Delayed skeletal muscle repair following inflammatory damage in simulated agent-based models of muscle regeneration.

Healthy skeletal muscle undergoes repair in response to mechanically localised strains during activities such as exercise. The ability of cells to transduce the external stimuli into a cascade of cell signalling responses is important to the process of muscle repair and regeneration. In chronic myopathies such as Duchenne muscular dystrophy and inflammatory myopathies, muscle is often subject to chronic necrosis and inflammation that perturbs tissue homeostasis and leads to non-localised, widespread damage across the tissue. Here we present an agent-based model that simulates muscle repair in response to both localised eccentric contractions similar to what would be experienced during exercise, and non-localised widespread inflammatory damage that is present in chronic disease. Computational modelling of muscle repair allows for in silico exploration of phenomena related to muscle disease. In our model, widespread inflammation led to delayed clearance of tissue damage, and delayed repair for recovery of initial fibril counts at all damage levels. Macrophage recruitment was delayed and significantly higher in widespread compared to localised damage. At higher damage percentages of 10%, widespread damage led to impaired muscle regeneration and changes in muscle geometry that represented alterations commonly observed in chronic myopathies, such as fibrosis. This computational work offers insight into the progression and aetiology of inflammatory muscle diseases, and suggests a focus on the muscle regeneration cascade in understanding the progression of muscle damage in inflammatory myopathies.

A Coupled Mechanobiological Model of Muscle Regeneration In Cerebral Palsy.

Cerebral palsy is a neuromusculoskeletal disorder associated with muscle weakness, altered muscle architecture, and progressive musculoskeletal symptoms that worsen with age. Pathological changes at the level of the whole muscle have been shown; however, it is unclear why this progression of muscle impairment occurs at the cellular level. The process of muscle regeneration is complex, and the interactions between cells in the muscle milieu should be considered in the context of cerebral palsy. In this work, we built a coupled mechanobiological model of muscle damage and regeneration to explore the process of muscle regeneration in typical and cerebral palsy conditions, and whether a reduced number of satellite cells in the cerebral palsy muscle environment could cause the muscle regeneration cycle to lead to progressive degeneration of muscle. The coupled model consisted of a finite element model of a muscle fiber bundle undergoing eccentric contraction, and an agent-based model of muscle regeneration incorporating satellite cells, inflammatory cells, muscle fibers, extracellular matrix, fibroblasts, and secreted cytokines. Our coupled model simulated damage from eccentric contraction followed by 28 days of regeneration within the muscle. We simulated cyclic damage and regeneration for both cerebral palsy and typically developing muscle milieus. Here we show the nonlinear effects of altered satellite cell numbers on muscle regeneration, where muscle repair is relatively insensitive to satellite cell concentration above a threshold, but relatively sensitive below that threshold. With the coupled model, we show that the fiber bundle geometry undergoes atrophy and fibrosis with too few satellite cells and excess extracellular matrix, representative of the progression of cerebral palsy in muscle. This work uses in silico modeling to demonstrate how muscle degeneration in cerebral palsy may arise from the process of cellular regeneration and a reduced number of satellite cells.

Remote Patient Monitoring with Wearable Sensors Following Knee Arthroplasty.

