Supraphysiologic Loads Research Articles

Bax Inhibitor-1 preserves pancreatic β-cell proteostasis by limiting proinsulin misfolding and programmed cell death

The prevalence of diabetes steadily increases worldwide mirroring the prevalence of obesity. Endoplasmic reticulum (ER) stress is activated in diabetes and contributes to β-cell dysfunction and apoptosis through the activation of a terminal unfolded protein response (UPR). Our results uncover a new role for Bax Inhibitor-One (BI-1), a negative regulator of inositol-requiring enzyme 1 (IRE1α) in preserving β-cell health against terminal UPR-induced apoptosis and pyroptosis in the context of supraphysiological loads of insulin production. BI-1-deficient mice experience a decline in endocrine pancreatic function in physiological and pathophysiological conditions, namely obesity induced by high-fat diet (HFD). We observed early-onset diabetes characterized by hyperglycemia, reduced serum insulin levels, β-cell loss, increased pancreatic lipases and pro-inflammatory cytokines, and the progression of metabolic dysfunction. Pancreatic section analysis revealed that BI-1 deletion overburdens unfolded proinsulin in the ER of β-cells, confirmed by ultrastructural signs of ER stress with overwhelmed IRE1α endoribonuclease (RNase) activity in freshly isolated islets. ER stress led to β-cell dysfunction and islet loss, due to an increase in immature proinsulin granules and defects in insulin crystallization with the presence of Rod-like granules. These results correlated with the induction of autophagy, ER phagy, and crinophagy quality control mechanisms, likely to alleviate the atypical accumulation of misfolded proinsulin in the ER. In fine, BI-1 in β-cells limited IRE1α RNase activity from triggering programmed β-cell death through apoptosis and pyroptosis (caspase-1, IL-1β) via NLRP3 inflammasome activation and metabolic dysfunction. Pharmaceutical IRE1α inhibition with STF-083010 reversed β-cell failure and normalized the metabolic phenotype. These results uncover a new protective role for BI-1 in pancreatic β-cell physiology as a stress integrator to modulate the UPR triggered by accumulating unfolded proinsulin in the ER, as well as autophagy and programmed cell death, with consequences on β-cell function and insulin secretion.In pancreatic β-cells, BI-1–/– deficiency perturbs proteostasis with proinsulin misfolding, ER stress, terminal UPR with overwhelmed IRE1α/XBP1s/CHOP activation, inflammation, β-cell programmed cell death, and diabetes.

Posterior Horn Lateral Meniscal Root Repair Via Double-Tunnel Transtibial Pullout With Meniscocapsular Release

Background: Lateral meniscal root tears often occur in the acute setting in concert with anterior cruciate ligament (ACL) tears. Severe changes in tibiofemoral biomechanics and joint degeneration are encountered when these injuries are either unrecognized or are treated with meniscectomy; therefore, meniscal root surgical repair is now preferred for longer-term benefits. The most common repair techniques include side-to-side and transtibial pull-out repair, which may be performed via single or double transtibial tunnel techniques. Indications: The primary indication for lateral meniscal root repair with double transtibial tunnels is suspicion for a lateral meniscal root tear based upon injury mechanism, physical examination findings, magnetic resonance imaging findings, and confirmation with diagnostic arthroscopy. Technique Description: The root attachment site is decorticated. Adhesions that cause lateral meniscal root retraction are arthroscopically released. Two separate transtibial tunnels are drilled 5 mm apart from the anterolateral tibia, entering the anterolateral tibia distal to Gerdy’s tubercle and entering the joint at the decorticated lateral root attachment site. Two suture tapes are passed through the torn lateral meniscal root in a vertical mattress configuration and shuttled with a passing suture through the tibial tunnels. The suture tapes are tied over a surgical button on the anterolateral tibia with the knee flexed to approximately 90° while the repair is viewed arthroscopically. Results: Lateral meniscal root repairs are safe and have very low reoperation rates. It has been reported that the transtibial pullout repair technique of the lateral meniscus significantly decreases lateral meniscus extrusion compared with other repair techniques in patients with combined ACL reconstruction. Zhuo et al also reported significantly improved postoperative clinical outcomes compared with the preoperative state in patients who underwent pullout repair for posterior lateral meniscal root avulsion tears. Discussion/Conclusion: The biomechanical and clinical evidence supports concomitant lateral meniscal root repair in the setting of concurrent ACL injury, and no studies to date have demonstrated a clear harm associated with this procedure. In addition, failure to repair the lateral meniscal root places supraphysiologic loads on the ACL graft and may increase the risk of graft failure. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Investigation of the efficacy of an innovative endoscope drying and storage method in a simulated ERCP setting.

