Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells.

Small animals do not replicate the severity of the human foreign-body response (FBR) to implants. Here we show that the FBR can be driven by forces generated at the implant surface that, owing to allometric scaling, increase exponentially with body size. We found that the human FBR is mediated by immune-cell-specific RAC2 mechanotransduction signalling, independently of the chemistry and mechanical properties of the implant, and that a pathological FBR that is human-like at the molecular, cellular and tissue levels can be induced in mice via the application of human-tissue-scale forces through a vibrating silicone implant. FBRs to such elevated extrinsic forces in the mice were also mediated by the activation of Rac2 signalling in a subpopulation of mechanoresponsive myeloid cells, which could be substantially reduced via the pharmacological or genetic inhibition of Rac2. Our findings provide an explanation for the stark differences in FBRs observed in small animals and humans, and have implications for the design and safety of implantable devices.

Mechanical lengthening of porcine small intestine with decreased forces.

INTRODUCTION: short bowel syndrome is marked by inadequate intestinal surface area to absorb nutrients. Current treatments are focused on medical management and surgical reconfiguration of the dilated intestine. We propose the use of spring-mediated distraction enterogenesis as a novel intervention to increase intestinal length. Given our previous success lengthening intestinal segments using springs with spring constant ~7 N/m that exerts 0.46 N or higher, we sought to determine the minimal force needed to lengthen porcine small intestinal segments, and to explore effects on intestine over time. METHODS: Juvenile Yucatan pigs underwent laparotomy with enterotomy to introduce nitinol springs intraluminally (n = 21 springs). Bowel segments (control, spring-distracted) were retrieved on post-operative day (POD) 7 and 14, and lengths measured. Thickness of cross-sectional intestinal layers were measured using H&E, and submucosal collagen fiber orientation measured using trichrome stained sections. RESULTS: all pigs survived to POD7 and 14. Spring constants of at least 2 N/m exerting a minimum force of 0.10 N significantly lengthened intestinal segments (p <0.0001). The stronger the spring force, the greater the induced thickness of various intestinal layers at POD7 and 14. Collagen fiber orientation was also more disordered because of stronger springs. CONCLUSION: a spring constant of approximately 2 N/m exerting 0.10 N and greater significantly lengthens intestinal segments and stimulates intestinal structural changes at POD7 and 14. This suggests a decreased force is capable of inducing spring-mediated distraction enterogenesis.

Biomechanical Force Prediction for Lengthening of Small Intestine during Distraction Enterogenesis.

Distraction enterogenesis has been extensively studied as a potential treatment for short bowel syndrome, which is the most common form of intestinal failure. Different strategies including parenteral nutrition and surgical lengthening to manage patients with short bowel syndrome are associated with high complication rates. More recently, self-expanding springs have been used to lengthen the small intestine using an intraluminal axial mechanical force, where this biomechanical force stimulates the growth and elongation of the small intestine. Differences in physical characteristics of patients with short bowel syndrome would require a different mechanical force-this is crucial in order to achieve an efficient and safe lengthening outcome. In this study, we aimed to predict the required mechanical force for each potential intestinal size. Based on our previous experimental observations and computational findings, we integrated our experimental measurements of patient biometrics along with mechanical characterization of the soft tissue into our numerical simulations to develop a series of computational models. These computational models can predict the required mechanical force for any potential patient where this can be advantageous in predicting an individual's tissue response to spring-mediated distraction enterogenesis and can be used toward a safe delivery of the mechanical force.

Biomechanics of small intestine during distraction enterogenesis with an intraluminal spring.

During recent years, distraction enterogenesis has been extensively studied as a treatment for short bowel syndrome, which is the most common cause of intestinal failure. Although different strategies such as parenteral nutrition and surgical lengthening have been used to manage the difficulties that patients with SBS deal with, these treatments are associated with high complication rates. Distraction enterogenesis uses mechanical force to increase the length and stimulate growth of the small intestine. In this study we combine in vivo experiments with computational modeling to explore the biomechanics of spring dependent distraction enterogenesis. We hypothesize that the self-expanding spring provides mechanical force for elastic tissue lengthening and triggers cellular proliferation. The additional growth of the intestine suggests signaling between mechanical stress and tissue response. We developed a computational modeling platform to test the correlation of applied mechanical force and tissue growth. We further validated our computational models with experimental measurements using spring-mediated distraction enterogenesis in a porcine model. This modeling platform can incorporate patient biometrics to estimate an individual's tissue response to spring mediated distraction enterogenesis.

Biomechanical signaling and collagen fiber reorientation during distraction enterogenesis.

