Hindfoot kinematics and kinetics - A combined in vivo and in silico analysis approach.

BACKGROUND: The complex anatomical structure of the foot-ankle imposes challenges to accurately quantify detailed hindfoot kinematics and estimate musculoskeletal loading parameters. Most systems used to capture or estimate dynamic joint function oversimplify the anatomical structure by reducing its complexity. RESEARCH QUESTION: Can four dimensional computed tomography (4D CT) imaging in combination with an innovative foot manipulator capture in vivo hindfoot kinematics during a simulated stance phase of walking and can talocrural and subtalar articular joint mechanics be estimated based on a detailed in silico musculoskeletal foot-ankle model. METHODS: A foot manipulator imposed plantar/dorsiflexion and inversion/eversion representing a healthy stance phase of gait in 12 healthy participants while simultaneously acquiring 4D CT images. Participant-specific 3D hindfoot rotations and translations were calculated based on bone-specific anatomical coordinate systems. Articular cartilage contact area and contact pressure of the talocrural and subtalar joints were estimated using an extended foot-ankle model updated with an elastic foundation contact model upon prescribing the participant-specific rotations measured in the 4D CT measurement. RESULTS: Plantar/dorsiflexion predominantly occurred at the talocrural joint (RoM 15.9±3.9°), while inversion/eversion (RoM 5.9±3.9°) occurred mostly at the subtalar joint, with the contact area being larger at the subtalar than at the talocrural joint. Contact pressure was evenly distributed between the talocrural and subtalar joint at the beginning of the simulated stance phase but was then redistributed from the talocrural to the subtalar joint with increasing dorsiflexion. SIGNIFICANCE: In a clinical case study, the healthy participants were compared with four patients after surgically treaded intra-articular calcaneal fracture. The proposed workflow was able to detect small but meaningful differences in hindfoot kinematics and kinetics, indicative of remaining hindfoot pathomechanics that may influence the onset and progression of degenerative joint diseases.

A Spontaneous In Situ Thiol-Ene Crosslinking Hydrogel with Thermo-Responsive Mechanical Properties.

The thermo-responsive behavior of Poly(N-isopropylacrylamide) makes it an ideal candidate to easily embed cells and allows the polymer mixture to be injected. However, P(NiPAAm) hydrogels possess minor mechanical properties. To increase the mechanical properties, a covalent bond is introduced into the P(NIPAAm) network through a biocompatible thiol-ene click-reaction by mixing two polymer solutions. Co-polymers with variable thiol or acrylate groups to thermo-responsive co-monomer ratios, ranging from 1% to 10%, were synthesized. Precise control of the crosslink density allowed customization of the hydrogel's mechanical properties to match different tissue stiffness levels. Increasing the temperature of the hydrogel above its transition temperature of 31 °C induced the formation of additional physical interactions. These additional interactions both further increased the stiffness of the material and impacted its relaxation behavior. The developed optimized hydrogels reach stiffnesses more than ten times higher compared to the state of the art using similar polymers. Furthermore, when adding cells to the precursor polymer solutions, homogeneous thermo-responsive hydrogels with good cell viability were created upon mixing. In future work, the influence of the mechanical micro-environment on the cell's behavior can be studied in vitro in a continuous manner by changing the incubation temperature.

In-silico techniques to inform and improve the personalized prescription of shoe insoles.

Background: Corrective shoe insoles are prescribed for a range of foot deformities and are typically designed based on a subjective assessment limiting personalization and potentially leading to sub optimal treatment outcomes. The incorporation of in silico techniques in the design and customization of insoles may improve personalized correction and hence insole efficiency. Methods: We developed an in silico workflow for insole design and customization using a combination of measured motion capture, inverse musculoskeletal modelling as well as forward simulation approaches to predict the kinematic response to specific insole designs. The developed workflow was tested on twenty-seven participants containing a combination of healthy participants (7) and patients with flatfoot deformity (20). Results: Average error between measured and simulated kinematics were 4.7 ± 3.1, 4.5 ± 3.1, 2.3 ± 2.3, and 2.3 ± 2.7° for the chopart obliquity, chopart anterior-posterior axis, tarsometatarsal first ray, and tarsometatarsal fifth ray joints respectively. Discussion: The developed workflow offers distinct advantages to previous modeling workflows such as speed of use, use of more accessible data, use of only open-source software, and is highly automated. It provides a solid basis for future work on improving predictive accuracy by adapting the currently implemented insole model and incorporating additional data such as plantar pressure.

