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Aims: To develop a rat model of temporomandibular joint (TMJ) pain and to characterize in it the development and temporal response of behavioral hypersensitivity as well as to evaluate if and to what extent a loading protocol is associated with histological changes in the TMJ consistent with osteoarthritic pathology. Methods: A novel rat model of TMJ pain was developed using a noninvasive, mechanical loading protocol. Rats were exposed to steady mouth-opening for 7 days (2 N force, 1 hour/day), and mechanical hyperalgesia (increased pain response) was measured during the loading period and for 14 days thereafter. Histological modifications in the joint cartilage were also evaluated. Outcomes for the mouth-opening exposure were compared to age-matched controls. Thresholds for evoking responses were compared using a ranked ANOVA with repeated measures. Results: Increased mechanical hypersensitivity in the temporomandibular region developed during daily loading and persisted even after the termination of the loading protocol. Histologic characterization revealed thinning of the cartilaginous structures of the joint and irregular zonal cellular arrangements in the condylar cartilage of rats subjected to the daily loading protocol. Conclusion: The injury model presented here is the first to demonstrate mechanically-induced behavioral hypersensitivity accompanied by osteoarthritic pathology in the TMJ. J Orofac Pain 2010;24:298-304. [ABSTRACT FROM AUTHOR]

Background: Matching disease and treatment mechanisms is a goal of the Precision Medicine Initiative. Pro- and anti-inflammatory cytokines (e.g., Tumor Necrosis Factor-alpha, Transforming Growth Factor-beta, and Interleukin-2, 10, and 12) have gained a significant amount of interest in their potential role in persistent pain for musculoskeletal (MSK) conditions. Manual therapy (MT) and exercise are two guideline-recommended approaches for treating MSK conditions. The objective of this narrative overview was to investigate of the effects of MT and exercise on pro- and anti-inflammatory cytokines and determine the factors that lead to variability in results., Methods: Two reviewers evaluated the direction and variabilities of MT and exercise literature. A red, yellow, and green light scoring system was used to define consistencies., Results: Consistencies in responses were seen with acute and chronic exercise and both pro- and anti-inflammatory cytokines. Chronic exercise is associated with a consistent shift towards a more anti-inflammatory cytokine profile (Transforming Growth Factor-beta, and Interleukin-2 and 13, whereas acute bouts of intense exercise can transiently increase pro-inflammatory cytokine levels. The influence of MT on cytokines was less commonly studied and yielded more variable results., Conclusion: Variability in findings is likely related to the subject and their baseline condition or disease, when measurement occurs, and the exercise intensity, duration, and an individual's overall health and fitness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Cook, Keter, Cade, Winkelstein and Reed.)

Low back pain is a prevalent condition that affects the global population. The lumbar facet capsular ligament is a source of pain since the collagenous tissue of the ligament is innervated with sensory neurons that deform with the capsule's stretch. Regional differences in the microstructural and macrostructural anatomy of the spinal facets affect its capsule's mechanical behavior. Although there are many studies of the cervical facet in human and rodent models, the lumbar capsular ligament's multiscale behavior is less well-defined. This study characterizes the macroscale and fiber-scale changes of the rat lumbar facet capsule during tensile failure loading. An integrated polarized light imaging setup captured local fiber alignment during 0.08 mm/s distraction of 7 lumbar facets. Force, displacement, strain, and circular variance were measured at several points along the failure curve: the first instance when the local collagen fiber network realigns differentially (anomalous realignment), yield, the first peak in force corresponding to the capsule's first failure, and peak force, defined as ultimate rupture. Those outcomes were compared across events. While each of force, displacement, and average maximum principal strain increased with applied tension, so did the circular variance of the collagen, suggesting that the fibers were becoming more disorganized. From the fiber alignment maps collected at each mechanical event, the number of anomalous realignment events were counted and found to increase dramatically with loading. The increased collagen disorganization and increasing regions of such disorganization in the facet capsule during loading can provide insights about how loading to the ligament afferent nerves may be activated and thereby produce pain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: To understand the facet capsular ligament's (FCL) role in cervical spine mechanics, the interactions between the FCL and other spinal components must be examined. One approach is to develop a subject-specific finite element (FE) model of the lower cervical spine, simulating the motion segments and their components' behaviors under physiological loading conditions. This approach can be particularly attractive when a patient's anatomical and kinematic data are available., Methods: We developed and demonstrated methodology to create 3D subject-specific models of the lower cervical spine, with a focus on facet capsular ligament biomechanics. Displacement-controlled boundary conditions were applied to the vertebrae using kinematics extracted from biplane videoradiography during planar head motions, including axial rotation, lateral bending, and flexion-extension. The FCL geometries were generated by fitting a surface over the estimated ligament-bone attachment regions. The fiber structure and material characteristics of the ligament tissue were extracted from available human cervical FCL data. The method was demonstrated by application to the cervical geometry and kinematics of a healthy 23-year-old female subject., Results: FCL strain within the resulting subject-specific model were subsequently compared to models with generic: (1) geometry, (2) kinematics, and (3) material properties to assess the effect of model specificity. Asymmetry in both the kinematics and the anatomy led to asymmetry in strain fields, highlighting the importance of patient-specific models. We also found that the calculated strain field was largely independent of constitutive model and driven by vertebrae morphology and motion, but the stress field showed more constitutive-equation-dependence, as would be expected given the highly constrained motion of cervical FCLs., Conclusions: The current study provides a methodology to create a subject-specific model of the cervical spine that can be used to investigate various clinical questions by coupling experimental kinematics with multiscale computational models., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Chronic joint pain is a major healthcare challenge with a staggering socioeconomic burden. Pain from synovial joints is mediated by the innervated collagenous capsular ligament that surrounds the joint and encodes nociceptive signals. The interstitial collagenase MMP-1 is elevated in painful joint pathologies and has many roles in collagen regulation and signal transduction. Yet, the role of MMP-1 in mediating nociception in painful joints remains poorly understood. The goal of this study was to determine whether exogenous intra-articular MMP-1 induces pain in the spinal facet joint and to investigate effects of MMP-1 on mediating the capsular ligament's collagen network, biomechanical response, and neuronal regulation. Intra-articular MMP-1 was administered into the cervical C6/C7 facet joints of rats. Mechanical hyperalgesia quantified behavioral sensitivity before, and for 28 days after, injection. On day 28, joint tissue structure was assessed using histology. Multiscale ligament kinematics were defined under tensile loading along with microstructural changes in the collagen network. The amount of degraded collagen in ligaments was quantified and substance P expression assayed in neural tissue since it is a regulatory of nociceptive signaling. Intra-articular MMP-1 induces behavioral sensitivity that is sustained for 28 days ( p < 0.01), absent any significant effects on the structure of joint tissues. Yet, there are changes in the ligament's biomechanical and microstructural behavior under load. Ligaments from joints injected with MMP-1 exhibit greater displacement at yield ( p = 0.04) and a step-like increase in the number of anomalous reorganization events of the collagen fibers during loading ( p ≤ 0.02). Collagen hybridizing peptide, a metric of damaged collagen, is positively correlated with the spread of collagen fibers in the unloaded state after MMP-1 ( p = 0.01) and that correlation is maintained throughout the sub-failure regime ( p ≤ 0.03). MMP-1 injection increases substance P expression in dorsal root ganglia ( p < 0.01) and spinal cord ( p < 0.01) neurons. These findings suggest that MMP-1 is a likely mediator of neuronal signaling in joint pain and that MMP-1 presence in the joint space may predispose the capsular ligament to altered responses to loading. MMP-1-mediated pathways may be relevant targets for treating degenerative joint pain in cases with subtle or no evidence of structural degeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ita, Singh, Troche, Welch and Winkelstein.)