Distraction enterogenesis has been extensively studied as a potential treatment for short bowel syndrome, which is the most common subset of intestinal failure. Spring distraction uses an intraluminal axial mechanical force to stimulate the growth and elongation of the small intestine. The tissue close to the distracted intestinal segment may also experience signaling to grow. In this study we examined the effects of distraction enterogenesis at different post-operative days on the thickness of small intestinal layers in the intestine proximal and distal to the distracted segment, as well as how the submucosal collagen fibers were reoriented. It was observed that not only different layers of intestine wall in distracted segment showed thickening due to the applied mechanical force but also adjacent tissues in both distal and proximal directions were impacted significantly where they showed thickening as well. The orientation of collagen fibers in submucosa layer was also significantly impacted due to the mechanical force in both distracted and adjacent tissue. The effect of the applied mechanical force on the main distracted tissue and the radial growth of the adjacent tissue strongly suggest actions of paracrine signaling.

How mechanical forces shape the developing eye.

In the vertebrate embryo, the eyes develop from optic vesicles that grow laterally outward from the brain tube and contact the overlying surface ectoderm. Within the region of contact, each optic vesicle and the surface ectoderm thicken to form placodes, which then invaginate to create the optic cup and lens pit, respectively. Eventually, the optic cup becomes the retina, while the lens pit closes to form the lens vesicle. Here, we review current hypotheses for the physical mechanisms that create these structures and present novel three-dimensional computer (finite-element) models to illustrate the plausibility and limitations of these hypotheses. Taken together, experimental and numerical results suggest that the driving forces for early eye morphogenesis are generated mainly by differential growth, actomyosin contraction, and regional apoptosis, with morphology mediated by physical constraints provided by adjacent tissues and extracellular matrix. While these studies offer new insight into the mechanics of eye development, future work is needed to better understand how these mechanisms are regulated to precisely control the shape of the eye.

A new hypothesis for foregut and heart tube formation based on differential growth and actomyosin contraction.

For decades, it was commonly thought that the bilateral heart fields in the early embryo fold directly towards the midline, where they meet and fuse to create the primitive heart tube. Recent studies have challenged this view, however, suggesting that the heart fields fold diagonally. As early foregut and heart tube morphogenesis are intimately related, this finding also raises questions concerning the traditional view of foregut formation. Here, we combine experiments on chick embryos with computational modeling to explore a new hypothesis for the physical mechanisms of heart tube and foregut formation. According to our hypothesis, differential anisotropic growth between mesoderm and endoderm drives diagonal folding. Then, active contraction along the anterior intestinal portal generates tension to elongate the foregut and heart tube. We test this hypothesis using biochemical perturbations of cell proliferation and contractility, as well as computational modeling based on nonlinear elasticity theory including growth and contraction. The present results generally support the view that differential growth and actomyosin contraction drive formation of the foregut and heart tube in the early chick embryo.

µCT-based trabecular anisotropy can be reproducibly computed from HR-pQCT scans using the triangulated bone surface.

The trabecular structure can be assessed at the wrist or tibia via high-resolution peripheral quantitative computed tomography (HR-pQCT). Yet on this modality, the performance of the existing methods, evaluating trabecular anisotropy is usually overlooked, especially in terms of reproducibility. We thus proposed to compare the TRI routine used by SCANCO Medical AG (Brüttisellen, Switzerland), the classical mean intercept length (MIL), and the grey-level structure tensor (GST) to the mean surface length (MSL), a new method for evaluating a second-order fabric tensor based on the triangulation of the bone surface. The distal radius of 24 fresh-frozen human forearms was scanned three times via HR-pQCT protocols (61µm, 82µm nominal voxel size), dissected, and imaged via micro computed tomography (µCT) at 16µm nominal voxel size. After registering the scans, we compared for each resolution the fabric tensors, determined by the mentioned techniques for 182 trabecular regions of interest. We then evaluated the reproducibility of the fabric information measured by HR-pQCT via precision errors. On µCT, TRI and GST were respectively the best and worst surrogates for MILµCT (MIL computed on µCT) in terms of eigenvalues and main direction of anisotropy. On HR-pQCT, however, MSL provided the best approximation of MILµCT. Surprisingly, surface-based approaches (TRI, MSL) also proved to be more precise than both MIL and GST. Our findings confirm that MSL can reproducibly estimate MILµCT, the current gold standard. MSL thus enables the direct mapping of the fabric-dependent material properties required in homogenised HR-pQCT-based finite element models.

Fast estimation of Colles' fracture load of the distal section of the radius by homogenized finite element analysis based on HR-pQCT.

