Cervical facet capsular ligament mechanics: Estimations based on subject-specific anatomy and kinematics.

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.

Characterization of the L4/L5 rat facet capsular ligament macromechanical and microstructural responses to tensile failure loading.

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.

Intra-articular MMP-1 in the spinal facet joint induces sustained pain and neuronal dysregulation in the DRG and spinal cord, and alters ligament kinematics under tensile loading.

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.

Comprehension Profile of Patient Education Materials in Endocrine Care.

Introduction: The internet is an ever-evolving resource to improve healthcare literacy among patients. The nature of the internet can make it difficult to condense educational materials in a manner applicable to a worldwide patient audience. Within the realm of endocrinology, there is lack of a comprehensive analysis regarding these pathologies in addition to education materials related to their medical work-up or management. The aim of this study was to assess contemporary online patient education material in endocrinology and management of care. Methods: Analysis of the readability of 1,500 unique online education materials was performed utilizing seven readability measures: Flesch Reading Ease (FRE), Flesch-Kincaid Grade Level (FKGL), Gunning Fog Index Readability Formula (FOG), Simple Measure of Gobbledygook Index (SMOG), Coleman-Liau Index (CLI), automated readability index (ARI), and Linsear Write Formula (LWF). Results: The average grade level readability scores from six measures (e.g., FKGL, FOG, SMOG, CLI, ARI, LWF) was more than or equal to 11 which corresponds to a reading level at or above the 11th grade. The average FRE between adrenal, diabetes, and thyroid-related education m aterial ranged between "fairly difficult" to "very difficult". Conclusions: The readability of contemporary online endocrine education material did not meet current readability recommendations for appropriate comprehension of the general audience.

Effect of deploying biomedical equipment technician on the functionality of medical equipment in the government hospitals of rural Nepal.

BACKGROUND: Medical equipment plays a crucial role in the provision of quality healthcare services, despite this more than 50% of equipment in developing countries are non-functioning due to a lack of appropriate human resources to maintain. To address this problem some government hospitals of Nepal have deployed a mid-level technical cadre called 'Biomedical Equipment Technician' (BMET). This study aims to evaluate the effectiveness of deploying a BMET on the functionality of medical equipment in government hospitals of rural Nepal. METHODS: We used a mixed-methods approach with a comparative research design. A comprehensive range of 2189 pieces of medical equipment at 22 hospitals with and without BMET were observed to assess their functional status. Medical equipment were stratified into 6 categories based on department and T tests were conducted. We collected qualitative data from 9 BMETs, 22 medical superintendents, and 22 health staff using semi-structured interviews and focus-group discussions. Thematic content analysis was conducted to explore how the BMET's work was perceived. FINDINGS: The quantity of non-functional devices in hospitals without BMETs was double that of hospitals with BMETs (14% and 7% respectively, p < 0.005). Results were similar across all departments including General (16% versus 3%, p = 0.056), Lab (15% versus 7%, p < 0.005) and Operation Theater (14% versus 5%, p < 0.005). Hospitals with BMETs had fewer overall non-functional devices requiring simple or advanced repair compared to hospitals without BMETs [3% versus 7% (p < 0.005) simple; 4% versus 6% (p < 0.005) advanced]. In our qualitative analysis, we found that BMETs were highly appreciated by hospital staff. Hospital workers perceived that having a BMET on staff, rather than twice-yearly visits from central-level maintenance technicians, is an effective way to keep medical equipment functional. However, without a favorable working environment, the BMET alone cannot perform optimally. CONCLUSIONS: Having a BMET at a rural government hospital has a substantial positive effect on the functional status of medical devices at the hospital. BMETs should be deployed at all rural hospitals to increase the functionality of medical devices, thereby improving the working environment and quality of health services provided.

Inhibiting the ß1integrin subunit increases the strain threshold for neuronal dysfunction under tensile loading in collagen gels mimicking innervated ligaments.

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 ß1 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 ß1 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.

Physiologic facet capsule stretch can induce pain & upregulate matrix metalloproteinase-3 in the dorsal root ganglia when preceded by a physiological mechanical or nonpainful chemical exposure.

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.

Evaluating the in vivo glial response to miniaturized parylene cortical probes coated with an ultra-fast degrading polymer to aid insertion.

