Regional SDF-1α Delivery to Injured Rotator Cuff Muscle Causes Localized Changes in Inflammatory Cell Response

Abstract Purpose Following rotator cuff tendon injury, the corresponding muscle undergoes degeneration, which has been found to occur asymmetrically. Thus, the goals of this study were 1) to develop an injection strategy for spatially localized Stromal-Derived Factor 1α (SDF-1α) loaded fragment delivery to two muscle regions in a rat model of severe rotator cuff tear and 2) to determine the degree of spatial cellular recruitment and subsequent muscle healing in response to these localized injections. Methods Hydrolytically-degradable heparin-containing hydrogel fragments were optimized for sustained release of SDF-1α over 7 + days in vivo. Fragments were then injected into either the muscle near the myotendinous junction (MTJ) or the muscle belly (MB) region of injured supraspinatus muscle. The presence of inflammatory cells (neutrophils, macrophage and T cell subsets) and stem cells (fibroadipogenic progenitor cells, satellite cells, mesenchymal stromal cells) in each region was assessed via flow cytometry 3- and 7-days following treatment. Muscle tissue was evaluated via immunohistochemical staining for regenerating muscle fibers (eMHC), fibrosis (collagen) and fatty infiltration (perilipin) 7 days post treatment. Results/Conclusion Delivery of SDF-1α to injured rotator cuff muscle caused alterations in the amount of adaptive and innate immune cells and stem cells, and resulted in increased muscle regeneration in the MTJ region. Regional differences in cell populations observed after local treatment demonstrated the technical feasibility of spatial material delivery and subsequent spatial cell recruitment in injured muscle. Thus, localized delivery using this biomaterial platform may be a useful tool to probe the effects of regional cell recruitment in spatially-complex orthopaedic injuries. Lay Summary We developed a spatially targeted injection strategy to study regional treatment effects in injured rotator cuff muscle. Our hydrogel delivery system provides sustained SDF-1α release over 10 days in vivo. Cellular analysis suggests that localized SDF-1α delivery modulates immune responses in both adaptive and innate cells. Regional variations in cell populations following treatment highlight the feasibility of spatial material delivery and targeted cell recruitment. However, spatial SDF-1α delivery did not induce regional differences in early muscle regeneration, despite these variations in cell populations. This approach offers a customizable platform for investigating regional tissue responses and developing treatments for complex injuries.