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Cells are continuously exposed to dynamic environmental cues that influence their behavior. Mechanical cues can influence cellular and genomic architecture, gene expression, and intranuclear mechanics, providing evidence of mechanosensing by the nucleus, and a mechanoreciprocity between the nucleus and environment. Force disruption at the tissue level through aging, disease, or trauma, propagates to the nucleus and can have lasting consequences on proper functioning of the cell and nucleus. While the influence of mechanical cues leading to axonal damage has been well studied in neuronal cells, the mechanics of the nucleus following high impulse loading is still largely unexplored. Using an in vitro model of traumatic neural injury, we show a dynamic nuclear behavioral response to impulse stretch (up to 170% strain per second) through quantitative measures of nuclear movement, including tracking of rotation and internal motion. Differences in nuclear movement were observed between low and high strain magnitudes. Increased exposure to impulse stretch exaggerated the decrease in internal motion, assessed by particle tracking microrheology, and intranuclear displacements, assessed through high-resolution deformable image registration. An increase in F-actin puncta surrounding nuclei exposed to impulse stretch additionally demonstrated a corresponding disruption of the cytoskeletal network. Our results show direct biophysical nuclear responsiveness in neuronal cells through force propagation from the substrate to the nucleus. Understanding how mechanical forces perturb the morphological and behavioral response can lead to a greater understanding of how mechanical strain drives changes within the cell and nucleus, and may inform fundamental nuclear behavior after traumatic axonal injury. STATEMENT OF SIGNIFICANCE: The nucleus of the cell has been implicated as a mechano-sensitive organelle, courting molecular sensors and transmitting physical cues in order to maintain cellular and tissue homeostasis. Disruption of this network due to disease or high velocity forces (e.g., trauma) can not only result in orchestrated biochemical cascades, but also biophysical perturbations. Using an in vitro model of traumatic neural injury, we aimed to provide insight into the neuronal nuclear mechanics and biophysical responses at a continuum of strain magnitudes and after repetitive loads. Our image-based methods demonstrate mechanically-induced changes in cellular and nuclear behavior after high intensity loading and have the potential to further define mechanical thresholds of neuronal cell injury.

In this study we aimedto democratize access to Convolutional Neural Networks (CNN) for segmenting cartilage volumes, generating state-of-the-art results for specialized, real-world applications in hospitals and research. Segmentation of cross-sectional and/or longitudinalMagnetic Resonance (MR) Images of articular cartilage facilitates both clinical management of joint damage/disease andfundamental research. Manual delineation of such images is a time-consuming task susceptible to high intra- and inter-operator variability and prone to errors. Thus, enabling reliable and efficient analyses of MRIs of cartilage requires automated segmentation of cartilage volumes. Two main limitations arise in the development of hospital- or population-specific Deep Learning (DL) models for image segmentation: specialized knowledge and specialized hardware. We present a relatively easy and accessible implementation of a DL model to automatically segment MR images of human knees with state-of-the-art accuracy. In representative examples we trained CNN models in six to eight hours and obtained results quantitatively comparable to the stateoftheart for every anatomical structure.We established and evaluated our methodsusing two publicly available MRI datasetsoriginating from the Osteoarthritis Initiative, Stryker Imorphics and Zuse Institute Berlin (ZIB), as representative test cases. We use Google Colabfor editing and adapting the Python codesand selecting the runtime environment leveraging high-performance GPUs.We designed our solution for novice users to apply to any dataset with relatively few adaptations requiring only basic programming skills. To facilitate adoption of our methods we provide a complete guideline for using our methods and software, as well as the software tools themselves. This article is protected by copyright. All rights reserved.

Healthy articular cartilage presents structural gradients defined by distinct zonal patterns through the thickness, which may be disrupted in the pathogenesis of several disorders. Analysis of textural patterns using quantitative MRI data may identify structural gradients of healthy or degenerating tissue that correlate with early osteoarthritis (OA).To quantify spatial gradients and patterns in MRI data, and to probe new candidate biomarkers for early severity of OA.Retrospective study.Fourteen volunteers receiving total knee replacement surgery (eight males/two females/four unknown, average age ± standard deviation: 68.1 ± 9.6 years) and 10 patients from the OA Initiative (OAI) with radiographic OA onset (two males/eight females, average age ± standard deviation: 57.7 ± 9.4 years; initial Kellgren-Lawrence [KL] grade: 0; final KL grade: 3 over the 10-year study).3.0-T and 14.1-T, biomechanics-based displacement-encoded imaging, fast spin echo, multi-slice multi-echo T2 mapping.We studied structure and strain in cartilage explants from volunteers receiving total knee replacement, or structure in cartilage of OAI patients with progressive OA. We calculated spatial gradients of quantitative MRI measures (eg, T2) normal to the cartilage surface to enhance zonal variations. We compared gradient values against histologically OA severity, conventional relaxometry, and/or KL grades.Multiparametric linear regression for evaluation of the relationship between residuals of the mixed effects models and histologically determined OA severity scoring, with a significance threshold at α = 0.05.Gradients of individual relaxometry and biomechanics measures significantly correlated with OA severity, outperforming conventional relaxometry and strain metrics. In human explants, analysis of spatial gradients provided the strongest relationship to OA severity (RSpatial gradients of quantitative MRI data may improve the predictive power of noninvasive imaging for early-stage degeneration.1 TECHNICAL EFFICACY: Stage 1.

Finite element (FE) modeling plays a well-established and increasingly significant role in analyses of articular cartilage at the organ, tissue, and cell scales: for example understanding the functional relationships among constituents, microstructure, and tissue function in diarthrodial joints. A constitutive model, the crux of an accurate FE model, formalizes the functional dependencies among physical variables (e.g., strain, stress, and energy), thereby providing the missing equations to close the system generated by the classical balance principals, while accounting for the specific behavior of cartilage. In the future, fully 3-D FE modeling of cartilage could provide clinical diagnostic tools for patient-specific analyses. Computational analyses of full, patient-specific knee joints under load, especially before and after surgical intervention, would facilitate: (1) investigating fundamental research questions, e.g., structure-function relationships, load support, and mechanobiological cellular stimuli; (2) assessing individual patients, e.g., assessing joint integrity, preventing damage, and prescribing therapies; and (3) advancing tissue engineering, i.e., building replacement materials for cartilage. Approaches to computational modeling generally aim to adopt the simplest possible formulation that can describe experimental data, yet the complexity of articular cartilage mechanics demands similarly complex models. This review discusses extant multi-phase, large-strain (i.e., finite-deformation) constitutive models for cartilage which have been implemented in 3-D nonlinear finite elements. These have paved the way toward 3-D patient-specific clinical tools and along with advances in the underlying continuum theories and computational methods provide the foundations of improved constitutive models for 3-D FE modeling of cartilage in the future.

