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Ana Rey-Rico,1 Jagadeesh K Venkatesan,1 Gertrud Schmitt,1 Angel Concheiro,2 Henning Madry,1,3 Carmen Alvarez-Lorenzo,2 Magali Cucchiarini1 1Center of Experimental Orthopedics, Saarland University Medical Center, Homburg, Germany; 2Department of Pharmacology, Pharmacy and Pharmaceutical Technology, R+ DPharma Group (GI-1645), Facultad de Farmacia and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain; 3Department of Orthopedics and Orthopedic Surgery, Saarland University Medical Center, Homburg, Germany Abstract: Recombinant adeno-associated virus (rAAV) vectors are clinically adapted vectors to durably treat human osteoarthritis (OA). Controlled delivery of rAAV vectors via polymeric micelles was reported to enhance the temporal and spatial presentation of the vectors into their targets. Here, we tested the feasibility of delivering rAAV vectors via poly (ethylene oxide) (PEO) and poly (propylene oxide) (PPO) (poloxamer and poloxamine) polymeric micelles as a means to overexpress the therapeutic factor transforming growth factor-beta (TGF-β) in human OA chondrocytes and in experimental human osteochondral defects. Application of rAAV-human transforming growth factor-beta using such micelles increased the levels of TGF-β transgene expression compared with free vector treatment. Overexpression of TGF-β with these systems resulted in higher proteoglycan deposition and increased cell numbers in OA chondrocytes. In osteochondral defect cultures, a higher deposition of type-II collagen and reduced hypertrophic events were noted. Delivery of therapeutic rAAV vectors via PEO-PPO-PEO micelles may provide potential tools to remodel human OA cartilage. Keywords: controlled delivery, human articular cartilage, rAAV gene transfer, TGF-β, poloxamer, poloxamine

Patrick Orth,1 Ana Rey-Rico,2 Jagadeesh K Venkatesan,2 Henning Madry,1,2 Magali Cucchiarini2 1Department of Orthopaedic Surgery, 2Center of Experimental Orthopaedics, Saarland University Medical Center, Homburg, Germany Abstract: Protocols based on the delivery of stem cells are currently applied in patients, showing encouraging results for the treatment of articular cartilage lesions (focal defects, osteoarthritis). Yet, restoration of a fully functional cartilage surface (native structural organization and mechanical functions) especially in the knee joint has not been reported to date, showing the need for improved designs of clinical trials. Various sources of progenitor cells are now available, originating from adult tissues but also from embryonic or reprogrammed tissues, most of which have already been evaluated for their chondrogenic potential in culture and for their reparative properties in vivo upon implantation in relevant animal models of cartilage lesions. Nevertheless, particular attention will be needed regarding their safe clinical use and their potential to form a cartilaginous repair tissue of proper quality and functionality in the patient. Possible improvements may reside in the use of biological supplements in accordance with regulations, while some challenges remain in establishing standardized, effective procedures in the clinics. Keywords: cartilage repair, knee, focal defects, osteoarthritis, stem cells, clinical trials