Controlled Non‐Viral Gene Delivery in Cartilage and Bone Repair: Current Strategies and Future Directions

Recent advances in the approval and commercialization of gene therapeutics have fostered the return of gene therapy to center stage. But despite new optimism, no Food and Drug Administration approved product exists for the treatment of orthopedic disorders. Non‐viral gene delivery is a promising alternative to recombinant protein administration and viral gene transduction for orthopedic tissue engineering. When applied using appropriately designed systems, it enables temporal control of the overexpression of therapeutic genes, leading to local production of regulatory factors at physiologically relevant levels. Incorporating genetic material into 3D scaffold biomaterials, that is, gene activated scaffolds or hydrogels, presents a particular opportunity to utilize non‐viral gene therapy for in situ transfection of host cells and the regeneration of damaged tissues and organs. But controlled non‐viral gene delivery for musculoskeletal regeneration depends on a multifactorial design in which the choice of gene delivery method, therapeutic gene, and supportive biomaterial play a central role for the success of this strategy. This paper reviews the different modalities of non‐viral gene delivery used for the repair of bone and cartilage, and explores the current challenges and opportunities for the engineering of functional orthopedic tissues using gene activated scaffolds.