3D-DXA Based Finite Element Modelling for Femur Strength Prediction: Evaluation Against QCT.

Osteoporosis is characterised by the loss of bone density resulting in an increased risk of fragility fractures. The clinical gold standard for diagnosing osteoporosis is based on the areal bone mineral density (aBMD) used as a surrogate for bone strength, in combination with clinical risk factors. Finite element (FE) analyses based on quantitative computed tomography (QCT) have been shown to estimate bone strength better than aBMD. However, their application in the osteoporosis clinics is limited due to exposure of patients to increased X-rays radiation dose. Statistical modelling methods (3D-DXA) enabling the estimation of 3D femur shape and volumetric bone density from dual energy X-ray absorptiometry (DXA) scan have been shown to improve osteoporosis management. The current study used 3D-DXA based FE analyses to estimate femur strength from the routine clinical DXA scans and compared its results against 151 QCT based FE analyses, in a clinical cohort of 157 subjects. The linear regression between the femur strength predicted by QCT-FE and 3D-DXA-FE models correlated highly (coefficient of determination R2 = 0.86) with a root mean square error (RMSE) of 397 N. In conclusion, the current study presented a 3D-DXA-FE modelling tool providing accurate femur strength estimates noninvasively, compared to QCT-FE models.

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research.

Intervertebral disc (IVD) degeneration is a major risk factor of low back pain. It is defined by a progressive loss of the IVD structure and functionality, leading to severe impairments with restricted treatment options due to the highly demanding mechanical exposure of the IVD. Degenerative changes in the IVD usually increase with age but at an accelerated rate in some individuals. To understand the initiation and progression of this disease, it is crucial to identify key top-down and bottom-up regulations' processes, across the cell, tissue, and organ levels, in health and disease. Owing to unremitting investigation of experimental research, the comprehension of detailed cell signaling pathways and their effect on matrix turnover significantly rose. Likewise, in silico research substantially contributed to a holistic understanding of spatiotemporal effects and complex, multifactorial interactions within the IVD. Together with important achievements in the research of biomaterials, manifold promising approaches for regenerative treatment options were presented over the last years. This review provides an integrative analysis of the current knowledge about (1) the multiscale function and regulation of the IVD in health and disease, (2) the possible regenerative strategies, and (3) the in silico models that shall eventually support the development of advanced therapies.

An intact fibula may contribute to allow early weight bearing in surgically treated tibial plateau fractures.

PURPOSE: The role of the proximal tibiofibular joint (PTFJ) in tibial plateau fractures is unknown. The purpose of this study was to assess, with finite-element (FE) calculations, differences in interfragmentary movement (IFM) in a split fracture of lateral tibial plateau, with and without intact fibula. It was hypothesized that an intact fibula could positively contribute to the mechanical stabilization of surgically reduced lateral tibial plateau fractures. METHODS: A split fracture of the lateral tibial plateau was recreated in an FE model of a human tibia. A three-dimensional FE model geometry of a human femur-tibia system was obtained from the VAKHUM project database, and was built from CT images from a subject with normal bone morphologies and normal alignment. The mesh of the tibia was reconverted into a geometry of NURBS surfaces. The fracture was reproduced using geometrical data from patient radiographs, and two models were created: one with intact fibula and other without fibula. A locking screw plate and cannulated screw systems were modelled to virtually reduce the fracture, and 80 kg static body weight was simulated. RESULTS: Under mechanical loads, the maximum interfragmentary movement achieved with the fibula was about 30% lower than without fibula, with both the cannulated screws and the locking plate. When the locking plate model was loaded, intact fibula contributed to lateromedial forces on the fractured fragments, which would be clinically translated into increased normal compression forces in the fractured plane. The intact fibula also reduced the mediolateral forces with the cannulated screws, contributing to stability of the construct. CONCLUSION: This FE model showed that an intact fibula contributes to the mechanical stability of the lateral tibial plateau. In combination with a locking plate fixation, early weight bearing may be allowed without significant IFM, contributing to an early clinical and functional recovery of the patient.

Virtual exploration of early stage atherosclerosis.