Summary Objective Deleterious impact loading to cartilage initiates post-traumatic osteoarthritis (OA). While cytokine and enzyme levels regulate disease progression, specific mechanical cues that elucidate cellular OA origins merit further investigation. We defined the dominant pericellular and cellular strain/stress transfer mechanisms following bulk-tissue injury associated with cell death. Method Using an in vitro model, we investigated rate-dependent loading and spatial localization of cell viability in acute indentation and time-course studies. Atomic force microscopy (AFM) and magnetic resonance imaging (MRI) confirmed depth-wise changes in cartilage micro-/macro-mechanics and structure post-indentation. To understand the transfer of loading to cartilage domains, we computationally modeled full-field strain and stress measures in interstitial matrix, pericellular and cellular regions. Results Chondrocyte viability decreased following rapid impact (80%/s) vs slow loading (0.1%/s) or unloaded controls. Viability was lost immediately during impact within regions near the indenter-tissue contact but did not change over 7 days of tissue culture. AFM studies revealed a loss of stiffness following 80%/s loading, and MRI studies confirmed an increased tensile and shear strain, but not relaxometry. Image-based patterns of chondrocyte viability closely matched computational estimates of amplified maximum principal and shear strain in interstitial matrix, pericellular and cellular regions. Conclusion Rapid indentation worsens chondrocyte death and degrades cartilage matrix stiffness in indentation regions. Cell death at high strain rates may be driven by elevated tensile strains, but not matrix stress. Strain amplification beyond critical thresholds in the pericellular matrix and cells may define a point of origin for early damage in post-traumatic OA.

Mechanotransduction plays a central role in evoking pain from the distal colon and rectum (colorectum) where embedded sensory nerve endings convert micromechanical stresses and strains into neural action potentials. The colorectum displays strong through-thickness and longitudinal heterogeneity with collagen concentrated in the submucosa thus indicating the significant load-bearing role of this layer. The density of sensory nerve endings is also significantly the greatest in the submucosa, suggesting a nociceptive function. Thus biomechanical heterogeneity in the colorectum influences the micromechanical stresses and strains surrounding afferent endings embedded within different layers of the colorectum which is critical for the mechanotransduction of various mechanical stimuli. In this study we aimed to: (1) calibrate and validate a three-layered computational model of the colorectum; (2) predict intra-tissue distributions of stresses and strains during mechanical stimulation of the colorectum ex vivo (i.e. circumferential stretching, punctuate probing, and mucosal shearing); and (3) establish a methodology to calculate local micromechanical stresses and strains surrounding afferent nerve endings embedded in the colorectum. We established three-layered FE models that include mucosa, submucosa, and muscular layers, and incorporated residual stretches, to calculate intra-tissue stresses and strains when the colorectum undergoes the mechanical stimuli used to characterize afferent neural encoding ex vivo. Finally, we established a methodology for detailed calculations of the local micromechanical stresses and strains surrounding afferent endings embedded in the colorectum and demonstrated this with a representative example. Our novel methodologies will bridge the existing neurophysiological and biomechanical evidence from experiments to advance our mechanistic understanding of colorectal mechanotransduction.

Irritable bowel syndrome afflicts 10–20% of the global population, causing visceral pain with increased sensitivity to colorectal distension and normal bowel movements. Understanding and predicting these biomechanics will further advance our understanding of visceral pain and complement the existing literature on visceral neurophysiology. We recently performed a series of experiments at three longitudinal segments (colonic, intermediate, and rectal) of the distal 30 mm of colorectums of mice. We also established and fitted constitutive models addressing mechanical heterogeneity in both the through-thickness and longitudinal directions of the colorectum. Afferent nerve endings, strategically located within the submucosa, are likely nociceptors that detect concentrations of mechanical stresses to evoke the perception of pain from the viscera. In this study, we aim to: (1) establish and validate a method for incorporating residual stresses into models of colorectums, (2) predict the effects of residual stresses on the intratissue mechanics within the colorectum, and (3) establish intratissue distributions of stretches and stresses within the colorectum in vivo. To these ends we developed two-layered, composite finite element models of the colorectum based on our experimental evidence and validated our approaches against independent experimental data. We included layer- and segment-specific residual stretches/stresses in our simulations via the prestrain algorithm built into the finite element software febio. Our models and modeling approaches allow researchers to predict both organ and intratissue biomechanics of the colorectum and may facilitate better understanding of the underlying mechanical mechanisms of visceral pain.

Summary Objective We recently demonstrated that low-energy mechanical impact to articular cartilage, usually considered non-injurious, can in fact cause microscale cracks (widths 30 μ m) in the collagen network of visually pristine human cartilage. While research on macro-scale cracks in cartilage and microcracks in bone abounds, how microcracks within cartilage initiate and propagate remains unknown. We quantified the extent to which microcracks initiate and propagate in the collagen network during mechanical loading representative of normal activities. Design We tested 76 full-thickness, cylindrical osteochondral plugs. We imaged untreated specimens (pristine phase) via second harmonic generation and assigned specimens to three low-energy impact groups (none, low, high), and thereafter to three cyclic compression groups (none, low, high) which simulate walking. We re-imaged specimens in the post-impact and post-cyclic compression phases to identify and track microcracks. Results Microcracks in the network of collagen did not present in untreated controls but did initiate and propagate under mechanical treatments. We found that the length and width of microcracks increased from post-impact to post-cyclic compression in tracked microcracks, but neither depth nor angle presented statistically significant differences. Conclusions The microcracks we initiated under low-energy impact loading increased in length and width during subsequent cyclic compression that simulated walking. The extent of this propagation depended on the combination of impact and cyclic compression. More broadly, the initiation and propagation of microcracks may characterize pathogenesis of osteoarthritis, and may suggest therapeutic targets for future studies.

Across spatial scales, biological systems exhibit exquisite hierarchy in architecture and function, leading to complex, observable phenomena. In the articular cartilage of our joints, the organization of molecule- to tissue-level structures governs the interplay of macromolecules and determines the biological activity of embedded cells (chondrocytes), motivating the development of new computational models to provide insight and understanding. We review recent work on multiscale modeling of cartilage, with an emphasis on finite element based methods, and emerging experimental approaches that enable calibration and validation. Through new nested modeling approaches, we are now able to dissect interactions of constituent macromolecules, and we envision the ability to soon define the mechanical microenvironment experienced by and within single cells that guide biological activity.

Colorectal hypersensitivity and sensitization of both mechanosensitive and mechanically insensitive afferents develop after intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) in the mouse, a model of postinfectious irritable bowel syndrome. In mice in which ∼80% of extrinsic colorectal afferents were labeled genetically using the promotor for vesicular glutamate transporter type 2 (VGLUT2), we systematically quantified the morphology of VGLUT2-positive axons in mouse colorectum 7–28 days following intracolonic TNBS treatment. After removal, the colorectum was distended (20 mmHg), fixed with paraformaldehyde, and optically cleared to image VGLUT2-positive axons throughout the colorectal wall thickness. We conducted vector path tracing of individual axons to allow systematic quantification of nerve fiber density and shape. Abundant VGLUT2-positive nerve fibers were present in most layers of the colorectum, except the serosal and longitudinal muscular layers. A small percentage of VGLUT2-positive myenteric plexus neurons was also detected. Intracolonic TNBS treatment significantly reduced the number of VGLUT2-positive nerve fibers in submucosal, myenteric plexus, and mucosal layers at day 7 post-TNBS, which mostly recovered by day 28. We also found that almost all fibers in the submucosa were meandering and curvy, with ∼10% showing pronounced curviness (quantified by the linearity index). TNBS treatment resulted in a significant reduction of the proportions of pronounced curvy fibers in the rectal region at 28 days post-TNBS. Altogether, the present morphological study reveals profound changes in the distribution of VGLUT2-positive fibers in mouse colorectum undergoing TNBS-induced colitis and draws attention to curvy fibers in the submucosa with potential roles in visceral nociception. NEW & NOTEWORTHY We conducted genetic labeling and optical clearing to visualize extrinsic sensory nerve fibers in whole-mount colorectum, which revealed widespread presence of axons in the submucosal layer. Remarkably, axons in the submucosa were meandering and curvy, in contrast to axons in other layers generally aligned with the basal tissues. Intracolonic TNBS treatment led to pronounced changes of nerve fiber density and curviness, suggesting nerve fiber morphologies as potentially contributing factors to sensory sensitization.