Effects of a 1 year aerobic and strength training on cognitive functioning after transient ischemic attack or minor stroke: A randomized controlled trial.

OBJECTIVES: Patients who have recently suffered a transient ischemic attack (TIA) or minor ischemic stroke are at increased risk of cognitive impairment. In the present study, we aimed to investigate the effect of a 1-year exercise intervention on cognitive functioning up to 2 years post intervention. MATERIAL AND METHODS: We conducted a single-blind randomized controlled trial to investigate the effect of an exercise intervention on cognitive functioning, compared with usual care, for up to 2 years. Patients with a TIA or minor stroke were randomly allocated to an intervention group receiving the 1-year exercise intervention (n = 60) or to usual care (n = 59). Outcome measures were assessed at baseline and after 1 and 2 years. We measured cognition with neuropsychological tests on three domains: (1) executive functioning, (2) attention-psychomotor speed, and (3) memory. Linear mixed models were used for longitudinal data to determine the effect of the exercise intervention on cognitive functioning. Statistical analyses were performed using IBM SPSS software 24.0. RESULTS: We found that over the two years study period -and corrected for age, sex, and educational level- the intervention group on average improved significantly more in executive functioning than the control group (ß = 0.13; 95 % CI [0.02 to 0.25]; p = 0.03). No significant intervention effects were found on either memory or attention-psychomotor speed. CONCLUSIONS: Our data show that a 1-year exercise intervention significantly improved executive functioning over time, compared to usual care. We recommend that health care professionals consider broadening standard secondary stroke prevention treatment in patients with TIA/minor stroke by adding exercise and physical activity.

Prolonged mechanical muscle loading increases mechanosensor gene and protein levels and causes a moderate fast-to-slow fiber type switch in mice.

Mechanosensing and subsequent mechanotransduction are indispensable for muscle plasticity. Nevertheless, a scarcity of literature exists regarding an all-encompassing understanding of the muscle mechanosensing machinery's response to prolonged loading, especially in conditions that resemble a natural physiological state of skeletal muscle. This study aimed to comprehensively explore the effects of prolonged mechanical loading on mechanosensitive components, skeletal muscle characteristics, and metabolism-related gene clusters. Twenty male C57BL/6J mice were randomly divided into two groups: control and prolonged mechanical loading. To induce prolonged mechanical loading on the triceps brachii (TRI) and biceps brachii (BIC) muscles, a 14-day period of tail suspension was implemented. In TRI only, prolonged mechanical loading caused a mild fast-to-slow fiber type shift together with increased mechanosensor gene and protein levels. It also increased transcription factors associated with slow muscle fibers while decreasing those related to fast-type muscle gene expression. Succinate dehydrogenase activity, a marker of muscle oxidative capacity, and genes involved in oxidative and mitochondrial turnover increased, whereas glycolytic-related genes decreased. Moreover, prolonged mechanical loading stimulated markers of muscle protein synthesis. Taken together, our data show a collective muscle-specific increase in mechanosensor gene and protein levels upon a period of prolonged mechanical loading in conditions that reflect a more natural physiological state of skeletal muscle in mice. We provide additional proof-of-concept that prolonged tail suspension-induced loading of the forelimbs triggers a muscle-specific fast-to-slow fiber type switch, and this coincides with increased protein synthesis-related signaling.NEW & NOTEWORTHY This study provides a comprehensive overview of the effects of prolonged loading on mechanosensitive components in conditions that better reflect the natural physiological state of skeletal muscle. Although the muscle mechanosensing machinery has been widely acknowledged for its responsiveness to altered loading, an inclusive understanding of its response to prolonged loading remains scarce. Our results show a fast-to-slow fiber type shift and an upregulation of mechanosensor gene and protein levels following prolonged loading.