MOTIVATION: Biological mechanisms contributing to atherogenesis are multiple and complex. The early stage of atherosclerosis (AS) is characterized by the accumulation of low-density lipoprotein (LDL) droplets, leading to the creation of foam cells (FC). To address the difficulty to explore the dynamics of interactions that controls this process, this study aimed to develop a model of agents and infer on the most influential cell- and molecule-related parameters. RESULTS: FC started to accumulate after six to eight months of simulated hypercholesterolemia. A sensitivity analysis revealed the strong influence of LDL oxidation rate on the risk of FC creation, which was exploited to model the antioxidant effect of statins. Combined with an empirical simulation of the drug ability to decrease the level of LDL, the virtual statins treatment led to reductions of oxidized LDL levels similar to reductions measured in vivo. AVAILABILITY AND IMPLEMENTATION: An Open source software was used to develop the agent-based model of early AS. Two different concentrations of LDL agents were imposed in the intima layer to simulate healthy and hypercholesterolemia groups of 'virtual patients'. The interactions programmed between molecules and cells were based on experiments and models reported in the literature. A factorial sensitivity analysis explored the respective effects of the less documented model parameters as (i) agent migration speed, (ii) LDL oxidation rate and (iii) concentration of autoantibody agents. Finally, the response of the model to known perturbations was assessed by introducing statins agents, able to reduce the oxidation rate of LDL agents and the LDL boundary concentrations. CONTACT: jerome.noailly@upf.eduSupplementary information: Supplementary data are available at Bioinformatics online.

Fixation of a split fracture of the lateral tibial plateau with a locking screw plate instead of cannulated screws would allow early weight bearing: a computational exploration.

PURPOSE: To assess, with finite element (FE) calculations, whether immediate weight bearing would be possible after surgical stabilization either with cannulated screws or with a locking plate in a split fracture of the lateral tibial plateau (LTP). METHODS: A split fracture of the LTP was recreated in a FE model of a human tibia. A three-dimensional FE model geometry of a human femur-tibia system was obtained from the VAKHUM project database, and was built from CT images from a subject with normal bone morphologies and normal alignment. The mesh of the tibia was reconverted into a geometry of NURBS surfaces. A split fracture of the lateral tibial plateau was reproduced by using geometrical data from patient radiographs. A locking screw plate (LP) and a cannulated screw (CS) systems were modelled to virtually reduce the fracture and 80 kg static body-weight was simulated. RESULTS: While the simulated body-weight led to clinically acceptable interfragmentary motion, possible traumatic bone shear stresses were predicted nearby the cannulated screws. With a maximum estimation of about 1.7 MPa maximum bone shear stresses, the Polyax system might ensure more reasonable safety margins. CONCLUSIONS: Split fractures of the LTP fixed either with locking screw plate or cannulated screws showed no clinically relevant IFM in a FE model. The locking screw plate showed higher mechanical stability than cannulated screw fixation. The locking screw plate might also allow full or at least partial weight bearing under static posture at time zero.

The interplay between biochemical mediators and mechanotransduction in chondrocytes: Unravelling the differential responses in primary knee osteoarthritis.

In primary or idiopathic osteoarthritis (OA), it is unclear which factors trigger the shift of articular chondrocyte activity from pro-anabolic to pro-catabolic. In fact, there is a controversy about the aetiology of primary OA, either mechanical or inflammatory. Chondrocytes are mechanosensitive cells, that integrate mechanical stimuli into cellular responses in a process known as mechanotransduction. Mechanotransduction occurs thanks to the activation of mechanosensors, a set of specialized proteins that convert physical cues into intracellular signalling cascades. Moderate levels of mechanical loads maintain normal tissue function and have anti-inflammatory effects. In contrast, mechanical over- or under-loading might lead to cartilage destruction and increased expression of pro-inflammatory cytokines. Simultaneously, mechanotransduction processes can regulate and be regulated by pro- and anti-inflammatory soluble mediators, both local (cells of the same joint, i.e., the chondrocytes themselves, infiltrating macrophages, fibroblasts or osteoclasts) and systemic (from other tissues, e.g., adipokines). Thus, the complex process of mechanotransduction might be altered in OA, so that cartilage-preserving chondrocytes adopt a different sensitivity to mechanical signals, and mechanic stimuli positively transduced in the healthy cartilage may become deleterious under OA conditions. This review aims to provide an overview of how the biochemical exposome of chondrocytes can alter important mechanotransduction processes in these cells. Four principal mechanosensors, i.e., integrins, Ca2+ channels, primary cilium and Wnt signalling (canonical and non-canonical) were targeted. For each of these mechanosensors, a brief summary of the response to mechanical loads under healthy or OA conditions is followed by a concise overview of published works that focus on the further regulation of the mechanotransduction pathways by biochemical factors. In conclusion, this paper discusses and explores how biological mediators influence the differential behaviour of chondrocytes under mechanical loads in healthy and primary OA.

