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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Misaligned spinal rods can induce high internal forces consistent with those observed to cause screw pullout and disc degeneration.

BACKGROUND CONTEXT: Manual contouring of spinal rods is often required intraoperatively for proper alignment of the rods within the pedicle screw heads. Residual misalignments are frequently reduced by using dedicated reduction devices. The forces exerted by these devices, however, are uncontrolled and may lead to excessive reaction forces. As a consequence, screw pullout might be provoked and surrounding tissue may experience unfavorable biomechanical loads. The corresponding loads and induced tissue deformations are however not well identified. Additionally, whether the forced reduction alters the biomechanical behavior of the lumbar spine during physiological movements postoperatively, remains unexplored. PURPOSE: To predict whether the reduction of misaligned posterior instrumentation might result in clinical complications directly after reduction and during a subsequent physiological flexion movement. STUDY DESIGN: Finite element analysis. METHODS: A patient-specific, total lumbar (L1-S1) spine finite element model was available from previous research. The model consists of poro-elastic intervertebral discs with Pfirrmann grade-dependent material parameters, with linear elastic bone tissue with stiffness values related to the local bone density, and with the seven major ligaments per spinal motion segment described as nonlinear materials. Titanium instrumentation was implemented in this model to simulate a L4, L5, and S1 posterolateral fusion. Next, coronal and sagittal misalignments of 6 mm each were introduced between the rod and the screw head at L4. These misalignments were computationally reduced and a physiological flexion movement of 15° was prescribed. Non-instrumented and well-aligned instrumented models were used as control groups. RESULTS: Pulling forces up to 1.0 kN were required to correct the induced misalignments of 6 mm. These forces affected the posture of the total lumbar spine, as motion segments were predicted to rotate up to 3 degrees and rotations propagated proximally to and even affect the L1-2 level. The facet contact pressures in the corrected misaligned models were asymmetrical suggesting non-physiological joint loading in the misaligned models. In addition, the discs and vertebrae experienced abnormally high forces as a result of the correction procedure. These effects were more pronounced after a 15° flexion movement following forced reduction. CONCLUSIONS: The results of this study indicate that the correction of misaligned posterior instrumentation can result in high forces at the screws consistent with those reported to cause screw pullout, and may cause high-tissue strains in adjacent and downstream spinal segments. CLINICAL SIGNIFICANCE: Proper alignment of spinal posterior instrumentation may reduce clinical complications secondary to unfavorable biomechanics.

Image-Based 3D Characterization of Abdominal Aortic Aneurysm Deformation After Endovascular Aneurysm Repair.

An abdominal aortic aneurysm (AAA) is a focal dilation of the abdominal aorta, that if not treated, tends to grow and may rupture. The most common treatment for AAAs is the endovascular aneurysm repair (EVAR), which requires that patients undergo Computed Tomography Angiography (CTA)-based post-operative lifelong surveillance due to the possible appearance of complications. These complications may again lead to AAA dilation and rupture. However, there is a lack of advanced quantitative image-analysis tools to support the clinicians in the follow-up. Currently, the approach is to evaluate AAA diameter changes along time to infer the progress of the patient and the post-operative risk of AAA rupture. An increased AAA diameter is usually associated with a higher rupture risk, but there are some small AAAs that rupture, whereas other larger aneurysms remain stable. This means that the diameter-based rupture risk assessment is not suitable for all the cases, and there is increasing evidence that the biomechanical behavior of the AAA may provide additional valuable information regarding the progression of the disease and the risk of rupture. Hence, we propose a promising methodology for post-operative CTA time-series registration and subsequent aneurysm biomechanical strain analysis. From these strains, quantitative image-based descriptors are extracted using a principal component analysis of the tensile and compressive strain fields. Evaluated on 22 patients, our approach yields a mean area under the curve of 88.6% when correlating the strain-based quantitative descriptors with the long-term patient prognosis. This suggests that the strain information directly extracted from the CTA images is able to capture the biomechanical behavior of the aneurysm without relying on finite element modeling and simulation. Furthermore, the extracted descriptors set the basis for possible future imaging biomarkers that may be used in clinical practice. Apart from the diameter, these biomarkers may be used to assess patient prognosis and to enable informed decision making after an EVAR intervention, especially in difficult uncertain cases.

Breaking the state of the heart: meshless model for cardiac mechanics.