OBJECTIVE: Despite the feasibility of short-term neural recordings using implantable microelectrodes, attaining reliable, chronic recordings remains a challenge. Most neural recording devices suffer from a long-term tissue response, including gliosis, at the device-tissue interface. It was hypothesized that smaller, more flexible intracortical probes would limit gliosis by providing a better mechanical match with surrounding tissue. APPROACH: This paper describes the in vivo evaluation of flexible parylene microprobes designed to improve the interface with the adjacent neural tissue to limit gliosis and thereby allow for improved recording longevity. The probes were coated with an ultrafast degrading tyrosine-derived polycarbonate (E5005(2K)) polymer that provides temporary mechanical support for device implantation, yet degrades within 2 h post-implantation. A parametric study of probes of varying dimensions and polymer coating thicknesses were implanted in rat brains. The glial tissue response and neuronal loss were assessed from 72 h to 24 weeks post-implantation via immunohistochemistry. MAIN RESULTS: Experimental results suggest that both probe and polymer coating sizes affect the extent of gliosis. When an appropriate sized coating dimension (100 µm × 100 µm) and small probe (30 µm × 5 µm) was implanted, a minimal post-implantation glial response was observed. No discernible gliosis was detected when compared to tissue where a sham control consisting of a solid degradable polymer shuttle of the same dimensions was inserted. A larger polymer coating (200 µm × 200 µm) device induced a more severe glial response at later time points, suggesting that the initial insertion trauma can affect gliosis even when the polymer shuttle degrades rapidly. A larger degree of gliosis was also observed when comparing a larger sized probe (80 µm × 5 µm) to a smaller probe (30 µm × 5 µm) using the same polymer coating size (100 µm × 100 µm). There was no significant neuronal loss around the implantation sites for most device candidates except the group with largest polymer coating and probe sizes. SIGNIFICANCE: These results suggest that: (1) the degree of mechanical trauma at device implantation and mechanical mismatches at the probe-tissue interface affect long term gliosis; (2) smaller, more flexible probes may minimize the glial response to provide improved tissue biocompatibility when used for chronic neural signal recording; and (3) some degree of glial scarring did not significantly affect neuronal distribution around the probe.

Collagen organization regulates stretch-initiated pain-related neuronal signals in vitro: Implications for structure-function relationships in innervated ligaments.

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.

Estimating axonal strain and failure following white matter stretch using contactin-associated protein as a fiduciary marker.

Axonal injury occurs during trauma when tissue-scale loads are transferred to individual axons. Computational models are used to understand this transfer and predict the circumstances that cause injury. However, these findings are limited by a lack of validating experimental work examining the mechanics of axons in their in situ state. As a first step towards validation for dynamic stretch, we use contactin-associated protein (Caspr), expressed at the nodes of Ranvier, as a fiduciary marker of quasistatic axonal stretch. We measured changes in the distance between immunolabled Caspr pairs along axons as a function of tissue-level stretch in chick embryo spinal cords harvested from different developmental periods. We then identified and characterized broken axons and adapted a kinematic model published previously by our group (Singh et al., 2015) to estimate average strain thresholds for axon mechanical failure. The distance between Caspr pairs increased with stretch, though not as much as predicted by simple continuum mechanics. For equivalent tissue stretch, greater numbers of broken axons were found at later stages of development. In adapting our kinematic model to predict a breaking threshold strain, we found that breaking thresholds decrease with development stage. When thresholds were split and classified based on kinematic behavior, non-affine, uncoupled axons had higher strain thresholds than affine, coupled axons, corroborating thresholds predicted from in vitro and in vivo preparations. These results provide a valuable launching point for generating more accurate multi-scale models in primary central nervous system injury.

Modeling the Insertion Mechanics of Flexible Neural Probes Coated with Sacrificial Polymers for Optimizing Probe Design.

