Evaluating the role of immunomodulation in synergizing BMP-induced bone repair

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Project Summary The use of bone morphogenetic proteins (BMPs) shows promise as therapeutics for improving bone repair; however, high supraphysiological concentrations required for the desired osteoinductive effect, costs, and patient variability have prevented the full advantages of BMP-based therapeutics from being realized. Thus, there is a clinical need to develop new bone tissue engineering approaches that promote osteogenesis at lower BMP doses and prevent adverse side effects. Healthy bone formation and remodeling requires a delicate balance between skeletal (e.g. osteoblasts) and immune (e.g. osteoclasts, macrophages, etc.) cells, which is often overlooked when developing new bone regeneration therapeutics. To address these limitations, we propose the use of immunomodulatory microparticles to enhance BMP-induced bone repair. Proteolytically- degradable hyaluronic acid hydrogels will be used to co-deliver BMP2 and immunomodulatory microparticles via cell-mediated hydrogel degradation. For the immunomodulatory microparticles, we have designed novel poly(alpha-ketoglutarate) microparticles (paKG MPs), which sustainably release alpha-ketoglutarate (aKG) upon hydrolytic degradation. aKG is known to regulate both osteoblast and osteoclast behavior. Furthermore, paKG MPs are highly tunable, enabling precise control over aKG release kinetics. In this project, the ability of paKG MPs to enhance BMP-induced osteogenesis will be investigated in vitro and in vivo. We hypothesize sustained aKG delivery will enable control over the balance between osteoblast and osteoclast signaling, leading to increased osteogenesis and bone formation. The proposed work will be accomplished through the following aims: (1) Develop hyaluronic acid hydrogels with combined, sustained delivery of BMP2 and aKG; and (2) Evaluate the effect of aKG on a) in vitro cell behavior and b) in vivo bone repair. A range of microparticle concentrations will be tested to optimize aKG delivery. In vitro cell behavior will be evaluated via viability, proliferation, metabolomics, differentiation (i.e. osteoblast and osteoclast markers), and mineral formation and resorption. In vivo bone repair will be assessed using a critical-sized cranial defect rat model.