Summary Objective We aimed to directly quantify the zone-specific evolution in morphology of collagen fibers and networks in human cartilage during the progression of early osteoarthritis. Collagen fibers exhibit depth-dependent orientations and diameters crucial to their mechanical roles. Cartilage degenerates in osteoarthritis, affecting the morphology of the collagen network and ultimately the intra-tissue mechanics. Design We obtained specimens of human cartilage from healthy human knees ( n = 3 ) and from total knee arthroplasties ( n = 5 ). We utilized TEM and custom image analyses to visualize and quantify distributions in principal orientation, dispersion (about the principal orientation), and diameter of collagen fibers in the early grades of OA within each through-thickness zone. We then used histological and statistical analyses to probe for significant changes in the zone-specific evolution in collagen-network morphology as a function of Osteoarthritis Research Society International (OARSI) grade. Results Dispersion in the alignment of collagen fibers increased with progression of early OA in both the superficial and deep zones, and decreased in the middle zone, while principal orientation did not change significantly. The non-normal and right-skewed distributions in fiber diameters did not evolve with the progression of OA. Conclusions We provide the research community with quantitative data (1) on the through-thickness morphology of collagen in healthy cartilage and (2) on the evolution of through-thickness morphology of collagen with progressing early OA. Such quantitative data facilitate an improved mechanistic understanding of the progression of OA, and may facilitate identifying image-based biomarkers and treatment targets, and ultimately finding clinical interventions for OA.

Abnormal colorectal biomechanics and mechanotransduction associate with an array of gastrointestinal diseases, including inflammatory bowel disease, irritable bowel syndrome, diverticula disease, anorectal disorders, ileus, and chronic constipation. Visceral pain, principally evoked from mechanical distension, has a unique biomechanical component that plays a critical role in mechanotransduction, the process of encoding mechanical stimuli to the colorectum by sensory afferents. To fully understand the underlying mechanisms of visceral mechanical neural encoding demands focused attention on the macro- and micro-mechanics of colon tissue. Motivated by biomechanical experiments on the colon and rectum, increasing efforts focus on developing constitutive frameworks to interpret and predict the anisotropic and nonlinear biomechanical behaviors of the multilayered colorectum. We will review the current literature on computational modeling of the colon and rectum as well as the mechanical neural encoding by stretch sensitive afferent endings, and then highlight our recent advances in these areas. Current models provide insight into organ- and tissue-level biomechanics as well as the stretch-sensitive afferent endings of colorectal tissues yet an important challenge in modeling theory remains. The research community has not connected the biomechanical models to those of mechanosensitive nerve endings to create a cohesive multiscale framework for predicting mechanotransduction from organ-level biomechanics.

When planning an implant-supported restoration, the dentist is faced with surgical and prosthetic technical issues as well as the patient's expectations. Many patients wish an immediate solution to an edentulous condition. This may be especially true in the esthetic zone, and that zone is determined by the patient. The dentist may consider when it is feasible to load the supporting implants with definitive or provisional prosthetics. In this work, many parameters were theoretically assessed for inclusion: bone density, cortical thickness, insertion torque, parafunction, bite load capacity, number of implants under load, implant/crown ratio, implant diameter, and length. After assessment, the most influential parameters were selected. An iteration, using patient age, implant diameter, bite load capacity, and cortical thickness, is now presented to aid the implant dentist in determining the feasibility for immediate functional loading of a just-placed dental implant in a healed site. Extensive testing is required to develop this concept. According to this iteration, most immediate functional loaded implants would fail. A future refined and definitive formula may enable the clinician to safely and immediately functionally load an implant with a definitive prosthesis. For access to the applet, please go to https://implantloading.shinyapps.io/shiny_app/.

Hydrogels have seen widespread application across biomedical sciences and there is considerable interest in using hydrogels, including agarose, for creating in vitro three-dimensional environments to grow cells and study mechanobiology and mechanotransduction. Recent advances in the preparation of agarose gels enable successful encapsulation of viable cells at gel concentrations as high as 5%. Agarose with a range of gel concentrations can thus serve as an experimental model mimicking changes in the 3-D microenvironment of cells during disease progression and can facilitate experiments aimed at probing the corresponding mechanobiology, e.g. the evolving mechanobiology of chondrocytes during the progression of osteoarthritis. Importantly, whether stresses (forces) or strains (displacement) drive mechanobiology and mechanotransduction is currently unknown. We can use experiments to quantify mechanical properties of hydrogels, and imaging to estimate microstructure and even strains; however, only computational models can estimate intra-gel stresses in cell-seeded agarose constructs because the required in vitro experiments are currently impossible. Finite element modeling is well-established for (computational) mechanical analyses, but accurate constitutive models for modeling the 3-D mechanical environments of cells within high-stiffness agarose are currently unavailable. In this study we aimed to establish a 3-D constitutive model of high-stiffness agarose with a range of gel concentrations. We applied a multi-step, physics-based optimization approach to separately fit subsets of model parameters and help achieve robust convergence. Our constitutive model, fitted to experimental data on progressive stress-relaxations, was able to predict reaction forces determined from independent experiments on cyclical loading. Our model has broad applications in finite element modeling aimed at interpreting mechanical experiments on agarose specimens seeded with cells, particularly in predicting distributions of intra-gel stresses. Our model and fitted parameters enable more accurate finite element simulations of high-stiffness agarose constructs, and thus better understanding of experiments aimed at mechanobiology, mechanotransduction, or other applications in tissue engineering.

