Development of Drug Delivery Technology for Stem Cell Based TMJ Regeneration

1 ABSTRACT 2 The temporomandibular joint (TMJ) is a complex joint system critical for dental occlusion, mastication, 3 respiration and speech. The TMJ is comprised of a network of muscles, ligaments, and a 4 fibrocartilaginous disc and condyle. Temporomandibular disorders (TMDs) afflict over 10 million 5 Americans at an annual cost of ~$4 billion, per the NIDCR. Degenerative types of TMDs, including 6 TMJ osteoarthritis (OA), are debilitating, compromise quality of life, and causes permanent tissue 7 loss. Current TMJ OA treatments are typically two-fold, involving either pain management or invasive 8 surgeries, such as total joint replacements with high failure rates. There is a paucity of minimally 9 invasive TMJ therapies that promote tissue regeneration. 10 Regenerative medicine promises the recreation functional tissue that is loss from disease. Thus 11 exploiting the regenerative capabilities of resident stem cells to repair TMJ may represent a minimally 12 invasive stem cell-based treatment for TMJ OA. We have identified fibrocartilage stem cells 13 (FCSCs) that reside in the TMJ condyle superficial zone. Transplanted FCSCs self-organize and 14 regenerate cartilage. Wnt/?Catenin signaling promotes proliferation and inhibits chondrogenic 15 differentiation of FCSCs. However, over-active Wnt/?Catenin deplete FCSCs and cause TMJ OA 16 in mice, rabbits and humans. These data suggest that inhibiting Wnt/?Catenin in FCSCs may serve 17 as a stem cell-based therapeutic strategy for the treatment of TMJ OA. In fact, we showed that 18 blocking Wnt via weekly TMJ intra-articular injections of the Wnt inhibitor sclerostin ameliorated TMJ 19 OA in a rabbit TMJ injury model. However, a pharmacological drug delivery system for chairside, 20 sustained release sclerostin administration to human TMJ OA patients has not been defined. 21 Based on our preliminary data, we hypothesize that delivery of an injectable, sustained release 22 hyaluronic acid-sclerostin hydrogel will target resident TMJ fibrocartilage stem cells to regenerate 23 TMJ.