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Degenerative disc disease (DDD), regardless of its phenotype and clinical grade, is widely associated with low back pain (LBP), which remains the single leading cause of disability worldwide. This work provides a quantitative methodology for comparatively investigating artificial IVD degeneration via two popular approaches: enzymatic denaturation and fatigue loading. An in-vitro animal study was used to study the time-dependent responses of forty fresh juvenile porcine thoracic IVDs in conjunction with inverse and forward finite element (FE) simulations. The IVDs were dissected from 6-month-old-juvenile pigs and equally assigned to 5 groups (intact, denatured, low-level, medium-level, high-level fatigue loading). Upon preloading, a sinusoid cyclic load (Peak-to-peak/0.1-to-0.8 MPa) was applied (0.01–10 Hz), and dynamic-mechanical-analyses (DMA) was performed. The DMA outcomes were integrated with a robust meta-model analysis to quantify the poroelastic IVD characteristics, while specimen-specific FE models were developed to study the detailed responses. The results demonstrated that enzymatic denaturation had a more significantly pronounced effect on the resistive strength and shock attenuation capabilities of the intervertebral discs. This can be attributed to the simultaneous disruption of the collagen fibers and water-proteoglycan bonds induced by trypsin digestion. Fatigue loading, on the other hand, primarily influenced the disc’s resistance to deformation in a frequency-dependent pattern, where alterations were most noticeable at low loading frequencies. This study confirms the intricate interplay between the biochemical changes induced by enzymatic processes and the mechanical behavior stemming from fatigue loading, suggesting the need for a comprehensive approach to closely mimic the interrelated multifaceted processes of human disc degeneration.

Recently, the glymphatic system has been proposed as a mechanism for waste clearance from the brain parenchyma. Glymphatic dysfunction has previously been shown to be associated with several neurological diseases, including Alzheimer's disease, traumatic brain injury, and stroke. As such, it may serve as an important target for therapeutic interventions. In the present study, very low‐intensity ultrasound (VLIUS) (center frequency, 1 MHz; pulse repetition frequency, 1 kHz; duty factor, 1%; spatial peak temporal average intensity [Ispta] = 3.68 mW cm2; and duration, 5 min) is found to significantly enhance the influx of cerebrospinal fluid tracers into the paravascular spaces of the brain, and further facilitate interstitial substance clearance from the brain parenchyma, including exogenous β‐amyloid. Notably, no evidence of brain damage is observed following VLIUS stimulation. VLIUS may enhance glymphatic influx via the transient receptor potential vanilloid‐4‐aquaporin‐4 pathway in astrocytes. This mechanism may provide insights into VLIUS‐regulated glymphatic function that modifies the natural course of central nervous system disorders related to waste clearance dysfunction. The study investigates the impact of very low‐intensity ultrasound (VLIUS) on glymphatic function, revealing its potential to enhance cerebrospinal fluid influx and β‐amyloid clearance in the brain through the TRPV4‐AQP4 pathway. The findings suggest that VLIUS can be a promising therapeutic approach for neurological disorders associated with glymphatic dysfunction, such as Alzheimer's disease and traumatic brain injury.

Understanding the effect of impact loading on the mechanical response of the intervertebral disc (IVD) is valuable for investigating injury mechanisms and devising effective therapeutic modalities. This study used 24 porcine thoracic motion segments to characterize the mechanical response of intact (N = 8), degenerated (Trypsin-denatured, N = 8), and repaired (Genepin-treated, N = 8) IVDs subject to impact loading. A meta-model analysis of poroelastic finite element simulations was used in combination with ex-vivo creep and impact tests to extract the material properties. Forward analyses using updated specimen-specific FE models were performed to evaluate the effect of impact duration. The maximum axial stress in the IVDs, Von-Mises stress in the endplates, and intradiscal pore pressure (IDP) were calculated, under a 400 N preload, subject to a sequence of impact loads for 10 impact durations (10–100 ms). The results were in good agreement with both creep and impact experiments (error < 10%). A significant difference was found in the maximum axial stress between the intact and degenerated disc groups. The IDP was also significantly lower in the degenerated disc group. The Von Mises stress in the adjacent endplates significantly increased with degeneration. It is concluded that the disc time-dependent response significantly changes with disc degeneration. Cross-linker Genipin has the potential to recover the hydraulic permeability and can potentially change the time dependent response, particularly in the IDP. This is the first study, to our best knowledge, which explores the effect of impact loading on the healthy, degenerated and repaired IVD using both creep and impact validation tests.