Stretch injury of the facet capsular ligament is a cause of neck pain, inducing axonal injury, neuronal hyperexcitability, and upregulation of pain neuromodulators. Although thresholds for pain and collagen reorganization have been defined and integrins can modulate pain signaling with joint trauma, little is known about the role of integrin signaling in neuronal dysfunction from tensile loading of the innervated capsular ligament. Using a well-characterized biomimetic collagen gel model of the capsular ligament's microstructure and innervation, this study evaluated extrasynpatic expression of N-Methyl-D-Aspartate receptor subtype 2B (NR2B) as a measure of neuronal dysfunction following tensile loading and determined mechanical thresholds for its upregulation in primary sensory neurons, with and without integrin inhibition. Collagen gels with dissociated dorsal root ganglion neurons (n = 16) were fabricated; a subset of gels (n = 8) was treated with the β1 integrin subunit inhibitor, TC-I15. Gels were stretched to failure in tension and then immunolabeled for axonal NR2B. Inhibiting the integrin subunit does not change the failure force (p = 0.12) or displacement (p = 0.44) but does reduce expression of the β1 subunit by 41% (p < 0.001) and decrease axonal NR2B expression after stretch (p = 0.018). Logistic regressions estimating the maximum principal strain threshold for neuronal dysfunction as evaluated by Analysis of Covariance determine that integrin inhibition increases (p = 0.029) the 50th percentile strain threshold (7.1%) above the threshold for upregulation in untreated gels (6.2%). These results suggest that integrin contributes to stretch-induced neuronal dysfunction via neuron-integrin-collagen interactions., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mechanical stress to the temporomandibular joint (TMJ) is an important factor in cartilage degeneration, with both clinical and preclinical studies suggesting that repeated TMJ overloading could contribute to pain, inflammation, and/or structural damage in the joint. However, the relationship between pain severity and early signs of cartilage matrix microstructural dysregulation is not understood, limiting the advancement of diagnoses and treatments for temporomandibular joint-osteoarthritis (TMJ-OA). Changes in the pericellular matrix (PCM) surrounding chondrocytes may be early indicators of OA. A rat model of TMJ pain induced by repeated jaw loading (1 h/day for 7 days) was used to compare the extent of PCM modulation for different loading magnitudes with distinct pain profiles (3.5N-persistent pain, 2N-resolving pain, or unloaded controls-no pain) and macrostructural changes previously indicated by Mankin scoring. Expression of PCM structural molecules, collagen VI and aggrecan NITEGE neo-epitope, were evaluated at Day 15 by immunohistochemistry within TMJ fibrocartilage and compared between pain conditions. Pericellular collagen VI levels increased at Day 15 in both the 2N (p = 0.003) and 3.5N (p = 0.042) conditions compared to unloaded controls. PCM width expanded to a similar extent for both loading conditions at Day 15 (2N, p < 0.001; 3.5N, p = 0.002). Neo-epitope expression increased in the 3.5N group over levels in the 2N group (p = 0.041), indicating pericellular changes that were not identified in the same groups by Mankin scoring of the pericellular region. Although remodeling occurs in both pain conditions, the presence of pericellular catabolic neo-epitopes may be involved in the macrostructural changes and behavioral sensitivity observed in persistent TMJ pain., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Orofacial pain is among the most common chronic pain conditions and can result from temporomandibular disorders (TMDs) of the temporomandibular joint (TMJ). Matrix metalloproteinases (MMPs) drive degeneration of TMJ tissues and likely mediate pain in TMJ disorders given their role in nociception. However, few studies have assessed MMPs in the TMJ innervated tissues nor in the context of pain. This study defined the extent of MMP-1, MMP-9, and MMP-2 in TMJ tissues from patients undergoing total joint replacement (TJR) or arthroplasty discectomy for painful TMJ disorders. Protein expression was probed by Western blot in TMJ disc and capsular ligaments taken during TJR (n = 6) or discectomy (n = 3) for osteoarthritis or internal derangement in an IRB-approved study. Pro- and active MMP-1, active MMP-9, and pro- and active MMP-2 are detectable. MMP-1 and MMP-9 correlate positively to each other (Kendall's τ = 0.63; p = 0.01), strengthening the hypothesis that they are mechanistically related in regulatory cascades. Active MMP-1 and active MMP-9 correlate positively with self-reported pain scores (τ ≥ 0.51; p ≤ 0.04), suggesting their involvement in peripheral nociception. Overall, neither MMPs nor pain correlate with the functional vertical opening of the jaw. MMP-1 varies with the observed stage of degeneration during surgery (p = 0.04). Neither overall MMPs nor pain correlate with the overall magnetic resonance imaging scores, corroborating the longstanding, but confounding, clinical observation that pain and radiological evidence of joint damage are not always related. Clinical significance: These findings suggest that MMPs mediate pain in innervated soft tissues and may be targets for diagnosing disease stage and treatments in painful TMJ disorders., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