(Background) Inertial Measurement Units (IMUs) provide a low-cost, portable solution to obtain functional measures similar to those captured with three-dimensional gait analysis, including spatiotemporal gait characteristics. The primary aim of this study was to determine the feasibility of a remote patient monitoring (RPM) workflow using ankle-worn IMUs measuring impact load, limb impact load asymmetry and knee range of motion in combination with patient-reported outcome measures. (Methods) A pilot cohort of 14 patients undergoing primary knee arthroplasty for osteoarthritis was prospectively enrolled. RPM in the community was performed weekly from 2 up to 6 weeks post-operatively using wearable IMUs. The following data were collected using IMUs: mobility (Bone Stimulus and cumulative impact load), impact load asymmetry and maximum knee flexion angle. In addition, scores from the Oxford Knee Score (OKS), EuroQol Five-dimension (EQ-5D) with EuroQol visual analogue scale (EQ-VAS) and 6 Minute Walk Test were collected. (Results) On average, the Bone Stimulus and cumulative impact load improved 52% (p = 0.002) and 371% (p = 0.035), compared to Post-Op Week 2. The impact load asymmetry value trended (p = 0.372) towards equal impact loading between the operative and non-operative limb. The mean maximum flexion angle achieved was 99.25° at Post-Operative Week 6, but this was not significantly different from pre-operative measurements (p = 0.1563). There were significant improvements in the mean EQ-5D (0.20; p = 0.047) and OKS (10.86; p < 0.001) scores both by 6 weeks after surgery, compared to pre-operative scores. (Conclusions) This pilot study demonstrates the feasibility of a reliable and low-maintenance workflow system to remotely monitor post-operative progress in knee arthroplasty patients. Preliminary data indicate IMU outputs relating to mobility, impact load asymmetry and range of motion can be obtained using commercially available IMU sensors. Further studies are required to directly correlate the IMU sensor outputs with patient outcomes to establish clinical significance.

Specimen-specific fracture risk curves of lumbar vertebrae under dynamic axial compression.

Underbody blast attacks of military vehicles by improvised explosives have resulted in high incidence of lumbar spine fractures below the thorocolumbar junction in military combatants. Fracture risk curves related to vertical loading at individual lumbar spinal levels can be used to assess the protective ability of new injury mitigation equipment. The objectives of this study were to derive fracture risk curves for the lumbar spine under high rate compression and identify how specimen-specific attributes and lumbar spinal level may influence fracture risk. In this study, we tested a sample of three-vertebra specimens encompassing all spinal levels between T12 to S1 in high-rate axial compression. Each specimen was tested with a non-injurious load, followed by a compressive force sufficient to induce vertebral body fracture. During testing, bone fracture was identified using measurements from acoustic emission sensors and changes in load cell readings. Following testing, the fractures were assessed using computed tomographic (CT) imaging. The CT images showed isolated fractures of trabecular bone, or fractures involving both cortical and trabecular bone. Results from the compressive force measurements in conjunction with a survival analysis demonstrated that the compressive force corresponding to fracture increased inferiorly as a function of lumbar spinal level. The axial rigidity (EA) measured at the mid-plane of the centre vertebra or the volumetric bone mineral density (vBMD) of the vertebral body trabecular bone most greatly influenced fracture risk. By including these covariates in the fracture risk curves, no other variables significantly affected fracture risk, including the lumbar spinal level. The fracture risk curves presented in this study may be used to assess the risk of injury at individual lumbar vertebra when exposed to dynamic axial compression.

Correction: Soleus muscle weakness in cerebral palsy: Muscle architecture revealed with Diffusion Tensor Imaging.

[This corrects the article DOI: 10.1371/journal.pone.0205944.].

Soleus muscle weakness in cerebral palsy: Muscle architecture revealed with Diffusion Tensor Imaging.

Cerebral palsy (CP) is associated with movement disorders and reduced muscle size. This latter phenomenon has been observed by computing muscle volumes from conventional MRI, with most studies reporting significantly reduced volumes in leg muscles. This indicates impaired muscle growth, but without knowing muscle fiber orientation, it is not clear whether muscle growth in CP is impaired in the along-fiber direction (indicating shortened muscles and limited range of motion) or the cross-fiber direction (indicating weak muscles and impaired strength). Using Diffusion Tensor Imaging (DTI) we can determine muscle fiber orientation and construct 3D muscle architectures which can be used to examine both along-fiber length and cross-sectional area. Such an approach has not been undertaken in CP. Here, we use advanced DTI sequences with fast imaging times to capture fiber orientations in the soleus muscle of children with CP and age-matched, able-bodied controls. Cross sectional areas perpendicular to the muscle fiber direction were reduced (37 ± 11%) in children with CP compared to controls, indicating impaired muscle strength. Along-fiber muscle lengths were not different between groups. This study is the first to demonstrate along-fiber and cross-fiber muscle architecture in CP using DTI and implicates impaired cross-sectional muscle growth in children with cerebral palsy.

