int J Mol Med. 2010;25(2):217–24.

    CAS  PubMed  Google Scholar 

  41. Kraus TM et al. Stem cells and basic fibroblast growth factor failed to improve tendon healing: an in vivo study using lentiviral gene transfer in a rat model. J Bone Joint Surg Am. 2014;96(9):761–9.

    Article  CAS  PubMed  Google Scholar 

  42. Lee DK. Achilles tendon repair with acellular tissue graft augmentation in neglected ruptures. J Foot Ankle Surg. 2007;46(6):451–5.

    Article  PubMed  Google Scholar 

  43. Lee DK. A preliminary study on the effects of acellular tissue graft augmentation in acute Achilles tendon ruptures. J Foot Ankle Surg. 2008;47(1):8–12.

    Article  PubMed  Google Scholar 

  44. Lohan A et al. Human hamstring tenocytes survive when seeded into a decellularized porcine Achilles tendon extracellular matrix. Connect Tissue Res. 2013;54(4–5):305–12.

    PubMed  Google Scholar 

  45. Lyras DN et al. The influence of platelet-rich plasma on angiogenesis during the early phase of tendon healing. Foot Ankle Int. 2009;30(11):1101–6.

    Article  PubMed  Google Scholar 

  46. Majewski M et al. Ex vivo adenoviral transfer of bone morphogenetic protein 12 (BMP-12) cDNA improves Achilles tendon healing in a rat model. Gene Ther. 2008;15(16):1139–46.

    Article  CAS  PubMed  Google Scholar 

  47. Majewski M et al. Improvement of tendon repair using muscle grafts transduced with TGF-beta1 cDNA. Eur Cell Mater. 2012;23:94–101. discussion 101–102.

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Mikic B et al. Achilles tendon characterization in GDF-7 deficient mice. J Orthop Res. 2006;24(4):831–41.

    Article  CAS  PubMed  Google Scholar 

  49. Monto RR. Platelet rich plasma treatment for chronic Achilles tendinosis. Foot Ankle Int. 2012;33(5):379–85.

    Article  PubMed  Google Scholar 

  50. Moraes VY et al. Platelet-rich therapies for musculoskeletal soft tissue injuries. Cochrane Database Syst Rev. 2014;4:Cd010071.

    PubMed  Google Scholar 

  51. Murawski CD et al. (2014) A single platelet-rich plasma injection for chronic midsubstance Achilles tendinopathy: a retrospective preliminary analysis. Foot Ankle Spec.

  52. Ning LJ et al. Preparation and characterization of decellularized tendon slices for tendon tissue engineering. J Biomed Mater Res A. 2012;100(6):1448–56.

    Article  PubMed  Google Scholar 

  53. Nirmalanandhan VS et al. Effect of scaffold material, construct length and mechanical stimulation on the in vitro stiffness of the engineered tendon construct. J Biomech. 2008;41(4):822–8.

    Article  PubMed  Google Scholar 

  54. Nourissat G et al. Mesenchymal stem cell therapy regenerates the native bone-tendon junction after surgical repair in a degenerative rat model. PLoS One. 2010;5(8):e12248.

    Article  PubMed Central  PubMed  Google Scholar 

  55. Okamoto N et al. Treating Achilles tendon rupture in rats with bone-marrow-cell transplantation therapy. J Bone Joint Surg Am. 2010;92(17):2776–84.

    Article  PubMed  Google Scholar 

  56. Owens Jr RF et al. Clinical and magnetic resonance imaging outcomes following platelet rich plasma injection for chronic midsubstance Achilles tendinopathy. Foot Ankle Int. 2011;32(11):1032–9.

    Article  PubMed  Google Scholar 

  57. Pelled G et al. Smad8/BMP2-engineered mesenchymal stem cells induce accelerated recovery of the biomechanical properties of the Achilles tendon. J Orthop Res. 2012;30(12):1932–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Pietschmann MF et al. Comparison of tenocytes and mesenchymal stem cells seeded on biodegradable scaffolds in a full-size tendon defect model. J Mater Sci Mater Med. 2013;24(1):211–20.

    Article  CAS  PubMed  Google Scholar 

  59. Rickert M et al. Adenovirus-mediated gene transfer of growth and differentiation factor-5 into tenocytes and the healing rat Achilles tendon. Connect Tissue Res. 2005;46(4–5):175–83.

    Article  CAS  PubMed  Google Scholar 

  60. Sadoghi P et al. The role of platelets in the treatment of Achilles tendon injuries. J Orthop Res. 2013;31(1):111–8.

    Article  CAS  PubMed  Google Scholar 

  61. Sarrafian TL et al. Comparison of Achilles tendon repair techniques in a sheep model using a cross-linked acellular porcine dermal patch and platelet-rich plasma fibrin matrix for augmentation. J Foot Ankle Surg. 2010;49(2):128–34.

    Article  PubMed  Google Scholar 

  62. Schepull T et al. Autologous platelets have no effect on the healing of human Achilles tendon ruptures: a randomized single-blind study. Am J Sports Med. 2011;39(1):38–47.

