The effect of trapeziometacarpal joint passive stiffness on mechanical loadings of cartilages.

Hypermobility of the trapeziometacarpal joint is commonly considered to be a potential risk factor for osteoarthritis. Nevertheless, the results remain controversial due to a lack of quantitative validation. The objective of this study was to evaluate the effect of joint laxity on the mechanical loadings of cartilage. A patient-specific finite element model of trapeziometacarpal joint passive stiffness was developed. The joint passive stiffness was modeled by creating linear springs all around the joint. The linear spring stiffness was determined by using an optimization process to fit force-displacement data measured during laxity tests performed on eight healthy volunteers. The estimated passive stiffness parameters were then included in a full thumb finite element simulation of a pinch grip task driven by muscle forces to evaluate the effect on trapeziometacarpal loading. The correlation between stiffness and the loading of cartilage in terms of joint contact pressure and maximum shear strain was analyzed. A significant negative correlation was found between the trapeziometacarpal joint passive stiffness and the contact pressure on trapezium cartilage during the simulated pinch grip task. These results therefore suggest that the hypermobility of the trapeziometacarpal joint could affect the contact pressure on trapezium cartilage and support the existence of an increased risk associated with hypermobility.

In silico analysis shows that dynamic changes in curvature guide cell migration over long distances.

In vitro experiments have shown that cell scale curvatures influence cell migration; cells avoid convex hills and settle in concave valleys. However, it is not known whether dynamic changes in curvature can guide cell migration. This study extends a previous in-silico model to explore the effects over time of changing the substrate curvature on cell migration guidance. By simulating a dynamic surface curvature using traveling wave patterns, we investigate the influence of wave height and speed, and find that long-distance cell migration guidance can be achieved on specific wave patterns. We propose a mechanistic explanation of what we call dynamic curvotaxis and highlight those cellular features that may be involved. Our results open a new area of study for understanding cell mobility in dynamic environments, from single-cell in vitro experiments to multi-cellular in vivo mechanisms.

Relationship between trapeziometacarpal joint morphological parameters and joint contact pressure: a possible factor of osteoarthritis development.

The trapeziometacarpal (TMC) joint is the one of the hand joints that is most affected by osteoarthritis (OA). The objective of this study was to determine if specific morphological parameters could be related to the amount of pressure endured by the joint which is one of the factors contributing to the development of this pathology. We developed 15 individualized 3D computer aided design (CAD) models of the TMC joint, each generated from the CT scan of a different participant. For each participant, we measured several crucial morphological parameters: the width and length of the trapezium bone and dorso-volar and ulno-radial curvature, of the trapezium and the metacarpal bone. Each CAD model was converted into a finite element model, of both bones and the cartilage located in between. The joint forces applied during pinch grip and power grip tasks were then applied in order to estimate the contact pressures on joint cartilage for each model. Correlations between joint contact pressures and morphology of the trapezium and the metacarpal bone were then analysed. Important variations of TMC joint pressures were observed. For both pinch and power grip tasks, the strongest correlation with joint contact pressure was with the dorso-volar curvature of the trapezium bone. Our findings indicate that dorso-volar curvature of the trapezium bone has a significant impact on mechanical loadings on the TMC joint. This contributes to understanding the prevalence of OA in certain patients.

In silico modelling of long bone healing involving osteoconduction and mechanical stimulation.

A lot of evidence has shown the importance of stimulating cell mechanically during bone repair. In this study, we modeled the challenging fracture healing of a large bone defect in tibial diaphysis. To fill the fracture gap, we considered the implantation of a porous osteoconductive biomaterial made of poly-lactic acid wrapped by a hydrogel membrane mimicking osteogenic properties of the periosteum. We identified the optimal loading case that best promotes the formation and differentiation into bone tissue. Our results support the idea that a patient's rehabilitation program should be adapted to reproduce optimal mechanical stimulations.

The effect of index finger distal interphalangeal joint arthrodesis on muscle forces and adjacent joint contact pressures.

