Impact of long-term rapamycin treatment on age-related osteoarthritis in common marmoset.

Objective: Pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) can attenuate experimental osteoarthritis (OA) in young, male preclinical models. However, the potential of mTOR inhibition as a therapeutic mechanism for OA remains unknown. The goal of this study was to determine if mTOR-inhibition by oral rapamycin can modify OA pathology in the common marmoset, a translational model of age-associated OA. Methods: microCT and histopathologic assessments of the knee were performed on formalin-fixed hindlimbs obtained from common marmosets treated with oral rapamycin (n=24; 1mg/kg/day) or parallel control group (n=41). Rapamycin started at 9.2±3.0 years old and lasted until death (2.1±1.5 years). In a subset of marmosets, contralateral hind limbs were collected to determine mTOR signaling in several joint tissues. Results: Rapamycin decreased P-RPS6Ser235/36 and increased P-Akt2Ser473 in cartilage, meniscus, and infrapatellar fat pad, suggesting inhibition of mTORC1 but not mTORC2 signaling. Rapamycin-treated marmosets had lower lateral synovium score versus control but there was no difference in the age-related increase in microCT or cartilage OA scores. Subchondral bone thickness and thickness variability were not different with age but were lower in rapamycin-treated geriatric marmosets, which was largely driven by females. Rapamycin also tended to worsen age-related meniscus calcification in female marmosets. Conclusion: Oral rapamycin attenuated mTORC1 signaling and may have caused feedback activation of mTORC2 signaling in joint tissues. Despite modifying site-specific aspects of synovitis, rapamycin did not modify the age-associated increase in OA in geriatric marmosets. Conversely, rapamycin may have had deleterious effects on meniscus calcification and lateral tibia subchondral bone, primarily in geriatric female marmosets.

A registration strategy to characterize DTI-observed changes in skeletal muscle architecture due to passive shortening.

Skeletal muscle architecture is a key determinant of muscle function. Architectural properties such as fascicle length, pennation angle, and curvature can be characterized using Diffusion Tensor Imaging (DTI), but acquiring these data during a contraction is not currently feasible. However, an image registration-based strategy may be able to convert muscle architectural properties observed at rest to their contracted state. As an initial step toward this long-term objective, the aim of this study was to determine if an image registration strategy could be used to convert the whole-muscle average architectural properties observed in the extended joint position to those of a flexed position, following passive rotation. DTI and high-resolution fat/water scans were acquired in the lower leg of seven healthy participants on a 3T MR system in +20° (plantarflexion) and -10° (dorsiflexion) foot positions. The diffusion and anatomical images from the two positions were used to propagate DTI fiber-tracts from seed points along a mesh representation of the aponeurosis of fiber insertion. The -10° and +20° anatomical images were registered and the displacement fields were used to transform the mesh and fiber-tracts from the +20° to the -10° position. Student's paired t-tests were used to compare the mean architectural parameters between the original and transformed fiber-tracts. The whole-muscle average fiber-tract length, pennation angle, curvature, and physiological cross-sectional areas estimates did not differ significantly. DTI fiber-tracts in plantarflexion can be transformed to dorsiflexion position without significantly affecting the average architectural characteristics of the fiber-tracts. In the future, a similar approach could be used to evaluate muscle architecture in a contracted state.

The common marmoset as a translational model of age-related osteoarthritis.

Age-related osteoarthritis (OA) is a degenerative joint disease characterized by pathological changes in nearly every intra- and peri-articular tissue that contributes to disability in older adults. Studying the etiology of age-related OA in humans is difficult due to an unpredictable onset and insidious nature. A barrier in developing OA modifying therapies is the lack of translational models that replicate human joint anatomy and age-related OA progression. The purpose of this study was to determine whether the common marmoset is a faithful model of human age-related knee OA. Semi-quantitative microCT scoring revealed greater radiographic OA in geriatric versus adult marmosets, and the age-related increase in OA prevalence was similar between marmosets and humans. Quantitative assessments indicate greater medial tibial cortical and trabecular bone thickness and heterogeneity in geriatric versus adult marmosets which is consistent with an age-related increase in focal subchondral bone sclerosis. Additionally, marmosets displayed an age-associated increase in synovitis and calcification of the meniscus and patella. Histological OA pathology in the medial tibial plateau was greater in geriatric versus adult marmosets driven by articular cartilage damage, proteoglycan loss, and altered chondrocyte cellularity. The age-associated increase in medial tibial cartilage OA pathology and meniscal calcification was greater in female versus male geriatric marmosets. Overall, marmosets largely replicate human OA as evident by similar 1) cartilage and skeletal morphology, 2) age-related progression in OA pathology, and 3) sex differences in OA pathology with increasing age. Collectively, these data suggest that the common marmoset is a highly translatable model of the naturally occurring, age-related OA seen in humans.

Assessment of Mechanically Induced Changes in Helical Fiber Microstructure Using Diffusion Tensor Imaging.