Cardiac modeling has recently emerged as a promising tool to study pathophysiology mechanisms and to predict treatment outcomes for personalized clinical decision support. Nevertheless, achieving convergence under large deformation and defining a robust meshing for realistic heart geometries remain challenging, especially when maintaining the computational cost reasonable. Smoothed particle hydrodynamics (SPH) appears to be a promising alternative to the finite element method (FEM) since it removes the burden of mesh generation. A point cloud is used where each point (particle) contains all the physical properties that are updated throughout the simulation. SPH was evaluated for solid mechanics applications in the last decade but its capacity to address the challenge of simulating the mechanics of the heart has never been evaluated. In this paper, a total Lagrangian formulation of a corrected SPH was used to solve three solid mechanics problems designed to test important features that a cardiac mechanics solver should have. SPH results, in terms of ventricle displacements and strains, were compared to results obtained with 11 different FEM-based solvers, by using synthetic cardiac data from a benchmark study. In particular, passive dilation and active contraction were simulated in an ellipsoidal left ventricle with the exponential anisotropic constitutive law of Guccione following the direction of fibers. The proposed meshless method is able to reproduce the results of three benchmark problems for cardiac mechanics. Hyperelastic material with fiber orientation and high Poisson ratio allows wall thickening/thinning when large deformation is present.

3D patient-specific finite element models of the proximal femur based on DXA towards the classification of fracture and non-fracture cases.

Osteoporotic bone fractures reduce quality of life and drastically increase mortality. Minimally irradiating imaging techniques such as dual-energy X-ray absorptiometry (DXA) allow assessment of bone loss through the use of bone mineral density (BMD) as descriptor. Yet, the accuracy of fracture risk predictions remains limited. Recently, DXA-based 3D modelling algorithms were proposed to analyse the geometry and BMD spatial distribution of the proximal femur. This study hypothesizes that such approaches can benefit from finite element (FE)-based biomechanical analyses to improve fracture risk prediction. One hundred and eleven subjects were included in this study and stratified in two groups: (a) 62 fracture cases, and (b) 49 non-fracture controls. Side fall was simulated using a static peak load that depended on patient mass and height. Local mechanical fields were calculated based on relationships between tissue stiffness and BMD. The area under the curve (AUC) of the receiver operating characteristic method evaluated the ability of calculated biomechanical descriptors to discriminate fracture and control cases. The results showed that the major principal stress was better discriminator (AUC > 0.80) than the volumetric BMD (AUC ≤ 0.70). High discrimination capacity was achieved when the analysis was performed by bone type, zone of fracture and gender/sex (AUC of 0.91 for women, trabecular bone and trochanter area), and outcomes suggested that the trabecular bone is critical for fracture discrimination. In conclusion, 3D FE models derived from DXA scans might significantly improve the prediction of hip fracture risk; providing a new insight for clinicians to use FE simulations in clinical practice for osteoporosis management.

Muscular tension significantly affects stability in standing posture.

BACKGROUND: Muscular co-contraction is a strategy commonly used by elders with the aim to increase stability. However, co-contraction leads to stiffness which in turns reduces stability. Some literature seems to suggest an opposite approach and to point out relaxation as a way to improve stability. Teaching relaxation is therefore becoming the aim of many studies letting unclear whether tension or relaxation are the most effective muscular strategy to improve stability. Relaxation is a misleading concept in our society. It is often confused with rest, while it should be addressed during stressing tasks, where it should aim to reduce energetic costs and increase stability. The inability to relax can be related to sub-optimal neuro-motor control, which can lead to increased stresses. RESEARCH QUESTION: The objective of the study is to investigate the effect of voluntary muscle contraction and relaxation over the stability of human standing posture, answering two specific research questions: (1) Does the muscular tension have an impact on stability of standing posture? (2) Could this impact be estimated by using a minimally invasive procedure? METHODS: By using a force plate, we analysed the displacement of the center of pressure of 30 volunteers during state of tension and relaxation in comparison with a control state, and with open and closed eyes. RESULTS: We found that tension significantly reduced the stability of subjects (15 out of 16 parameters, p < 0.003). SIGNIFICANCE: Our results show that daily situations of stress can lead to decreased stability. Such a loss might actually increase the risk of chronic joint overload or fall. Finally, breathing has direct effect over the management of pain and stress, and the results reported here point out the need to explicitly explore the troubling fact that a large portion of population might not be able to properly breath.

Theoretical Explorations Generate New Hypotheses About the Role of the Cartilage Endplate in Early Intervertebral Disk Degeneration.

