Tissue-Engineered Tendon for Enthesis Regeneration in a Rat Rotator Cuff Model

Abstract

Healing of rotator cuff (RC) injuries with current suture or augmented scaffold techniques fails to regenerate the enthesis and instead forms a weaker fibrovascular scar that is prone to subsequent failure. Regeneration of the enthesis is the key to improving clinical outcomes for RC injuries. We hypothesized that the utilization of our tissue-engineered tendon to repair either an acute or a chronic full-thickness supraspinatus tear would regenerate a functional enthesis and return the biomechanics of the tendon back to that found in native tissue. Engineered tendons were fabricated from bone marrow-derived mesenchymal stem cells utilizing our well-described fabrication technology. Forty-three rats underwent unilateral detachment of the supraspinatus tendon followed by acute (immediate) or chronic (4 weeks retracted) repair by using either our engineered tendon or a trans-osseous suture technique. Animals were sacrificed at 8 weeks. Biomechanical and histological analyses of the regenerated enthesis and tendon were performed. Statistical analysis was performed by using a one-way analysis of variance with significance set at p < 0.05. Acute repairs using engineered tendon had improved enthesis structure and lower biomechanical failures compared with suture repairs. Chronic repairs with engineered tendon had a more native-like enthesis with increased fibrocartilage formation, reduced scar formation, and lower biomechanical failure compared with suture repair. Thus, the utilization of our tissue-engineered tendon showed improve enthesis regeneration and improved function in chronic RC repairs compared with suture repair. Clinical Significance: Our engineered tendon construct shows promise as a clinically relevant method for repair of RC injuries.

Biologics and stem cell‐based therapies for rotator cuff repair

“…Finally, immediate repair after laceration also does not mimic the clinical scenario in which tendon tears are usually left untreated for weeks or months prior to repair. To model delayed repair, a few groups recently carried out supraspinatus tendon detachment followed by surgical repair 3–16 weeks later . Prolonged unloading resulted in tendon retraction, muscle atrophy, fatty infiltration, and fibrotic scarring.…”

“…While MSCs delivered within such carriers generally showed some positive indicators of improved healing (such as improved histology, fibrocartilage deposition, or expression of enthesis markers), functional outcomes have been mixed. Although some studies reported improved mechanical properties, others observed no differences relative to carrier or suture controls by the final timepoint . An alternative strategy to direct differentiation is transduction of transcription factors that may induce a tenogenic cell fate, such as the transcription factors Scx or Mkx .…”

“…To model delayed repair, a few groups recently carried out supraspinatus tendon detachment followed by surgical repair 3-16 weeks later. 34,[42][43][44][45][46][47] Prolonged unloading resulted in tendon retraction, muscle atrophy, fatty infiltration, and fibrotic scarring. Despite eventual repair, these studies generally suggested that the pathological events associated with unloading cannot be reversed by simple reattachment.…”

“…43,59,[120][121][122][123] The use of a carrier vehicle is advantageous since it ensures proper localization of delivered cells; the environment provided by the scaffolds has the additional potential to improve host cell proliferation or differentiation. While MSCs delivered within such carriers generally showed some positive indicators of improved healing (such as improved histology, fibrocartilage deposition, or expression of enthesis markers), 46,120,122 functional outcomes have been mixed. Although some studies reported improved mechanical properties, 120,123 others observed no differences relative to carrier or suture controls by the final timepoint.…”

“…Although some studies reported improved mechanical properties, 120,123 others observed no differences relative to carrier or suture controls by the final timepoint. 39,46,121 An alternative strategy to direct differentiation is transduction of transcription factors that may induce a tenogenic cell fate, such as the transcription factors Scx or Mkx. 71,124,125 For rotator cuff, bMSCs transduced with Scx improved fibrocartilage and mechanical outcomes after acute injury (compared to naive bMSCs), suggesting that delivery of tenogenic cells may have greater therapeutic value relative to naive stem cells.…”