Characterization of clinical data for patient stratification in moderate osteoarthritis with support vector machines, regulatory network models, and verification against osteoarthritis Initiative data.

Knee osteoarthritis (OA) diagnosis is based on symptoms, assessed through questionnaires such as the WOMAC. However, the inconsistency of pain recording and the discrepancy between joint phenotype and symptoms highlight the need for objective biomarkers in knee OA diagnosis. To this end, we study relationships among clinical and molecular data in a cohort of women (n = 51) with Kellgren-Lawrence grade 2-3 knee OA through a Support Vector Machine (SVM) and a regulation network model. Clinical descriptors (i.e., pain catastrophism, depression, functionality, joint pain, rigidity, sensitization and synovitis) are used to classify patients. A Youden's test is performed for each classifier to determine optimal binarization thresholds for the descriptors. Thresholds are tested against patient stratification according to baseline WOMAC data from the Osteoarthritis Initiative, and the mean accuracy is 0.97. For our cohort, the data used as SVM inputs are knee OA descriptors, synovial fluid proteomic measurements (n = 25), and transcription factor activation obtained from regulatory network model stimulated with the synovial fluid measurements. The relative weights after classification reflect input importance. The performance of each classifier is evaluated through ROC-AUC analysis. The best classifier with clinical data is pain catastrophism (AUC = 0.9), highly influenced by funcionality and pain sensetization, suggesting that kinesophobia is involved in pain perception. With synovial fluid proteins used as input, leptin strongly influences every classifier, suggesting the importance of low-grade inflammation. When transcription factors are used, the mean AUC is limited to 0.608, which can be related to the pleomorphic behaviour of osteoarthritic chondrocytes. Nevertheless, funcionality has an AUC of 0.7 with a decisive importance of FOXO downregulation. Though larger and longitudinal cohorts are needed, this unique combination of SVM and regulatory network model shall help to stratify knee OA patients more objectively.

Unveiling interactions between intervertebral disc morphologies and mechanical behavior through personalized finite element modeling.

Introduction: Intervertebral Disc (IVD) Degeneration (IDD) is a significant health concern, potentially influenced by mechanotransduction. However, the relationship between the IVD phenotypes and mechanical behavior has not been thoroughly explored in local morphologies where IDD originates. This work unveils the interplays among morphological and mechanical features potentially relevant to IDD through Abaqus UMAT simulations. Methods: A groundbreaking automated method is introduced to transform a calibrated, structured IVD finite element (FE) model into 169 patient-personalized (PP) models through a mesh morphing process. Our approach accurately replicates the real shapes of the patient's Annulus Fibrosus (AF) and Nucleus Pulposus (NP) while maintaining the same topology for all models. Using segmented magnetic resonance images from the former project MySpine, 169 models with structured hexahedral meshes were created employing the Bayesian Coherent Point Drift++ technique, generating a unique cohort of PP FE models under the Disc4All initiative. Machine learning methods, including Linear Regression, Support Vector Regression, and eXtreme Gradient Boosting Regression, were used to explore correlations between IVD morphology and mechanics. Results: We achieved PP models with AF and NP similarity scores of 92.06\% and 92.10\% compared to the segmented images. The models maintained good quality and integrity of the mesh. The cartilage endplate (CEP) shape was represented at the IVD-vertebra interfaces, ensuring personalized meshes. Validation of the constitutive model against literature data showed a minor relative error of 5.20%. Discussion: Analysis revealed the influential impact of local morphologies on indirect mechanotransduction responses, highlighting the roles of heights, sagittal areas, and volumes. While the maximum principal stress was influenced by morphologies such as heights, the disc's ellipticity influenced the minimum principal stress. Results suggest the CEPs are not influenced by their local morphologies but by those of the AF and NP. The generated free-access repository of individual disc characteristics is anticipated to be a valuable resource for the scientific community with a broad application spectrum.

Dataset of Finite Element Models of Normal and Deformed Thoracolumbar Spine.

