The temporomandibular joint (TMJ) condyle consists of fibrocartilage tissue and is substantially understudied. Patients with either trauma or chronic degeneration of TMJ fibrocartilage are severely debilitated. Currently, there are no effective treatments that regenerate permanently damaged or degenerated fibrocartilage tissue, largely due to our severe lack of knowledge in TMJ fibrocartilage biology. Few studies have specifically elucidated and defined TMJ fibrocartilage cellular constituents or assessed the regenerative properties of the TMJ. Our preliminary data demonstrate, for the first time, the presence of putative stem/progenitor cells in the TMJ condyle. To test the application of putative TMJ stem/progenitor cells for regeneration, we have established a surgical TMJ condyle replacement model in vivo. Accordingly, our long- term goals are1) to isolate and comprehensively characterize putative TMJ stem/progenitor cells; 2) determine the regenerative potential of characterized TMJ stem/progenitor cells in biomaterial scaffolds. Our overall hypothesis is the TMJ harbors stem/progenitor cells that can be harnessed in biomaterial scaffolds for TMJ regeneration. Our goal is to regenerate TMJ fibrocartilage that gradually approximates the native tissue in multiple, reiterative in vivo experiments in skeletally mature animal models. Overall, these studies are anticipated to not only to enhance our understanding of fibrocartilage biology and regeneration, but may also contribute to the development of novel regenerative therapies for fibrocartilage injuries and diseases. PUBLIC HEALTH RELEVANCE: There are no clinical therapies to regenerate diseased or damaged temporomandibular joint (TMJ) fibrocartilage. The long-term goals of our proposal are to characterize putative TMJ stem/progenitor cells and to determine their potential to regenerate TMJ fibrocartilage using 3D biomaterial scaffolds. We propose to develop tissue-engineering strategies for biological TMJ condyle substitutes and anticipate these studies to be critical for the development of regenerative treatments for patients suffering from TMJ disease or injury.