Combining in silico and in vitro experiments to characterize the role of fascicle twist in the Achilles tendon.

The Achilles tendon (AT), the largest tendon in the human body has a unique structural feature, that is the fascicles in the AT display spiral twist. However, their functional and structural roles are still unclear. We used subject-specific computational models and tissue mechanical experiment to quantitatively characterize the role of fascicle twist in the Achilles tendon. Ten subject-specific finite element (FE) models of the Achilles tendon were developed from ultrasound images. Fascicle twist was implemented in these models using the material coordinate system available in our FE framework. Five different angles (0~60°) were implemented and material property optimization was performed for each of them (total 50 sets) using results from uniaxial stretch experiment. We showed that fascicle twist allows for even distribution of stress across the whole tendon, thus improving tissue strength. The predicted rupture load increased up to 40%. A number of connective tissues display similar fascicle twists in their structure. The resulting non-uniform strain distribution has been hypothesized as a primary factor in tissue degeneration and injuries. Therefore, our technique will be used to design biomechanically informed training and rehabilitation protocols for management of connective tissue injuries and degeneration.

Statistical modeling of the equine third metacarpal bone incorporating morphology and bone mineral density.

The objective of this study was to describe the three-dimensional shape and subchondral bone mineral density (BMD) variation of the equine distal third metacarpal bone (MC3) using a statistical shape model. The association between form and function builds upon previous two-dimensional observations of MC3 epiphyseal structure. It was expected that the main source of variation would be an increase in overall MC3 bone size, correlated to an increase in subchondral BMD. Geometry and bone mineral density was obtained from CT image data of 40 healthy Thoroughbred horses. This was used to create a statistical shape model, in which the first ten components described 75% of the variation in geometry and BMD. The first principal component described an increase in overall size of the MC3 distal epiphysis, coupled with higher BMD on the disto-palmar and dorso-proximal surfaces. The second component was qualitatively described as an increased convexity of the sagittal ridge at the dorsal junction of the epiphysis and the metaphysis, coupled to increased BMD in that region. The third component showed an increase in lateral condylar surface area relative to medial condylar area. As the condyle reduced in relative surface area, the BMD at both dorsal condyles increased. The statistical shape analysis produced a compact description of 3-D shape and sub-chondral bone mineral density variation for the third metacarpal bone. This study uniquely illustrates the shape variations in a sample population of MC3 bones, and the corresponding changes in subchondral BMD.

Determining skeletal muscle architecture with Laplacian simulations: a comparison with diffusion tensor imaging.

Determination of skeletal muscle architecture is important for accurately modeling muscle behavior. Current methods for 3D muscle architecture determination can be costly and time-consuming, making them prohibitive for clinical or modeling applications. Computational approaches such as Laplacian flow simulations can estimate muscle fascicle orientation based on muscle shape and aponeurosis location. The accuracy of this approach is unknown, however, since it has not been validated against other standards for muscle architecture determination. In this study, muscle architectures from the Laplacian approach were compared to those determined from diffusion tensor imaging in eight adult medial gastrocnemius muscles. The datasets were subdivided into training and validation sets, and computational fluid dynamics software was used to conduct Laplacian simulations. In training sets, inputs of muscle geometry, aponeurosis location, and geometric flow guides resulted in good agreement between methods. Application of the method to validation sets showed no significant differences in pennation angle (mean difference [Formula: see text] or fascicle length (mean difference 0.9 mm). Laplacian simulation was thus effective at predicting gastrocnemius muscle architectures in healthy volunteers using imaging-derived muscle shape and aponeurosis locations. This method may serve as a tool for determining muscle architecture in silico and as a complement to other approaches.

Prophylactic knee bracing alters lower-limb muscle forces during a double-leg drop landing.