Adult spine deformity (ASD) is prevalent and leads to a sagittal misalignment in the vertebral column. Computational methods, including Finite Element (FE) Models, have emerged as valuable tools for investigating the causes and treatment of ASD through biomechanical simulations. However, the process of generating personalised FE models is often complex and time-consuming. To address this challenge, we present a dataset of FE models with diverse spine morphologies that statistically represent real geometries from a cohort of patients. These models are generated using EOS images, which are utilized to reconstruct 3D surface spine models. Subsequently, a Statistical Shape Model (SSM) is constructed, enabling the adaptation of a FE hexahedral mesh template for both the bone and soft tissues of the spine through mesh morphing. The SSM deformation fields facilitate the personalization of the mean hexahedral FE model based on sagittal balance measurements. Ultimately, this new hexahedral SSM tool offers a means to generate a virtual cohort of 16807 thoracolumbar FE spine models, which are openly shared in a public repository.

The role of the pulmonary veins on left atrial flow patterns and thrombus formation.

Atrial fibrillation (AF) is the most common human arrhythmia, forming thrombi mostly in the left atrial appendage (LAA). However, the relation between LAA morphology, blood patterns and clot formation is not yet fully understood. Furthermore, the impact of anatomical structures like the pulmonary veins (PVs) have not been thoroughly studied due to data acquisition difficulties. In-silico studies with flow simulations provide a detailed analysis of blood flow patterns under different boundary conditions, but a limited number of cases have been reported in the literature. To address these gaps, we investigated the influence of PVs on LA blood flow patterns and thrombus formation risk through computational fluid dynamics simulations conducted on a sizeable cohort of 130 patients, establishing the largest cohort of patient-specific LA fluid simulations reported to date. The investigation encompassed an in-depth analysis of several parameters, including pulmonary vein orientation (e.g., angles) and configuration (e.g., number), LAA and LA volumes as well as their ratio, flow, and mass-less particles. Our findings highlight the total number of particles within the LAA as a key parameter for distinguishing between the thrombus and non-thrombus groups. Moreover, the angles between the different PVs play an important role to determine the flow going inside the LAA and consequently the risk of thrombus formation. The alignment between the LAA and the main direction of the left superior pulmonary vein, or the position of the right pulmonary vein when it exhibits greater inclination, had an impact to distinguish the control group vs. the thrombus group. These insights shed light on the intricate relationship between PV configuration, LAA morphology, and thrombus formation, underscoring the importance of comprehensive blood flow pattern analyses.

Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis.

Osteoarthritis (OA) is a debilitating joint disease characterized by articular cartilage degradation, inflammation and pain. An extensive range of in vivo and in vitro studies evidences that mechanical loads induce changes in chondrocyte gene expression, through a process known as mechanotransduction. It involves cascades of complex molecular interactions that convert physical signals into cellular response(s) that favor either chondroprotection or cartilage destruction. Systematic representations of those interactions can positively inform early strategies for OA management, and dynamic modelling allows semi-quantitative representations of the steady states of complex biological system according to imposed initial conditions. Yet, mechanotransduction is rarely integrated. Hence, a novel mechano-sensitive network-based model is proposed, in the form of a continuous dynamical system: an interactome of a set of 118 nodes, i.e., mechano-sensitive cellular receptors, second messengers, transcription factors and proteins, related among each other through a specific topology of 358 directed edges is developed. Results show that under physio-osmotic initial conditions, an anabolic state is reached, whereas initial perturbations caused by pro-inflammatory and injurious mechanical loads leads to a catabolic profile of node expression. More specifically, healthy chondrocyte markers (Sox9 and CITED2) are fully expressed under physio-osmotic conditions, and reduced under inflammation, or injurious loadings. In contrast, NF-κB and Runx2, characteristic of an osteoarthritic chondrocyte, become activated under inflammation or excessive loading regimes. A literature-based evaluation shows that the model can replicate 94% of the experiments tested. Sensitivity analysis based on a factorial design of a treatment shows that inflammation has the strongest influence on chondrocyte metabolism, along with a significant deleterious effect of static compressive loads. At the same time, anti-inflammatory therapies appear as the most promising ones, though the restoration of structural protein production seems to remain a major challenge even in beneficial mechanical environments. The newly developed mechano-sensitive network model for chondrocyte activity reveals a unique potential to reflect load-induced chondroprotection or articular cartilage degradation in different mechano-chemical-environments.