Background and study aims Drying after cleaning and disinfection is essential in the reprocessing of endoscopes since microorganisms can grow and form biofilms on wet surfaces. In this experimental non-clinical study, we investigated the efficacy of a novel, fast-drying method when reprocessing duodenoscopes. Methods During a series of 40 tests, three duodenoscopes were exposed to an artificial test soil containing supraphysiological loads of four types of gut microorganisms in a non-clinical ERCP simulation, followed by reprocessing and drying with the PlasmaTYPHOON. Cultures of the distal tip and working channel were acquired immediately after automated decontamination and after drying with the PlasmaTYPHOON. Cobalt chloride paper tests and borescope inspections were used to evaluate drying efficacy. Results Contamination of the working channels dropped from 86.4 % post-decontamination to 33.6 % post-drying, with 94 % of the positive post-drying samples belonging to one duodenoscope. This duodenoscope showed persistent contamination with P. aeruginosa in the working channel. The other two duodenoscopes only showed low levels of P. aeruginosa in post-decontamination channel samples, but not after drying. Cobalt chloride paper tests and borescope inspections revealed good drying efficacy. Conclusions Positive cultures for gut microorganisms were often found in wet endoscopes post-decontamination. The PlasmaTYPHOON is an effective fast-drying method capable of abolishing nearly all remaining microorganisms after decontamination provided no biofilm has developed, even when using a supraphysiological concentration of bacterial load. The clinical use of the PlasmaTYPHOON has the potential to reduce endoscope contamination, the use of wet contaminated endoscopes and therefore the risk of patient infection.

The release of osteoclast-stimulating factors on supraphysiological loading by osteoprogenitors coincides with expression of genes associated with inflammation and cytoskeletal arrangement

Supraphysiological loading induced by unstable orthopedic implants initiates osteoclast formation, which results in bone degradation. We aimed to investigate which mechanosensitive cells in the peri-implant environment produce osteoclast-stimulating factors and how the production of these factors is stimulated by supraphysiological loading. The release of osteoclast-stimulating factors by different types of isolated bone marrow-derived hematopoietic and mesenchymal stem cells from six osteoarthritic patients was analyzed after one hour of supraphysiological loading (3.0 ± 0.2 Pa, 1 Hz) by adding their conditioned medium to osteoclast precursors. Monocytes produced factors that enhanced osteoclastogenesis by 1.6 ± 0.07-fold and mesenchymal stem cells by 1.4 ± 0.07-fold. Medium from osteoprogenitors and pre-osteoblasts enhanced osteoclastogenesis by 1.3 ± 0.09-fold and 1.4 ± 0.03-fold, respectively, where medium from four patients elicited a response and two did not. Next generation sequencing analysis of osteoprogenitors revealed that genes encoding for inflammation-related pathways and cytoskeletal rearrangements were regulated differently between responders and non-responders. Our data suggest that released osteoclast-stimulating soluble factors by progenitor cells in the bone marrow after supraphysiological loading may be related to cytoskeletal arrangement in an inflammatory environment. This connection could be relevant to better understand the aseptic loosening process of orthopedic implants.