Anterior cruciate ligament (ACL) injury can be a painful, debilitating and costly consequence of participating in sporting activities. Prophylactic knee bracing aims to reduce the number and severity of ACL injury, which commonly occurs during landing maneuvers and is more prevalent in female athletes, but a consensus on the effectiveness of prophylactic knee braces has not been established. The lower-limb muscles are believed to play an important role in stabilizing the knee joint. The purpose of this study was to investigate the changes in lower-limb muscle function with prophylactic knee bracing in male and female athletes during landing. Fifteen recreational athletes performed double-leg drop landing tasks from 0.30m and 0.60m with and without a prophylactic knee brace. Motion analysis data were used to create subject-specific musculoskeletal models in OpenSim. Static optimization was performed to calculate the lower-limb muscle forces. A linear mixed model determined that the hamstrings and vasti muscles produced significantly greater flexion and extension torques, respectively, and greater peak muscle forces with bracing. No differences in the timings of peak muscle forces were observed. These findings suggest that prophylactic knee bracing may help to provide stability to the knee joint by increasing the active stiffness of the hamstrings and vasti muscles later in the landing phase rather than by altering the timing of muscle forces. Further studies are necessary to quantify whether prophylactic knee bracing can reduce the load placed on the ACL during intense dynamic movements.

Subject-specific finite element analysis to characterize the influence of geometry and material properties in Achilles tendon rupture.

Achilles tendon injuries including rupture are one of the most frequent musculoskeletal injuries, but the mechanisms for these injuries are still not fully understood. Previous in vivo and experimental studies suggest that tendon rupture mainly occurs in the tendon mid-section and predominantly more in men than women due to reasons yet to be identified. Therefore we aimed to investigate possible mechanisms for tendon rupture using finite element (FE) analysis. Specifically, we have developed a framework for generating subject-specific FE models of human Achilles tendon. A total of ten 3D FE models of human Achilles tendon were generated. Subject-specific geometries were obtained using ultrasound images and a mesh morphing technique called Free Form Deformation. Tendon material properties were obtained by performing material optimization that compared and minimized difference in uniaxial tension experimental results with model predictions. Our results showed that both tendon geometry and material properties are highly subject-specific. This subject-specificity was also evident in our rupture predictions as the locations and loads of tendon ruptures were different in all specimens tested. A parametric study was performed to characterize the influence of geometries and material properties on tendon rupture. Our results showed that tendon rupture locations were dependent largely on geometry while rupture loads were more influenced by tendon material properties. Future work will investigate the role of microstructural properties of the tissue on tendon rupture and degeneration by using advanced material descriptions.

Altered load transfer in the pelvis in the presence of periprosthetic osteolysis.

Periprosthetic osteolysis in the retroacetabular region with cancellous bone loss is a recognized phenomenon in the long-term follow-up of total hip replacement. The effects on load transfer in the presence of defects are less well known. A validated, patient-specific, 3D finite element (FE) model of the pelvis was used to assess changes in load transfer associated with periprosthetic osteolysis adjacent to a cementless total hip arthroplasty (THA) component. The presence of a cancellous defect significantly increased (p < 0.05) von Mises stress in the cortical bone of the pelvis during walking and a fall onto the side. At loads consistent with single leg stance, this was still less than the predicted yield stress for cortical bone. During higher loads associated with a fall onto the side, highest stress concentrations occurred in the superior and inferior pubic rami and in the anterior column of the acetabulum with larger cancellous defects.

Subject-specific evaluation of patellofemoral joint biomechanics during functional activity.

