Project Summary Temporomandibular disorders affect ~35 million people in the US, with 3-8 times more women affected than men. Approximately 30% of temporomandibular disorder patients experience mechanical dysfunction of the articular disc (an avascular tissue) in the temporomandibular joint (TMJ), a load-bearing joint during oral function. However, the etiology of the temporomandibular disc dysfunction/displacement (TMDD) sub-population is poorly understood, including why women are disproportionately affected. Logical TMDD candidate bio-indicators include craniofacial morphology, TMJ biomechanics, disc nutrient availability, and disc metabolism, each of which show varying degrees of sexual dimorphism. These factors interact such that subject-specific craniofacial morphology drives TMJ biomechanics, and biomechanics regulates TMJ disc nutrient availability and cellular metabolism/homeostasis. Study results from the preceding R01 proved that in pigs the avascular TMJ disc nutrient environment is heavily dependent upon mechanical strain-dependent nutrient diffusion, and the nutrient environment has a profound effect on disc cell proliferation and differentiation leading to tissue dysfunction. Therefore, TMJ biomechanical and mechanobiological differences between sexes driven by craniofacial morphology in humans may be critical. Our preliminary data have demonstrated sex-differences in human TMJ loading due to sexual dimorphisms in craniofacial morphology, plus we have identified a TMJ morphologic phenotype that may also explain sex-differences in TMDD occurrence. Therefore, it is now necessary to determine sex differences in the mechanical strain-dependent nutrient transport properties and nutrient level- dependent energy metabolism of the human TMJ disc and investigate the plausible associations of craniofacial morphology and TMJ biomechanics through the mechanobiological pathway on TMDD development and progression. The central hypothesis of the proposed study is that craniofacial morphologic differences between sexes, as well as between healthy controls and TMDD patients, drive the differences of TMJ biomechanics and disc mechanobiology which can be used to predict individuals at greatest risk for TMDD development and progression. The long-term objectives are to understand the mechanobiological etiology of temporomandibular disorders, to identify risk factors specific for TMDD development, and to define TMDD mechanobiological mechanisms of progression. Through the identification of potential morphologic, biomechanical, and biological risk factors for TMDD development and progression, this work has promising clinical translation and lays the foundation for future human studies. Specific outcomes of the proposed study include: determination of the mechanical strain dependency of the temporomandibular disc nutrient environment and its impact on cell viability and energy metabolism in human tissues, an enhanced understanding of how subject-specific mo...