In innervated collagenous tissues, tissue scale loading may contribute to joint pain by transmitting force through collagen fibers to the embedded mechanosensitive axons. However, the highly heterogeneous collagen structures of native tissues make understanding this relationship challenging. Recently, collagen gels with embedded axons were stretched and the resulting axon signals were measured, but these experiments were unable to measure the local axon strain fields. Computational discrete fiber network models can directly determine axon strain fields due to tissue scale loading. Therefore, this study used a discrete fiber network model to identify how heterogeneous collagen networks (networks with multiple collagen fiber densities) change axon strain due to tissue scale loading. In this model, a composite cylinder (axon) was embedded in a Delaunay network (collagen). Homogeneous networks with a single collagen volume fraction and two types of heterogeneous networks with either a sparse center or dense center were created. Measurements of fiber forces show higher magnitude forces in sparse regions of heterogeneous networks and uniform force distributions in homogeneous networks. The average axon strain in the sparse center networks decreases when compared to homogeneous networks with similar collagen volume fractions. In dense center networks, the average axon strain increases compared to homogeneous networks. The top 1% of axon strains are unaffected by network heterogeneity. Based on these results, the interaction of tissue scale loading, collagen network heterogeneity, and axon strains in native musculoskeletal tissues should be considered when investigating the source of joint pain., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Temporomandibular joint (TMJ) pain is among the most prevalent musculoskeletal conditions and can result from atypical joint loading. Although TMJ pain is typically self-resolving, 15% of patients develop chronic TMJ pain that is recalcitrant to therapy and may be attributed to changes in pain processing centers. Although TMJ overloading induces pain and osteoarthritis, whether neuronal modifications in the trigeminal sensory system contribute to persistent TMJ pain is unknown., Objective: This study investigates changes in excitatory neuropeptides and synaptic transmission proteins in cases of transient and persistent TMJ sensitivity in a rat model., Methods: Rats underwent repeated jaw loading that produces transient (2N-load) or persistent (3.5N-load) sensitivity. In both groups, immunolabeling was used to assess substance P in the spinal trigeminal nucleus caudalis (Sp5C) and glutamate transporter 1 in the ventroposteriomedial thalamus early after loading. Synaptosomal Western blots were used to measure synaptic proteins in the caudal medulla and thalamus at a later time after loading., Results: Substance P increases transiently in the Sp5C early after loading that induces persistent sensitivity. However, glutamate transporter 1 is unchanged in the ventroposteriomedial thalamus. At a later time, synaptosomal Western blots show loss of the presynaptic tethering protein, synapsin, and the inhibitory scaffolding protein, gephyrin, in the thalamus with persistent, but not transient, sensitivity. No changes are identified in synapsin, phosphorylated synapsin, homer, or gephyrin in the caudal medulla., Conclusions: Substance P in the Sp5C and later loss of inhibitory synapses in the thalamus likely contribute to, or indicate, persistent TMJ pain., Competing Interests: E.J. Granquist is a consultant for Zimmer Biomet. The remaining authors have no conflicts of interest to declare. Funding support from by the Catherine D. Sharpe Foundation, Oral and Maxillofacial Surgery Foundation, Oral and Maxillofacial Surgery Schoenleber Research Fund, and NIH/NIAMS (T32-AR007132).Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Adaptations in brain communication are associated with multiple pain disorders and are hypothesized to promote the transition from acute to chronic pain. Despite known increases in brain synaptic activity, it is unknown if and how changes in pathways and networks contribute to persistent pain. A tunable rat model that induces transient or persistent temporomandibular joint pain was used to characterize brain network and subcircuit changes when sensitivity is detected in both transient and persistent pain groups and later when sensitivity is present only for the persistent pain group. Brain activity was measured by F-FDG positron emission tomography imaging and used to construct intersubject correlation networks; network connectivity distributions, diagnostics, and community structure were assessed. Activation of subcircuits was tested by structural equation modeling. Findings reveal differences in the brain networks at day 7 between the persistent and transient pain groups, a time when peripheral sensitivity is detected in both groups, but spontaneous pain occurs only in the persistent pain group. At day 7, increased (P ≤ 0.01) clustering, node strength, network segregation, and activation of prefrontal-limbic pathways are observed only in the group that develops persistent pain. Later, increased clustering and node strength are more pronounced with persistent pain, particularly within the limbic system, and decrease when pain resolves. Pretreatment with intra-articular etanercept to attenuate pain confirms that these adaptations are associated with pain onset. Results suggest that early and sustained brain changes can differentiate persistent and transient pain, implying they could be useful as prognostic biomarkers for persistent pain and in identifying therapeutic targets.

Neuropathic injury is accompanied by chronic inflammation contributing to the onset and maintenance of pain after an initial insult. In addition to their roles in promoting immune cell activation, inflammatory mediators like secretory phospholipase A 2 (sPLA 2 ) modulate nociceptive and excitatory neuronal signaling during the initiation of pain through hydrolytic activity. Despite having a known role in glial activation and cytokine release, it is unknown if sPLA 2 contributes to the maintenance of painful neuropathy and spinal hyperexcitability later after neural injury. Using a well-established model of painful nerve root compression, this study investigated if inhibiting spinal sPLA 2 7 days after painful injury modulates the behavioral sensitivity and/or spinal dorsal horn excitability that is typically evident. The effects of sPLA 2 inhibition on altered spinal glutamatergic signaling was also probed by measuring spinal intracellular glutamate levels and spinal glutamate transporter (GLAST and GLT1) and receptor (mGluR5, GluR1, and NR1) expression. Spinal sPLA 2 inhibition at day 7 abolishes behavioral sensitivity, reduces both evoked and spontaneous neuronal firing in the spinal cord, and restores the distribution of neuronal phenotypes to those of control conditions. Inhibiting spinal sPLA 2 also increases intracellular glutamate concentrations and restores spinal expression of GLAST, GLT1, mGluR5, and GluR1 to uninjured expression with no effect on NR1. These findings establish a role for spinal sPLA 2 in maintaining pain and central sensitization after neural injury and suggest this may be via exacerbating glutamate excitotoxicity in the spinal cord.

Degeneration is a hallmark of painful joint disease and is mediated by many proteases that degrade joint tissues, including collagenases. We hypothesized that purified bacterial collagenase would initiate nociceptive cascades in the joint by degrading the capsular ligament's matrix and activating innervating pain fibers. Intra-articular collagenase in the rat facet joint was investigated for its effects on behavioral sensitivity, joint degeneration, and nociceptive pathways in the peripheral and central nervous systems. In parallel, a co-culture collagen gel model of the ligament was used to evaluate effects of collagenase on microscale changes to the collagen fibers and embedded neurons. Collagenase induced sensitivity within one day, lasting for 3 weeks (p < 0.001) but did not alter ligament structure, cartilage health, or chondrocyte homeostasis. Yet, nociceptive mediators were increased in the periphery (substance P, pERK, and MMP-1; p ≤ 0.039) and spinal cord (substance P and MMP-1; p ≤ 0.041). The collagen loss (p = 0.008) induced by exposing co-cultures to collagenase was accompanied by altered neuronal activity (p = 0.002) and elevated neuronal MMP-1 (p < 0.001), suggesting microscale collagen degradation mediates sensitivity in vivo. The induction of sustained sensitivity and nociception without joint damage may explain the clinical disconnect in which symptomatic joint pain patients present without radiographic evidence of joint destruction.