Patellofemoral joint pain is a common problem experienced by active adults. However, relatively little is known about patellofemoral joint load and its distribution across the medial and lateral facets of the patella. In this study, biomechanical experiments and computational modeling were used to study patellofemoral contact mechanics in four healthy adults during stair ambulation. Subject-specific anatomical and gait data were recorded using magnetic resonance imaging, dynamic X-ray fluoroscopy, video motion capture, and multiple force platforms. From these data, in vivo tibiofemoral joint kinematics and knee muscle forces were computed and then applied to a deformable finite-element model of the patellofemoral joint. The contact force acting on the lateral facet of the patella was 4-6 times higher than that acting on the medial facet. The peak average patellofemoral contact stresses were 8.2±1.0 MPa and 5.9±1.3 MPa for the lateral and medial patellar facets, respectively. Peak normal compressive stress and peak octahedral shear stress occurred near toe-off of the contralateral leg and were higher on the lateral facet than the medial facet; furthermore, the peak compressive stress (11.5±3.0 MPa) was higher than the peak octahedral shear stress (5.2±0.9 MPa). The dominant stress pattern on the lateral patellar facet corresponded well to the location of maximum cartilage thickness. Higher loading of the lateral facet is also consistent with the clinical observation that the lateral compartment of the patellofemoral joint is more prone to osteoarthritis than the medial compartment. Predicted cartilage contact stress maps near contralateral toe-off showed three distinctly different patterns: peak stresses located on the lateral patellar facet; peak stresses located centrally between the medial and lateral patellar facets; and peak stresses located superiorly on both the medial and lateral patellar facets.

Integrating degenerative mechanisms in bone and cartilage: a multiscale approach.

At the whole organ level, degenerative mechanisms in bone and cartilage are primarily attributed to modifications in loading pattern. Either a change in magnitude or location can initiate a degenerative path. At the micro scale we often see changes in structure such as porosity increase in bone and fibrillation in cartilage. These changes contribute to a reduced structural integrity that weakens the bulk strength of tissue. Finally, at the cell level we have modeling and remodeling pathways that may be disrupted through disease, drugs and altered stimulus from the micro and macro scales. In order to understand this entire process and the roles each level plays a multiscale modeling framework is necessary. This framework can take whole body loadings and pass information through finer spatial scales in order to understand how everyday dynamic movements influence micro and cellular response. In a similar manner, cellular and microstructural processes regulate whole bulk properties and modify whole organ strength. In this study we highlight the multiscale links developed as part of the open-source ontologies for the Physiome Project using the lower limb as an example. We consider the influence of remodeling in (i) anabolic treatments in cortical bone; and (ii) subchondral bone and cartilage degeneration.

A multiscale framework based on the physiome markup languages for exploring the initiation of osteoarthritis at the bone-cartilage interface.

The initiation of osteoarthritis (OA) has been linked to the onset and progression of pathologic mechanisms at the cartilage-bone interface. Most importantly, this degenerative disease involves cross-talk between the cartilage and subchondral bone environments, so an informative model should contain the complete complex. In order to evaluate this process, we have developed a multiscale model using the open-source ontologies developed for the Physiome Project with cartilage and bone descriptions at the cellular, micro, and macro levels. In this way, we can effectively model the influence of whole body loadings at the macro level and the influence of bone organization and architecture at the micro level, and have cell level processes that determine bone and cartilage remodeling. Cell information is then passed up the spatial scales to modify micro architecture and provide a macro spatial characterization of cartilage inflammation. We evaluate the framework by linking a common knee injury (anterior cruciate ligament deficiency) to proinflammatory mediators as a possible pathway to initiate OA. This framework provides a "virtual bone-cartilage" tool for evaluating hypotheses, treatment effects, and disease onset to inform and strengthen clinical studies.

Model predictions of increased knee joint loading in regions of thinner articular cartilage after patellar tendon adhesion.