Tunable elastomer materials with vascular tissue-like rupture mechanics behavior

Purpose. Laboratory models of human arterial tissues are advantageous to examine the mechanical response of blood vessels in a simplified and controllable manner. In the present study, we investigated three silicone-based materials for replicating the mechanical properties of human arteries documented in the literature. Methods. We performed uniaxial tensile tests up to rupture on Sylgard184, Sylgard170 and DowsilEE-3200 under different curing conditions and obtained their True (Cauchy) stress-strain behavior and Poisson’s ratios by means of digital image correlation (DIC). For each formulation, we derived the constitutive parameters of the 3-term Ogden model and designed numerical simulations of tubular models under a radial pressure of 250 mmHg. Results. Each material exhibits evident non-linear hyperelasticity and dependence on the curing condition. Sylgard184 is the stiffest formulation, with the highest shear moduli and ultimate stresses at relative low strains (μ 184 = 0.52–0.88 MPa, σ 184 = 15.90–16.54 MPa, ε 184 = 0.72–0.96). Conversely, Sylgard170 and DowsilEE-3200 present significantly lower shear moduli and ultimate stresses that are closer to data reported for arterial tissues (μ 170 = 0.33–0.7 MPa σ 170 = 2.61–3.67 MPa, ε 170 = 0.69–0.81; μ dow = 0.02–0.09 MPa σ dow = 0.83–2.05 MPa, ε dow = 0.91–1.05). Under radial pressure, all formulations except DowsilEE-3200 at 1:1 curing ratio undergo circumferential stresses that remain in the elastic region with values ranging from 0.1 to 0.18 MPa. Conclusion. Sylgard170 and DowsilEE-3200 appear to better reproduce the rupture behavior of vascular tissues within their typical ultimate stress and strain range. Numerical models demonstrate that all three materials achieve circumferential stresses similar to human common carotid arteries (Sommer et al 2010), making these formulations suited for cylindrical laboratory models under physiological and supraphysiological loading.

Nonlinear micro finite element models based on digital volume correlation measurements predict early microdamage in newly formed bone

Bone regeneration in critical-sized defects is a clinical challenge, with biomaterials under constant development aiming at enhancing the natural bone healing process. The delivery of bone morphogenetic proteins (BMPs) in appropriate carriers represents a promising strategy for bone defect treatment but optimisation of the spatial-temporal release is still needed for the regeneration of bone with biological, structural, and mechanical properties comparable to the native tissue. Nonlinear micro finite element (μFE) models can address some of these challenges by providing a tool able to predict the biomechanical strength and microdamage onset in newly formed bone when subjected to physiological or supraphysiological loads. Yet, these models need to be validated against experimental data. In this study, experimental local displacements in newly formed bone induced by osteoinductive biomaterials subjected to in situ X-ray computed tomography compression in the apparent elastic regime and measured using digital volume correlation (DVC) were used to validate μFE models. Displacement predictions from homogeneous linear μFE models were highly correlated to DVC-measured local displacements, while tissue heterogeneity capturing mineralisation differences showed negligible effects. Nonlinear μFE models improved the correlation and showed that tissue microdamage occurs at low apparent strains. Microdamage seemed to occur next to large cavities or in biomaterial-induced thin trabeculae, independent of the mineralisation. While localisation of plastic strain accumulation was similar, the amount of damage accumulated in these locations was slightly higher when including material heterogeneity. These results demonstrate the ability of the nonlinear μFE model to capture local microdamage in newly formed bone tissue and can be exploited to improve the current understanding of healing bone and mechanical competence. This will ultimately aid the development of BMPs delivery systems for bone defect treatment able to regenerate bone with optimal biological, mechanical, and structural properties.

A Potential Role of Acute Choroidal Expansion in Nonarteritic Anterior Ischemic Optic Neuropathy.