Painful cervical radiculopathy is characterized by chronic neuroinflammation that lowers endogenous antioxidant responses leading to the development of oxidative stress and pain after neural trauma. Therefore, antioxidants such as secoisolariciresinol diglucoside (SDG), that promote antioxidant signaling and reduce oxidative damage may also provide pain relief. This study investigated if repeated systemic administration of synthetic SDG after a painful root compression reduces the established pain, oxidative stress and spinal glial activation that are typically evident. SDG was administered on days 1-3 after compression and the extent of oxidative damage in the dorsal root ganglia (DRG) and spinal cord was measured at day 7 using the oxidative stress markers 8-hydroxguanosine (8-OHG) and nitrotyrosine. Spinal microglial and astrocytic activation were also separately evaluated at day 7 after compression. In addition to reducing pain, SDG treatment reduced both spinal 8-OHG and nitrotyrosine, as well as peripheral 8-OHG in the DRG. Moreover, SDG selectively reduced glial activation by decreasing the extent of astrocytic but not microglial activation. These findings suggest that synthetic SDG may attenuate existing radicular pain by suppressing the oxidative stress and astrocytic activation that develop after painful injury, possibly identifying it as a potent therapeutic for painful radiculopathies.

Cervical nerve root injury induces a host of inflammatory mediators in the spinal cord that initiate and maintain neuronal hyperexcitability and pain. Secretory phospholipase A2 (sPLA2) is an enzyme that has been implicated as a mediator of pain onset and maintenance in inflammation and neural injury. Although sPLA2 modulates nociception and excitatory neuronal signaling in vitro, its effects on neuronal activity and central sensitization early after painful nerve root injury are unknown. This study investigated whether inhibiting spinal sPLA2 at the time of nerve root compression (NRC) modulates the pain, dorsal horn hyperexcitability, and spinal genes involved in glutamate signaling, nociception, and inflammation that are seen early after injury. Rats underwent a painful C7 NRC injury with immediate intrathecal administration of the sPLA2 inhibitor thioetheramide-phosphorlycholine. Additional groups underwent either injury alone or sham surgery. One day after injury, behavioral sensitivity, spinal neuronal excitability, and spinal cord gene expression for glutamate receptors (mGluR5 and NR1) and transporters (GLT1 and EAAC1), the neuropeptide substance P, and pro-inflammatory cytokines (TNFα, IL1α, and IL1β) were assessed. Treatment with the sPLA2 inhibitor prevented mechanical allodynia, attenuated neuronal hyperexcitability in the spinal dorsal horn, restored the proportion of spinal neurons classified as wide dynamic range, and reduced genes for mGluR5, substance P, IL1α, and IL1β to sham levels. These findings indicate spinal regulation of central sensitization after painful neuropathy and suggest that spinal sPLA2 is implicated in those early spinal mechanisms of neuronal excitability, perhaps via glutamate signaling, neurotransmitters, or inflammatory cascades.

Treating persistent neuropathic pain remains a major clinical challenge. Current conventional treatment approaches carry a substantial risk of toxicity and provide only transient pain relief. In this work, we show that the activity and expression of the inflammatory mediator secretory phospholipase-A 2 (sPLA 2 ) enzyme increases in the spinal cord after painful nerve root compression. We then develop phospholipid micelle-based nanoparticles that release their payload in response to sPLA 2 activity. Using a rodent model of neuropathic pain, phospholipid micelles loaded with the sPLA 2 inhibitor, thioetheramide-PC (TEA-PC), are administered either locally or intravenously at the time of painful injury or 1-2 days afterward. Local micelle administration immediately after compression prevents pain for up to 7 days. Delayed intravenous administration of the micelles attenuates existing pain. These findings suggest that sPLA 2 inhibitor-loaded micelles can be a promising anti-inflammatory nanotherapeutic for neuropathic pain treatment.

Introduction: Although nonlinear burst and tonic SCS are believed to treat neuropathic pain via distinct pain pathways, the effectiveness of these modalities on brain activity in vivo has not been investigated. This study compared neuronal firing patterns in the brain after nonlinear burst and tonic SCS in a rat model of painful radiculopathy., Methods: Neuronal activity was recorded in the ACC or S1 before and after nonlinear burst or tonic SCS on day 7 following painful cervical nerve root compression (NRC) or sham surgery. The amplitude of nonlinear burst SCS was set at 60% and 90% motor threshold to investigate the effect of lower amplitude SCS on brain activity. Neuronal activity was recorded during and immediately following light brush and noxious pinch of the paw. Change in neuron firing was measured as the percent change in spikes post-SCS relative to pre-SCS baseline., Results: ACC activity decreases during brush after 60% nonlinear burst compared to tonic (p < 0.05) after NRC and compared to 90% nonlinear burst (p < 0.04) and pre-SCS baseline (p < 0.03) after sham. ACC neuron activity decreases (p < 0.01) during pinch after 60% and 90% nonlinear burst compared to tonic for NRC. The 60% of nonlinear burst decreases (p < 0.02) ACC firing during pinch in both groups compared to baseline. In NRC S1 neurons, tonic SCS decreases (p < 0.01) firing from baseline during light brush; 60% nonlinear burst decreases (p < 0.01) firing from baseline during brush and pinch., Conclusions: Nonlinear burst SCS reduces firing in the ACC from a painful stimulus; a lower amplitude nonlinear burst appears to have the greatest effect. Tonic and nonlinear burst SCS may have comparable effects in S1., (© 2020 International Neuromodulation Society.)

Occupational whole-body vibration (WBV) increases the risk of developing low back and neck pain; yet, there has also been an increased use of therapeutic WBV in recent years. Although the resonant frequency (fr) of the spine decreases as the exposure acceleration increases, effects of varying the vibration profile, including peak-to-peak displacement (sptp), root-mean-squared acceleration (arms), and frequency (f), on pain onset are not known. An established in vivo rat model of WBV was used to characterize the resonance of the spine using sinusoidal sweeps. The relationship between arms and fr was defined and implemented to assess behavioral sensitivity-a proxy for pain. Five groups were subjected to a single 30-min exposure, each with a different vibration profile, and a sham group underwent only anesthesia exposure. The behavioral sensitivity was assessed at baseline and for 7 days following WBV-exposure. Only WBV at 8 Hz induced behavioral sensitivity, and the higher arms exposure at 8 Hz led to a more robust pain response. These results suggest that the development of pain is frequency-dependent, but further research into the mechanisms leading to pain is warranted to fully understand which WBV profiles may be detrimental or beneficial., (Copyright © 2020 by ASME.)