Patellar tendon adhesion is a complication from anterior cruciate ligament (ACL) reconstruction that may affect patellofemoral and tibiofemoral biomechanics. A computational model was used to investigate the changes in knee joint mechanics due to patellar tendon adhesion under normal physiological loading during gait. The calculations showed that patellar tendon adhesion up to the level of the anterior tibial plateau led to patellar infera, increased patellar flexion, and increased anterior tibial translation. These kinematic changes were associated with increased patellar contact force, a distal shift in peak patellar contact pressure, a posterior shift in peak tibial contact pressure, and increased peak tangential contact sliding distance over one gait cycle (i.e., contact slip). Postadhesion, patellar and tibial contact locations corresponded to regions of thinner cartilage. The predicted distal shift in patellar contact was in contrast to other patellar infera studies. Average patellar and tibial cartilage pressure did not change significantly following patellar tendon adhesion; however, peak medial tibial pressure increased. These results suggest that changes in peak tibial cartilage pressure, contact slip, and the migration of contact to regions of thinner cartilage are associated with patellar tendon adhesion and may be responsible for initiating patellofemoral pain and knee joint structural damage observed following ACL reconstruction.

Non-invasive assessment of soft-tissue artifact and its effect on knee joint kinematics during functional activity.

The soft-tissue interface between skin-mounted markers and the underlying bones poses a major limitation to accurate, non-invasive measurement of joint kinematics. The aim of this study was twofold: first, to quantify lower limb soft-tissue artifact in young healthy subjects during functional activity; and second, to determine the effect of soft-tissue artifact on the calculation of knee joint kinematics. Subject-specific bone models generated from magnetic resonance imaging (MRI) were used in conjunction with X-ray images obtained from single-plane fluoroscopy to determine three-dimensional knee joint kinematics for four separate tasks: open-chain knee flexion, hip axial rotation, level walking, and a step-up. Knee joint kinematics was derived using the anatomical frames from the MRI-based, 3D bone models together with the data from video motion capture and X-ray fluoroscopy. Soft-tissue artifact was defined as the degree of movement of each marker in the anteroposterior, proximodistal and mediolateral directions of the corresponding anatomical frame. A number of different skin-marker clusters (total of 180) were used to calculate knee joint rotations, and the results were compared against those obtained from fluoroscopy. Although a consistent pattern of soft-tissue artifact was found for each task across all subjects, the magnitudes of soft-tissue artifact were subject-, task- and location-dependent. Soft-tissue artifact for the thigh markers was substantially greater than that for the shank markers. Markers positioned in the vicinity of the knee joint showed considerable movement, with root mean square errors as high as 29.3mm. The maximum root mean square errors for calculating knee joint rotations occurred for the open-chain knee flexion task and were 24.3 degrees , 17.8 degrees and 14.5 degrees for flexion, internal-external rotation and abduction-adduction, respectively. The present results on soft-tissue artifact, based on fluoroscopic measurements in healthy adult subjects, may be helpful in developing location- and direction-specific weighting factors for use in global optimization algorithms aimed at minimizing the effects of soft-tissue artifact on calculations of knee joint rotations.

Evaluation of predicted knee-joint muscle forces during gait using an instrumented knee implant.

Musculoskeletal modeling and optimization theory are often used to determine muscle forces in vivo. However, convincing quantitative evaluation of these predictions has been limited to date. The present study evaluated model predictions of knee muscle forces during walking using in vivo measurements of joint contact loading acquired from an instrumented implant. Joint motion, ground reaction force, and tibial contact force data were recorded simultaneously from a single subject walking at slow, normal, and fast speeds. The body was modeled as an 8-segment, 21-degree-of-freedom articulated linkage, actuated by 58 muscles. Joint moments obtained from inverse dynamics were decomposed into leg-muscle forces by solving an optimization problem that minimized the sum of the squares of the muscle activations. The predicted knee muscle forces were input into a 3D knee implant contact model to calculate tibial contact forces. Calculated and measured tibial contact forces were in good agreement for all three walking speeds. The average RMS errors for the medial, lateral, and total contact forces over the entire gait cycle and across all trials were 140 +/- 40 N, 115 +/- 32 N, and 183 +/- 45 N, respectively. Muscle coordination predicted by the model was also consistent with EMG measurements reported for normal walking. The combined experimental and modeling approach used in this study provides a quantitative framework for evaluating model predictions of muscle forces in human movement.