Distal interphalangeal joint arthrodesis is a frequent surgical operation performed to treat severe arthritis. Nevertheless, the angle selected when fusing the joint is arbitrarily chosen without any quantified data concerning its mechanical effects, thus preventing the optimal choice for the patient. In the current study, we realized an experiment and developed a numerical model to investigate the effect of fusion angle on the biomechanics of adjacent non-operated joints. Six participants performed a pinch grip task while arthrodesis was simulated with a metal splint. Kinematic and force data were recorded during this task and used in a biomechanical model to estimate contact pressures in adjacent joints. The biomechanical model involved combining a multibody system and a finite element method. Results showed that the angle of any distal interphalangeal joint arthrodesis influences index finger kinematics and maximal grip force in several participants. For one participant, in the arthrodesis simulation, we observed an increase of 1.9 MPa in the proximal interphalangeal joint contact pressure. Our results provide quantified information about the biomechanical consequences of this surgical operation and its potential long-term effects.

Mechanobiological model to study the influence of screw design and surface treatment on osseointegration.

This study aims at suggesting a new approach to peri-implant healing models, providing a set of taxis-diffusion-reaction equations under the combined influence of mechanical and biochemical factors. Early events of osseointegration were simulated for titanium screw implants inserted into a pre-drilled trabecular bone environment, up to 12 weeks of peri-implant bone healing. Simulations showed the ability of the model to reproduce biological events occurring at the implant interface through osteogenesis. Implants with shallow healing chamber showed higher proportions of lamellar bone, enhanced by the increase of mechanical stimulation. Osteoconduction was observed through the surface treatment model and similar bone healing patterns compared to in vivo studies.

Local tissue effects and peri-implant bone healing induced by implant surface treatment: an in vivo study in the sheep.

OBJECTIVE: The aim of this study was to assess, through biological analysis, the local effects and osseointegration of dental implants incorporating surface micro/nanofeatures compared with implants of identical design without surface treatment. BACKGROUND: Known to impact bone cell behavior, surface chemical and topography modifications target improved osseointegration and long-term success of dental implants. Very few studies assess the performance of implants presenting both micro- and nanofeatures in vivo on the animal models used in preclinical studies for medical device certification. METHODS: Implant surfaces were characterized in terms of topography and surface chemical composition. After 4 weeks and 13 weeks of implantation in sheep femoral condyles, forty implants were evaluated through micro-computed tomography, histopathologic, and histomorphometric analyses. RESULTS: No local adverse effects were observed around implants. Histomorphometric analyses showed significantly higher bone-to-implant contact in the coronal region of the surface-treated implant at week 4 and week 13, respectively, was 79.3 ± 11.2% and 86.4 ± 6.7%, compared with the untreated implants (68.3 ± 8.8% and 74.8 ± 13%). Micro-computed tomography analyses revealed that healing patterns differed between coronal and apical regions, with higher coronal bone-to-implant contact at week 13. Histopathologic results showed, at week 13, bone healing around the surface-treated implant with undistinguishable defect margins, while the untreated implant still presented bone condensation and traces of the initial drill defect. CONCLUSION: Our results suggest that the surface-treated implant not only shows no deleterious effects on local tissues but also promotes faster bone healing around the implant.

Mechanical performance comparison of two surgical constructs for wrist four-corner arthrodesis via dorsal and radial approaches.

BACKGROUND: Four-corner arthrodesis, which involves fusing four carpal bones while removing the scaphoid bone, is a standard surgery for the treatment of advanced stages of wrist arthritis. Nowadays, it can be performed using a dorsal approach by fixing a plate to the bones and a new radial approach is in development. To date, there is no consensus on the biomechanically optimal and most reliable surgical construct for four-corner arthrodesis. METHODS: To evaluate them biomechanically and thus assist the surgeon in choosing the best implant orientation, radial or dorsal, the two different four-corner arthrodesis surgical constructs were virtually simulated on a 3D finite element model representing all major structures of the wrist. Two different realistic load sets were applied to the model, representing common tasks for the elderly. FINDINGS: Results consistency was assessed by comparing with the literature the force magnitude computed on the carpal bones. The Von Mises stress distribution in the radial and dorsal plates were calculated. Stress concentration was located at the plate-screw interface for both surgical constructs, with a maximum stress value of 413 MPa for the dorsal plate compared to 326 MPa for the radial plate, meaning that the stress levels are more unfavourable in the dorsal approach. INTERPRETATION: Although some bending stress was found in one load case, the radial plate was mechanically more robust in the other load case. Despite some limitations, this study provides, for the first time, quantified evidence that the newly developed radial surgical construct is mechanically as efficient as the dorsal surgical construct.

Estimation of joint contact pressure in the index finger using a hybrid finite element musculoskeletal approach.

