Special issue on rotator cuff biology and healing
Cell- and gene-based approaches to tendon regeneration

https://doi.org/10.1016/j.jse.2011.11.015Get rights and content

Repair of rotator cuff tears in experimental models has been significantly improved by the use of enhanced biologic approaches, including platelet-rich plasma, bone marrow aspirate, growth factor supplements, and cell- and gene-modified cell therapy. Despite added complexity, cell-based therapies form an important part of enhanced repair, and combinations of carrier vehicles, growth factors, and implanted cells provide the best opportunity for robust repair. Bone marrow–derived mesenchymal stem cells provide a stimulus for repair in flexor tendons, but application in rotator cuff repair has not shown universally positive results. The use of scaffolds such as platelet-rich plasma, fibrin, and synthetic vehicles and the use of gene priming for stem cell differentiation and local anabolic and anti-inflammatory impact have both provided essential components for enhanced tendon and tendon-to-bone repair in rotator cuff disruption. Application of these research techniques in human rotator cuff injury has generally been limited to autologous platelet-rich plasma, bone marrow concentrate, or bone marrow aspirates combined with scaffold materials. Cultured mesenchymal progenitor therapy and gene-enhanced function have not yet reached clinical trials in humans. Research in several animal species indicates that the concept of gene-primed stem cells, particularly embryonic stem cells, combined with effective culture conditions, transduction with long-term integrating vectors carrying anabolic growth factors, and development of cells conditioned by use of RNA interference gene therapy to resist matrix metalloproteinase degradation, may constitute potential advances in rotator cuff repair. This review summarizes cell- and gene-enhanced cell research for tendon repair and provides future directions for rotator cuff repair using biologic composites.

Section snippets

Tendon healing

Healing of the rotator cuff or flexor tendons in most locations goes through the traditional phases of an initial inflammatory response, characterized by acute inflammation, with accumulation of hemorrhage and leukocytes, local synthesis of bioactive and chemotactic factors, and the stimulation of angiogenesis.53 These culminate in the initiation of tenocyte proliferation, migration of tenocytes into the wound, and an increased synthesis of collagen and vascular structures to form immature

Treatment methods

Depending on the results of physical examination, radiographs, and magnetic resonance imaging (MRI) examination, initial therapy is often nonsurgical, including rest and modifications to shoulder action, and use of nonsteroidal anti-inflammatory drugs. This if often followed by corticosteroid injections, physical therapy, and surface-acting agents, such as extracorporeal shockwave therapy, pulsed magnetic therapy, laser phototherapy, deep ultrasound therapy, and muscle stimulation. Failures in

Current strategies for rotator cuff repair

Primary repair of rotator cuff injury often results in inadequate strength of the repair or limited mobility. Cell implantation, growth factor injections or depot composites, and gene-enhanced cell therapy aim to improve the quality and mechanical function of rotator cuff repair. Relying on native intrinsic and extrinsic repair systems lends itself well to augmented repair with biologic scaffolds with or without the addition of growth factors.53, 61, 62

Future directions

Repair of Achilles tendon rupture and rotator cuff tears in experimental models has been significantly improved by the use of enhanced biologic approaches. Most evidence indicates that cultured bone marrow–derived MSCs will not be particularly useful as a standalone supplement to debridement and suture repair of the affected tendon at the tendon-bone interface. The use of a scaffold as a carrier vehicle, as well as the use of stem cells as transport vectors for local anabolic and

Disclaimer

The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.

References (147)

  • A.J. Friedenstein

    Precursor cells of mechanocytes

    Int Rev Cytol

    (1976)
  • R. James et al.

    Tendon: biology, biomechanics, repair, growth factors, and evolving treatment options

    J Hand Surg Am

    (2008)
  • P. Kebriaei et al.

    Treatment of graft-versus-host-disease with mesenchymal stromal cells

    Cytotherapy

    (2011)
  • H.M. Kim et al.

    Technical and biological modifications for enhanced flexor tendon repair

    J Hand Surg Am

    (2010)
  • J. Lou et al.

    BMP-12 gene transfer augmentation of lacerated tendon repair

    J Orthop Res

    (2001)
  • T. Majima et al.

    Alginate and chitosan polyion complex hybrid fibers for scaffolds in ligament and tendon tissue engineering

    J Orthop Sci

    (2005)
  • V. Mehta et al.

    Characterization of adenovirus-mediated gene transfer in rabbit flexor tendons

    J Hand Surg Am

    (2005)
  • T. Meyerrose et al.

    Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors

    Adv Drug Deliv Rev

    (2010)
  • H.A. Awad et al.

    Autologous mesenchymal stem cell-mediated repair of tendon

    Tissue Eng

    (1999)
  • A. Bedi et al.

    Doxycycline-mediated inhibition of matrix metalloproteinases improves healing after rotator cuff repair

    Am J Sports Med

    (2010)
  • M.E. Bernardo et al.

    Mesenchymal stromal cells

    Ann N Y Acad Sci

    (2009)
  • W. Bi et al.

    Sox9 is required for cartilage formation

    Nat Genet

    (1999)
  • P. Bolt et al.