Mechanical overloading of the temporomandibular joint (TMJ) and biochemical changes, like inflammation and hypoxia, contribute to cartilage degeneration and pain associated with osteoarthritis (OA). Yet, how overloading contributes to early dysregulation of chondrocytes is not understood, limiting the development of diagnostics and treatments for TMJ OA. Hypoxia-inducible factors (HIF)-1α/2α in chondrocytes were evaluated at Days 8 and 15 in a rat TMJ pain model induced by jaw loading (1 h/day for 7 days) using immunohistochemistry and compared between cases that induce persistent (3.5 N), acute (2 N), or no (0 N) sensitivity. Hypoxia was measured on Day 8 by immunolabeling of the tracer EF5 and 18 F-EF5 PET imaging. To assess the role of tumor necrosis factor (TNF) in painful TMJ loading, intra-articular etanercept was given before loading. Orofacial sensitivity was evaluated during and after loading. Facial grimace, TNF-α, HIF-2α, and hypoxia levels in the TMJ were measured after loading. HIF-2α was elevated (P = .03) after 3.5 N loading at Day 8, but HIF-1α was unchanged. EF5 uptake increased on Day 8 in the 3.5 N group (P < .048) by tissue assay and 18 F-EF5 PET. At Day 8, both HIF-2α (P = .01) and EF5 uptake (P = .005) were correlated with loading magnitude. Etanercept attenuated sensitivity (P < .01) and the facial grimace on Day 7 (P = .01). It also reduced (P < .01) HIF-2α and EF5 uptake on Day 8; but TNF-α levels were not different from controls at that time. Findings suggest that TMJ loading that induces persistent sensitivity upregulates the catabolic factor HIF-2α and reduces oxygen levels in the cartilage, which may be TNF-driven., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Although burst and high-frequency (HF) spinal cord stimulation (SCS) relieve neuropathic pain, their effects on neuronal hyperexcitability have not been compared. Specifically, it is unknown how the recharge components of burst SCS-either actively balanced or allowed to passively return-and/or different frequencies of HF SCS compare in altering neuronal activity. Neuronal firing rates were measured in the spinal dorsal horn on day 7 after painful cervical nerve root compression in the rat. Motor thresholds (MTs) and evoked neuronal recordings were collected during noxious stimuli before (baseline) and after delivery of SCS using different SCS modes: 10 kHz HF, 1.2 kHz HF, burst with active recharge, or burst with passive recharge. Spontaneous firing rates were also evaluated at baseline and after SCS. The average MT for 10 kHz SCS was significantly higher (p < 0.033) than any other mode. Burst with passive recharge was the only SCS mode to significantly reduce evoked (p = 0.019) and spontaneous (p = 0.0076) firing rates after noxious pinch. This study demonstrates that HF and burst SCS have different MTs and effects on both evoked and spontaneous firing rates, indicating they have different mechanisms of providing pain relief. Since burst with passive recharge was the only waveform to reduce firing, that waveform may be important in the neurophysiological response to stimulation.

Developing effective therapies for back pain associated with intervertebral disc (IVD) degeneration is a research priority since it is a major socioeconomic burden and current conservative and surgical treatments have limited success. Polyphenols are naturally occurring compounds in plant-derived foods and beverages, and evidence suggests dietary supplementation with select polyphenol preparations can modulate diverse neurological and painful disorders. This study tested whether supplementation with a select standardized Bioactive-Dietary-Polyphenol-Preparation (BDPP) may alleviate pain symptoms associated with IVD degeneration. Painful IVD degeneration was surgically induced in skeletally-mature rats by intradiscal saline injection into three consecutive lumbar IVDs. Injured rats were given normal or BDPP-supplemented drinking water. In-vivo hindpaw mechanical allodynia and IVD height were assessed weekly for 6 weeks following injury. Spinal column, dorsal-root-ganglion (DRG) and serum were collected at 1 and 6 weeks post-operative (post-op) for analyses of IVD-related mechanical and biological pathogenic processes. Dietary BDPP significantly alleviated the typical behavioral sensitivity associated with surgical procedures and IVD degeneration, but did not modulate IVD degeneration nor changes of pro-inflammatory cytokine levels in IVD. Gene expression analyses suggested BDPP might have an immunomodulatory effect in attenuating the expression of pro-inflammatory cytokines in DRGs. This study supports the idea that dietary supplementation with BDPP has potential to alleviate IVD degeneration-related pain, and further investigations are warranted to identify the mechanisms of action of dietary BDPP., Competing Interests: The authors have declared that no competing interests exist.

Abnormal loading of a joint's ligamentous capsule causes pain by activating the capsule's nociceptive afferent fibers, which reside in the capsule's collagenous matrix alongside fibroblast-like synoviocytes (FLS) and transmit pain to the dorsal root ganglia (DRG). This study integrated FLS into a DRG-collagen gel model to better mimic the anatomy and physiology of human joint capsules; using this new model, the effect of FLS on multiscale biomechanics and cell physiology under load was investigated. Primary FLS cells were co-cultured with DRGs at low or high concentrations, to simulate variable anatomical FLS densities, and failed in tension. Given their roles in collagen degradation and nociception, matrix-metalloproteinase (MMP-1) and neuronal expression of the neurotransmitter substance P were probed after gel failure. The amount of FLS did not alter (p > 0.3) the gel failure force, displacement, or stiffness. FLS doubled regional strains at both low (p < 0.01) and high (p = 0.01) concentrations. For high FLS, the collagen network showed more reorganization at failure (p < 0.01). Although total MMP-1 and neuronal substance P were the same regardless of FLS concentration before loading, protein expression of both increased after failure, but only in low FLS gels (p ≤ 0.02). The concentration-dependent effect of FLS on microstructure and cellular responses implies that capsule regions with different FLS densities experience variable microenvironments. This study presents a novel DRG-FLS co-culture collagen gel system that provides a platform for investigating the complex biomechanics and physiology of human joint capsules, and is the first relating DRG and FLS interactions between each other and their surrounding collagen network., (Copyright © 2019 by ASME.)