The knowledge of local stress distribution in hand joints is crucial to understand injuries and osteoarthritis occurrence. However, determining cartilage contact stresses remains a challenge, requiring numerical models including both accurate anatomical components and realistic tendon force actuation. Contact forces in finger joints have frequently been calculated but little data is available on joint contact pressures. This study aimed to develop and assess a hybrid biomechanical model of the index finger to estimate in-vivo joint contact pressure during a static maximal strength pinch grip task. A finite element model including bones, cartilage, tendons, and ligaments was developed, with tendon force transmission based on a tendon-pulley system. This model was driven by realistic tendon forces estimated from a musculoskeletal model and motion capture data for six subjects. The hybrid model outputs agreed well with the experimental measurement of fingertip forces and literature data on the physiological distribution of tendon forces through the index finger. Mean contact pressures were 6.9 ± 2.7 MPa, 6.2 ± 1.0 MPa and 7.2 ± 1.3 MPa for distal, proximal interphalangeal and metacarpophalangeal joints, respectively. Two subjects had higher mean contact pressure in the distal joint than in the other two joints, suggesting a mechanical cause for the prevalence of osteoarthritis in the index distal joint. The inter-subject variability in joint contact pressure could be explained by different neuromuscular strategies employed for the task. This first application of an effective hybrid model to the index finger is promising for estimating hand joint stresses under daily grip tasks and simulating surgical procedures.

Actomyosin, vimentin and LINC complex pull on osteosarcoma nuclei to deform on micropillar topography.

Cell deformation occurs in many critical biological processes, including cell extravasation during immune response and cancer metastasis. These cells deform the nucleus, their largest and stiffest organelle, while passing through narrow constrictions in vivo and the underlying mechanisms still remain elusive. It is unclear which biochemical actors are responsible and whether the nucleus is pushed or pulled (or both) during deformation. Herein we use an easily-tunable poly-L-lactic acid micropillar topography, mimicking in vivo constrictions to determine the mechanisms responsible for nucleus deformation. Using biochemical tools, we determine that actomyosin contractility, vimentin and nucleo-cytoskeletal connections play essential roles in nuclear deformation, but not A-type lamins. We chemically tune the adhesiveness of the micropillars to show that pulling forces are predominantly responsible for the deformation of the nucleus. We confirm these results using an in silico cell model and propose a comprehensive mechanism for cellular and nuclear deformation during confinement. These results indicate that microstructured biomaterials are extremely versatile tools to understand how forces are exerted in biological systems and can be useful to dissect and mimic complex in vivo behaviour.

Investigating unset endodontic sealers' eugenol and hydrocortisone roles in modulating the initial steps of inflammation.

INTRODUCTION: Endodontic treatment success is achieved not only when the cement provides a hermetic seal but also when the injured periapical tissue is regenerated. However, an exaggerated inflammatory reaction hinders tissue regeneration and it has been shown that dental materials affect the inflammatory response through modulation of cytokine secretion. This work was set to investigate the effects of the presence of hydrocortisone in zinc oxide eugenol sealers (Endomethasone N) on modulating the initial steps of inflammation in vitro. MATERIAL AND METHODS: Hydrocortisone and eugenol leaching from Endomethasone N and Pulp Canal Sealer (PCS) were quantified by ELISA and spectrofluorometry, respectively. The effects of Endomethasone N and Pulp Canal Sealer were studied on lipopolysaccharides (LPS)-stimulated human periodontal ligament (hPDL) cells. Cytokine (IL-6, TNF-α) secretion from cells was quantified by ELISA. Inflammatory cell (THP-1) adhesion to activated endothelial cells, their migration and activation were studied in vitro. RESULTS: Endomethasone N decreased secretion of IL-6 and TNF-α from hPDL cells. THP-1 adhesion to activated endothelial cells (HUVECs) and migration significantly decreased with Endomethasone N while no effect was observed with PCS. Activation of THP-1 decreased with both materials' extracts but was significantly lower with Endomethasone N than with PCS. CONCLUSION: These results performed in vitro show that Endomethasone N anti-inflammatory effects are due to the presence of hydrocortisone. CLINICAL RELEVANCE: Endomethasone N has potential local anti-inflammatory effects which appear to be due to its hydrocortisone rather than eugenol content. Decreasing the inflammatory response is a pre-requisite to initiate the periapical healing.

A Biophysical Model for Curvature-Guided Cell Migration.