Noninvasive methods to detect microstructural changes in collagen-based fibrous tissues are necessary to differentiate healthy from damaged tissues in vivo but are sparse. Diffusion Tensor Imaging (DTI) is a noninvasive imaging technique used to quantitatively infer tissue microstructure with previous work primarily focused in neuroimaging applications. Yet, it is still unclear how DTI metrics relate to fiber microstructure and function in musculoskeletal tissues such as ligament and tendon, in part because of the high heterogeneity inherent to such tissues. To address this limitation, we assessed the ability of DTI to detect microstructural changes caused by mechanical loading in tissue-mimicking helical fiber constructs of known structure. Using high-resolution optical and micro-computed tomography imaging, we found that static and fatigue loading resulted in decreased sample diameter and a re-alignment of the macro-scale fiber twist angle similar with the direction of loading. However, DTI and micro-computed tomography measurements suggest microstructural differences in the effect of static versus fatigue loading that were not apparent at the bulk level. Specifically, static load resulted in an increase in diffusion anisotropy and a decrease in radial diffusivity suggesting radially uniform fiber compaction. In contrast, fatigue loads resulted in increased diffusivity in all directions and a change in the alignment of the principal diffusion direction away from the constructs' main axis suggesting fiber compaction and microstructural disruptions in fiber architecture. These results provide quantitative evidence of the ability of DTI to detect mechanically induced changes in tissue microstructure that are not apparent at the bulk level, thus confirming its potential as a noninvasive measure of microstructure in helically architected collagen-based tissues, such as ligaments and tendons.

Moving forward: A review of continuous kinetics and kinematics during handcycling propulsion.

Wheelchair users (WCUs) face high rates of shoulder overuse injuries. As exercise is recommended to reduce cardiovascular disease prevalent among WCUs, it is becoming increasingly important to understand the mechanisms behind shoulder soft-tissue injury in WCUs. Understanding the kinetics and kinematics during upper-limb propulsion is the first step toward evaluating soft-tissue injury risk in WCUs. This paper examines continuous kinetic and kinematic data available in the literature. Attach-unit and recumbent handcycling are examined and compared. Athletic modes of propulsion such as recumbent handcycling are important considering the higher contact forces, speed, and power outputs experienced during these activities that could put users at increased risk of injury. Understanding the underlying kinetics and kinematics during various propulsion modes can lend insight into shoulder loading, and therefore injury risk, during these activities and inform future exercise guidelines for WCUs.

Propulsion kinetics of recumbent handcycling during high and moderate intensity exercise.

People with spinal cord injuries (PwSCI) are at high risk of developing cardiovascular disease (CVD). While regular exercise can reduce risk of CVD, PwSCI face various barriers to exercise, including high rates of upper limb injuries, especially in the shoulder. Handcycling high intensity interval training (HIIT), which consists of periods of high intensity exercise followed by rest, is a potential exercise solution, but the musculoskeletal safety of HIIT is still unknown. In this study, we characterized three-dimensional continuous applied forces at the handle during handcycling HIIT and moderate intensity continuous training (MICT). These applied forces can give an early indication of joint loading, and therefore injury risk, at the shoulder. In all three directions (tangential, radial, and lateral), the maximum applied forces during HIIT were larger than those in MICT at all timepoints, which may indicate higher contact forces and loads on the shoulder during HIIT compared to MICT. The tangential and radial forces peaked twice in a propulsion cycle, while the lateral forces peaked once. Throughout the exercises, the location of tangential peak 2 and radial peak 1 was later in HIIT compared to MICT. This difference in maximum force location could indicate either altered kinematics or muscular fatigue at the end of the exercise protocol. These changes in kinematics should be more closely examined using motion capture or other modeling techniques. If we combine this kinetic data with kinematic data during propulsion, we can create musculoskeletal models that more accurately predict contact forces and injury risk during handcycling HIIT in PwSCI.

Elastic Modulus and Its Relation to Apparent Mineral Density in Juvenile Equine Bones of the Lower Limb.

Density-modulus relationships are necessary to develop finite element models of bones that may be used to evaluate local tissue response to different physical activities. It is unknown if juvenile equine trabecular bone may be described by the same density-modulus as adult equine bone, and how the density-modulus relationship varies with anatomical location and loading direction. To answer these questions, trabecular bone cores from the third metacarpal (MC3) and proximal phalanx (P1) bones of juvenile horses (age <1 yr) were machined in the longitudinal (n = 134) and transverse (n = 90) directions and mechanically tested in compression. Elastic modulus was related to apparent computed tomography density of each sample using power law regressions. We found that density-modulus relationships for juvenile equine trabecular bone were significantly different for each anatomical location (MC3 versus P1) and orientation (longitudinal versus transverse). Use of the incorrect density-modulus relationship resulted in increased root mean squared percent error of the modulus prediction by 8-17%. When our juvenile density-modulus relationship was compared to one of an equivalent location in adult horses, the adult relationship resulted in an approximately 80% increase in error of the modulus prediction. Moving forward, more accurate models of young bone can be developed and used to evaluate potential exercise regimens designed to encourage bone adaptation.