Fractures of the distal section of the radius (Colles' fractures) occur earlier in life than other osteoporotic fractures. Therefore, they can be interpreted as a warning signal for later, more deleterious fractures of vertebral bodies or the femoral neck. In the past decade, the advent of HR-pQCT allowed a detailed architectural analysis of the distal radius and an automated but time-consuming estimation of its strength with linear micro-finite element (µFE) analysis. Recently, a second generation of HR-pQCT scanner (XtremeCT II, SCANCO Medical, Switzerland) with a resolution beyond 61 µm became available for even more refined biomechanical investigations in vivo. This raises the question how biomechanical outcome variables compare between the original (LR) and the new (HR) scanner resolution. Accordingly, the aim of this work was to validate experimentally a patient-specific homogenized finite element (hFE) analysis of the distal section of the human radius for the fast prediction of Colles' fracture load based on the last generation HR-pQCT. Fourteen pairs of fresh frozen forearms (mean age = 77.5±9) were scanned intact using the high (61 µm) and the low (82 µm) resolution protocols that correspond to the new and original HR-pQCT systems. From each forearm, the 20mm most distal section of the radius were dissected out, scanned with µCT at 16.4 µm and tested experimentally under compression up to failure for assessment of stiffness and ultimate load. Linear and nonlinear hFE models together with linear micro finite element (µFE) models were then generated based on the µCT and HR-pQCT reconstructions to predict the aforementioned mechanical properties of 24 sections. Precision errors of the short term reproducibility of the FE analyses were measured based on the repeated scans of 12 sections. The calculated failure loads correlated strongly with those measured in the experiments: accounting for donor as a random factor, the nonlinear hFE provided a marginal coefficient of determination (Rm2) of 0.957 for the high resolution (HR) and 0.948 for the low resolution (LR) protocols, the linear hFE with Rm2 of 0.957 for the HR and 0.947 for the LR protocols. Linear µFE predictions of the ultimate load were similar with an Rm2 of 0.950 for the HR and 0.954 for the LR protocols, respectively. Nonlinear hFE strength computation led to precision errors of 2.2 and 2.3% which were higher than the ones calculated based on the linear hFE (1.6 and 1.9%) and linear µFE (1.2 and 1.6%) for the HR and LR protocols respectively. Computation of the fracture load with nonlinear hFE demanded in average 6h of CPU time which was 3 times faster than with linear µFE, while computation with linear hFE took only a few minutes. This study delivers an extensive experimental and numerical validation for the application of an accurate and fast hFE diagnostic tool to help in identifying individuals who may be at risk of an osteoporotic wrist fracture and to follow up pharmacological and other treatments in such patients.

An over-nonlocal implicit gradient-enhanced damage-plastic model for trabecular bone under large compressive strains.

PURPOSE: Investigation of trabecular bone strength and compaction is important for fracture risk prediction. At 1-2% compressive strain, trabecular bone undergoes strain softening, which may lead to numerical instabilities and mesh dependency in classical local damage-plastic models. The aim of this work is to improve our continuum damage-plastic model of bone by reducing the influence of finite element mesh size under large compression. METHODOLOGY: This spurious numerical phenomenon may be circumvented by incorporating the nonlocal effect of cumulated plastic strain into the constitutive law. To this end, an over-nonlocal implicit gradient model of bone is developed and implemented into the finite element software ABAQUS using a user element subroutine. The ability of the model to detect the regions of bone failure is tested against experimental stepwise loading data of 16 human trabecular bone biopsies. FINDINGS: The numerical outcomes of the nonlocal model revealed reduction of finite element mesh dependency compared with the local damage-plastic model. Furthermore, it helped reduce the computational costs of large-strain compression simulations. ORIGINALITY: To the best of our knowledge, the proposed model is the first to predict the failure and densification of trabecular bone up to large compression independently of finite element mesh size. The current development enables the analysis of trabecular bone compaction as in osteoporotic fractures and implant migration, where large deformation of bone plays a key role.

Finite element analysis predicts experimental failure patterns in vertebral bodies loaded via intervertebral discs up to large deformation.

Vertebral compression fractures are becoming increasingly common. Patient-specific nonlinear finite element (FE) models have shown promise in predicting yield strength and damage pattern but have not been experimentally validated for clinically relevant vertebral fractures, which involve loading through intervertebral discs with varying degrees of degeneration up to large compressive strains. Therefore, stepwise axial compression was applied in vitro on segments and performed in silico on their FE equivalents using a nonlocal damage-plastic model including densification at large compression for bone and a time-independent hyperelastic model for the disc. The ability of the nonlinear FE models to predict the failure pattern in large compression was evaluated for three boundary conditions: healthy and degenerated intervertebral discs and embedded endplates. Bone compaction and fracture patterns were predicted using the local volume change as an indicator and the best correspondence was obtained for the healthy intervertebral discs. These preliminary results show that nonlinear finite element models enable prediction of bone localisation and compaction. To the best of our knowledge, this is the first study to predict the collapse of osteoporotic vertebral bodies up to large compression using realistic loading via the intervertebral discs.