The latest experiments have shown that adherent cells can migrate according to cell-scale curvature variations via a process called curvotaxis. Despite identification of key cellular factors, a clear understanding of the mechanism is lacking. We employ a mechanical model featuring a detailed description of the cytoskeleton filament networks, the viscous cytosol, the cell adhesion dynamics, and the nucleus. We simulate cell adhesion and migration on sinusoidal substrates. We show that cell adhesion on three-dimensional curvatures induces a gradient of pressure inside the cell that triggers the internal motion of the nucleus. We propose that the resulting out-of-equilibrium position of the nucleus alters cell migration directionality, leading to cell motility toward concave regions of the substrate, resulting in lower potential energy states. Altogether, we propose a simple mechanism explaining how intracellular mechanics enable the cells to react to substratum curvature, induce a deterministic cell polarization, and break down cells basic persistent random walk, which correlates with latest experimental evidences.

The consequence of substrates of large-scale rigidity on actin network tension in adherent cells.

There is compelling evidence that substrate stiffness affects cell adhesion as well as cytoskeleton organization and contractile activity. This work was designed to study the cytoskeletal contractile activity of single cells plated on micropost substrates of different stiffness using a numerical model simulating the intracellular tension of individual cells. We allowed cells to adhere onto micropost substrates of various rigidities and used experimental traction force data to infer cell contractility using a numerical model. The model shows that higher substrate stiffness leads to an increase in intracellular tension. The strength of this model is its ability to calculate the mechanical state of each cell in accordance to its individual cytoskeletal structure. This is achieved by regenerating a numerical cytoskeleton based on microscope images of the actin network of each cell. The resulting numerical structure consequently represents pulling characteristics on its environment similar to those generated by the cell in-vivo. From actin imaging we can calculate and better understand how forces are transmitted throughout the cell.

Curvotaxis directs cell migration through cell-scale curvature landscapes.

Cells have evolved multiple mechanisms to apprehend and adapt finely to their environment. Here we report a new cellular ability, which we term "curvotaxis" that enables the cells to respond to cell-scale curvature variations, a ubiquitous trait of cellular biotopes. We develop ultra-smooth sinusoidal surfaces presenting modulations of curvature in all directions, and monitor cell behavior on these topographic landscapes. We show that adherent cells avoid convex regions during their migration and position themselves in concave valleys. Live imaging combined with functional analysis shows that curvotaxis relies on a dynamic interplay between the nucleus and the cytoskeleton-the nucleus acting as a mechanical sensor that leads the migrating cell toward concave curvatures. Further analyses show that substratum curvature affects focal adhesions organization and dynamics, nuclear shape, and gene expression. Altogether, this work identifies curvotaxis as a new cellular guiding mechanism and promotes cell-scale curvature as an essential physical cue.

In silico CDM model sheds light on force transmission in cell from focal adhesions to nucleus.

Cell adhesion is crucial for many types of cell, conditioning differentiation, proliferation, and protein synthesis. As a mechanical process, cell adhesion involves forces exerted by the cytoskeleton and transmitted by focal adhesions to extracellular matrix. These forces constitute signals that infer specific biological responses. Therefore, analyzing mechanotransduction during cell adhesion could lead to a better understanding of the mechanobiology of adherent cells. For instance this may explain how, the shape of adherent stem cells influences their differentiation or how the stiffness of the extracellular matrix affects adhesion strength. To assess the mechanical signals involved in cell adhesion, we computed intracellular forces using the Cytoskeleton Divided Medium model in endothelial cells adherent on micropost arrays of different stiffnesses. For each cell, focal adhesion location and forces measured by micropost deflection were used as an input for the model. The cytoskeleton and the nucleoskeleton were computed as systems of multiple tensile and compressive interactions. At the end of computation, the systems respected mechanical equilibrium while exerting the exact same traction force intensities on focal adhesions as the observed cell. The results indicate that not only the level of adhesion forces, but also the shape of the cell has an influence on intracellular tension and on nucleus strain. The combination of experimental micropost technology with the present CDM model constitutes a tool able to estimate the intracellular forces.

Computational Tension Mapping of Adherent Cells Based on Actin Imaging.