Single-unit recording neural probes have significant advantages towards improving signal-to-noise ratio and specificity for signal acquisition in brain-to-computer interface devices. Long-term effectiveness is unfortunately limited by the chronic injury response, which has been linked to the mechanical mismatch between rigid probes and compliant brain tissue. Small, flexible microelectrodes may overcome this limitation, but insertion of these probes without buckling requires supporting elements such as a stiff coating with a biodegradable polymer. For these coated probes, there is a design trade-off between the potential for successful insertion into brain tissue and the degree of trauma generated by the insertion. The objective of this study was to develop and validate a finite element model (FEM) to simulate insertion of coated neural probes of varying dimensions and material properties into brain tissue. Simulations were performed to predict the buckling and insertion forces during insertion of coated probes into a tissue phantom with material properties of brain. The simulations were validated with parallel experimental studies where probes were inserted into agarose tissue phantom, ex vivo chick embryonic brain tissue, and ex vivo rat brain tissue. Experiments were performed with uncoated copper wire and both uncoated and coated SU-8 photoresist and Parylene C probes. Model predictions were found to strongly agree with experimental results (<10% error). The ratio of the predicted buckling force-to-predicted insertion force, where a value greater than one would ideally be expected to result in successful insertion, was plotted against the actual success rate from experiments. A sigmoidal relationship was observed, with a ratio of 1.35 corresponding to equal probability of insertion and failure, and a ratio of 3.5 corresponding to a 100% success rate. This ratio was dubbed the "safety factor", as it indicated the degree to which the coating should be over-designed to ensure successful insertion. Probability color maps were generated to visually compare the influence of design parameters. Statistical metrics derived from the color maps and multi-variable regression analysis confirmed that coating thickness and probe length were the most important features in influencing insertion potential. The model also revealed the effects of manufacturing flaws on insertion potential.

Characterization of the three-dimensional kinematic behavior of axons in central nervous system white matter.

Traumatic injury to axons in white matter of the brain and spinal cord occurs primarily via tensile stretch. During injury, the stress and strain experienced at the tissue level is transferred to the microscopic axons. How this transfer occurs, and the primary constituents dictating this transfer must be better understood to develop more accurate multi-scale models of injury. Previous studies have characterized axon tortuosity and kinematic behavior in 2-dimensions (2-D), where axons have been modeled to exhibit non-affine (discrete), affine (composite-like), or switching behavior. In this study, we characterize axon tortuosity and model axon kinematic behavior in 3-dimensions (3-D). Embryonic chick spinal cords at different development stages were excised and stretched. Cords were then fixed, transversely sectioned, stained, and imaged. 3-D axon tortuosity was measured from confocal images using a custom-built MATLAB script. 2-D kinematic models previously described in Bain et al. (J Biomech Eng 125(6):798, 2003) were extended, re-derived, and validated for the 3-D case. Results showed that 3-D tortuosity decreased with stretch, exhibiting similar trends with changes in development as observed in the 2-D studies. Kinematic parameters also displayed similar general trends. Axons demonstrated more affine behavior with increasing stretch and development. In comparison with 2-D results, a smaller percentage of the populations of 3-D axons were predicted to follow pure non-affine behavior. The data and kinematic models presented herein can be incorporated into multi-scale CNS injury models, which can advance the accuracy of the models and improve the potential to identify axonal injury thresholds.

Coating flexible probes with an ultra fast degrading polymer to aid in tissue insertion.

We report a fabrication process for coating neural probes with an ultrafast degrading polymer to create consistent and reproducible devices for neural tissue insertion. The rigid polymer coating acts as a probe insertion aid, but resorbs within hours post-implantation. Despite the feasibility for short term neural recordings from currently available neural prosthetic devices, most of these devices suffer from long term gliosis, which isolates the probes from adjacent neurons, increasing the recording impedance and stimulation threshold. The size and stiffness of implanted probes have been identified as critical factors that lead to this long term gliosis. Smaller, more flexible probes that match the mechanical properties of brain tissue could allow better long term integration by limiting the mechanical disruption of the surrounding tissue during and after probe insertion, while being flexible enough to deform with the tissue during brain movement. However, these small flexible probes inherently lack the mechanical strength to penetrate the brain on their own. In this work, we have developed a micromolding method for coating a non-functional miniaturized SU-8 probe with an ultrafast degrading tyrosine-derived polycarbonate (E5005(2K)). Coated, non-functionalized probes of varying dimensions were reproducibly fabricated with high yields. The polymer erosion/degradation profiles of the probes were characterized in vitro. The probes were also mechanically characterized in ex vivo brain tissue models by measuring buckling and insertion forces during probe insertion. The results demonstrate the ability to produce polymer coated probes of consistent quality for future in vivo use, for example to study the effects of different design parameters that may affect tissue response during long term chronic intra-cortical microelectrode neural recordings.