An Innovative miR‐Activated Scaffold for the Delivery of a miR‐221 Inhibitor to Enhance Cartilage Defect Repair

The development of treatments to restore damaged cartilage that can provide functional recovery with minimal risk of revision surgery remains an unmet clinical need. Gene therapy shows increased promise as an innovative solution for enhanced tissue repair. Within this study a novel microRNA (miR)-activated scaffold is developed for enhanced mesenchymal stem/stromal cells (MSC) chondrogenesis and cartilage repair through the delivery of an inhibitor to microRNA-221 (miR-221), which is known to have a negative effect of chondrogenesis. To fabricate the miR-activated scaffolds, composite type II collagen-containing scaffolds designed specifically for cartilage repair are first manufactured by lyophilization and then functionalized with glycosaminoglycan-binding enhanced transduction (GET) system nanoparticles (NPs) encapsulating the miR-221 inhibitor. Subsequently, scaffolds are cultured with human-derived MSCs in vitro under chondrogenic conditions for 28 days. The miR-activated scaffolds successfully transfect human MSCs with the miR-221 cargo in a sustained and controlled manner up to 28 days. The silencing of miR-221 in human MSCs using the miR-activated scaffold promotes an improved and more robust cell-mediated chondrogenic response with repressed early-stage events related to MSC hypertrophy. Taken together, this innovative miR-activated scaffold for the delivery of a miR-221 inhibitor demonstrates capability to improve chondrogenesis with promise to enhance cartilage defect repair.