The History and Future of Neuromusculoskeletal Biomechanics.

The Executive Council of the International Society of Biomechanics has initiated and overseen the commemorations of the Society's 50th Anniversary in 2023. This included multiple series of lectures at the ninth World Congress of Biomechanics in 2022 and XXIXth Congress of the International Society of Biomechanics in 2023, all linked to special issues of International Society of Biomechanics' affiliated journals. This special issue of the Journal of Applied Biomechanics is dedicated to the biomechanics of the neuromusculoskeletal system. The reader is encouraged to explore this special issue which comprises 6 papers exploring the current state-of the-art, and future directions and roles for neuromusculoskeletal biomechanics. This editorial presents a very brief history of the science of the neuromusculoskeletal system's 4 main components: the central nervous system, musculotendon units, the musculoskeletal system, and joints, and how they biomechanically integrate to enable an understanding of the generation and control of human movement. This also entails a quick exploration of contemporary neuromusculoskeletal biomechanics and its future with new fields of application.

Signatures of disease progression in knee osteoarthritis: insights from an integrated multi-scale modeling approach, a proof of concept.

Introduction: Knee osteoarthritis (KOA) is characterized by articular cartilage degeneration. It has been widely accepted that the mechanical joint environment plays a significant role in the onset and progression of this disease. In silico models have been used to study the interplay between mechanical loading and cartilage degeneration, hereby relying mainly on two key mechanoregulatory factors indicative of collagen degradation and proteoglycans depletion. These factors are the strain in collagen fibril direction (SFD) and maximum shear strain (MSS) respectively. Methods: In this study, a multi-scale in silico modeling approach was used based on a synergy between musculoskeletal and finite element modeling to evaluate the SFD and MSS. These strains were evaluated during gait based on subject-specific gait analysis data collected at baseline (before a 2-year follow-up) for a healthy and progressive early-stage KOA subject with similar demographics. Results: The results show that both SFD and MSS factors allowed distinguishing between a healthy subject and a KOA subject, showing progression at 2 years follow-up, at the instance of peak contact force as well as during the stance phase of the gait cycle. At the peak of the stance phase, the SFD were found to be more elevated in the KOA patient with the median being 0.82% higher in the lateral and 0.4% higher in the medial compartment of the tibial cartilage compared to the healthy subject. Similarly, for the MSS, the median strains were found to be 3.6% higher in the lateral and 0.7% higher in the medial tibial compartment of the KOA patient compared to the healthy subject. Based on these intersubject SFD and MSS differences, we were additionally able to identify that the tibial compartment of the KOA subject at risk of progression. Conclusion/discussion: We confirmed the mechanoregulatory factors as potential biomarkers to discriminate patients at risk of disease progression. Future studies should evaluate the sensitivity of the mechanoregulatory factors calculated based on this multi-scale modeling workflow in larger patient and control cohorts.

In Silico Biomarkers of Motor Function to Inform Musculoskeletal Rehabilitation and Orthopedic Treatment.

In this review, we elaborate on how musculoskeletal (MSK) modeling combined with dynamic movement simulation is gradually evolving from a research tool to a promising in silico tool to assist medical doctors and physical therapists in decision making by providing parameters relating to dynamic MSK function and loading. This review primarily focuses on our own and related work to illustrate the framework and the interpretation of MSK model-based parameters in patients with 3 different conditions, that is, degenerative joint disease, cerebral palsy, and adult spinal deformities. By selecting these 3 clinical applications, we also aim to demonstrate the differing levels of clinical readiness of the different simulation frameworks introducing in silico model-based biomarkers of motor function to inform MSK rehabilitation and treatment, with the application for adult spinal deformities being the most recent of the 3. Based on these applications, barriers to clinical integration and positioning of these in silico technologies within standard clinical practice are discussed in the light of specific challenges related to model assumptions, required level of complexity and personalization, and clinical implementation.

