Development of Drug Delivery Technology for Stem Cell-Based TMJ Regeneration

Summary The temporomandibular jointTMJis a complex joint system critical for dentalocclusionmasticationrespiration and speechThe TMJ is comprised of a network of musclesligamentsand a fibrocartilaginous disc and condyleTMJ trauma and degenerative diseasesincluding TMJ osteoarthritisOAare debilitating and compromise quality of lifeTMJ diseasesafflict overmillion Americans at an annual cost of$billion and are one of NIDCR s researchprioritiesCurrent treatments for TMJ OA are typically two fold extremesinvolving either painmanagement or invasive surgeriesincluding total joint replacements with high failure ratesThereis a paucity of minimally invasive and directed TMJ therapies that target pathological mechanismsand promote innate tissue regenerationOne barrier preventing the development of targeted TMJregenerative therapies is the deficient knowledge underlying the role of stem cells in TMJ healthand diseaseExploiting the regenerative capabilities of resident stem cells to repair TMJ tissues represents aminimally invasive stem cell based treatment for TMJ OAWe have identified TMJ fibrocartilagestem cellsFCSCsthat reside in the TMJ condyle superficial zoneOver active WntCatenindeplete FCSCs and cause TMJ OA in micerabbits and humansWe showed blocking Wnt via weekly TMJintra articular injections of the Wnt inhibitor sclerostin ameliorated TMJ OA in a rabbit TMJinjury modelThus therapeutic application of exogenous sclerostin maintains the pool of FCSCsand repairs TMJThese data suggest that sclerostin mediated WntCatenin inhibition inFCSCs represents a stem cell based therapeutic strategy for TMJ regenerationHoweverapharmacological drug delivery system for bench side sclerostin administration in human TMJ OApatients has not been definedBased on our preliminary datawe hypothesize that delivery of injectablesustained releasesclerostin in HA hydrogel will target resident TMJ fibrocartilage stem cells toregenerate TMJWe will develop sustained release sclerostin therapy for Wnt inhibition inFCSCs by encapsulating sclerostin in HA hydrogelWe will use an established rabbit TMJinjury model to demonstrate injectable sustained release sclerostin as a therapeuticregenerative strategy for TMJ OAOur long term goal is to develop a minimallyinvasive TMJ regenerative therapy through targeteddrug based modulation of resident TMJfibrocartilage stem cellsSpecific AimDevelop injectable hyaluronic acid sustained release sclerostin hydrogel to inhibitWntCatenin and promote chondrogenic differentiation in TMJ fibrocartilage stem cellsSpecific AimDetermine the efficacy of injectable hyaluronic acid sustained release sclerostinto ameliorate TMJ osteoarthritis Project Narrative An innovative targeting treatment for TMJ osteoarthritis is being developed by collective effort between Wnt Scientific LLC and TMJ Biology and Regenerative Medicine Laboratory at Columbia UniversityThe innovative treatment is to deliver recombinant sclerostina potent Wnt signal inhibitorin hyaluronic acid hydrogel carrier