The center of resistance (CRES) is regarded as the fundamental reference point for predictable tooth movement. The methods used to estimate the CRES of teeth range from traditional radiographic and physical measurements to in vitro analysis on models or cadaver specimens. Techniques involving finite element analysis of high-dose micro-CT scans of models and single teeth have shown a lot of promise, but little has been done with newer, low-dose, and low resolution cone beam computed tomography (CBCT) images. Also, the CRES for only a few select teeth (i.e., maxillary central incisor, canine, and first molar) have been described; the rest have been largely ignored. There is also a need to describe the methodology of determining the CRES in detail, so that it becomes easy to replicate and build upon. This study used routine CBCT patient images for developing tools and a workflow to obtain finite element models for locating the CRES of maxillary teeth. The CBCT volume images were manipulated to extract three-dimensional (3D) biological structures relevant in determining the CRES of the maxillary teeth by segmentation. The segmented objects were cleaned and converted into a virtual mesh made up tetrahedral (tet4) triangles having a maximum edge length of 1 mm with 3matic software. The models were further converted into a solid volumetric mesh of tetrahedrons with a maximum edge length of 1 mm for use in finite element analysis. The engineering software, Abaqus, was used to preprocess the models to create an assembly and set material properties, interaction conditions, boundary conditions, and load applications. The loads, when analyzed, simulated the stresses and strains on the system, aiding in locating the CRES. This study is the first step in accurate prediction of tooth movement.

MRI-based mathematical and computational modelling studies can contribute to a better understanding of the mechanisms governing cartilage’s mechanical performance and cartilage disease. In addition, distinct modelling of cartilage is needed to optimize artificial cartilage production. These studies have opened up the prospect of further deepening our understanding of cartilage function. Furthermore, these studies reveal the initiation of an engineering-level approach to how cartilage disease affects material properties and cartilage function. Aimed at researchers in the field of MRI-based cartilage simulation, research articles pertinent to MRI-based cartilage modelling were identified, reviewed, and summarized systematically. Various MRI applications for cartilage modelling are highlighted, and the limitations of different constitutive models used are addressed. In addition, the clinical application of simulations and studied diseases are discussed. The paper’s quality, based on the developed questionnaire, was assessed, and out of 79 reviewed papers, 34 papers were determined as high-quality. Due to the lack of the best constitutive models for various clinical conditions, researchers may consider the effect of constitutive material models on the cartilage disease simulation. In the future, research groups may incorporate various aspects of machine learning into constitutive models and MRI data extraction to further refine the study methodology. Moreover, researchers should strive for further reproducibility and rigorous model validation and verification, such as gait analysis.

Articular cartilage has pronounced through-the-thickness heterogeneity in both ultrastructure and mechanical function. The tissue undergoes a combination of large deformations in vivo, where shear is critical in both failure and chondrocyte death. Yet the microstructure mechanical response of cartilage to multi-axial large shear deformations is unknown. We harvested a total of 42 cartilage specimens from seven matched locations across the lateral femoral condyles and patellofemoral grooves of six human male donors (30.2±8.8 yrs old, M±SD). With each specimen we applied a range of quasi-static, multi-axial large (simple) shear displacements both parallel and perpendicular to the local split-line direction (SLD). Shear stresses in cartilage specimens from the patellofemoral grooves were higher, and more energy was dissipated, at all applied strains under loading parallel to the local SLD versus perpendicular, while specimens from the lateral condyles were mechanically anisotropic only under larger strains of 20% and 25%. Cartilage also showed significant intra-donor variability at larger shear strains but no significant inter-donor variability. Overall, shear strain-energy dissipation was almost constant at 5% applied shear strain and increased nonlinearly with increasing shear magnitude. Our results suggest that full understanding of cartilage mechanics requires large-strain analyses to account for nonlinear, anisotropic and location-dependent effects not fully realized at small strains.

Skin wrinkling, especially in the facial area, is a prominent sign of aging and is a growing area of research aimed at developing cosmetics and dermatological treatments. To better understand and treat undesirable skin wrinkles, it is vitally important to elucidate the underlying mechanisms of skin wrinkling, a largely mechanical process. Human skin, a multi-layer composite, has six mechanically distinct layers: from the outermost inward they are the stratum corneum, viable epidermis, dermal-epidermal-junction, papillary dermis, reticular dermis, and hypodermis. To better address the through-thickness hierarchy, and the development of wrinkling within this complicated hierarchy, we established a six-layered model of human skin realized with finite element modeling, by leveraging available morphological and biomechanical data on human skin of the forehead. Exercising our new model we aimed to quantify the effects of three potential mechanisms of wrinkle formation: (1) skin compression due to muscle contraction (dynamic wrinkles); (2) age-related volumetric tissue loss (static wrinkles); and (3) the combined effects of both mechanisms. Since hydration of the stratum corneum significantly affects its stiffness we also aimed to quantify the influence its hydration with these three potential mechanisms of wrinkle formation. Our six-layered skin model, combined with the proposed wrinkling mechanisms, successfully predicts the formation of dynamic and static wrinkles in the forehead consistent with the experimental literature. We observed three wrinkling modes in the forehead where the deepest wrinkles could reach to the reticular dermis. With further refinement our new six-layered model of human skin can be applied to study other region-specific wrinkle types such as the "crow's feet" and the nasolabial folds.

Mechanical distension beyond a particular threshold evokes visceral pain from distal colon and rectum (colorectum), and thus biomechanics plays a central role in visceral nociception. In this study we focused on the layered structure of the colorectum through the wall thickness and determined the biomechanical properties of layer-separated colorectal tissue. We harvested the distal 30 mm of mouse colorectum and dissected this tissue into inner and outer composite layers. The inner composite consists of the mucosa and submucosa, whereas the outer composite includes the muscular layers and serosa. We divided each composite axially into three 10-mm-long segments and conducted biaxial mechanical extension tests and opening-angle measurements for each tissue segment. In addition, we quantified the thickness of the rich collagen network in the submucosa by nonlinear imaging via second-harmonic generation (SHG). Our results reveal that the inner composite is slightly stiffer in the axial direction, whereas the outer composite is stiffer circumferentially. The stiffness of the inner composite in the axial direction is about twice that in the circumferential direction, consistent with the orientations of collagen fibers in the submucosa approximately ±30° to the axial direction. Submucosal thickness measured by SHG showed no difference from proximal to distal colorectum under the load-free condition, which likely contributes to the comparable tension stiffness of the inner composite along the colorectum. This, in turn, strongly indicates the submucosa as the load-bearing structure of the colorectum. This further implies nociceptive roles for the colorectal afferent endings in the submucosa, which likely encode tissue-injurious mechanical distension.NEW & NOTEWORTHY Visceral pain from distal colon and rectum (colorectum) is usually elicited from mechanical distension/stretch, rather than from heating, cutting, or pinching, which usually evoke pain from the skin. We conducted layer-separated biomechanical tests on mouse colorectum and identified an unexpected role of submucosa as the load-bearing structure of the colorectum. Outcomes of this study will focus attention on sensory nerve endings in the submucosa that likely encode tissue-injurious distension/stretch to cause visceral pain.