PurposeNonarteritic anterior ischemic optic neuropathy (NAION) has been associated with a thickened choroid at the optic nerve head (ONH). Here, we use computational modeling to better understand how choroidal expansion and choroidal geometry influence tissue deformation within the ONH relative to intraocular pressure (IOP) and intracranial pressure (ICP) effects.MethodsUsing a model of the posterior eye that included the sclera, peripapillary sclera, annular ring, pia mater, dura mater, neural tissues, Bruch's membrane, choroid, and lamina cribrosa, we examined how varying material properties of ocular tissues influenced ONH deformations under physiological and supra-physiological, or “pathological,” conditions. We considered choroidal expansion (c. 35 µL of expansion), elevated IOP (30 mm Hg), and elevated ICP (20 mm Hg), and calculated peak strains in the ONH relative to a baseline condition representing an individual in the upright position.ResultsSupra-physiological choroidal expansion had the largest impact on strains in the prelaminar neural tissue. In addition, compared to a tapered choroid, a “blunt” choroid insertion at the ONH resulted in higher strains. Elevated IOP and ICP caused the highest strains within the lamina cribrosa and retrolaminar neural tissue, respectively.ConclusionsAcute choroidal expansion caused large deformations of the ONH and these deformations were impacted by choroid geometry. These results are consistent with the concept that compartment syndrome due to the choroid geometry and/or expansion at the ONH contributes to NAION. Prolonged deformations due to supra-physiological loading may induce a mechanobiological response or ischemia, highlighting the potential impact of choroidal expansion on biomechanical strains in the ONH.

Ex vivo biomechanical testing of Funkquist B dorsal laminectomy between the sixth and seventh cervical vertebrae in dogs

ABSTRACT: Dorsal laminectomy is routinely performed for spinal cord compressions or stenosis of the cervical vertebral canal. However, despite good results, relevant complications have been described in dogs. Considering the incomplete understanding of the necessity for complementary surgical stabilization after performing laminectomies in the cervical region, this study compared the resistance and range of motion (ROM) of the cervical spinal column subjected to Funkquist B laminectomy between the sixth and seventh vertebrae in dogs. Forty-four cervical vertebral columns (C2-T1) of dogs, with an average weight of 26.2±3.8 kg, were selected using radiography and computed tomography. Four experimental groups (n=11) were established according to the mechanical test: two control groups (flexion and extension control) and two laminectomy groups (flexion and extension laminectomies). Numerical results of the maximum load for measuring the resistance and ROM of the columns of the two control groups and the two laminectomy groups were compared. The laminectomy groups showed a lower maximum load, regardless of the mechanical test performed (P<0.001). The ROM was not influenced by laminectomy, the type of mechanical test (ventral flexion or extension), or its interaction (P<0.05). There was no interaction between the effect of the laminectomy factors (yes or no) and the effect of the mechanical tests for ventral flexion or extension (P<0.05). In conclusion, Funkquist B dorsal cervical laminectomy between C6 and C7 decreases mechanical resistance with a supraphysiological loading force but does not alter the ROM, suggesting that it can be used without additional mechanical stabilization in dogs.

Effect of Stem Positioning on Biomechanical Performance of a Novel Cementless Short-Stem Canine Total Hip Implant.

The aim of this study was to evaluate the effect of stem positioning on the biomechanical performance of a novel, collared, short-stem total hip implant under compression and torsion ex vivo. Six canine cadaveric femurs were implanted with a collared short-stem femoral implant. Canal flare index (CFI), stem angle, absolute and relative cut heights and relative size were measured radiographically and used as independent variables. Biomechanical performance of the construct was evaluated using physiologic loading (loading) and supraphysiologic loading (failure) protocols. During loading protocols, compressive stiffness was influenced by absolute cut height (p = 0.018). During failure protocols, peak torque was influenced by CFI (p = 0.004) and craniocaudal relative size (p = 0.005). Peak load and torsional stiffness were not impacted by any of the radiographic variables (p > 0.05). Three of six femurs developed longitudinal fractures originating at the medial calcar at the time of failure. The biomechanical performance of the collared short-stem implant was positively impacted by preserving more of the femoral neck, having a higher CFI and using a smaller implant size relative to the femoral neck isthmus.

Nicotine Affects Murine Aortic Stiffness and Fatigue Response During Supraphysiological Cycling.