Peak Tibiofemoral Contact Forces Estimated Using IMU-Based Approaches Are Not Significantly Different from Motion Capture-Based Estimations in Patients with Knee Osteoarthritis.

Altered tibiofemoral contact forces represent a risk factor for osteoarthritis onset and progression, making optimization of the knee force distribution a target of treatment strategies. Musculoskeletal model-based simulations are a state-of-the-art method to estimate joint contact forces, but they typically require laboratory-based input and skilled operators. To overcome these limitations, ambulatory methods, relying on inertial measurement units, have been proposed to estimated ground reaction forces and, consequently, knee contact forces out-of-the-lab. This study proposes the use of a full inertial-capture-based musculoskeletal modelling workflow with an underlying probabilistic principal component analysis model trained on 1787 gait cycles in patients with knee osteoarthritis. As validation, five patients with knee osteoarthritis were instrumented with 17 inertial measurement units and 76 opto-reflective markers. Participants performed multiple overground walking trials while motion and inertial capture methods were synchronously recorded. Moderate to strong correlations were found for the inertial capture-based knee contact forces compared to motion capture with root mean square error between 0.15 and 0.40 of body weight. The results show that our workflow can inform and potentially assist clinical practitioners to monitor knee joint loading in physical therapy sessions and eventually assess long-term therapeutic effects in a clinical context.

Anterior Tibiotalar Fat Pad Involvement in Ankle Osteoarthritis: MRI Features in Patients 1 Year After a Lateral Ankle Sprain.

OBJECTIVE: To investigate the characteristics of the anterior tibiotalar fat pad (ATFP) in the ankle joint in a population of patients 1 year after an ankle sprain and its correlation with systemic factors and local articular pathology. DESIGN: The study is a secondary analysis of an observational case-control study. We included 206 patients who were followed 6-12 months after ankle sprain. T1 MRI scans were assessed for signal intensity and area of ATFP by mapping the fat pad using dedicated imaging software (Mimics 18.0). Quantitative values of intensity and area were generated. Linear regression analysis was used to examine the association between both local and systemic factors and the ATFP. Variables with a P value <0.2 were entered in 5 stepwise multivariate models: (1) age-sex-body mass index (BMI); (2) anamnesis; (3) physical examination; (4) radiographic findings; and (5) MRI findings. Predictors in these separate models were entered in the final model. RESULTS: The final multivariate model showed a significant positive association between age (P = 0.04; 95% confidence interval [CI] = 1.13 ± 1.06), BMI (P = 0.05; 95% CI = 3.61 ± 3.53), and sex (P < 0.01; 95% CI = -49.26 ± 30.04) with T1 intensity. The final model also showed a significant negative association between age (P < 0.01; 95% CI = -0.57 ± 0.34), diffuse cartilage loss in the lateral talus (P = 0.03; 95% CI = -0.71 ± 0.63), and Kellgren and Lawrence score in the tibiotalar joint (P < 0.01; 95%CI = -21.61 ± 7.24) and ATFP area. A positive association was found between BMI (P < 0.01; 95% CI = 2.25 ± 1.15) and ATFP area. CONCLUSION: This study demonstrates a correlation between ATFP and both systemic factors and local pathology in the ankle joint.

Musculoskeletal-Modeling-Based, Full-Body Load-Assessment Tool for Ergonomists (MATE): Method Development and Proof of Concept Case Studies.

A new ergonomic-risk-assessment tool was developed that combines musculoskeletal-model-based loading estimates with insights from fatigue failure theory to evaluate full-body musculoskeletal loading during dynamic tasks. Musculoskeletal-modeling output parameters, i.e., joint contact forces and muscle forces, were combined with tissue-specific injury thresholds that account for loading frequency to determine the injury risk for muscles, lower back, and hip cartilage. The potential of this new risk-assessment tool is demonstrated for defining ergonomic interventions in terms of lifting characteristics, back and shoulder exoskeleton assistance, box transferring, stoop lifting, and an overhead wiring task, respectively. The MATE identifies the risk of WMSDs in different anatomical regions during occupational tasks and allows for the evaluation of the impact of interventions that modify specific lifting characteristics, i.e., load weight versus task repetition. Furthermore, and in clear contrast to currently available ergonomic assessment scores, the effects of the exoskeleton assistance level on the risk of WMSDs of full-body musculoskeletal loading (in particular, the muscles, lower back, and hips) can be evaluated and shows small reductions in musculoskeletal loading but not in injury risk. Therefore, the MATE is a risk-assessment tool based on a full-body, musculoskeletal-modeling approach combined with insights from the fatigue failure theory that shows the proof of concept of a shoulder and back exoskeleton. Furthermore, it accounts for subject-specific characteristics (age and BMI), further enhancing individualized ergonomic-risk assessment.