Visceral pain is one of the principal complaints of patients with irritable bowel syndrome, and this pain is reliably evoked by mechanical distension and stretch of distal colon and rectum (colorectum). This study focuses on the biomechanics of the colorectum that could play critical roles in mechanical neural encoding. We harvested the distal 30 mm of the colorectum from mice, divided evenly into three 10-mm-long segments (colonic, intermediate and rectal), and conducted biaxial mechanical stretch tests and opening-angle measurements for each tissue segment. In addition, we determined the collagen fiber orientations and contents across the thickness of the colorectal wall by nonlinear imaging via second harmonic generation (SHG). Our results reveal a progressive increase in tissue compliance and prestress from colonic to rectal segments, which supports prior electrophysiological findings of distinct mechanical neural encodings by afferents in the lumbar splanchnic nerves (LSN) and pelvic nerves (PN) that dominate colonic and rectal innervations, respectively. The colorectum is significantly more viscoelastic in the circumferential direction than in the axial direction. In addition, our SHG results reveal a rich collagen network in the submucosa and orients approximately ±30° to the axial direction, consistent with the biaxial test results presenting almost twice the stiffness in axial direction versus the circumferential direction. Results from current biomechanical study strongly indicate the prominent roles of local tissue biomechanics in determining the differential mechanical neural encoding functions in different regions of the colorectum. NEW & NOTEWORTHY Mechanical distension and stretch—not heat, cutting, or pinching—reliably evoke pain from distal colon and rectum. We report different local mechanics along the longitudinal length of the colorectum, which is consistent with the existing literature on distinct mechanotransduction of afferents innervating proximal and distal regions of the colorectum. This study draws attention to local mechanics as a potential determinant factor for mechanical neural encoding of the colorectum, which is crucial in visceral nociception.

Visceral pain from the distal colon and rectum (colorectum) is a major complaint of patients with irritable bowel syndrome. Mechanotransduction of colorectal distension/stretch appears to play a critical role in visceral nociception, and further understanding requires improved knowledge of the micromechanical environments at different sub-layers of the colorectum. In this study, we conducted nonlinear imaging via second harmonic generation to quantify the thickness of each distinct through-thickness layer of the colorectum, as well as the principal orientations, corresponding dispersions in orientations, and the distributions of diameters of collagen fibers within each of these layers. From C57BL/6 mice of both sexes (8–16 weeks of age, 25–35g), we dissected the distal 30 mm of the large bowel including the colorectum, divided these into three even segments, and harvested specimens (~8×8 mm(2)) from each segment. We stretched the specimens either by colorectal distension to 20 mmHg (reference) or 80 mmHg (deformed) or by biaxial stretch to 10 mN (reference) or 80 mN (deformed), and fixed them with 4% paraformaldehyde. We then conducted SHG imaging through the wall thickness and analyzed post-hoc using custom-built software to quantify the orientations of collagen fibers in all distinct layers. We also quantified the thickness of each layer of the colorectum, and the corresponding distributions of collagen density and diameters of fibers. We found collagen concentrated in the submucosal layer. The average diameter of collagen fibers was greatest in the submucosal layer, followed by the serosal and muscular layers. Collagen fibers aligned with muscle fibers in the two muscular layers, whereas their orientation varied greatly with location in the serosal layer. In colonic segments, thick collagen fibers in the submucosa presented two major orientations aligned approximately ±30 degrees to the axial direction, and form a patterned network. Our results indicate the submucosa is likely the principal passive load-bearing structure of the colorectum. In addition, afferent endings in those collagen-rich regions present likely candidates of colorectal nociceptors to encode noxious distension/stretch.

Mechanotransduction, the encoding of local mechanical stresses and strains at sensory endings into neural action potentials at the viscera, plays a critical role in evoking visceral pain, e.g., in the distal colon and rectum (colorectum). The wall of the colorectum is structurally heterogeneous, including two major composites: the inner consists of muscular and submucosal layers, and the outer consists of circular muscular, intermuscular, longitudinal muscular, and serosal layers. In fact the colorectum presents biomechanical heterogenity across both the longitudinal and through-thickness directions thus highlighting the differential roles of sensory nerve endings within different regions of the colorectum in visceral mechanotransduction. We determined constitutive models and model parameters for individual layers of the colorectum from three longitudinal locations (colonic, intermediate, and distal) using nonlinear optimization to fit our experimental results from biaxial extension tests on layer-separated colorectal tissues (mouse model, 7 × 7 mm(2), Siri et al., Am. J. Physiol. Gastrointest. Liver Physiol. 316, G473-G481 and 317, G349-G358), and quantified the thicknesses of the layers. In this study we also quantified the residual stretches stemming from separating colorectal specimens into inner and outer composites and we completed new pressure-diameter mechanical testing to provide an additional validation case. We implemented the constitutive equations and created two-layered, 3-D finite element models using FEBio (University of Utah), and incorporated the residual stretches. We validated the modeling framework by comparing FE-predicted results for both biaxial extension testing of bulk specimens of colorectum and pressure-diameter testing of bulk segments against corresponding experimental results independent of those used in our model fitting. We present the first theoretical framework to simulate the biomechanics of distal colorectum, including both longitudinal and through-thickness heterogeneity, based on constitutive modeling of biaxial extension tests of colon tissues from mice. Our constitutive models and modeling framework facilitate analyses of both fundamental questions (e.g., the impact of organ/tissue biomechanics on mechanotransduction of the sensory nerve endings, structure-function relationships, and growth and remodeling in health and disease) and specific applications (e.g., device design, minimally invasive surgery, and biomedical research).

Human joints, particularly those of extremities, experience a significant range of temperatures in vivo. Joint temperature influences the mechanics of both joint and cartilage, and the mechanics of cartilage can affect the temperature of both joint and cartilage. Thermal treatments and tissue repairs, such as thermal chondroplasty, and ex vivo tissue engineering may also expose cartilage to supraphysiological temperatures. Furthermore, although cartilage undergoes principally compressive loads in vivo, shear strain plays a significant role at larger compressive strains. Thus, we aimed to determine whether and how the bulk mechanical responses of cartilage undergoing large-strain shear change (1) within the range of temperatures relevant in vivo, and (2) both during and after supraphysiological thermal treatments. We completed large-strain shear tests (10 and 15%) at four thermal conditions: 24∘C and 40∘C to span the in vivo range, and 70∘C and 24∘C repeated after 70∘C to explore mechanics during and after potential treatments. We calculated the bulk mechanical responses (strain-energy dissipation densities, peak-to-peak shear stresses, and peak-effective shear moduli) as of function of temperature and used statistical methods to probe significant differences. To probe the mechanisms underlying differences we assessed specimens, principally the type II collagen, with imaging (second harmonic generation and transmission electron microscopies, and histology) and assessed the temperature-dependent mechanics of type II collagen molecules within cartilage using steered molecular dynamics simulations. Our results suggest that the bulk mechanical responses of cartilage depend significantly on temperature both within the in vivo range and at supraphysiological temperatures, showing significant reductions in all mechanical measures with increasing temperature. Using imaging and simulations we determined that one underlying mechanism explaining our results may be changes in the molecular deformation profiles of collagen molecules versus temperature, likely compounded at larger length scales. These new insights into the mechanics of cartilage and collagen may suggest new treatment targets for damaged or osteoarthritic cartilage.