Background: Neck pain from cervical facet loading is common and induces inflammation and upregulation of nerve growth factor (NGF) that can sensitize the joint afferents. Yet, the mechanisms by which these occur and whether afferents can be pre-conditioned by certain nonpainful stimuli are unknown. This study tested the hypothesis that a nonpainful mechanical or chemical insult predisposes a facet joint to generate pain after a later exposure to typically nonpainful distraction., Methods: Rats were exposed to either a nonpainful distraction or an intra-articular subthreshold dose of NGF followed by a nonpainful distraction two days later. Mechanical hyperalgesia was measured daily and C6 dorsal root ganglia (DRG) tissue was assayed for NGF and matrix metalloproteinase-3 (MMP-3) expression on day 7., Findings: The second distraction increased joint displacement and strains compared to its first application (p = 0.0011). None of the initial exposures altered behavioral sensitivity in either of the groups being pre-conditioned or in controls; but, sensitivity was established in both groups receiving a second distraction within one day that lasted until day 7 (p < 0.024). NGF expression in the DRG was increased in both groups undergoing a pre-conditioning exposure (p < 0.0232). Similar findings were observed for MMP-3 expression, with a pre-conditioning exposure increasing levels after an otherwise nonpainful facet distraction., Interpretation: These findings suggest that nonpainful insults to the facet joint, when combined, can generate painful outcomes, possibly mediated by upregulation of MMP-3 and mature NGF., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Temporomandibular joint (TMJ) osteoarthritis (OA) is a degenerative disease of the joint that can produce persistent orofacial pain as well as functional and structural changes to its bone, cartilage, and ligaments. Despite advances in the clinical utility and reliability of the Diagnostic Criteria for Temporomandibular Disorders, clinical tools inadequately predict which patients will develop chronic TMJ pain and degeneration, limiting clinical management. The challenges of managing and treating TMJ OA are due, in part, to a limited understanding of the mechanisms contributing to the development and maintenance of TMJ pain. OA is initiated by multiple factors, including injury, aging, abnormal joint mechanics, and atypical joint shape, which can produce microtrauma, remodeling of joint tissues, and synovial inflammation. TMJ microtrauma and remodeling can increase expression of cytokines, chemokines, and catabolic factors that damage synovial tissues and can activate free nerve endings in the joint. Although studies have separately investigated inflammation-driven orofacial pain, acute activity of the trigeminal nerve, or TMJ tissue degeneration and/or damage, the temporal mechanistic factors leading to chronic TMJ pain are undefined. Limited understanding of the interaction between degeneration, intra-articular chemical factors, and pain has further restricted the development of targeted, disease-modifying drugs to help patients avoid long-term pain and invasive procedures, like TMJ replacement. A range of animal models captures features of intra-articular inflammation, joint overloading, and tissue damage. Although those models traditionally measure peripheral sensitivity as a surrogate for pain, recent studies recognize the brain's role in integrating, modulating, and interpreting nociceptive inputs in the TMJ, particularly in light of psychosocial influences on TMJ pain. The articular and neural contributors to TMJ pain, imaging modalities with clinical potential to identify TMJ OA early, and future directions for clinical management of TMJ OA are reviewed in the context of evidence in the field.

No abstract.

A general multi-scale strategy is presented for modeling the mechanical environment of a group of neurons that were embedded within a collagenous matrix. The results of the multi-scale simulation are used to estimate the local strains that arise in neurons when the extracellular matrix is deformed. The distribution of local strains was found to depend strongly on the configuration of the embedded neurons relative to the loading direction, reflecting the anisotropic mechanical behavior of the neurons. More importantly, the applied strain on the surrounding extracellular matrix is amplified in the neurons for all loading configurations that are considered. In the most severe case, the applied strain is amplified by at least a factor of 2 in 10% of the neurons' volume. The approach presented in this paper provides an extension to the capability of past methods by enabling the realistic representation of complex cell geometry into a multi-scale framework. The simulation results for the embedded neurons provide local strain information that is not accessible by current experimental techniques.

Although pre-clinical models of pain are useful for defining relationships between biological mechanisms and pain, common methods testing peripheral sensitivity do not translate to the human pain experience. Facial grimace scales evaluate affective pain levels in rodent models by capturing and scoring spontaneous facial expression. But, the Rat Grimace Scale (RGS) has not assessed the common disorder of temporomandibular joint (TMJ) pain. A rat model of TMJ pain induced by jaw loading (1 hr/day for 7 days) was used to investigate the time course of RGS scores and compare them between different loading magnitudes with distinct peripheral sensitivity profiles (0N-no sensitivity, 2N-acute sensitivity, 3.5N-persistent sensitivity). In the 3.5N group, RGS is elevated over baseline during the loading period and one day after loading and is correlated with peripheral sensitivity (ρ = -0.48, p = 0.002). However, RGS is not elevated later when that group exhibits peripheral sensitivity and moderate TMJ condylar cartilage degeneration. Acutely, RGS is elevated in the 3.5N loading group over the other loading groups (p < 0.001). These findings suggest that RGS is an effective tool for detecting spontaneous TMJ pain and that spontaneous pain is detectable in rats that develop persistent TMJ sensitivity, but not in rats with acute resolving sensitivity.

Painful neuropathic injuries are accompanied by robust inflammatory and oxidative stress responses that contribute to the development and maintenance of pain. After neural trauma the inflammatory enzyme cyclooxygenase-2 (COX-2) increases concurrent with pain onset. Although pre-treatment with the COX-2 inhibitor, meloxicam, before a painful nerve root compression prevents the development of pain, the pathophysiological mechanisms are unknown. This study evaluated if pre-treatment with meloxicam prior to painful root injury prevents pain by reducing spinal inflammation and peripheral oxidative stress. Glial activation and expression of the inflammatory mediator secreted phospholipase A 2 (sPLA 2 ) in the spinal cord were assessed at day 7 using immunohistochemistry. The extent of oxidative damage was measured using the oxidative stress marker, 8-hydroxyguanosine (8-OHG) and localization of 8-OHG with neurons, microglia and astrocytes in the spinal cord and peripherally in the dorsal root ganglion (DRG) at day 7. In addition to reducing pain, meloxicam reduced both spinal microglial and astrocytic activation at day 7 after nerve root compression. Spinal sPLA 2 was also reduced with meloxicam treatment, with decreased production in neurons, microglia and astrocytes. Oxidative damage following nerve root compression was found predominantly in neurons rather than glial cells. The expression of 8-OHG in DRG neurons at day 7 was reduced with meloxicam. These findings suggest that meloxicam may prevent the onset of pain following nerve root compression by suppressing inflammation and oxidative stress both centrally in the spinal cord and peripherally in the DRG., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Repeated loading of ligamentous tissues during repetitive occupational and physical tasks even within physiological ranges of motion has been implicated in the development of pain and joint instability. The pathophysiological mechanisms of pain after repetitive joint loading are not understood. Within the cervical spine, excessive stretch of the facet joint and its capsular ligament has been implicated in the development of pain. Although a single facet joint distraction (FJD) at magnitudes simulating physiologic strains is insufficient to induce pain, it is unknown whether repeated stretching of the facet joint and ligament may produce pain. This study evaluated if repeated loading of the facet at physiologic nonpainful strains alters the capsular ligament's mechanical response and induces pain. Male rats underwent either two subthreshold facet joint distractions (STFJDs) or sham surgeries each separated by 2 days. Pain was measured before the procedure and for 7 days; capsular mechanics were measured during each distraction and under tension at tissue failure. Spinal glial activation was also assessed to probe potential pathophysiologic mechanisms responsible for pain. Capsular displacement significantly increased (p = 0.019) and capsular stiffness decreased (p = 0.008) during the second distraction compared to the first. Pain was also induced after the second distraction and was sustained at day 7 (p < 0.048). Repeated loading weakened the capsular ligament with lower vertebral displacement (p = 0.041) and peak force (p = 0.014) at tissue rupture. Spinal glial activation was also induced after repeated loading. Together, these mechanical, physiological, and neurological findings demonstrate that repeated loading of the facet joint even within physiologic ranges of motion can be sufficient to induce pain, spinal inflammation, and alter capsular mechanics similar to a more injurious loading exposure.

