Osteoarthritis (OA) is a disease of the articular cartilage characterized by pain and functional limitations that can severely affect one's quality of life. Current treatments, including analgesics, microfracture, and autologous chondrocyte implantation, do not typically restore complete function; tissue engineering is a viable technology to meet this need in patient care. Our lab has engineered a system of self-assembling human mesenchymal stem cell sheets incorporated with growth factor-releasing hydrogel microspheres. This system of self-assembled, microsphere-incorporated stem cell sheets is capable of forming cartilage in the presence of exogenous growth factor or with growth factor released from the incorporated microspheres. Incorporation of microspheres allows for scaffold-free formation of stem cell based cartilage constructs which allows for the benefits of a scaffold free system, such as early mechanical strength and high cell density which maintains the cell-cell interactions necessary for chondrogenesis. Current literature demonstrates directed differentiation of stem cells down the chondrogenic lineage via delivery of RNA interference (RNAi), to control differentiation at the genetic level versus a growth factor based differentiation that typically affects a single signaling pathway. This work aims to engineer novel polymer microspheres specifically designed for RNAi delivery for controlled 3D presentation to both spatially and temporally regulate differentiation, overcoming many limitations of current techniques such as repeat application and exogenous delivery. Sustained delivery past the initial dosing will be necessary to inhibit gene expression in tissue engineering strategies using RNAi where repeat application within the interior of the constructs is not feasible. Moreover, a tunable degradation profile of the polymer to release the payload allows for temporal control of delivery. Thus, the role of spatial and temporal presentation of prochondrogenic siRNAs and/or miRNAs to block the expression of genes that inhibit chondrogenesis will be examined within a biologically relevant 3D stem cell model that recapitulates native cartilage development. We hypothesize that these RNAi loaded polymer microsphere incorporated sheets can heal full thickness articular cartilage defects. Our tissue engineering approaches are designed to be highly translational in nature, accomplishing the goal of true tissue regeneration. Because the delivery and release system is tunable, the release profile can be adapted to deliver a wide spectrum of bioactive factors, making this system a potentially powerful tool in the process of cartilage regeneration.
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