Summary Objective Given the structural changes associated with the progression of Osteoarthritis (OA), we hypothesized that patterns of through-thickness, large-strain shear evolve with early-stage OA. We therefore aimed to determine whether and how patterns of shear strains change during early-stage OA to 1) gain insight into the progression of OA by quantifying changes in local deformations; 2) gauge the potential of patterns in shear strain to serve as image-based biomarkers of early-stage OA; and 3) provide high-resolution, through-thickness data for proposing, fitting, and validating constitutive models for cartilage. Design We completed displacement-driven, large-strain shear tests (5, 10, 15%) on 44 specimens of variably advanced osteoarthritic human articular cartilage as determined by both Osteoarthritis Research Society International (OARSI) grade and PLM-CO score. We recorded the through-thickness deformations with a stereo-camera system and processed these data using digital image correlation (DIC) to determine full-thickness patterns of strains and relative zonal recruitments, i.e., the average shear strain in a through-thickness zone weighted by its relative thickness and normalized by the applied strain. Results We observed three general shapes for the curves of averaged through-thickness, Green–Lagrange shear strains during progression of OA. We also observed that during the progression of OA only the deep zone is recruited differently under shear in a statistically significant way. Conclusions We propose that changes in through-thickness patterns of shear strain could provide sensitive biomarkers for early clinical detection of OA. The relative zonal recruitment of the deep zone decreases with progressing OA (OARSI grade) and microstructural remodeling (PLM-CO score), which do not consistently affect recruitment of the superficial and middle zones.

Both computational mechanics and medical imaging play an increasingly significant role in the study of biological systems at the scales of the organism, organ system, organ, tissue, cell, and molecule. Synergies among fundamental image-based experiments, new mathematical models, and computational methods enable studies of numerous phenomena and processes, e.g., microphysical (mechanobiological) cellular stimuli and response, structure-function relationships in tissues, surgical interventions, organ and tissue integrity, disease initiation and progression, and engineered tissue replacements. In this chapter, we explore the use of continuum modeling in a finite element framework that is suitable for the study of complex biological tissues and engineered systems. Important to this framework is the integration of continuum mechanical modeling with image-based data acquisition. Imaging can provide a noninvasive assessment of tissues and materials, allowing for the generation of data that is minimally influenced by the acquisition method, and that can guide material parameter selection, define boundary conditions or morphology, or enable precise validation studies. We present complex models and experimental approaches, using articular cartilage as a primary study system, that can be readily expanded to a broad range of soft biological tissues and engineered materials. Additionally, we discuss the use of imaging to acquire measures of geometry, morphology, diffusion, strain, and material properties.

Medical imaging performed in vivo captures geometries under Donnan osmotic loading, even when the articulating joint is otherwise mechanically unloaded. Hence patient-specific finite element (FE) models constructed from such medical images of cartilage represent osmotically induced prestretched/prestressed states. When applying classical modeling approaches to patient-specific simulations of cartilage a theoretical inconsistency arises: the in-vivo imaged geometry (used to construct the model) is not an unloaded, stress-free reference configuration. Furthermore when fitting nonlinear constitutive models that include osmotic swelling (to obtain material parameters), if one assumes that experimental data-generated from osmotically loaded cartilage-begin from a stress-free reference configuration the fitted stress-stretch relationship (parameters) obtained will actually describe a different behavior. In this study we: (1) establish a practical computational method to include osmotically induced prestretch/prestress in image-driven simulations of cartilage; and (2) investigate the influence of considering the prestretched/prestressed state both when fitting fiber-reinforced, biphasic constitutive models of cartilage that include osmotic swelling and when simulating cartilage responses. Our results highlight the importance of determining the prestretched/prestressed state within cartilage induced by osmotic loading in the imaged configuration prior to solving boundary value problems of interest. With our new constitutive model and modeling methods, we aim to improve the fidelity of FE-based, patient-specific biomechanical simulations of joints and cartilage. Improved simulations can provide medical researchers with new information often unavailable in a clinical setting, information that may contribute to better insight into the pathophysiology of cartilage diseases.

Finite element (FE) simulations are increasingly valuable in assessing and improving the performance of biomedical devices and procedures. Due to high computational demands such simulations may become difficult or even infeasible, especially when considering nearly incompressible and anisotropic material models prevalent in analyses of soft tissues. Implementations of GPGPU-based explicit FEs predominantly cover isotropic materials, e.g. the neo-Hookean model. To elucidate the computational expense of anisotropic materials, we implement the Gasser-Ogden-Holzapfel dispersed, fiber-reinforced model and compare solution times against the neo-Hookean model. Implementations of GPGPU-based explicit FEs conventionally rely on single-point (under) integration. To elucidate the expense of full and selective-reduced integration (more reliable) we implement both and compare corresponding solution times against those generated using underintegration. To better understand the advancement of hardware, we compare results generated using representative Nvidia GPGPUs from three recent generations: Fermi (C2075), Kepler (K20c), and Maxwell (GTX980). We explore scaling by solving the same boundary value problem (an extension-inflation test on a segment of human aorta) with progressively larger FE meshes. Our results demonstrate substantial improvements in simulation speeds relative to two benchmark FE codes (up to 300[Formula: see text] while maintaining accuracy), and thus open many avenues to novel applications in biomechanics and medicine. ispartof: Computer Methods in Biomechanics and Biomedical Engineering vol:20 issue:16 pages:1643-1657 ispartof: location:England status: published

The remarkable mechanical properties of cartilage derive from an interplay of isotropically distributed, densely packed and negatively charged proteoglycans; a highly anisotropic and inhomogeneously oriented fiber network of collagens; and an interstitial electrolytic fluid. We propose a new 3D finite strain constitutive model capable of simultaneously addressing both solid (reinforcement) and fluid (permeability) dependence of the tissue's mechanical response on the patient-specific collagen fiber network. To represent fiber reinforcement, we integrate the strain energies of single collagen fibers-weighted by an orientation distribution function (ODF) defined over a unit sphere-over the distributed fiber orientations in 3D. We define the anisotropic intrinsic permeability of the tissue with a structure tensor based again on the integration of the local ODF over all spatial fiber orientations. By design, our modeling formulation accepts structural data on patient-specific collagen fiber networks as determined via diffusion tensor MRI. We implement our new model in 3D large strain finite elements and study the distributions of interstitial fluid pressure, fluid pressure load support and shear stress within a cartilage sample under indentation. Results show that the fiber network dramatically increases interstitial fluid pressure and focuses it near the surface. Inhomogeneity in the tissue's composition also increases fluid pressure and reduces shear stress in the solid. Finally, a biphasic neo-Hookean material model, as is available in commercial finite element codes, does not capture important features of the intra-tissue response, e.g., distributions of interstitial fluid pressure and principal shear stress.