The biomechanical fingerprint of hip and knee osteoarthritis patients during activities of daily living.

BACKGROUND: Osteoarthritis is a highly prevalent disease affecting the hip and knee joint and is characterized by load-mediated pain and decreased quality of life. Dependent on involved joint, patients present antalgic movement compensations, aiming to decrease loading on the involved joint. However, the associated alterations in mechanical loading of the ipsi- and contra-lateral lower limb joints, are less documented. Here, we documented the biomechanical fingerprint of end-stage hip and knee osteoarthritis patients in terms of ipsilateral and contralateral hip and knee loading during walking and stair ambulation. METHODS: Three-dimensional motion-analysis was performed in 20 hip, 18 knee osteoarthritis patients and 12 controls during level walking and stair ambulation. Joint contact forces were calculated using a standard musculoskeletal modelling workflow in Opensim. Involved and contralateral hip and knee joint loading was compared against healthy controls using independent t-tests (p < 0.05). FINDINGS: Both hip and knee cohorts significantly decreased loading of the involved joint during gait and stair ambulation. Hip osteoarthritis patients presented no signs of ipsilateral knee nor contralateral leg overloading, during walking and stair ascending. However, knee osteoarthritis patients significantly increased loading at the ipsilateral hip, and contralateral hip and knee joints during stair ambulation compared to controls. INTERPRETATION: The biomechanical fingerprint in knee and hip osteoarthritis patients confirmed antalgic movement strategies to unload the involved leg during gait. Only during stair ambulation in knee osteoarthritis patients, movement adaptations were confirmed that induced unbalanced intra- and inter-limb loading conditions, which are known risk factors for secondary osteoarthritis.

Comparison of the Effect of Dressage Rider Skill Level on Physical Fitness Parameters and Posture on an Equestrian Simulator.

In dressage riding, rider posture plays an important role in the performance of the exercises. The purpose of this study was to compare physical fitness and posture on an equestrian simulator between different competitive dressage rider skill levels. Participants (ten expert and twelve novice competitive dressage riders) performed a physiotherapeutic screening test and an equestrian simulator test. The expert rider group (G2) had less variability in both left (P = .002) and right (P = .021) rein force during medium canter on the simulator compared to the novice rider group (G1). The shoulder angle of the expert riders was larger in all gaits. These findings indicate that the ability to maintain a constant force on the reins and a dynamically stable hand position during riding on a simulator are important indicators for good rider performance. Expert riders presented a trend toward a more stable posture on the simulator as indicated by the reduced trunk variability (P = .034 vs. CV = 0.011) and smaller trunk ROM (P = .012 vs. CV = 0.011) and knee ROM (P = .033 vs. CV = 0.011) in the collected canter and collected walk respectively. These kinematic differences underscore their capability of maintaining a continued and constant force on the reins, but these findings require further research. No significant differences were found between groups in the physiotherapeutic screening. This underlines the difficulty in identifying the physical factors contributing to better rider performance. In conclusion, the current study shows that "stable rein contact" is the main difference between novice and expert competitive dressage riders on the simulator.

Imaging-based musculoskeletal models alter muscle and joint contact forces but do not improve the agreement with experimentally measured electromyography signals in children with cerebral palsy.

