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PublicationDefining Multi-Scale Relationships Between Biomechanics & Neuronal Dysfunction In Ligament Pain Using Integrated Experimental & Computational Approaches(2017-01-01) Zhang, SijiaCapsular ligaments can encode the mechanical state of joints owing to their innervation. For example, the spinal facet capsular ligament that encloses the facet joint is innervated by mechanoreceptors and nociceptors, and is a major source of neck and low back pain from aberrant spinal motions. The cervical facet capsule is commonly injured by its excessive stretch during neck trauma. Although supraphysiologic deformation of the facet capsular ligament can activate its afferents and induce pain, the local biomechanical and neuronal mechanisms underlying sensory transduction for pain from mechanical inputs remain unclear. The studies in this thesis use integrated in vitro, in vivo and in silico methods to investigate the interplay between the mechanical and nociceptive functions of the cervical facet capsular ligament. Tissue-level mechanics, collagen network restructuring and neuronal dysfunction are all assessed across length scales using a neuron collagen construct (NCC) system as well as animal and computational modeling. Afferent activation, nociception and dysfunction are found to depend on the macro-scale tissue strains. Yet, relationships between macroscopic stretch and micro-scale pathophysiology in the facet capsule is confounded by its heterogeneous fibrous architecture. Studies in this thesis show that localized collagen disorganization is associated with excessive network-level reorganization and fiber-level stretch using network analysis and finite element-based modeling. Integrated imaging of the extracellular matrix structure and neuronal dysfunction in the NCC system provides evidence for collagen network organization and local fiber kinematics as mediators of pain-related neuronal signaling. Stretch-induced production of nociceptive neuropeptides in NCCs is prevented by inhibiting collagen-binding integrins, supporting a role of cell-matrix adhesion in converting noxious mechanical stimuli in to pain signals. Further, neuronal mechanotransduction that initiates pain is found to involve the intracellular RhoA/Rho kinase ROCK. In vivo studies in the rat suggest that intra-articular ROCK likely contributes to the development of central sensitization and facet joint pain, possibly via neuropeptide-mediated synaptic transmission and spinal microglial activation. Collectively, these findings establish the role of collagen networks and fibers in translating macroscopic ligament stretch in to neuronal pain signals and identify mechanotransductive signaling cascades that have clinical relevance as possible treatment for trauma-induced facet pain.