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BME PhD Proposal Seminar

K-307, Med 3-6408

“Development of Bilayer Hydrogels for Spatiotemporally-Controlled Delivery of siRNA Nanoparticles”

Presented by: Dominic W. Malcolm
Supervised by: Prof. Danielle Benoit

Abstract: Musculoskeletal diseases often result in damage to multiple tissue types, as musculoskeletal tissues are commonly composed of complex, multicomponent structures. These diseases are common causes of disability in the US. For example, osteoarthritis (OA) is projected to affect over 25% of the US adult population by 2030. While OA treatments are mostly palliative, reparative approaches for osteochondral defects of OA require multiple invasive surgeries, result in donor site morbidity, and lack long-term clinical success, motivating tissue engineering (TE) approaches. TE approaches involve integration of cells and exogenous signals to promote tissue formation within biomaterial scaffolds. Developmentally, tissue formation is governed by a milieu of multiple signals that are regulated intracellularly by microRNA (miRNA), endogenous small interfering RNA (siRNA). miRNA are master regulators of mesenchymal stem cell (MSC) differentiation due to their ability to regulate specific genes through RNA interference (RNAi). However, use of RNAi strategies as a regenerative medicine approach has been stalled, as delivery systems to provide spatiotemporally controlled delivery of these molecules do not exist. To overcome this obstacle, we are further developing our polymeric nanoparticle (NP) siRNA delivery system by introducing spatially and temporally controlled release mechanisms within hydrogel scaffolds. To accomplish this goal, we propose the following specific aims: (1) Achieve osteogenic and chondrogenic differentiation in human MSCs via NP-mediated RNAi delivery; (2) Employ controlled release chemistries to achieve tunable, sustained release of siRNA-NPs within hydrogel scaffolds; (3) Manipulate spatiotemporally controlled siRNA delivery to generate multicomponent osteochondral tissue in vitro. Novel strategies for the clinical and therapeutic impact of siRNA and miRNA delivery, controlled release chemistries, and patterned biomaterials developed in this project will apply to a broad array of biomaterial, drug delivery, and tissue engineering approaches, thus significantly contributing to the advancement of these fields.