BACKGROUND: Musculoskeletal simulations are used to estimate muscle-tendon and joint contact forces (JCF). Personalizing the model's femoral geometry has been shown to improve the accuracy of JCF calculations. It is, however, unknown if the personalized geometry improves the agreement between estimated muscle activations and experimentally measured electromyography (EMG) signals. RESEARCH QUESTION: Does personalizing the musculoskeletal geometry improve the agreement between estimated muscle activations and EMG signals in terms of timing? METHODS: We retrospectively analysed data from Bosmans et al. [5], which included three-dimensional motion capture data, EMG signals of eight lower limb muscles on each leg, and magnetic resonance imaging (MRI) data from seven children with cerebral palsy. For each patient we created a generic-scaled model and MRI-based model, which accounted for the subject-specific musculoskeletal geometry. We calculated muscle activations, muscle-tendon forces and JCF. Muscle activations were compared to the EMG signals using coefficient of determination and cosines similarity. RESULTS: MRI-based models altered the magnitude of muscle activations and had a large impact on JCF but did not change the muscle activations profiles and therefore did not improve the agreement with EMG signals. SIGNIFICANCE: MRI-based models do not alter the shape of muscle activations. Hence, if detailed muscle activations are a desired output of the simulations, EMG-informed modeling approaches should be used for musculoskeletal simulation in children with cerebral palsy. Furthermore, our study highlighted that altered JCF does not necessarily mean accurate muscle activations. To improve patient-specific simulations, future work should focus on developing methods to estimate cost functions representative for the neural control of children with cerebral palsy.

Using musculoskeletal modelling to estimate knee joint loading pre and post high tibial osteotomy.

BACKGROUND: Both medial knee osteoarthritis and associated varus alignment have been proposed to alter knee joint loading and consequently overloading the medial compartment. Individuals with knee osteoarthritis and varus deformity are candidates for coronal plane corrective surgery, high tibial osteotomy. This study evaluated knee loading and contact location for a control group, a pre-surgery cohort and the same cohort 12 months post-surgery using a musculoskeletal modelling approach. METHODS: Joint kinematics during gait were measured in 30 knee osteoarthritis patients, before and after high tibial osteotomy, and 28 healthy adults. Using a musculoskeletal model that incorporated patient-specific mechanical tibial femoral angle, the resulting muscle, ligament, and contact forces were calculated and the medial - lateral condyle load distribution was analysed. FINDINGS: Surgery changed medial compartment contact force throughout stance relative to pre-surgery. This reduction in medial compartment contact force pre- vs post-HTO is observed despite a significant increase in post-surgery walking speed compared to pre-HTO, where increased speed is typically associated with increased joint loading. INTERPRETATION: This study has estimated the effects of high tibial osteotomy on knee loading using a generic model that incorporates a detailed knee model to better understand tibiofemoral contact loading. The findings support the aim of surgery to unload the medial knee compartment and lateralise joint contact forces.

Unique shape variations of hind and midfoot bones in flatfoot subjects-A statistical shape modeling approach.

Flatfoot deformity is a prevalent hind- and midfoot disorder. Given its complexity, single-plane radiological measurements omit case-specific joint interaction and bone shape variations. Three-dimensional medical imaging assessment using statistical shape models provides a complete approach in characterizing bone shape variations unique to flatfoot condition. This study used statistical shape models to define specific bone shape variations of the subtalar, talonavicular, and calcaneocuboid joints that characterize flatfoot deformity, that differentiate them from healthy controls. Bones of the aforementioned joints were segmented from computed tomography scans of 40 feet. The three-dimensional hindfoot alignment angle categorized the population into 18 flatfoot subjects (≥7° valgus) and 22 controls. Statistical shape models for each joint were defined using the entire study cohort. For each joint, an average weighted shape parameter was calculated for each mode of variation, and then compared between flatfoot and controls. Significance was set at p < 0.05, with values between 0.05 ≤ p < 0.1 considered trending towards significance. The flatfoot population showed a more adducted talar head, inferiorly inclined talar neck, and posteriorly orientated medial subtalar articulation compare to controls, coupled with more navicular eversion, shallower navicular cup, and more prominent navicular tuberosity. The calcaneocuboid joint presented trends of a more adducted calcaneus, more abducted cuboid, narrower calcaneal roof, and less prominent cuboid beak compared to controls. Statistical shape model analysis identified unique shape variations which may enhance understanding and computer-aided models of the intricacies of flatfoot, leading to better diagnosis and, ultimately, surgical treatment.