Development of aortic aneurysms includes significant morphological changes within the tissue: collagen content increases, elastin content reduces and smooth muscle cells degenerate. We seek to quantify the impact of these changes on the passive mechanical response of aneurysms in the supra-physiological loading range via mechanical testing and constitutive modeling. We perform uniaxial extension tests on circumferentially and axially oriented strips from five thoracic (65.6 years ± 13.4, mean ± SD) and eight abdominal (63.9 years ± 11.4) aortic fusiform aneurysms to investigate both continuous and discontinuous softening during supra-physiological loading. We determine the significance of the differences between the fitted model parameters: diseased thoracic versus abdominal tissues, and healthy (Weisbecker et al., J. Mech. Behav. Biomed. Mater. 12, 93-106, 2012) versus diseased tissues. We also test correlations among these parameters and age, Body Mass Index (BMI) and preoperative aneurysm diameter, and investigate histological cuts. Tissue response is anisotropic for all tests and the anisotropic pseudo-elastic damage model fits the data well for both primary loading and discontinuous softening which we interpret as damage. We found statistically relevant differences between model parameters fitted to diseased thoracic versus abdominal tissues, as well as between those fitted to healthy versus diseased tissues. Only BMI correlated with fitted model parameters in abdominal aortic aneurysmal tissues. publisher: Elsevier articletitle: Human thoracic and abdominal aortic aneurysmal tissues: Damage experiments, statistical analysis and constitutive modeling journaltitle: Journal of the Mechanical Behavior of Biomedical Materials articlelink: http://dx.doi.org/10.1016/j.jmbbm.2014.10.003 content_type: article copyright: Copyright © 2014 Elsevier Ltd. All rights reserved. ispartof: Journal of the Mechanical Behavior of Biomedical Materials vol:41 pages:92-107 ispartof: location:Netherlands status: published

We propose a fully automated methodology for hexahedral meshing of patient-specific structures of the human knee obtained from magnetic resonance images, i.e. femoral/tibial cartilages and menisci. We select eight patients from the Osteoarthritis Initiative and validate our methodology using MATLAB on a laptop computer. We obtain the patient-specific meshes in an average of three minutes, while faithfully representing the geometries with well-shaped elements. We hope to provide a fundamentally different means to test hypotheses on the mechanisms of disease progression by integrating our patient-specific FE meshes with data from individual patients. Download both our meshes and software at http://im.engr.uconn.edu/downloads.php.

Accurate estimation of peak wall stress (PWS) is the crux of biomechanically motivated rupture risk assessment for abdominal aortic aneurysms aimed to improve clinical outcomes. Such assessments often use the finite element (FE) method to obtain PWS, albeit at a high computational cost, motivating simplifications in material or element formulations. These simplifications, while useful, come at a cost of reliability and accuracy. We achieve research-standard accuracy and maintain clinically applicable speeds by using novel computational technologies. We present a solution using our custom finite element code based on graphics processing unit (GPU) technology that is able to account for added complexities involved with more physiologically relevant solutions, e.g. strong anisotropy and heterogeneity. We present solutions up to 17× faster relative to an established finite element code using state-of-the-art nonlinear, anisotropic and nearly-incompressible material descriptions. We show a realistic assessment of the explicit GPU FE approach by using complex problem geometry, biofidelic material law, double-precision floating point computation and full element integration. Due to the increased solution speed without loss of accuracy, shown on five clinical cases of abdominal aortic aneurysms, the method shows promise for clinical use in determining rupture risk of abdominal aortic aneurysms. publisher: Elsevier articletitle: Rupture risk in abdominal aortic aneurysms: A realistic assessment of the explicit GPU approach journaltitle: Journal of Biomechanics articlelink: http://dx.doi.org/10.1016/j.jbiomech.2017.02.019 content_type: article copyright: © 2017 Elsevier Ltd. All rights reserved. ispartof: Journal of Biomechanics vol:56 pages:1-9 ispartof: location:United States status: published

Super-resolution microscopy recently revealed that, unlike the soma and dendrites, the axon membrane skeleton is structured as a series of actin rings connected by spectrin filaments that are held under tension. Currently, the structure-function relationship of the axonal structure is unclear. Here, we used atomic force microscopy (AFM) to show that the stiffness of the axon plasma membrane is significantly higher than the stiffnesses of dendrites and somata. To examine whether the structure of the axon plasma membrane determines its overall stiffness, we introduced a coarse-grain molecular dynamics model of the axon membrane skeleton that reproduces the structure identified by super-resolution microscopy. Our proposed computational model accurately simulates the median value of the Young’s modulus of the axon plasma membrane determined by atomic force microscopy. It also predicts that because the spectrin filaments are under entropic tension, the thermal random motion of the voltage-gated sodium channels (Nav), which are bound to ankyrin particles, a critical axonal protein, is reduced compared to the thermal motion when spectrin filaments are held at equilibrium. Lastly, our model predicts that because spectrin filaments are under tension, any axonal injuries that lacerate spectrin filaments will likely lead to a permanent disruption of the membrane skeleton due to the inability of spectrin filaments to spontaneously form their initial under-tension configuration., Author summary Super-resolution microscopy has suggested that the actin cytoskeleton structure differ between various neuronal subcompartments. To determine the possible implication of the differing actin cytoskeleton structure, we determined the stiffness of the plasma membrane of neuronal subcompartments using atomic force microscopy (AFM). We found that axons are almost ~6 fold stiffer than the soma and ~2 fold stiffer than dendrites. By using a particle-based model for the surface membrane skeleton of the axon that comprises actin rings connected with spring filaments to represent the axonal structure, we show that regions neighboring actin rings are stiffer than areas between these rings. In these in between sub-regions, the spectrin filaments determine stiffness. Our modeling also shows that because the spectrin filaments are under tension, the thermal jitter of the actin-associated ankyrin particles, connected to the middle area of spectrin filaments, is minimal. As a result, we propose that the sodium channels bound to ankyrin particles will maintain an ordered distribution along the axon. We also predict that laceration of the spectrin filaments due to injury will cause a permanent damage to the axon since spontaneous repair of the spectrin network is not possible as spectrin filaments are under entropic tension.

SUMMARY Finite element models reconstructed from medical imaging data, for example, computed tomography or MRI scans, generally represent geometries under in vivo load. Classical finite element approaches start from an unloaded reference configuration. We present a generalized prestressing algorithm based on a concept introduced by Gee et al. (Int. J. Num. Meth. Biomed. Eng. 26:52-72, 2012) in which an incremental update of the displacement field in the classical approach is replaced by an incremental update of the deformation gradient field. Our generalized algorithm can be implemented in existing finite element codes with relatively low implementation effort on the element level and is suitable for material models formulated in the current or initial configurations. Applicable to any finite element simulations started from preloaded geometries, we demonstrate the algorithm and its convergence properties on an academic example and on a segment of a thoracic aorta meshed from MRI data. Furthermore, we present an example to discuss the influence of neglecting prestresses in geometries obtained from medical images, a topic on which conflicting statements are found in the literature. Copyright © 2014 John Wiley & Sons, Ltd.

Mechanical analysis of articular cartilage is best accomplished via integrative approaches combining multi-modal imaging, mechanical experiments, and mathematical modeling. Healthy cartilage is a load-bearing and lubricating tissue lining the bony ends in diarthrodial joints. Unfortunately, degenerative processes like osteoarthritis lead to progressive damage and ultimately to complete destruction of cartilage, in part through mechanics-mediated mechanisms. We aim to describe the synergy of imaging and modeling to measure and characterize the structural and material properties of cartilage, including tissue morphology, shape, and estimates of intra-tissue distributions of strain and stress. Displacement-encoded MRI and fiber-reinforced constitutive models emerge as excellent approaches for direct measurement and estimation of the mechanics, e.g. displacements and stresses, respectively, within the tissue. We review the application of these approaches for the study of healthy and degenerated cartilage, and challenges that arise when extending these approaches to investigate chondrocyte signaling at the single cell level.

