Title: Engineering Controllable Release Delivery Systems to Treat Skeletal and Cardiac Muscle Injury

 Abstract: Muscle tissue is a critical tissue for health and lifespan that is necessary for many critical functions including movement, metabolism, and blood circulation, among others. When muscle injuries occur, the immune system orchestrates a complex and dynamic process to guide tissue repair, which involves a balance of inflammatory and reparative activity. This delicate balance can be tipped towards inflammatory activities when injury is severe, resulting in damage to nearby healthy tissue and delayed or dysfunctional repair. Preventing excessive damage is especially critical for non-regenerative cardiac muscle, in which damage becomes permanent. Existing therapeutics, like steroids or NSAIDs, provide indiscriminate immune suppression that reduces inflammation but also hampers repair processes.

Regulatory T cells (Treg) are the body’s own highly sophisticated system for regulating immunologic activity. These cells can provide powerful immune suppression while amplifying repair pathways through direct stimulation of local cells. Our research group has previously developed a polymeric delivery system comprised of poly(lactic-co-glycolic acid) (PLGA) degradable microparticles (MP) loaded with the Treg-attracting protein, CCL22. In our previous work, we have demonstrated CCL22MP attracts Tregs to the injection site and can both suppress disadvantageous inflammation and promote tissue repair.

            Here we investigate new techniques to control the release rate of CCL22 and other biologic peptides to understand how widely applicable this technology is. We find that changes to the PLGA polymer terminating group results in significantly altered material properties and degradation rate, modulated internalization by macrophages, and accelerated release rate of CCL22 by 2 orders of magnitude. We apply this new understanding to generate a new formulation of CCL22MP terminated with polyethylene glycol and evaluate it for the first time in models of skeletal muscle and cardiac injury. In skeletal muscle injury, CCL22MP treatment significantly accelerated limb function and reduced the area of injury. Additionally, a hybrid hydrogel and MP technology was developed to localize CCL22MP treatment to the heart. We observe variable efficacy in cardiac injury models, in which models with more severe damage show greater potential benefit. Future studies evaluating this treatment in more clinically relevant settings will better inform optimal use case for CCL22MP after injury.

Chair:

Dr. Steven R. Little, Department of Chemical and Petroleum Engineering, University of Pittsburgh

Committee Members:

Dr. Heth R. Turnquist, Department of Surgery and Immunology, University of Pittsburgh

Dr. William Wagner, Department of Chemical and Petroleum Engineering, University of Pittsburgh

Dr. Ipsita Banerjee, Department of Chemical and Petroleum Engineering, University of Pittsburgh