Unconfined Compression Experimental Protocol for Cartilage Explants and Hydrogel Constructs: From Sample Preparation to Mechanical Characterization.

Mechanical characterization of articular cartilage and cell-seeded hydrogel constructs is a challenging task due to the complex biphasic behavior of these materials. Here we describe a step-by-step unconfined compression testing protocol for inverse mechanical characterization of these materials from sample preparation to parameter identification. Examples from our ongoing experiments on alginate hydrogel constructs and preserved and damaged cartilage explants obtained from human hip samples are presented.

Probabilistic planning for ligament-balanced TKA-Identification of critical ligament properties.

Total knee arthroplasty (TKA) failures are often attributed to unbalanced knee ligament loading. The current study aims to develop a probabilistic planning process to optimize implant component positioning that achieves a ligament-balanced TKA. This planning process accounts for both subject-specific uncertainty, in terms of ligament material properties and attachment sites, and surgical precision related to the TKA process typically used in clinical practice. The consequent uncertainty in the implant position parameters is quantified by means of a surrogate model in combination with a Monte Carlo simulation. The samples for the Monte Carlo simulation are generated through Bayesian parameter estimation on the native knee model in such a way that each sample is physiologically relevant. In this way, a subject-specific uncertainty is accounted for. A sensitivity analysis, using the delta-moment-independent sensitivity measure, is performed to identify the most critical ligament parameters. The designed process is capable of estimating the precision with which the targeted ligament-balanced TKA can be realized and converting this into a success probability. This study shows that without additional subject-specific information (e.g., knee kinematic measurements), a global success probability of only 12% is estimated. Furthermore, accurate measurement of reference strains and attachment sites critically improves the success probability of the pre-operative planning process. To allow more precise planning, more accurate identification of these ligament properties is required. This study underlines the relevance of investigating in vivo or intraoperative measurement techniques to minimize uncertainty in ligament-balanced pre-operative planning results, particularly prioritizing the measurement of ligament reference strains and attachment sites.

Mechanosensors control skeletal muscle mass, molecular clocks, and metabolism.

BACKGROUND: Skeletal muscles (SkM) are mechanosensitive, with mechanical unloading resulting in muscle-devastating conditions and altered metabolic properties. However, it remains unexplored whether these atrophic conditions affect SkM mechanosensors and molecular clocks, both crucial for their homeostasis and consequent physiological metabolism. METHODS: We induced SkM atrophy through 14 days of hindlimb suspension (HS) in 10 male C57BL/6J mice and 10 controls (CTR). SkM histology, gene expressions and protein levels of mechanosensors, molecular clocks and metabolism-related players were examined in the m. Gastrocnemius and m. Soleus. Furthermore, we genetically reduced the expression of mechanosensors integrin-linked kinase (Ilk1) and kindlin-2 (Fermt2) in myogenic C2C12 cells and analyzed the gene expression of mechanosensors, clock components and metabolism-controlling genes. RESULTS: Upon hindlimb suspension, gene expression levels of both core molecular clocks and mechanosensors were moderately upregulated in m. Gastrocnemius but strongly downregulated in m. Soleus. Upon unloading, metabolism- and protein biosynthesis-related genes were moderately upregulated in m. Gastrocnemius but downregulated in m. Soleus. Furthermore, we identified very strong correlations between mechanosensors, metabolism- and circadian clock-regulating genes. Finally, genetically induced downregulations of mechanosensors Ilk1 and Fermt2 caused a downregulated mechanosensor, molecular clock and metabolism-related gene expression in the C2C12 model. CONCLUSIONS: Collectively, these data shed new lights on mechanisms that control muscle loss. Mechanosensors are identified to crucially control these processes, specifically through commanding molecular clock components and metabolism.