We were the first to examine the mechanical responses of skeletally mature bovine femoral cartilage under large-strain simple shear (up to ±20%) using a multiaxial shear testing device. Since shear loading is critical in both tissue failure and chondrocyte responses, we aimed to probe (1) anisotropy with respect to the split-line direction (principal alignment of the collagen fibers near the articulating surface), (2) heterogeneity between femoral condyles, and (3) the influence of local cartilage thickness. We harvested a total of 48 cuboid cartilage specimens from four bovine knee joints. With each specimen we applied shear strains both parallel and perpendicular to the local split-line direction at a rate of 75μm/min and calculated the peak-to-peak shear stresses, shear strain-energy dissipation densities, and peak effective shear moduli. The Wilcoxon signed rank test revealed that the medial condyle was anisotropic in some mechanical measures at applied shear strains above 5%, while the lateral condyle was mechanically isotropic at all applied shear strains. The Kruskal-Wallis test revealed no significant differences in the median mechanical behavior of the lateral and medial condyles. Spearman׳s rank correlations revealed statistically significant negative monotonic correlations among thickness and most of our mechanical measures for both lateral and medial condyles at most applied strains and directions of applied shear. These results suggest that large-strain analyses account for nonlinear, anisotropic and location-dependent effects not fully realized at small strains. Our findings may inspire new experiments and models that consider anisotropy and heterogeneity of cartilage in ways previously ignored.

Summary Objective We aimed to determine the minimum mechanical impact to cause microstructural damage in the network of collagen (microcracking) within human cartilage and hypothesized that energies below 0.1 J or 1 mJ/mm 3 would suffice. Design We completed 108 low-energy impact tests (0.05, 0.07, or 0.09 J; 0.75 or 1.0 m/s 2 ) using healthy cartilage specimens from six male donors (30.2 ± 8.8 yrs old). Before and after impact we acquired, imaging the second harmonic generation (SHG), ten images from each specimen (50 μ m depth, 5 μ m step size), resulting in 2160 images. We quantified both the presence and morphology of microcracks. We then correlated test parameters (predictors) impact energy/energy dissipation density, nominal stress/stress rate, and strain/strain rate to microcracking and tested for significance. Where predictors significantly correlated with microstructural outcomes we fitted binary logistic regression plots with 95% confidence intervals (CIs). Results No specimens presented visible damage following impact. We found that impact energy/energy dissipation density and nominal stress/stress rate were significant ( P 3 , an energy dissipation density of 1.68 mJ/mm 3 , a nominal stress of 4.18 MPa, and a nominal stress rate of 689 MPa/s all corresponded to a 50% probability of microcracking in the network of collagen. Conclusions An impact energy density of 1.0 mJ/mm 3 corresponded to a ∼20% probability of microcracking. Such changes may initiate a degenerative cascade leading to post-traumatic osteoarthritis.

Osteoarthritis and articular cartilage injuries are common conditions in human joints and a frequent cause of pain and disability. Unfortunately, cartilage is avascular and has limited capabilities for self-repair. Despite the societal impact, there is little information on the dynamic process of cartilage degeneration. We performed a series of cyclic unconfined compression tests motivated by in vivo loading conditions and designed to generate mechanical fatigue. We examined the functional (both stress-stretch and creep) responses of the tissue after recovery from a specified number of loading cycles, as well as histology and second harmonic generation microscopy images. The effect of compaction was complimented by the effect of fatigue in our unconfined compression tests. A three-way, repeated-measures mixed model ANOVA showed significant differences between loading with a physiologically relevant low magnitude, and two more severe loading magnitudes, in terms of the resulting specimen stiffness, time to equilibrium and thickness. There was a statistically significant effect of loading frequency on a specimen's time to equilibrium and significant interaction of force and frequency on specimen thickness and time to equilibrium. Increasing the number of loading cycles significantly impacted a specimen's effective stiffness and resulting thickness. We attribute permanent loss of mechanical function under cyclic loading to rearrangement and disruption of the collagen network and resulting proteoglycan (PG) aggregation, as seen in histological and second harmonic generation images, as a result of induced mechanical fatigue.

Carmen Cuffari,1 David Pierce,2 Bartosz Korczowski,3 Krzysztof Fyderek,4 Heather Van Heusen,5 Stuart Hossack,6 Hong Wan,5 Alena YZ Edwards,7 Patrick Martin5 1Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Shire, Basingstoke, UK; 3Medical College, University of Rzeszów, Rzeszów, Poland; 4University Children’s Hospital of Cracow, Cracow, Poland; 5Shire, Wayne, PA, USA; 6Covance Clinical Research Unit Limited, Leeds, UK; 7ICON Early Phase Services, Marlow, Buckinghamshire, UK Background: Limited data are available on mesalamine (5-aminosalicylic acid; 5-ASA) use in pediatric ulcerative colitis (UC).Aim: To evaluate pharmacokinetic and safety profiles of 5-ASA and metabolite acetyl-5-ASA (Ac-5-ASA) after once-daily, oral administration of multimatrix mesalamine to children and adolescents with UC.Methods: Participants (5–17years of age; 18–82 kg, stratified by weight) with UC received multimatrix mesalamine 30, 60, or 100mg/kg/day once daily (to 4,800mg/day) for 7 days. Blood samples were collected pre-dose on days 5 and 6. On days 7 and 8, blood and urine samples were collected and safety was evaluated. 5-ASA and Ac-5-ASA plasma and urine concentrations were analyzed by non-compartmental methods and used to develop a population pharmacokinetic model.Results: Fifty-two subjects (21 [30mg/kg]; 22 [60mg/kg]; 9 [100mg/kg]) were randomized. On day 7, systemic exposures of 5-ASA and Ac-5-ASA exhibited a dose-proportional increase between 30 and 60mg/kg/day cohorts. For 30, 60, and 100mg/kg/day doses, mean percentages of 5-ASA absorbed were 29.4%, 27.0%, and 22.1%, respectively. Simulated steady-state exposures and variabilities for 5-ASA and Ac-5-ASA (coefficient of variation approximately 50% and 40%–45%, respectively) were similar to those observed previously in adults at comparable doses. Treatment-emergent adverse events were reported by ten subjects. Events were similar among different doses and age groups with no new safety signals identified.Conclusion: Children and adolescents with UC receiving multimatrix mesalamine demonstrated 5-ASA and Ac-5-ASA pharmacokinetic profiles similar to historical adult data. Multimatrix mesalamine was well tolerated across all dose and age groups. ClinicalTrials.gov Identifier: NCT01130844. Keywords: ulcerative colitis, mesalamine, pharmacology

We present a study of accuracy and execution speed using a novel implementation of a nonlinear anisotropic fiber-reinforced material model within a Total Lagrangian Explicit Dynamic (TLED) finite element (FE) framework, developed for execution on Graphics Processing Units. Full integration and selective-reduced integration have been developed for tri-linear hexahedral elements and tested in comparison to the classical under-integrated TLED scheme. Comparison is performed with respect to an established FE code. Results indicate that by using the presented method, excellent accuracy can be retained while greatly accelerating solution times.