Mechanical effects of the surface ectoderm on optic vesicle morphogenesis in the chick embryo.

Precise shaping of the eye is crucial for proper vision. Here, we use experiments on chick embryos along with computational models to examine the mechanical factors involved in the formation of the optic vesicles (OVs), which grow outward from the forebrain of the early embryo. First, mechanical dissections were used to remove the surface ectoderm (SE), a membrane that contacts the outer surfaces of the OVs. Principal components analysis of OV shapes suggests that the SE exerts asymmetric loads that cause the OVs to flatten and shear caudally during the earliest stages of eye development and later to bend in the caudal and dorsal directions. These deformations cause the initially spherical OVs to become pear-shaped. Exposure to the myosin II inhibitor blebbistatin reduced these effects, suggesting that cytoskeletal contraction controls OV shape by regulating tension in the SE. To test the physical plausibility of these interpretations, we developed 2-D finite-element models for frontal and transverse cross-sections of the forebrain, including frictionless contact between the SE and OVs. With geometric data used to specify differential growth in the OVs, these models were used to simulate each experiment (control, SE removed, no contraction). For each case, the predicted shape of the OV agrees reasonably well with experiments. The results of this study indicate that differential growth in the OV and external pressure exerted by the SE are sufficient to cause the global changes in OV shape observed during the earliest stages of eye development.

Experimental validation of finite element analysis of human vertebral collapse under large compressive strains.

Osteoporosis-related vertebral fractures represent a major health problem in elderly populations. Such fractures can often only be diagnosed after a substantial deformation history of the vertebral body. Therefore, it remains a challenge for clinicians to distinguish between stable and progressive potentially harmful fractures. Accordingly, novel criteria for selection of the appropriate conservative or surgical treatment are urgently needed. Computer tomography-based finite element analysis is an increasingly accepted method to predict the quasi-static vertebral strength and to follow up this small strain property longitudinally in time. A recent development in constitutive modeling allows us to simulate strain localization and densification in trabecular bone under large compressive strains without mesh dependence. The aim of this work was to validate this recently developed constitutive model of trabecular bone for the prediction of strain localization and densification in the human vertebral body subjected to large compressive deformation. A custom-made stepwise loading device mounted in a high resolution peripheral computer tomography system was used to describe the progressive collapse of 13 human vertebrae under axial compression. Continuum finite element analyses of the 13 compression tests were realized and the zones of high volumetric strain were compared with the experiments. A fair qualitative correspondence of the strain localization zone between the experiment and finite element analysis was achieved in 9 out of 13 tests and significant correlations of the volumetric strains were obtained throughout the range of applied axial compression. Interestingly, the stepwise propagating localization zones in trabecular bone converged to the buckling locations in the cortical shell. While the adopted continuum finite element approach still suffers from several limitations, these encouraging preliminary results towards the prediction of extended vertebral collapse may help in assessing fracture stability in future work.

Modeling and experimental validation of trabecular bone damage, softening and densification under large compressive strains.

Vertebral fractures represent a major health problem and involve the progressive collapse of trabecular bone over large compressive strains. This collapse is driven by local failure and interaction of the trabecular rod and plate elements, which translates into stress softening and densification at the material level. Current constitutive models for trabecular bone are essentially limited to infinitesimal strains. Accordingly, the aim of this work was to extend our current phenomenological model of trabecular bone (Garcia et al., 2009) for the simulation of large compressive strains by including post-yield softening and densification. A constitutive model of trabecular bone based on both volume fraction and trabecular orientation was formulated in a proper theoretical framework, implemented in commercial FE software and validated with human vertebral sections subjected to large compressive strains. As it is for infinitesimal strains, the evolution of plastic strains and damage is described by local internal variables. An isotropic softening rule was controlled by the cumulated plastic strain and a non-linear elastic spring was added to account for densification of the porous material in moderate-to-large compressive strains beyond a given threshold. To avoid convergence problems occurring as a result of softening, a consistent visco-plastic regularization approach was adopted. The experimental results for 37 vertebral sections from previous work (Dall'Ara et al., 2010) were used to validate the constitutive model for compressive loading up to 45% of the average axial deformation. This validation study showed that the model provides both qualitative predictions of damage localization on the cortex and quantitative predictions of dissipated energy (ρ(C)=0.912) of vertebral body behavior under large compressive strains. Since the evolution of the internal variables was considered in local manner, a mesh sensitivity analysis of the finite element model was conducted via two different mesh sizes and revealed that strain localization was dominated by trabecular bone heterogeneity. To our knowledge, this model is the first to simulate collapse of trabecular bone and may help improve the biomechanical understanding of several musculoskeletal conditions such as vertebral fractures or orthopedic implant migration.