Nicotine exposure is a major risk factor for several cardiovascular diseases. Although the deleterious effects of nicotine on aortic remodeling processes have been studied to some extent, the biophysical consequences are not fully elucidated. In this investigation, we applied quasi-static and dynamic loading to quantify ways in which exposure to nicotine affects the mechanical behavior of murine arterial tissue. Segments of thoracic aortas from C57BL/6 mice exposed to 25 mg/kg/day of subcutaneous nicotine for 28 days were subjected to uniaxial tensile loading in an open-circumferential configuration. Comparing aorta segments from nicotine-treated mice relative to an equal number of control counterparts, stiffness in the circumferential direction was nearly twofold higher (377 kPa ± 165 kPa versus 191 kPa ± 65 kPa, n = 5, p = 0.03) at 50% strain. Using a degradative power-law fit to fatigue data at supraphysiological loading, we observed that nicotine-treated aortas exhibited significantly higher peak stress, greater loss of tension, and wider oscillation band than control aortas (p ≤ 0.01 for all three variables). Compared to simple stress relaxation tests, fatigue cycling is shown to be more sensitive and versatile in discerning nicotine-induced changes in mechanical behavior over many cycles. Supraphysiological fatigue cycling thus may have broader potential to reveal subtle changes in vascular mechanics caused by other exogenous toxins or pathological conditions.

A High-Throughput Mechanical Activator for Cartilage Engineering Enables Rapid Screening of in vitro Response of Tissue Models to Physiological and Supra-Physiological Loads

Articular cartilage is crucially influenced by loading during development, health, and disease. However, our knowledge of the mechanical conditions that promote engineered cartilage maturation or tissue repair is still incomplete. Current in vitro models that allow precise control of the local mechanical environment have been dramatically limited by very low throughput, usually just a few specimens per experiment. To overcome this constraint, we have developed a new device for the high throughput compressive loading of tissue constructs: the High Throughput Mechanical Activator for Cartilage Engineering (HiT-MACE), which allows the mechanoactivation of 6 times more samples than current technologies. With HiT-MACE we were able to apply cyclic loads in the physiological (e.g., equivalent to walking and normal daily activity) and supra-physiological range (e.g., injurious impacts or extensive overloading) to up to 24 samples in one single run. In this report, we compared the early response of cartilage to physiological and supra-physiological mechanical loading to the response to IL-1β exposure, a common but rudimentary in vitro model of cartilage osteoarthritis. Physiological loading rapidly upregulated gene expression of anabolic markers along the TGF-β1 pathway. Notably, TGF-β1 or serum was not included in the medium. Supra-physiological loading caused a mild catabolic response while IL-1β exposure drove a rapid anabolic shift. This aligns well with recent findings suggesting that overloading is a more realistic and biomimetic model of cartilage degeneration. Taken together, these findings showed that the application of HiT-MACE allowed the use of larger number of samples to generate higher volume of data to effectively explore cartilage mechanobiology, which will enable the design of more effective repair and rehabilitation strategies for degenerative cartilage pathologies.

Pulmonary function with expiratory resistive loading in healthy volunteers.

Expiratory flow limitation is a key characteristic in obstructive pulmonary diseases. To study abnormal lung mechanics isolated from heterogeneities of obstructive disease, we measured pulmonary function in healthy adults with expiratory loading. Thirty-seven volunteers (25±5 yr) completed spirometry and body plethysmography under control and threshold expiratory loading of 7, 11 cmH2O, and a subset at 20 cmH2O (n = 11). We analyzed the shape of the flow-volume relationship with rectangular area ratio (RAR; Ma et al., Respir Med 2010). Airway resistance was increased (p<0.0001) with 7 and 11 cmH2O loading vs control (9.20±1.02 and 11.76±1.68 vs. 2.53± 0.80 cmH2O/L/s). RAR was reduced (p = 0.0319) in loading vs control (0.45±0.07 and 0.47±0.09L vs. 0.48±0.08). FEV1 was reduced (p<0.0001) in loading vs control (3.24±0.81 and 3.23±0.80 vs. 4.04±1.05 L). FVC was reduced (p<0.0001) in loading vs control (4.11±1.01 and 4.14±1.03 vs. 5.03±1.34 L). Peak expiratory flow (PEF) was reduced (p<0.0001) in loading vs control (6.03±1.67 and 6.02±1.84 vs. 8.50±2.81 L/s). FEV1/FVC (p<0.0068) was not clinically significant and FRC (p = 0.4) was not different in loading vs control. Supra-physiologic loading at 20 cmH2O did not result in further limitation. Expiratory loading reduced FEV1, FVC, PEF, but there were no clinically meaningful differences in FEV1/FVC, FRC, or RAR. Imposed expiratory loading likely leads to high airway pressures that resist dynamic airway compression. Thus, a concave expiratory flow-volume relationship was consistently absent–a key limitation for model comparison with pulmonary function in COPD. Threshold loading may be a useful strategy to increase work of breathing or induce dynamic hyperinflation.

