Engineered stem cell niche matrices for rotator cuff tendon regenerative engineering

Abstract

Rotator cuff (RC) tears represent a large proportion of musculoskeletal injuries attended to at the clinic and thereby make RC repair surgeries one of the most widely performed musculoskeletal procedures. Despite the high incidence rate of RC tears, operative treatments have provided minimal functional gains and suffer from high re-tear rates. The hypocellular nature of tendon tissue poses a limited capacity for regeneration. In recent years, great strides have been made in the area of tendonogenesis and differentiation towards tendon cells due to a greater understanding of the tendon stem cell niche, development of advanced materials, improved scaffold fabrication techniques, and delineation of the phenotype development process. Though in vitro models for tendonogenesis have shown promising results, in vivo models have been less successful. The present work investigates structured matrices mimicking the tendon microenvironment as cell delivery vehicles in a rat RC tear model. RC injuries augmented with a matrix delivering rat mesenchymal stem cells (rMSCs) showed enhanced regeneration over suture repair alone or repair with augmentation, at 6 and 12-weeks post-surgery. The local delivery of rMSCs led to increased mechanical properties and improved tissue morphology. We hypothesize that the mesenchymal stem cells function to modulate the local immune and bioactivity environment through autocrine/paracrine and/or cell homing mechanisms. This study provides evidence for improved tendon healing with biomimetic matrices and delivered MSCs with the potential for translation to larger, clinical animal models. The enhanced regenerative healing response with stem cell delivering biomimetic matrices may represent a new treatment paradigm for massive RC tendon tears.

Biologics and stem cell‐based therapies for rotator cuff repair

“…Differentiation can be carried out in vitro to create an engineered tendon/enthesis construct prior to implantation, or naive MSCs can be delivered within a biomimetic matrix to promote the proper cell fate in situ . Commonly used scaffolds for rotator cuff include electrospun fibers, xenograft tendon scaffolds, or hydrogels (typically fibrin or type I collagen gels) . 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.…”

“…[116][117][118][119] Commonly used scaffolds for rotator cuff include electrospun fibers, xenograft tendon scaffolds, or hydrogels (typically fibrin or type I collagen gels). 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.…”

“…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.…”

“…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. 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.…”

Insulin immobilized PCL‐cellulose acetate micro‐nanostructured fibrous scaffolds for tendon tissue engineering

“…In a clinical setting, matrices can act as delivery vehicles for cells and biochemical factors. Electrospun fiber matrices are popular and suitable scaffolds for tendon applications, due to their biomimicry to fibers found in natural extracellular matrix (ECM), high surface to volume ratio, and ease of fabrication …”