Biomaterials to enhance the efficacy of MSCs for rotator cuff repair

PROJECT SUMMARY Rotator cuff tears are present in approximately 20% of the population and result in mechanical unloading of the rotator cuff muscle. As a result, the muscle undergoes atrophy, which negatively impacts clinical outcomes of surgical repair. Recent work has shown reduction in rotator cuff muscle degeneration after transplantation of mesenchymal-derived stem cells (MSCs). However, MSC-based therapies for musculoskeletal diseases have been plagued by sub-optimal efficacy, due, in part, to lack of effective methods to 1) reach therapeutically relevant numbers of highly potent cells, and 2) retain cells at the site of injury once transplanted. Therefore, we hypothesize that that culture and injection of MSCs on microparticle carriers designed to promote therapeutic potency (reduced senescence and a pro- regenerative secretome) will result in greater cellular retention in the damaged muscle, and improved supraspinatus muscle regeneration after tendon reattachment. The objective of this application is to determine 1) the relationship between biomaterial carrier properties, cell metabolism, and therapeutic fitness of seeded MSCs, and 2) how transplanting cells with high fitness on materials to improve local retention ultimately affects 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 altering the biochemical composition of the biomaterial carrier on metabolism and replicative senescence of human MSCs during expansion, 2) Evaluate effects of altering the biochemical composition of the biomaterial carrier on secretion of pro-regenerative factors by human MSCs, and 3) Evaluate the effects of transplantation of MSCs after culture on carriers determined from Aims 1&2 on regeneration in the rat supraspinatus muscle after tendon reattachment. The proposed work is innovative because it focuses on design of material substrates to engineer the secretome of transplanted cells in order to promote tissue healing after rotator cuff tear, as well as provides an important early metabolomics-based screening technique for the effects of substrate properties on cellular therapeutic fitness. 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, and may further lead to more effective cell-based therapies for a wide variety of diseases.