Finite element modeling of shape memory alloy stent insertion in the vessel with consideration of vessel damage

One of the common methods to resolve artery stenosis is the insertion of a shape memory alloy stent in the artery. The use of shape memory alloys in the manufacturing of self-expandable stent has expanded because of the superelastic behavior of this alloy. In this paper, we simulated a shape memory alloy stent insertion in an artery to explore stress and damage effects arising from the stent insertion on the artery by using ABAQUS software. To simulate the mechanical behavior of artery, we considered the effect of the inelastic arterial properties (stress softening and recoverable inelastic deformation) that activated under supraphysiological loading in the stenting process, and to simulate stent behavior, the Souza model is used. These two models were applied in ABAQUS by UMAT codes. By using the damage model, the amount of damage in the artery, which is one of the factors of restenosis, is investigated. Also, in this paper, we have used real diseased artery geometry, which was specified from high-resolution magnetic resonance images, therefore the analysis is more in line with reality and it is possible to determine the location of the maximum stress and damage in the artery.

Modeling of Damage Evolution in a Patient-Specific Stenosed Artery upon Stent Deployment

Computational models provide a powerful tool for pre-clinical assessment of medical devices and early evaluation of potential risks to the patient in terms of plaque fragmentation and in-stent restenosis (ISR). Using a suitable constitutive model for arterial tissue is key for the development of a reliable computational model. Although some inelastic phenomena such as stress softening and permanent deformation likely occur due to the supra-physiological loading of arterial tissue during the stenting procedure, hyperelastic constitutive models have been employed in most of the previously developed computational models. This study presents a finite element model for stent deployment into a patient-specific stenosed artery while inelastic arterial behaviors due to supra-physiological loading of the tissue have been considered. Specifically, the maximum stress in the plaque and the arterial layers which is the main cause of plaque fracture during stent deployment and the surgically-induced injury (damage) in the arterial wall, as the main cause of ISR, are presented. The results are compared with the commonly-used hyperelastic behavior for arterial layers. Furthermore, the effects of arterial material parameter variation, analogues to different patients, are investigated. A higher amount of damage is predicted for the artery which shows a higher stress in a specific strain.

Biomechanical Comparison of FiberTape Device Repair Techniques of Ligamentous Lisfranc Injury in Cadaveric Model