Proximal Junction Failure in Spine Surgery: Integrating Geometrical and Biomechanical Global Descriptors Improves GAP Score-Based Assessment.

STUDY DESIGN: Retrospective observational study. OBJECTIVE: Biomechanical and geometrical descriptors are used to improve global alignment and proportion (GAP) prediction accuracy to detect proximal junctional failure (PJF). SUMMARY OF BACKGROUND DATA: PJF is probably the most important complication after sagittal imbalance surgery. The GAP score has been introduced as an effective predictor for PJF, but it fails in certain situations. In this study, 112 patient records were gathered (57 PJF; 55 controls) with biomechanical and geometrical descriptors measured to stratify control and failure cases. PATIENTS AND METHODS: Biplanar EOS radiographs were used to build 3-dimensional full-spine models and determine spinopelvic sagittal parameters. The bending moment (BM) was calculated as the upper body mass times, the effective distance to the body center of mass at the adjacent upper instrumented vertebra +1. Other geometrical descriptors such as full balance index (FBI), spino-sacral angle (SSA), C7 plumb line/sacrofemoral distance ratio (C7/SFD ratio), T1-pelvic angle (TPA), and cervical inclination angle (CIA) were also evaluated. The respective abilities of the GAP, FBI, SSA, C7/SFD, TPA, CIA, body weight, body mass index, and BM to discriminate PJF cases were analyzed through receiver operating characteristic curves and corresponding areas under the curve (AUC). RESULTS: GAP (AUC = 0.8816) and FBI (AUC = 0.8933) were able to discriminate PJF cases but the highest discrimination power (AUC = 0.9371) was achieved with BM at upper instrumented vertebra + 1. Parameter cutoff analyses provided quantitative thresholds to characterize the control and failure groups and led to improved PJF discrimination, with GAP and BM being the most important contributors. SSA (AUC = 0.2857), C7/SFD (AUC = 0.3143), TPA (AUC = 0.5714), CIA (AUC = 0.4571), body weight (AUC = 0.6319), and body mass index (AUC = 0.7716) did not adequately predict PJF. CONCLUSION: BM reflects the quantitative biomechanical effect of external loads and can improve GAP accuracy. Sagittal alignments and mechanical integrated scores could be used to better prognosticate the risk of PJF.

Cartilaginous endplates: A comprehensive review on a neglected structure in intervertebral disc research.

The cartilaginous endplates (CEP) are key components of the intervertebral disc (IVD) necessary for sustaining the nutrition of the disc while distributing mechanical loads and preventing the disc from bulging into the adjacent vertebral body. The size, shape, and composition of the CEP are essential in maintaining its function, and degeneration of the CEP is considered a contributor to early IVD degeneration. In addition, the CEP is implicated in Modic changes, which are often associated with low back pain. This review aims to tackle the current knowledge of the CEP regarding its structure, composition, permeability, and mechanical role in a healthy disc, how they change with degeneration, and how they connect to IVD degeneration and low back pain. Additionally, the authors suggest a standardized naming convention regarding the CEP and bony endplate and suggest avoiding the term vertebral endplate. Currently, there is limited data on the CEP itself as reported data is often a combination of CEP and bony endplate, or the CEP is considered as articular cartilage. However, it is clear the CEP is a unique tissue type that differs from articular cartilage, bony endplate, and other IVD tissues. Thus, future research should investigate the CEP separately to fully understand its role in healthy and degenerated IVDs. Further, most IVD regeneration therapies in development failed to address, or even considered the CEP, despite its key role in nutrition and mechanical stability within the IVD. Thus, the CEP should be considered and potentially targeted for future sustainable treatments.

The effect of sustained compression on oxygen metabolic transport in the intervertebral disc decreases with degenerative changes.