    BMP-14 gene therapy increases tendon tensile strength in a rat model of Achilles tendon injury

    J Bone Joint Surg Am

    (2007)
  • D.L. Butler et al.

    The use of mesenchymal stem cells in collagen-based scaffolds for tissue-engineered repair of tendons

    Nat Protoc

    (2010)
  • D.L. Butler et al.

    Functional tissue engineering for tendon repair: a multidisciplinary strategy using mesenchymal stem cells, bioscaffolds, and mechanical stimulation

    J Orthop Res

    (2008)
  • D. Cao et al.

    In vitro tendon engineering with avian tenocytes and polyglycolic acids: a preliminary report

    Tissue Eng

    (2006)
  • Y. Cao et al.

    Bridging tendon defects using autologous tenocyte engineered tendon in a hen model

    Plast Reconstr Surg

    (2002)
  • A.I. Caplan

    Adult mesenchymal stem cells for tissue engineering versus regenerative medicine

    J Cell Physiol

    (2007)
  • A.I. Caplan

    Mesenchymal stem cells

    J Orthop Res

    (1991)
  • A.I. Caplan et al.

    Mesenchymal stem cells as trophic mediators

    J Cell Biochem

    (2006)
  • R. Castricini et al.

    Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial

    Am J Sports Med

    (2011)
  • C.H. Chang et al.

    Rotator cuff repair with periosteum for enhancing tendon-bone healing: a biomechanical and histological study in rabbits

    Knee Surg Sports Traumatol Arthrosc

    (2009)
  • J. Chang et al.

    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

    (1997)
  • J. Chang et al.

    Studies in flexor tendon wound healing: neutralizing antibody to TGF-beta1 increases postoperative range of motion

    Plast Reconstr Surg

    (2000)
  • C.H. Chen et al.

    Enhancement of rotator cuff tendon-bone healing with injectable periosteum progenitor cells-BMP-2 hydrogel in vivo

    Knee Surg Sports Traumatol Arthrosc

    (2011)
  • E.V. Cheung et al.

    Strategies in biologic augmentation of rotator cuff repair: a review

    Clin Orthop Relat Res

    (2010)
  • A.K. Chong et al.

    Bone marrow-derived mesenchymal stem cells influence early tendon-healing in a rabbit Achilles tendon model

    J Bone Joint Surg Am

    (2007)
  • M.L. da Silva et al.

    In search of the in vivo identity of mesenchymal stem cells

    Stem Cells

    (2008)
  • M.L. da Silva et al.

    MSC frequency correlates with blood vessel density in equine adipose tissue

    Tissue Eng Part A

    (2009)
  • B. Delorme et al.

    Culture and characterization of human bone marrow mesenchymal stem cells

    Methods Mol Med

    (2007)
  • B. Delorme et al.

    Specific lineage-priming of bone marrow mesenchymal stem cells provides the molecular framework for their plasticity

    Stem Cells

    (2009)
  • Ellera Gomes JL, da Silva RC, Silla LM, Abreu MR, Pellanda R. Conventional rotator cuff repair complemented by the aid...
  • D.D. Frisbie et al.

    Evaluation of adipose-derived stromal vascular fraction or bone marrow-derived mesenchymal stem cells for treatment of osteoarthritis

    J Orthop Res

    (2009)
  • T. Funakoshi et al.

    Application of tissue engineering techniques for rotator cuff regeneration using a chitosan-based hyaluronan hybrid fiber scaffold

    Am J Sports Med

    (2005)
  • T.G. Gerich et al.

    Gene transfer to the rabbit patellar tendon: potential for genetic enhancement of tendon and ligament healing

    Gene Ther

    (1996)
  • A. Giordano et al.

    From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells

    J Cell Physiol

    (2007)
  • E.E. Godwin et al.

    Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon

    Equine Vet J

    (2012)
  • A.H. Gomoll et al.

    Rotator cuff disorders: recognition and management among patients with shoulder pain

    Arthritis Rheum

    (2004)
  • M. Gott et al.

    Tendon phenotype should dictate tissue engineering modality in tendon repair: a review

    Discov Med

    (2011)
  • D.J. Guest et al.

    Equine embryonic stem-like cells and mesenchymal stromal cells have different survival rates and migration patterns following their injection into damaged superficial digital flexor tendon

    Equine Vet J

    (2010)
  • Cited by (78)

    • Gene delivery into cells and tissues

      2020, Principles of Tissue Engineering
    • Gold nanoparticles for the in situ polymerization of near-infrared responsive hydrogels based on fibrin

      2019, Acta Biomaterialia
      Citation Excerpt :

      Fibrin scaffolds have also been employed as three-dimensional matrices containing growth factors and embryonic stem cells prone to differentiate into neurons in animal models of spinal cord injury [18]. Tendon regeneration and bone-tendon junction repair have also been accelerated in animal models after the application of mesenchymal stem cells engrafted in fibrin matrices [19]. Accelerated healing of acute and chronic non-healing cutaneous wounds has been achieved in patients treated with fibrin-based sprays containing autologous mesenchymal stem cells [20].

    View all citing articles on Scopus

    Institutional review board: not applicable (review article).

    View full text