Category:Trauma; Basic Sciences/Biologics; Midfoot/Forefoot; SportsIntroduction/Purpose:Lisfranc ligamentous injuries are complex. Controversy exists regarding their treatment and preferred method of fixation. Fixation methods employing a FiberTape device and interference screw fixation have been described as an alternative to traditional screw fixation. The purpose of this biomechanical study was to evaluate two methods of fixation utilizing interference screw fixation with FiberTape augmentation in a cadaveric model.Methods:9 paired cadaveric feet (mid tibia/fibula) were separated into two groups based on fixation method: FiberTape alone and FiberTape with supplementary limb into the middle cuneiform via anchor. At three joints of the midfoot (second metatarsal - medial cuneiform, intermediate cuneiform - medial cuneiform, second metatarsal - intermediate cuneiform), the diastasis and relative angular displacement between bones in the coronal plane were measured for static and cyclic loading. Measurements were obtained for the native (pre-injured), injured, and post-fixation in static loading. Fixed specimens then underwent stepwise increases in cyclic loading performed at 1 Hz and 100 cycles, at 100 N intervals from 500 to 1800 N ground reaction force. The Achilles tendon was also loaded to simulate postoperative weightbearing. Failure of fixation was defined as diastasis at the second metatarsal - medial cuneiform joint greater than 2 millimeters.Results:FiberTape specimens demonstrated diastasis failures of 3 of 9 (33%) specimens at cyclic loads of 1000 N. Conversely, FiberTape with supplementary limb specimens all survived past this loading magnitude, with 1 failing at supraphysiologic loads (>1200 N). The difference in diastasis at the second metatarsal-medial cuneiform joint was statistically significant between the two groups at forces of 1600N (p = 0.019) and 1800N (p = 0.029). There were no significant differences between the other joint diastases and relative angular displacements.Conclusion:The use of FiberTape for fixation of ligamentous Lisfranc injuries appears to provide a biomechanically viable alternative for withstanding early post-operative protected weightbearing. Furthermore, the use of a supplementary limb in addition to the FiberTape fixation method appears to enhance its biomechanical efficacy under cyclic loading especially at higher loads.

The Management of Acute Lumbar Stress Reactions of the Pedicle and Pars in Professional Athletes Playing Collision Sports.

Acute stress reactions in the lumbar spine most commonly occur in athletes at the pars interarticularis followed by the pedicle. These reactions occur as a result of repetitive microtrauma from supraphysiological loads applied to the lumbar spine. Characteristic motions such as trunk extension and twisting are also thought to play a role and may be sport-specific. Other risk factors include increased lumbar lordosis, hamstring and thoracolumbar fascia tightness, and abdominal weakness. On physical examination, pain is typically reproduced with lumbar hyperextension. Currently, magnetic resonance imaging or nuclear imaging remain the most sensitive imaging modalities for identifying acute lesions. In the elite athlete, management of these conditions can be challenging, particularly in those playing collision sports such as American football, hockey, or rugby. Nonoperative treatment is the treatment of choice with rehabilitation programs focused on pain-free positioning and progressive strengthening. Operative treatment is rare, but may be warranted for patients symptomatic for >12 months. Specialized diagnosis protocols as well as treatment and return to play guidelines from 4 physicians treating elite athletes playing collision sports are presented and reviewed.

A damage model for collagen fibres with an application to collagenous soft tissues.

We propose a mechanical model to account for progressive damage in collagen fibres within fibrous soft tissues. The model has a similar basis to the pseudoelastic model that describes the Mullins effect in rubber but it also accounts for the effect of cross-links between collagen fibres. We show that the model is able to capture experimental data obtained from rat tail tendon fibres, and the combined effect of damage and collagen cross-links is illustrated for a simple shear test. The proposed three-dimensional framework allows a straightforward implementation in finite-element codes, which are needed to analyse more complex boundary-value problems for soft tissues under supra-physiological loading or tissues weakened by disease.

Molecular-level collagen damage explains softening and failure of arterial tissues: A quantitative interpretation of CHP data with a novel elasto-damage model

The present experimental-modelling study provides a quantitative interpretation of mechanical data and damage measurements obtained from collagen hybridizing peptide (CHP) techniques on overstretched sheep cerebral arterial tissues. To this aim, a structurally-motivated constitutive model is developed in the framework of continuum damage mechanics. The model includes two internal variables for describing the effects of collagen triple-helical unfolding via interstrand delamination: one governs plastic mechanisms in collagen fibers, leading to a stress softening response of the tissue at the macroscale; the other one describes the loss of fiber structural integrity, leading to tissue final failure. The proposed model is calibrated using the obtained mechanical experimental data, showing excellent fitting capabilities. The predicted evolution of internal variables agree well with independent measurements of molecular-level CHP-based damage data, obtaining an independent a posteriori validation of damage predictions. Moreover, available data on inelastic tissue elongation following supraphysiological loads are successfully reproduced. These outcomes further the hypothesis that the accumulation of interstrand delamination is a primary cause for the evolution of inelastic mechanisms in tissues, and in particular of stress softening up to failure.