Osteoporosis is a continuous process of loss of bone tissue. Compared to women, osteoporosis in men is associated with greater morbidity and mortality. In this study, we conducted tomographic and biomechanical evaluations of trabecular and cortical bone in the early stage of male osteoporosis. Male Wistar rats were subjected to orchiectomy and sham operation. Four weeks after being castrated, decreased levels of testosterone in plasma were found and resulted in concurrent bone loss. Separately, the orchiectomy led to significant tomographic alterations in the trabecular bone number, trabecular separation, and trabecular pattern factor. Data of a mechanistic compression test further showed that the orchiectomy diminished the maximum loading force, displacement at maximum load, energy at maximum load, and ultimate stress. Interestingly, orchiectomy-triggered changes in the maximum loading force and tomographic parameters were highly correlated. In contrast, tomographic and biomechanical analyses showed that 4 weeks after rats were orchiectomized, the thickness, area, maximum loading force, bone stiffness, energy at maximum load, and ultimate stress of the cortical bone were not changed. Taken together, this study showed specific differences in the microarchitecture and strength of trabecular bone in the early stage of male osteoporosis.

The selection of an ideal screw size plays a crucial role in the success of spinal instrumentation as larger diameter screws are thought to provide better fixation strength but increase the risk of pedicle failure during insertion. On the other hand, smaller diameter screws are with lesser risk of pedicle breakage but are thought to compromise the stability of the instrumentation. By investigating the relationship between screw diameter and the pullout strength of pedicle screws after fatigue loading, this study seeks to find quantitative biomechanical data for surgeons in determining the most ideal diameter size screws when performing surgical implementations on osteoporotic vertebrae. Twenty-seven osteoporotic (BMD ranged: 0.353–0.848 g/cm2) thoracic vertebrae (T3-T8) were harvested from 5 human cadavers. Two sizes of poly-axial screws (5.0 mm × 35 and 4.35 mm × 35) were implanted into each pedicles of the vertebrae by an experienced surgeon. Specimens were randomly distributed into control group, fatigue group of 5000 and 10,000 cycles with peak-to-peak loadings of 10–100 N at 1 Hz. Each specimen was then axial pullout tested at a constant rate of 5 mm/min. The ultimate pullout strength (N) & stiffness (N/mm) were obtained for analysis. The results showed that although the larger diameter screws achieved superior pullout strength immediately after the implantation, both sizes of screws exhibited comparable pullout strengths post fatigue loading. This indicates that the smaller diameter screws may be considered for surgical techniques performed on osteoporotic vertebrae for reduced risk of pedicle breakage without sacrificing fixation strength.

Accumulating evidence has shown transcranial low-intensity ultrasound can be potentially a non-invasive neural modulation tool to treat brain diseases. However, the underlying mechanism remains elusive and the majority of studies on animal models applying rather high-intensity ultrasound that cannot be safely used in humans. Here, we showed low-intensity ultrasound was able to activate neurons in the mouse brain and repeated ultrasound stimulation resulted in adult neurogenesis in specific brain regions. In vitro calcium imaging studies showed that a specific ultrasound stimulation mode, which combined with both ultrasound-induced pressure and acoustic streaming mechanotransduction, is required to activate cultured cortical neurons. ASIC1a and cytoskeletal proteins were involved in the low-intensity ultrasound-mediated mechanotransduction and cultured neuron activation, which was inhibited by ASIC1a blockade and cytoskeleton-modified agents. In contrast, the inhibition of mechanical-sensitive channels involved in bilayer-model mechanotransduction like Piezo or TRP proteins did not repress the ultrasound-mediated neuronal activation as efficiently. The ASIC1a-mediated ultrasound effects in mouse brain such as immediate response of ERK phosphorylation and DCX marked neurogenesis were statistically significantly compromised by ASIC1a gene deletion. Collated data suggest that ASIC1a is the molecular determinant involved in the mechano-signaling of low-intensity ultrasound that modulates neural activation in mouse brain.

Morphological changes of the nucleus pulposus (NP) cells occur concomitantly as part of the intervertebral disc (IVD) degeneration and excessive mechanical loading has been speculated as a significant key factor for contributing to such morphological changes. Therefore, we hypothesize that stress exerted on NP cells can cause a deformity of nucleus in response. The changes of cell morphology is observed in degenerative nucleus pulposus. One of the reasons for degeneration of NP is due to overloading of NP especially in the obese population. So the nucleus deformity caused by stress/force is of our study interest. To delineate the effects and role of mechanical stress, we developed a 3D assay using hydrogel cultures with a circular hole generated with needle indentation to simulate a local stress concentration along the edge of the hole. A stressed zone, encompassing 100 μm of range from the circular edge, is defined based on stress concentration calculation to enable quantitative analysis against the control zone. Our results demonstrated that the circular hole produces stress-induced morphological changes in NP cells. The tangential elongation of NP cells and their nucleus shape changes in the stressed zone are significantly increased compared to the non-stressed control zone. It is proposed that the cell elongation is a direct response to elevated stress within the stressed zone. Subsequently we found the stress induced morphological changes of the NP cells can be significantly reduced by inhibiting ASIC3. This suggests ASIC3 plays an important role of play in mechano-signaling of NP cells.

