Activating latent growth factors for cartilage regeneration

Project summary Articular cartilage lesions are prevalent disorders affecting millions of AmericansDeprived of spontaneous healing capacitycartilage lesions may further deteriorate and lead to the onset of osteoarthritisOAOA represents a leading cause of chronic disabilities in the U Sand ultimately warrants total joint arthroplastyA common aspiration in orthopedic medicine is to regenerate the damaged articular cartilageCurrentlyarthroscopic microfracture is a popular clinical procedure that debrides damaged cartilage tissue and induces bleeding from bone marrow to fill cartilage defectsHowevermicrofracture yields fibrous tissue or fibrocartilage at bestwhich has inferior mechanical properties than articular hyaline cartilagePrevious workincluding our preliminary datademonstrates that certain cytokines such as transforming growth factor betaandTGFand TGFinduces hyaline cartilage formation by endogenous cellsSpecificallywe showed that delivery of exogenous TGFin an anatomically correctporous scaffoldwithout cell transplantationwas sufficient for the regeneration of an entire articular cartilage layer in vivowith functional recoveryA substantial barrier towards translation of existing work into a clinical therapy is the cost of exogenous growth factorsproteins and peptidesand development of growth factors as a productThe literature shows that the synovial joint harbors substantial amounts of TGF sbut in latent formsThe innate TGF s in latent forms are dormant in homeostasis but are activated upon injury or tissue repairOur preliminary work further demonstrated that ascorbate can readily activate latent TGF s in a way that can be harnessed towards repair of focal cartilage defects in a rabbit model and also avoid the OA development in a rat modelOur central hypothesis that endogenouslatent TGF s in synovial fluid and other joint tissueswhen focally activated at defect sitemay induce repair of cartilage defectsTogetherour preliminary studies strongly suggest that ascorbate can be locally delivered to activate latent TGF s in a way that benefit cartilage regeneration in focal defectsThe overall objective of the present SBIR Phase I proposal is to improve the ascorbate laden prototypes for optimal pro chondrogenesisThe benefit of this approach as an adjunctive procedure of the current clinical gold standard of arthroscopy procedures is a substantial factor in favor of translation ultimately towards clinical application Public Health Relevance Articular cartilage lesions and OA are prevalent disorders affecting millions of AmericansWe have developed a prototype device that activates endogenous healing potential of articular cartilage as an adjunctive procedure of the current clinical gold standard of minimally invasive arthroscopy proceduresThis technology demonstrated also the effectiveness in stopping and even reversing OA developmentSuccess of the technology has immediate and immense impact on the public health