Multi-laminate annulus fibrosus repair scaffold with an interlamellar matrix enhances impact resistance, prevents herniation and assists in restoring spinal kinematics

Focal defects in the annulus fibrosus (AF) of the intervertebral disc (IVD) arising from herniation have detrimental impacts on the IVD's mechanical function. Thus, biomimetic-based repair strategies must restore the mechanical integrity of the AF to help support and restore native spinal loading and motion. Accordingly, an annulus fibrosus repair patch (AFRP); a collagen-based multi-laminate scaffold with an angle-ply architecture has been previously developed, which demonstrates similar mechanical properties to native outer AF (oAF). To further enhance the mimetic nature of the AFRP, interlamellar (ILM) glycosaminoglycan (GAG) was incorporated into the scaffolds. The ability of the scaffolds to withstand simulated impact loading and resist herniation of native IVD tissue while contributing to the restoration of spinal kinematics were assessed separately. The results demonstrate that incorporation of a GAG-based ILM significantly increased (p < 0.001) the impact strength of the AFRP (2.57 ± 0.04 MPa) compared to scaffolds without (1.51 ± 0.13 MPa). Additionally, repair of injured functional spinal units (FSUs) with an AFRP in combination with sequestering native NP tissue and a full-thickness AF tissue plug enabled the restoration of creep displacement (p = 0.134), short-term viscous damping coefficient (p = 0.538), the long-term viscous (p = 0.058) and elastic (p = 0.751) damping coefficients, axial neutral zone (p = 0.908), and axial range of motion (p = 0.476) to an intact state. Lastly, the AFRP scaffolds were able to prevent native IVD tissue herniation upon application of supraphysiologic loads (5.28 ± 1.24 MPa). Together, these results suggest that the AFRP has the strength to sequester native NP and AF tissue and/or implants, and thus, can be used in a composite repair strategy for IVDs with focal annular defects thereby assisting in the restoration of spinal kinematics.

Mechanical loading releases osteoclastogenesis-modulating factors through stimulation of the P2X7 receptor in hematopoietic progenitor cells.

Mechanical instability of bone implants stimulate osteoclast differentiation and peri-implant bone loss, leading to prosthetic loosening. It is unclear which cells at the periprosthetic interface transduce mechanical signals into a biochemical response, and subsequently facilitate bone loss. We hypothesized that mechanical overloading of hematopoietic bone marrow progenitor cells, which are located near to the inserted bone implants, stimulates the release of osteoclast-inducing soluble factors. Using a novel in vitro model to apply mechanical overloading, we found that hematopoietic progenitor cells released adenosine triphosphate (ATP) after only 2 min of mechanical loading. The released ATP interacts with its specific receptor P2X7 to stimulate the release of unknown soluble factors that inhibit (physiological loading) or promote (supraphysiological loading) the differentiation of multinucleated osteoclasts derived from bone marrow cultures. Inhibition of ATP-receptor P2X7 by Brilliant Blue G completely abolished the overloading-induced stimulation of osteoclast formation. Likewise, stimulation of P2X7 receptor on hematopoietic cells by BzATP enhanced the release of osteoclastogenesis-stimulating signaling molecules to a similar extent as supraphysiological loading. Supraphysiological loading affected neither gene expression of inflammatory markers involved in aseptic implant loosening (e.g., interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α, and PTGES2) nor expression of the osteoclast modulators receptor activator of nuclear factor κ-Β ligandand osteoprotegerin. Our findings suggest that murine hematopoietic progenitor cells are a potential key player in local mechanical loading-induced bone implant loosening via the ATP/P2X7-axis. Our approach identifies potential therapeutic targets to prevent prosthetic loosening.