Inter-subject networks are used to model correlations between brain regions and are particularly useful for metabolic imaging techniques, like 18F-2-deoxy-2-(18F)fluoro-D-glucose (FDG) positron emission tomography (PET). Since FDG PET typically produces a single image, correlations cannot be calculated over time. Little focus has been placed on the basic properties of inter-subject networks and if they are affected by group size and image normalization. FDG PET images were acquired from rats (n = 18), normalized by whole brain, visual cortex, or cerebellar FDG uptake, and used to construct correlation matrices. Group size effects on network stability were investigated by systematically adding rats and evaluating local network connectivity (node strength and clustering coefficient). Modularity and community structure were also evaluated in the differently normalized networks to assess meso-scale network relationships. Local network properties are stable regardless of normalization region for groups of at least 10. Whole brain-normalized networks are more modular than visual cortex- or cerebellum-normalized network (p < 0.00001); however, community structure is similar at network resolutions where modularity differs most between brain and randomized networks. Hierarchical analysis reveals consistent modules at different scales and clustering of spatially-proximate brain regions. Findings suggest inter-subject FDG PET networks are stable for reasonable group sizes and exhibit multi-scale modularity.

Background: Painful intervertebral disc (IVD) degeneration has tremendous societal costs and few effective therapies. Intradiscal tumor necrosis factor-alpha (TNFα) is commonly associated with low back pain, but the direct relationship remains unclear., Purpose: Treatment strategies for low back pain require improved understanding of the complex relationships between pain, intradiscal pro-inflammatory cytokines, and structural IVD degeneration. A rat in vivo lumbar IVD puncture model was used to 1) determine the role of TNFα in initiating painful IVD degeneration, and 2) identify statistical relationships between painful behavior, IVD degeneration, and intradiscal pro-inflammatory cytokine expression., Methods: Lumbar IVDs were punctured anteriorly and injected with TNFα, anti-TNFα, or saline and compared with sham and naive controls. Hindpaw mechanical hyperalgesia was assayed weekly to determine pain over time. 6-weeks post-surgery, animals were sacrificed, and IVD degeneration, IVD height, and intradiscal TNFα and interleukin-1 beta (IL-1β) expressions were assayed., Results: Intradiscal TNFα injection increased pain and IVD degeneration whereas anti-TNFα alleviated pain to sham level. Multivariate step-wise linear regression identified pain threshold was predicted by IVD degeneration and intradiscal TNFα expression. Pain threshold was also linearly associated with IVD height loss and IL-1β., Discussion: The significant associations between IVD degeneration, height loss, inflammation, and painful behavior highlight the multifactorial nature of painful IVD degeneration and the challenges to diagnose and treat a specific underlying factor. We concluded that TNFα is an initiator of painful IVD degeneration and its early inhibition can mitigate pain and degeneration. Intradiscal TNFα inhibition following IVD injury may warrant investigation for its potential to alter downstream painful IVD degeneration processes., Competing Interests: Conflict of interest The authors declare no potential conflict of interests.

The complexity of multi-axis spine testing often makes it challenging to compare results from different studies. The aim of this work was to develop and implement a standardized testing protocol across three six-axis spine systems, compare them, and provide stiffness and phase angle limits against which other test systems can be compared. Standardized synthetic lumbar specimens (n=5), comprising three springs embedded in polymer at each end, were tested on each system using pure moments in flexion-extension, lateral bending, and axial rotation. Tests were performed using sine and triangle waves with an amplitude of 8Nm, a frequency of 0.1Hz, and with axial preloads of 0 and 500N. The stiffness, phase angle, and R 2 value of the moment against rotation in the principal axis were calculated at the center of each specimen. The tracking error was adopted asa measure of each test system to minimize non-principal loads, defined as the root mean squared difference between actual and target loads. All three test systems demonstrated similar stiffnesses, with small (<14%) but significant differences in 4 of 12 tests. More variability was observed in the phase angle between the principal axis moment and rotation, with significant differences in 10 of 12 tests. Stiffness and phase angle limits were calculated based on the 95% confidence intervals from all three systems. These recommendations can be used with the standard specimen and testing protocol by other research institutions to ensure equivalence of different spine systems, increasing the ability to compare in vitro spine studies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Injury to the spinal facet capsule, an innervated ligament with heterogeneous collagen organization, produces pain. Although mechanical facet joint trauma activates embedded afferents, it is unclear if, and how, the varied extracellular microstructure of its ligament affects sensory transduction for pain from mechanical inputs. To investigate the effects of macroscopic deformations on afferents in collagen matrices with different organizations, an in vitro neuron-collagen construct (NCC) model was used. NCCs with either randomly organized or parallel aligned collagen fibers were used to mimic the varied microstructure in the facet capsular ligament. Embryonic rat dorsal root ganglia (DRG) were encapsulated in the NCCs; axonal outgrowth was uniform and in all directions in random NCCs, but parallel in aligned NCCs. NCCs underwent uniaxial stretch (0.25 ± 0.06 strain) corresponding to sub-failure facet capsule strains that induce pain. Macroscopic NCC mechanics were measured and axonal expression of phosphorylated extracellular signal-regulated kinase (pERK) and the neurotransmitter substance P (SP) was assayed at 1 day to assess neuronal activation and nociception. Stretch significantly upregulated pERK expression in both random and aligned gels (p < 0.001), with the increase in pERK being significantly higher (p = 0.013) in aligned than in random NCCs. That increase likely relates to the higher peak force (p = 0.025) and stronger axon alignment (p < 0.001) with stretch direction in the aligned NCCs. In contrast, SP expression was greater in stretched NCCs (p < 0.001) regardless of collagen organization. These findings suggest that collagen organization differentially modulates pain-related neuronal signaling and support structural heterogeneity of ligament tissue as mediating sensory function. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:770-777, 2018., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

The facet capsular ligaments encapsulate the bilateral spinal facet joints and are common sources of painful injury due to afferent innervation. These ligaments exhibit architectural complexity, which is suspected to contribute to the experimentally observed lack of co-localization between macroscopic strain and microstructural tissue damage. The heterogeneous and multiscale nature of this ligament, combined with challenges in experimentally measuring its microscale mechanics, hinders the ability to understand sensory mechanisms under normal or injurious loading. Therefore, image-based, subject-specific, multiscale finite-element models were constructed to predict the mechanical responses of the human cervical facet capsular ligament under uniaxial tensile stretch. The models precisely simulated the force-displacement responses for all samples ([Formula: see text]) and showed promise in predicting the magnitude and location of peak regional strains at two different displacements. Yet, there was a loss of agreement between the model and experiment in terms of fiber organization at large tissue stretch, possibly due to a lack of accounting for tissue failure. The mean fiber stretch ratio predicted by the models was found to be significantly higher in regions that exhibited anomalous fiber realignment experimentally than in regions with normal realignment ([Formula: see text]). The development of microstructural abnormalities was associated with the predicted fiber-level stretch ([Formula: see text]), but not with the elemental maximum principal stress or maximum principal strain by logistic regression. The multiscale models elucidate a potential mechanical basis for predicting injury-prone tissue domains and for defining the relationships between macroscopic ligament stretch and microscale pathophysiology in the subfailure regime.

