Rotator cuff tears are common musculotendinous injuries with a high risk of permanent functional disability. Following surgical repair, sub-optimal patient outcomes are directly correlated with poor muscle quality
namely, injury site fatty infiltration, fibrosis, and muscle atrophy. Muscle resident fibro-adipogenic progenitor cells (FAPs) have been identified as key regulators of post-injury skeletal muscle regeneration and repair by maintaining a pro-myogenic environment. In this work, human FAPs (hFAPs) were encapsulated into hyaluronic acid (HyA)-based hydrogels functionalized with bsp-RGD(15) cell adhesion peptide, heparin, and a matrix metalloproteinase (MMP)-cleavable crosslinker. Hydrogel-encapsulated hFAPs increased expression of the pro-myogenic marker UCP1 and production of the anti-inflammatory cytokine IL-10 while downregulating the expression of the fibrotic marker αSMA over time. A murine model of unilateral rotator cuff transection, denervation, and delayed repair was treated with the HyA hydrogel or PBS and compared to a contralateral, non-injured control limb. Muscle histology 6 weeks post-repair revealed that the hydrogel reduced fibrosis, FI, and muscle atrophy while supporting vascularization of the injured tissue region. Collectively, these results suggest that the HyA hydrogel alone can promote muscle regeneration in a clinically relevant delayed repair model of rotator cuff tear, which is hypothesized due to controlled FAP differentiation into pro-myogenic lineages.