Bridging Temporomandibular Joint Structure, Function, and Pain: An Integrated Multiscale Perspective

The temporomandibular joint (TMJ) features unique tissue structures that support its complex functional demands. Alterations in these structures are often linked to jaw dysfunction, with pain being one of the most prevalent symptoms. However, the mechanisms underlying TMJ pain and its relationship with structural deterioration or functional impairment remain poorly understood. A comprehensive understanding of the interplay among TMJ structure, function, and pain is essential for uncovering disease mechanisms and developing effective therapies. To date, TMJ research in humans and animal models has been predominantly conducted in separate domains of structure, function, and pain, limiting integrative insights. Clinical studies also show inconsistent correlations among joint structural changes, jaw dysfunctions, and craniofacial pain, complicating diagnosis and treatments. This review aims to bridge these traditionally fragmented areas by synthesizing current knowledge across macroscopic and microscopic scales in human and animal models. TMJ diseases involve spatially proximate cellular, extracellular, and neural components that undergo multiscale spatiotemporal changes. These components experience complex mechanical loading during joint movement, triggering mechanical, neural, and immune responses that interact bidirectionally to influence TMJ integrity and pain. In turn, the brain modulates motor output and autonomic function, further affecting joint mechanics and cellular and nociceptive responses. To holistically and quantitatively assess these spatiotemporal dynamic processes, we propose a multiscale and multiphysics framework that integrates joint and tissue biomechanics, biochemical signals, cellular responses, nociception, and psychosocial influences. Realizing this vision requires a transdisciplinary effort and the development and adaptation of advanced methods to study TMJ at unprecedented resolution and details. By unifying structural, functional, and pain-related data, this integrated multiscale approach holds promise for elucidating new mechanisms of TMJ development, disease onset and progression, and pain chronicity. Ultimately, it may guide more effective diagnostics and treatments, including the combined use of physical therapy, neuromodulation, and biologically targeted interventions.