The role of computational modeling for biomechanics research and related clinical care will be increasingly prominent. The biomechanics community has been developing computational models routinely for exploration of the mechanics and mechanobiology of diverse biological structures. As a result, a large array of models, data, and discipline-specific simulation software has emerged to support endeavors in computational biomechanics. Sharing computational models and related data and simulation software has first become a utilitarian interest, and now, it is a necessity. Exchange of models, in support of knowledge exchange provided by scholarly publishing, has important implications. Specifically, model sharing can facilitate assessment of reproducibility in computational biomechanics and can provide an opportunity for repurposing and reuse, and a venue for medical training. The community's desire to investigate biological and biomechanical phenomena crossing multiple systems, scales, and physical domains, also motivates sharing of modeling resources as blending of models developed by domain experts will be a required step for comprehensive simulation studies as well as the enhancement of their rigor and reproducibility. The goal of this paper is to understand current perspectives in the biomechanics community for the sharing of computational models and related resources. Opinions on opportunities, challenges, and pathways to model sharing, particularly as part of the scholarly publishing workflow, were sought. A group of journal editors and a handful of investigators active in computational biomechanics were approached to collect short opinion pieces as a part of a larger effort of the IEEE EMBS Computational Biology and the Physiome Technical Committee to address model reproducibility through publications. A synthesis of these opinion pieces indicates that the community recognizes the necessity and usefulness of model sharing. There is a strong will to facilitate model sharing, and there are corresponding initiatives by the scientific journals. Outside the publishing enterprise, infrastructure to facilitate model sharing in biomechanics exists, and simulation software developers are interested in accommodating the community's needs for sharing of modeling resources. Encouragement for the use of standardized markups, concerns related to quality assurance, acknowledgement of increased burden, and importance of stewardship of resources are noted. In the short-term, it is advisable that the community builds upon recent strategies and experiments with new pathways for continued demonstration of model sharing, its promotion, and its utility. Nonetheless, the need for a long-term strategy to unify approaches in sharing computational models and related resources is acknowledged. Development of a sustainable platform supported by a culture of open model sharing will likely evolve through continued and inclusive discussions bringing all stakeholders at the table, e.g., by possibly establishing a consortium.

Integrins modulate chemically-induced nociception in a variety of inflammatory and neuropathic pain models. Yet, the role of integrins in mechanically-induced pain remains undefined, despite its well-known involvement in cell adhesion and mechanotransduction. Excessive spinal facet capsular ligament stretch is a common injury that induces morphological and functional changes in its innervating afferent neurons and can lead to pain. However, the local mechanisms underlying the translation from tissue deformation to pain signaling are unclear, impeding effective treatment. Therefore, the involvement of the integrin subunit β1 in pain signaling from facet injury was investigated in complementary in vivo and in vitro studies. An anatomical study in the rat identified expression of the integrin subunit β1 in dorsal root ganglion (DRG) neurons innervating the facet, with greater expression in peptidergic than non-peptidergic DRG neurons. Painful facet capsule stretch in the rat upregulated the integrin subunit β1 in small- and medium-diameter DRG neurons at day 7. Inhibiting the α2β1 integrin in a DRG-collagen culture prior to its stretch injury prevented strain-induced increases in axonal substance P (SP) in a dose-dependent manner. Together, these findings suggest that integrin subunit β1-dependent pathways may contribute to SP-mediated pain from mechanical injury of the facet capsular ligament.

Neurotrauma is a common source for a host of neurological disorders, including chronic pain. Pathological changes underlying neural injury and pain are complex due to the multiscale spatiotemporal nature of the nervous system and its response to insults. Understanding the combined influence of tissue mechanics, neuronal and glial activation, and molecular processes on the development and maintenance of pain has recently gained attention. The growing knowledge about nociceptive mechanisms has inspired the design of novel therapeutic materials and compounds for neuronal regulation. Primary mechanical insults and secondary inflammatory responses can induce morphological changes, electrophysiological abnormalities, and altered neurotransmitter release associated with neuronal dysfunction, degeneration, and/or death in both central and peripheral nervous systems. Such responses in afferent and spinal dorsal horn neurons directly and indirectly potentiate pain. Using separate radiculopathy and joint pain models, the mechanical, nociceptive, and inflammatory aspects of pain are reviewed. In that context, biomaterials and compounds with material advantages, neuroprotective benefits, or anti-inflammatory effects to mitigate pain are identified. Several promising techniques to promote neuronal survival and axonal regeneration after injury, including bioactive scaffolds, blocking growth-inhibitory molecules, and active drug delivery, are highlighted. Similar biomaterials-based strategies and molecular intervention have shown promise in attenuating various types of pain. Advancing these and other approaches will help advance and deepen the mechanistic understanding underlying trauma-induced pain across different length scales.

Excessive deformation of nerve fibres (axons) in the spinal facet capsular ligaments (FCLs) can be a cause of pain. The axons are embedded in the fibrous extracellular matrix (ECM) of FCLs, so understanding how local fibre organization and micromechanics modulate their mechanical behaviour is essential. We constructed a computational discrete-fibre model of an axon embedded in a collagen fibre network attached to the axon by distinct fibre-axon connections. This model was used to relate the axonal deformation to the fibre alignment and collagen volume concentration of the surrounding network during transverse, axial and shear deformations. Our results showed that fibre alignment affects axonal deformation only during transverse and axial loading, but higher collagen volume concentration results in larger overall axonal strains for all loading cases. Furthermore, axial loading leads to the largest stretch of axonal microtubules and induces the largest forces on axon's surface in most cases. Comparison between this model and a multiscale continuum model for a representative case showed that although both models predicted similar averaged axonal strains, strain was more heterogeneous in the discrete-fibre model., (© 2017 The Author(s).)