    Article  PubMed  Google Scholar 

  63. Schon LC et al. Efficacy of a mesenchymal stem cell loaded surgical mesh for tendon repair in rats. J Transl Med. 2014;12:110.

    Article  PubMed Central  PubMed  Google Scholar 

  64. Selek O et al. Mesenchymal stem cell application improves tendon healing via anti-apoptotic effect (animal study). Acta Orthop Traumatol Turc. 2014;48(2):187–95.

    Article  PubMed  Google Scholar 

  65. Shah V et al. Dose-response effect of an intra-tendon application of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in a rat Achilles tendinopathy model. J Orthop Res. 2013;31(3):413–20.

    Article  CAS  PubMed  Google Scholar 

  66. Smyth NA et al. Establishing proof of concept: platelet-rich plasma and bone marrow aspirate concentrate may improve cartilage repair following surgical treatment for osteochondral lesions of the talus. World J Orthop. 2012;3(7):101–8.

    Article  PubMed Central  PubMed  Google Scholar 

  67. Solchaga LA et al. Comparison of the effect of intra-tendon applications of recombinant human platelet-derived growth factor-BB, platelet-rich plasma, steroids in a rat Achilles tendon collagenase model. J Orthop Res. 2014;32(1):145–50.

    Article  CAS  PubMed  Google Scholar 

  68. Soomekh DJ. Current concepts for the use of platelet-rich plasma in the foot and ankle. Clin Podiatr Med Surg. 2011;28(1):155–70.

    Article  PubMed  Google Scholar 

  69. Suckow MA et al. Repair of experimental Achilles tenotomy with porcine renal capsule material in a rat model. J Mater Sci Mater Med. 2007;18(6):1105–10.

    Article  CAS  PubMed  Google Scholar 

  70. Suwalski A et al. Accelerated Achilles tendon healing by PDGF gene delivery with mesoporous silica nanoparticles. Biomaterials. 2010;31(19):5237–45.

    Article  CAS  PubMed  Google Scholar 

  71. Tang SW et al. Stringent requirement for spatial arrangement of extracellular matrix in supporting cell morphogenesis and differentiation. BMC Cell Biol. 2014;15:10.

    Article  PubMed Central  PubMed  Google Scholar 

  72. Tohidnezhad M et al. Platelet-released growth factors can accelerate tenocyte proliferation and activate the anti-oxidant response element. Histochem Cell Biol. 2011;135(5):453–60.

    Article  CAS  PubMed  Google Scholar 

  73. Uysal CA et al. Adipose-derived stem cells enhance primary tendon repair: biomechanical and immunohistochemical evaluation. J Plast Reconstr Aesthet Surg. 2012;65(12):1712–9.

    Article  PubMed  Google Scholar 

  74. Vannini F et al. Platelet-rich plasma for foot and ankle pathologies: a systematic review. Foot Ankle Surg. 2014;20(1):2–9.

    Article  CAS  PubMed  Google Scholar 

  75. Virchenko O et al. CDMP-2 injection improves early tendon healing in a rabbit model for surgical repair. Scand J Med Sci Sports. 2005;15(4):260–4.

    Article  CAS  PubMed  Google Scholar 

  76. Webb WR et al. The application of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) scaffolds for tendon repair in the rat model. Biomaterials. 2013;34(28):6683–94.

    Article  CAS  PubMed  Google Scholar 

  77. Wisbeck JM et al. Xenograft scaffold full-wrap reinforcement of Krackow Achilles tendon repair. Orthopedics. 2012;35(3):e331–334.

    PubMed  Google Scholar 

  78. Yao J et al. Viability and proliferation of pluripotential cells delivered to tendon repair sites using bioactive sutures—an in vitro study. J Hand Surg [Am]. 2011;36(2):252–8.

    Article  Google Scholar 

  79. Yeh LC et al. Bone morphogenetic protein-7 regulates differentially the mRNA expression of bone morphogenetic proteins and their receptors in rat Achilles and patellar tendon cell cultures. J Cell Biochem. 2008;104(6):2107–22.

    Article  CAS  PubMed  Google Scholar 

  80. Yin Z et al. The effect of decellularized matrices on human tendon stem/progenitor cell differentiation and tendon repair. Acta Biomater. 2013;9(12):9317–29.

    Article  CAS  PubMed  Google Scholar 

  81. Zantop T et al. Extracellular matrix scaffolds are repopulated by bone marrow-derived cells in a mouse model of Achilles tendon reconstruction. J Orthop Res. 2006;24(6):1299–309.

    Article  PubMed  Google Scholar 

  82. Zhang J et al. HGF mediates the anti-inflammatory effects of PRP on injured tendons. PLoS One. 2013;8(6):e67303.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Each author certifies that he or she has no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Daniel Grande.

Additional information

This article is part of the Topical Collection on Biological Adjuvants in Orthopedic Surgery

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shapiro, E., Grande, D. & Drakos, M. Biologics in Achilles tendon healing and repair: a review. Curr Rev Musculoskelet Med 8, 9–17 (2015). https://doi.org/10.1007/s12178-015-9257-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12178-015-9257-z

Keywords

Navigation