Altered cell nutrition in the intervertebral disk (IVD) is considered a main cause for disk degeneration (DD). The cartilage endplate (CEP) provides a major path for the diffusion of nutrients from the peripheral vasculature to the IVD nucleus pulposus (NP). In DD, sclerosis of the adjacent bony endplate is suggested to be responsible for decreased diffusion and disk cell nutrition. Yet, experimental evidence does not support this hypothesis. Hence, we evaluated how moderate CEP composition changes related to tissue degeneration can affect disk nutrition and cell viability. A novel composition-based permeability formulation was developed for the CEP, calibrated, validated, and used in a mechano-transport finite element IVD model. Fixed solute concentrations were applied at the outer surface of the annulus and the CEP, and three cycles of daily mechanical load were simulated. The CEP model indicated that CEP permeability increases with the degeneration/aging of the tissue, in accordance with recent measurements reported in the literature. Additionally, our results showed that CEP degeneration might be responsible for mechanical load-induced NP dehydration, which locally affects oxygen and lactate levels, and reduced glucose concentration by 16% in the NP-annulus transition zone. Remarkably, CEP degeneration was a condition sine-qua-non to provoke cell starvation and death, while simulating the effect of extracellular matrix depletion in DD. This theoretical study cast doubts about the paradigm that CEP calcification is needed to provoke cell starvation, and suggests an alternative path for DD whereby the early degradation of the CEP plays a key role.

Comparison of patient-specific computational models vs. clinical follow-up, for adjacent segment disc degeneration and bone remodelling after spinal fusion.

Spinal fusion is a standard surgical treatment for patients suffering from low back pain attributed to disc degeneration. However, results are somewhat variable and unpredictable. With fusion the kinematic behaviour of the spine is altered. Fusion and/or stabilizing implants carrying considerable load and prevent rotation of the fused segments. Associated with these changes, a risk for accelerated disc degeneration at the adjacent levels to fusion has been demonstrated. However, there is yet no method to predict the effect of fusion surgery on the adjacent tissue levels, i.e. bone and disc. The aim of this study was to develop a coupled and patient-specific mechanoregulated model to predict disc generation and changes in bone density after spinal fusion and to validate the results relative to patient follow-up data. To do so, a multiscale disc mechanoregulation adaptation framework was developed and coupled with a previously developed bone remodelling algorithm. This made it possible to determine extra cellular matrix changes in the intervertebral disc and bone density changes simultaneously based on changes in loading due to fusion surgery. It was shown that for 10 cases the predicted change in bone density and degeneration grade conforms reasonable well to clinical follow-up data. This approach helps us to understand the effect of surgical intervention on the adjacent tissue remodelling. Thereby, providing the first insight for a spine surgeon as to which patient could potentially be treated successfully by spinal fusion and in which patient has a high risk for adjacent tissue changes.

Coupled Immunological and Biomechanical Model of Emphysema Progression.

Chronic Obstructive Pulmonary Disease (COPD) is a disabling respiratory pathology, with a high prevalence and a significant economic and social cost. It is characterized by different clinical phenotypes with different risk profiles. Detecting the correct phenotype, especially for the emphysema subtype, and predicting the risk of major exacerbations are key elements in order to deliver more effective treatments. However, emphysema onset and progression are influenced by a complex interaction between the immune system and the mechanical properties of biological tissue. The former causes chronic inflammation and tissue remodeling. The latter influences the effective resistance or appropriate mechanical response of the lung tissue to repeated breathing cycles. In this work we present a multi-scale model of both aspects, coupling Finite Element (FE) and Agent Based (AB) techniques that we would like to use to predict the onset and progression of emphysema in patients. The AB part is based on existing biological models of inflammation and immunological response as a set of coupled non-linear differential equations. The FE part simulates the biomechanical effects of repeated strain on the biological tissue. We devise a strategy to couple the discrete biological model at the molecular /cellular level and the biomechanical finite element simulations at the tissue level. We tested our implementation on a public emphysema image database and found that it can indeed simulate the evolution of clinical image biomarkers during disease progression.

Sensitivity analysis of geometrical parameters to study haemodynamics and thrombus formation in the left atrial appendage.

The left atrial appendage (LAA) is a complex and heterogeneous protruding structure of the left atrium (LA). In atrial fibrillation patients, it is the location where 90% of the thrombi are formed. However, the role of the LAA in thrombus formation is not fully known yet. The main goal of this work is to perform a sensitivity analysis to identify the most relevant LA and LAA morphological parameters in atrial blood flow dynamics. Simulations were run on synthetic ellipsoidal left atria models where different parameters were individually studied: pulmonary veins and mitral valve dimensions; LAA shape; and LA volume. Our computational analysis confirmed the relation between large LAA ostia, low blood flow velocities and thrombus formation. Additionally, we found that pulmonary vein configuration exerted a critical influence on LAA blood flow patterns. These findings contribute to a better understanding of the LAA and to support clinical decisions for atrial fibrillation patients.