Intervertebral disc metabolic transport is essential to the functional spine and provides the cells with the nutrients necessary to tissue maintenance. Disc degenerative changes alter the tissue mechanics, but interactions between mechanical loading and disc transport are still an open issue. A poromechanical finite element model of the human disc was coupled with oxygen and lactate transport models. Deformations and fluid flow were linked to transport predictions by including strain-dependent diffusion and advection. The two solute transport models were also coupled to account for cell metabolism. With this approach, the relevance of metabolic and mechano-transport couplings were assessed in the healthy disc under loading-recovery daily compression. Disc height, cell density and material degenerative changes were parametrically simulated to study their influence on the calculated solute concentrations. The effects of load frequency and amplitude were also studied in the healthy disc by considering short periods of cyclic compression. Results indicate that external loads influence the oxygen and lactate regional distributions within the disc when large volume changes modify diffusion distances and diffusivities, especially when healthy disc properties are simulated. Advection was negligible under both sustained and cyclic compression. Simulating degeneration, mechanical changes inhibited the mechanical effect on transport while disc height, fluid content, nucleus pressure and overall cell density reductions affected significantly transport predictions. For the healthy disc, nutrient concentration patterns depended mostly on the time of sustained compression and recovery. The relevant effect of cell density on the metabolic transport indicates the disturbance of cell number as a possible onset for disc degeneration via alteration of the metabolic balance. Results also suggest that healthy disc properties have a positive effect of loading on metabolic transport. Such relation, relevant to the maintenance of the tissue functional composition, would therefore link disc function with disc nutrition.

In silico evaluation of a new composite disc substitute with a L3-L5 lumbar spine finite element model.

When the intervertebral disc is removed to relieve chronic pain, subsequent segment stabilization should restore the functional mechanics of the native disc. Because of partially constrained motions and the lack of intrinsic rotational stiffness ball-on-socket implants present many disadvantages. Composite disc substitutes mimicking healthy disc structures should be able to assume the role expected for a disc substitute with fewer restrictions than ball-on-socket implants. A biomimetic composite disc prototype including artificial nucleus fibre-reinforced annulus and endplates was modelled as an L4-L5 disc substitute within a L3-L5 lumbar spine finite element model. Different device updates, i.e. changes of material properties fibre distributions and volume fractions and nucleus placements were proposed. Load- and displacement-controlled rotations were simulated with and without body weight applied. The original prototype reduced greatly the flexibility of the treated segment with significant adjacent level effects under displacement-controlled or hybrid rotations. Device updates allowed restoring large part of the global axial and sagittal rotational flexibility predicted with the intact model. Material properties played a major role, but some other updates were identified to potentially tune the device behaviour against specific motions. All device versions altered the coupled intersegmental shear deformations affecting facet joint contact through contact area displacements. Loads in the bony endplates adjacent to the implants increased as the implant stiffness decreased but did not appear to be a strong limitation for the implant biomechanical and mechanobiological functionality. In conclusion, numerical results given by biomimetic composite disc substitutes were encouraging with greater potential than that offered by ball-on-socket implants.

Relationship Between the Choice of Clinical Treatment, Gait Functionality and Kinetics in Patients With Comparable Knee Osteoarthritis.

Objective: The objective of this study was to investigate the relationship between the choice of clinical treatment, gait functionality, and kinetics in patients with comparable knee osteoarthritis. Design: This was an observational case-control study. Setting: The study was conducted in a university biomechanics laboratory. Participants: Knee osteoarthritis patients were stratified into the following groups: clinical treatment (conservative/total knee replacement (TKR) planned), sex (male/female), age (60-67/68-75), and body mass index (BMI) (<30/≥30). All patients had a Kellgren-Lawrence score of 2 or 3 (N = 87). Main Outcome Measures: All patients underwent gait analysis, and two groups of dependent variables were extracted: • Spatiotemporal gait variables: gait velocity, stride time, and double-support time, which are associated with patient functionality. • Kinetic gait variables: vertical, anterior-posterior, and mediolateral ground reaction forces, vertical free moment, joint forces, and moments at the ankle, knee, and hip. Multifactorial and multivariate analyses of variance were performed. Results: Functionality relates to treatment decisions, with patients in the conservative group walking 25% faster and spending 24% less time in the double-support phase. However, these differences vary with age and are reduced in older subjects. Patients who planned to undergo TKR did not present higher knee forces, and different joint moments between clinical treatments depended on the age and BMI of the subjects. Conclusions: Knee osteoarthritis is a multifactorial disease, with age and BMI being confounding factors. The differences in gait between the two groups were mitigated by confounding factors and risk factors, such as being a woman, elderly, and obese, reducing the variability of the gait compression loads. These factors should always be considered in gait studies of patients with knee osteoarthritis to control for confounding effects.