Background Cervical spondylotic myelopathy (CSM) is a degenerative cervical disease in which the spinal cord is compressed. Patients with CSM experience balance disturbance because of impaired proprioception. The weighting of the sensory inputs for postural control in patients with CSM is unclear. Therefore, this study investigated the weighting of sensory systems in patients with CSM. Method Twenty-four individuals with CSM (CSM group) and 24 age-matched healthy adults (healthy control group) were analyzed in this observational study. The functional outcomes (modified Japanese Orthopaedic Association Scale [mJOA], Japanese Orthopaedic Association Cervical Myelopathy Questionnaire [JOACMEQ], Nurick scale) and static balance (eyes-open and eyes-closed conditions) were assessed for individuals with CSM before surgery, 3 and 6 months after surgery. Time-domain and time–frequency-domain variables of the center of pressure (COP) were analyzed to examine the weighting of the sensory systems. Results In the CSM group, lower extremity function of mJOA and Nurick scale significantly improved 3 and 6 months after surgery. Before surgery, the COP mean velocity and total energy were significantly higher in the CSM group than in the control group for both vision conditions. Compared with the control group, the CSM group exhibited lower energy content in the moderate-frequency band (i.e., proprioception) and higher energy content in the low-frequency band (i.e., cerebellar, vestibular, and visual systems) under the eyes-open condition. The COP mean velocity of the CSM group significantly decreased 3 months after surgery. The energy content in the low-frequency band (i.e., visual and vestibular systems) of the CSM group was closed to that of the control group 6 months after surgery under the eyes-open condition. Conclusion Before surgery, the patients with CSM may have had compensatory sensory weighting for postural control, with decreased weighting on proprioception and increased weighting on the other three sensory inputs. After surgery, the postural control of the patients with CSM improved, with decreased compensation for the proprioceptive system from the visual and vestibular inputs. However, the improvement remained insufficient because the patients with CSM still had lower weighting on proprioception than the healthy adults did. Therefore, patients with CSM may require balance training and posture education after surgery. Trial registration Trial Registration number: NCT03396055 Name of the registry: ClinicalTrials.gov Date of registration: January 10, 2018 - Retrospectively registered Date of enrolment of the first participant to the trial: October 19, 2015

PurposeThe subtle impairments of the disc due to anular punctures may have an immediate effect on the functional integrity due to the altered intradiscal pressure, hence the subsequent catabolic degradation. This study evaluates functional restoration of needle puncture injured intervertebral discs with a newly developed injectable hydrogel using the quantitative discomanometry (QD) test. The proposed hydrogel is composed of gelatin and poly (γ-glutamic acid) (γ-PGA) and crosslinked with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC).MethodsThirty-six bovine motion segments were distributed into six groups. Needle puncture injured discs were created in all discs except for those in the first group (intact). The second group included injured discs that received no treatment (injury). The remaining four groups included injured discs repaired with injected hydrogels fabricated with different polymer solutions and EDC concentrations including: gelatin/γ-PGA solution crosslinked with the EDC solution at a 10:1 and 40:1 ratio to form the GP/E(10:1) and GP/E(40:1) groups, respectively, and gelatin and γ-PGA solution crosslinked with the EDC solution at a 10:1 ratio to form the G/E(10:1) or P/E(10:1) groups. The QD tests were performed to evaluate disc integrity of all six groups.ResultsAmong all hydrogel repair groups, the GP/E(10:1) group was found to have the highest leakage and saturate pressure and was the only group comparable to the intact one.ConclusionsRestoration of disc integrity secondary to needle puncture injury can be achieved via the repair with the newly developed gelatin hydrogel incorporated with γ-PGA and EDC.Graphical abstractThese slides can be retrieved under Electronic Supplementary Material.

Patients with cervical myelopathy may manifest impairments in functional activities and balance control caused by compression of the spinal cord. The objective of the current study was to determine long-term changes in the upright balance control of patients with cervical myelopathy who had undergone cervical decompression surgery. This is a prospective cohort study from the preoperative phase to 3 months, 6 months, and 1 year postsurgery. Fifty-three patients with cervical myelopathy were recruited for the cervical myelopathy group and 22 age-matched healthy controls were recruited for the control group. Functional assessments including Japanese Orthopedic Association Cervical Myelopathy Evaluation Questionnaire-Lower Extremity Function (JOACMEQ-LEF) and 10-second step test; as well as balance assessments including postural sway (center-of-pressure: COP) were performed for both groups. The JOACMEQ-LEF (p = 0.036) scores of the myelopathy group improved postoperatively, and a significant decrease in COP variables of postural sway was observed. The upright posture was less stable in the myelopathy group than in the control group (p < 0.05) both before and after surgery. The effect size and standard response mean of the COP variables ranged from −0.49 to 0.03 at 3 months, 6 months, and 1 year postsurgery. The upright balance control had improved significantly 6 months after decompression surgery. However, the balance control of the patients who had undergone decompression surgery remained less stable than that of the age-matched healthy controls. Balance training should be initiated before 6 months postsurgery to accelerate balance control recovery in patients with cervical myelopathy.