PROJECT SUMMARY Complete rotator cuff tears are a debilitating tendon injury that result in the atrophy and fatty degeneration of the corresponding muscle. Clinical outcomes following treatment of rotator cuff injuries are directly related to the quality of the rotator cuff muscle. Therefore, methods to reverse degenerative changes in the muscle would greatly improve overall outcomes for patients with rotator cuff tears. Due to the key relation between endogenous cell recruitment and tissue healing found in other types of muscle injury, we believe that the co-delivery of both stromal derived factor 1α (SDF-1α) and tumor necrosis factor-stimulated gene-6 (TSG-6) from glycosaminoglycan-based carriers tailored for each molecule will create a microenvironment in the rotator cuff muscle that will encourage recruitment and engraftment of anti-inflammatory macrophages and MSCs and therefore promote muscle regeneration after rotator cuff tendon tears. The objective of this application is to determine the relationship between local engraftment of bone marrow-derived cells and the level of regeneration of rotator cuff muscle after surgical repair of the torn tendon. This objective will be approached through the following specific aims: 1) Evaluate the effects of sustained release of SDF-1α on local cell recruitment and tissue regeneration in the rat supraspinatus muscle after tendon reattachment and 2)Evaluate the effects of co-release of SDF-1α and TSG-6 on local cell recruitment and tissue regeneration in the rat supraspinatus muscle after tendon reattachment. The proposed work is innovative because it employs a well-controlled, injectable carrier to achieve sustained release as well as enhance the effects of protein therapeutics to recruit endogenous cells in order to reverse muscle atrophy after rotator cuff tears. Results from these studies are expected to have an important positive impact because they will lead to more efficacious regenerative medicine therapies for rotator cuff tears, as well as provide greater mechanistic understanding of which cells participate in healing of degenerate muscle.