Regulatory network-based model to simulate the biochemical regulation of chondrocytes in healthy and osteoarthritic environments.

In osteoarthritis (OA), chondrocyte metabolism dysregulation increases relative catabolic activity, which leads to cartilage degradation. To enable the semiquantitative interpretation of the intricate mechanisms of OA progression, we propose a network-based model at the chondrocyte level that incorporates the complex ways in which inflammatory factors affect structural protein and protease expression and nociceptive signals. Understanding such interactions will leverage the identification of new potential therapeutic targets that could improve current pharmacological treatments. Our computational model arises from a combination of knowledge-based and data-driven approaches that includes in-depth analyses of evidence reported in the specialized literature and targeted network enrichment. We achieved a mechanistic network of molecular interactions that represent both biosynthetic, inflammatory and degradative chondrocyte activity. The network is calibrated against experimental data through a genetic algorithm, and 81% of the responses tested have a normalized root squared error lower than 0.15. The model captures chondrocyte-reported behaviors with 95% accuracy, and it correctly predicts the main outcomes of OA treatment based on blood-derived biologics. The proposed methodology allows us to model an optimal regulatory network that controls chondrocyte metabolism based on measurable soluble molecules. Further research should target the incorporation of mechanical signals.

Immuno-Modulatory Effects of Intervertebral Disc Cells.

Low back pain is a highly prevalent, chronic, and costly medical condition predominantly triggered by intervertebral disc degeneration (IDD). IDD is often caused by structural and biochemical changes in intervertebral discs (IVD) that prompt a pathologic shift from an anabolic to catabolic state, affecting extracellular matrix (ECM) production, enzyme generation, cytokine and chemokine production, neurotrophic and angiogenic factor production. The IVD is an immune-privileged organ. However, during degeneration immune cells and inflammatory factors can infiltrate through defects in the cartilage endplate and annulus fibrosus fissures, further accelerating the catabolic environment. Remarkably, though, catabolic ECM disruption also occurs in the absence of immune cell infiltration, largely due to native disc cell production of catabolic enzymes and cytokines. An unbalanced metabolism could be induced by many different factors, including a harsh microenvironment, biomechanical cues, genetics, and infection. The complex, multifactorial nature of IDD brings the challenge of identifying key factors which initiate the degenerative cascade, eventually leading to back pain. These factors are often investigated through methods including animal models, 3D cell culture, bioreactors, and computational models. However, the crosstalk between the IVD, immune system, and shifted metabolism is frequently misconstrued, often with the assumption that the presence of cytokines and chemokines is synonymous to inflammation or an immune response, which is not true for the intact disc. Therefore, this review will tackle immunomodulatory and IVD cell roles in IDD, clarifying the differences between cellular involvements and implications for therapeutic development and assessing models used to explore inflammatory or catabolic IVD environments.

Patient-Specific Variations in Local Strain Patterns on the Surface of a Trussed Titanium Interbody Cage.

Introduction: 3D printed trussed titanium interbody cages may deliver bone stimulating mechanobiological strains to cells attached at their surface. The exact size and distribution of these strains may depend on patient-specific factors, but the influence of these factors remains unknown. Therefore, this study aimed to determine patient-specific variations in local strain patterns on the surface of a trussed titanium interbody fusion cage. Materials and Methods: Four patients eligible for spinal fusion surgery with the same cage size were selected from a larger database. For these cases, patient-specific finite element models of the lumbar spine including the same trussed titanium cage were made. Functional dynamics of the non-operated lumbar spinal segments, as well as local cage strains and caudal endplate stresses at the operated segment, were evaluated under physiological extension/flexion movement of the lumbar spine. Results: All patient-specific models revealed physiologically realistic functional dynamics of the operated spine. In all patients, approximately 30% of the total cage surface experienced strain values relevant for preserving bone homeostasis and stimulating bone formation. Mean caudal endplate contact pressures varied up to 10 MPa. Both surface strains and endplate contact pressures varied more between loading conditions than between patients. Conclusions: This study demonstrates the applicability of patient-specific finite element models to quantify the impact of patient-specific factors such as bone density, degenerative state of the spine, and spinal curvature on interbody cage loading. In the future, the same framework might be further developed in order to establish a pipeline for interbody cage design optimizations.