Forces transiting through the cytoskeleton are known to play a role in adherent cell activity. Up to now few approaches haves been able to determine theses intracellular forces. We thus developed a computational mechanical model based on a reconstruction of the cytoskeleton of an adherent cell from fluorescence staining of the actin network and focal adhesions (FA). Our custom made algorithm converted the 2D image of an actin network into a map of contractile interactions inside a 2D node grid, each node representing a group of pixels. We assumed that actin filaments observed under fluorescence microscopy, appear brighter when thicker, we thus presumed that nodes corresponding to pixels with higher actin density were linked by stiffer interactions. This enabled us to create a system of heterogeneous interactions which represent the spatial organization of the contractile actin network. The contractility of this interaction system was then adapted to match the level of force the cell truly exerted on focal adhesions; forces on focal adhesions were estimated from their vinculin expressed size. This enabled the model to compute consistent mechanical forces transiting throughout the cell. After computation, we applied a graphical approach on the original actin image, which enabled us to calculate tension forces throughout the cell, or in a particular region or even in single stress fibers. It also enabled us to study different scenarios which may indicate the mechanical role of other cytoskeletal components such as microtubules. For instance, our results stated that the ratio between intra and extra cellular compression is inversely proportional to intracellular tension.

Computational model combined with in vitro experiments to analyse mechanotransduction during mesenchymal stem cell adhesion.

The shape that stem cells reach at the end of adhesion process influences their differentiation. Rearrangement of cytoskeleton and modification of intracellular tension may activate mechanotransduction pathways controlling cell commitment. In the present study, the mechanical signals involved in cell adhesion were computed in in vitro stem cells of different shapes using a single cell model, the so-called Cytoskeleton Divided Medium (CDM) model. In the CDM model, the filamentous cytoskeleton and nucleoskeleton networks were represented as a mechanical system of multiple tensile and compressive interactions between the nodes of a divided medium. The results showed that intracellular tonus, focal adhesion forces as well as nuclear deformation increased with cell spreading. The cell model was also implemented to simulate the adhesion process of a cell that spreads on protein-coated substrate by emitting filopodia and creating new distant focal adhesion points. As a result, the cell model predicted cytoskeleton reorganisation and reinforcement during cell spreading. The present model quantitatively computed the evolution of certain elements of mechanotransduction and may be a powerful tool for understanding cell mechanobiology and designing biomaterials with specific surface properties to control cell adhesion and differentiation.

Simulation of bone tissue formation within a porous scaffold under dynamic compression.

A computational model of mechanoregulation is proposed to predict bone tissue formation stimulated mechanically by overall dynamical compression within a porous polymeric scaffold rendered by micro-CT. Dynamic compressions of 0.5-5% at 0.0025-0.025 s(-1) were simulated. A force-controlled dynamic compression was also performed by imposing a ramp of force from 1 to 70 N. The model predicts homogeneous mature bone tissue formation under strain levels of 0.5-1% at strain rates of 0.0025-0.005 s(-1). Under higher levels of strain and strain rates, the scaffold shows heterogeneous mechanical behaviour which leads to the formation of a heterogeneous tissue with a mixture of mature bone and fibrous tissue. A fibrous tissue layer was also predicted under the force-controlled dynamic compression, although the same force magnitude was found promoting only mature bone during a strain-controlled compression. The model shows that the mechanical stimulation of bone tissue formation within a porous scaffold closely depends on the loading history and on the mechanical behaviour of the scaffold at local and global scales.

Computational modelling of the mechanical environment of osteogenesis within a polylactic acid-calcium phosphate glass scaffold.

A computational model based on finite element method (FEM) and computational fluid dynamics (CFD) is developed to analyse the mechanical stimuli in a composite scaffold made of polylactic acid (PLA) matrix with calcium phosphate glass (Glass) particles. Different bioreactor loading conditions were simulated within the scaffold. In vitro perfusion conditions were reproduced in the model. Dynamic compression was also reproduced in an uncoupled fluid-structure scheme: deformation level was studied analyzing the mechanical response of scaffold alone under static compression while strain rate was studied considering the fluid flow induced by compression through fixed scaffold. Results of the model show that during perfusion test an inlet velocity of 25 microm/s generates on scaffold surface a fluid flow shear stress which may stimulate osteogenesis. Dynamic compression of 5% applied on the PLA-Glass scaffold with a strain rate of 0.005 s(-1) has the benefit to generate mechanical stimuli based on both solid shear strain and fluid flow shear stress on large scaffold surface area. Values of perfusion inlet velocity or compression strain rate one order of magnitude lower may promote cell proliferation while values one order of magnitude higher may be detrimental for cells. FEM-CFD scaffold models may help to determine loading conditions promoting bone formation and to interpret experimental results from a mechanical point of view.