Mechanical Biomarkers in Bone Using Image-Based Finite Element Analysis.

PURPOSE OF REVIEW: The purpose of this review is to summarize insights gained by finite element (FE) model-based mechanical biomarkers of bone for in vivo assessment of bone development and adaptation, fracture risk, and fracture healing. RECENT FINDINGS: Muscle-driven FE models have been used to establish correlations between prenatal strains and morphological development. Postnatal ontogenetic studies have identified potential origins of bone fracture risk and quantified the mechanical environment during stereotypical locomotion and in response to increased loading. FE-based virtual mechanical tests have been used to assess fracture healing with higher fidelity than the current clinical standard; here, virtual torsion test data was a better predictor of torsional rigidity than morphometric measures or radiographic scores. Virtual mechanical biomarkers of strength have also been used to deepen the insights from both preclinical and clinical studies with predictions of strength of union at different stages of healing and reliable predictions of time to healing. Image-based FE models allow for noninvasive measurement of mechanical biomarkers in bone and have emerged as powerful tools for translational research on bone. More work to develop nonirradiating imaging techniques and validate models of bone during particularly dynamic phases (e.g., during growth and the callus region during fracture healing) will allow for continued progress in our understanding of how bone responds along the lifespan.

Spatial Variation in Young Ovine Cortical Bone Properties.

Significant effort continues to be made to understand whether differences exist in the structural, compositional, and mechanical properties of cortical bone subjected to different strain modes or magnitudes. We evaluated juvenile sheep femora (age = 4 months) from the anterior and posterior quadrants at three points along the diaphysis as a model system for variability in loading. Micro-CT scans (50 micron) were used to measure cortical thickness and mineral density. Three point bending tests were performed to measure the flexural modulus, strength, and post-yield displacement. There was no difference in cortical thickness or density between anterior or posterior quadrants; however, density was consistently higher in the middle diaphysis. Interestingly, bending modulus and strength were higher in anterior quadrants compared to posterior quadrants. Together, our results suggest that there is a differential spatial response of bone in terms of elastic bending modulus and mechanical strength. The origins of this difference may lie within the variation in ongoing mineralization, in combination with the collagen-rich plexiform structure, and whether this is related to strain mode remains to be explored. These data suggest that in young ovine cortical bone, modulation of strength occurs via potentially complex interactions of both mineral and collagen-components that may be different in regions of bone exposed to variable amounts of strain. Further work is needed to confirm the physiological load state of bone during growth to better elucidate the degree to which these variations are a function of the local mechanical environment.

Multidirectional basketball activities load different regions of the tibia: A subject-specific muscle-driven finite element study.

The tibia is a common site for bone stress injuries, which are believed to develop from microdamage accumulation to repetitive sub-yield strains. There is a need to understand how the tibia is loaded in vivo to understand how bone stress injuries develop and design exercises to build a more robust bone. Here, we use subject-specific, muscle-driven, finite element simulations of 11 basketball players to calculate strain and strain rate distributions at the midshaft and distal tibia during six activities: walking, sprinting, lateral cut, jumping after landing, changing direction from forward-to-backward sprinting, and changing direction while side shuffling. Maximum compressive strains were at least double maximum tensile strains during the stance phase of all activities. Sprinting and lateral cut had the highest compressive (-2,862 ± 662 µÎµ and -2,697 ± 495 µÎµ, respectively) and tensile (973 ± 208 µÎµ and 942 ± 223 µÎµ, respectively) strains. These activities also had the highest strains rates (peak compressive strain rate = 64,602 ± 19,068 µÎµ/s and 37,961 ± 14,210 µÎµ/s, respectively). Compressive strains principally occurred in the posterior tibia for all activities; however, tensile strain location varied. Activities involving a change in direction increased tensile loads in the anterior tibia. These observations may guide preventative and management strategies for tibial bone stress injuries. In terms of prevention, the strain distributions suggest individuals should perform activities involving changes in direction during growth to adapt different parts of the tibia and develop a more fatigue resistant bone. In terms of management, the greater strain and strain rates during sprinting than jumping suggests jumping activities may be commenced earlier than full pace running. The greater anterior tensile strains during changes in direction suggest introduction of these types of activities should be delayed during recovery from an anterior tibial bone stress injury, which have a high-risk of healing complications.

Anisotropic Foams via Frontal Polymerization.

The properties of foams, an important class of cellular solids, are most sensitive to the volume fraction and openness of its elementary compartments; size, shape, orientation, and the interconnectedness of the cells are other important design attributes. Control of these morphological traits would allow the tailored fabrication of useful materials. While approaches like ice templating have produced foams with elongated cells, there is a need for rapid, versatile, and energy-efficient methods that also control the local order and macroscopic alignment of cellular elements. Here, a fast and convenient method is described to obtain anisotropic structural foams using frontal polymerization. Foams are fabricated by curing mixtures of dicyclopentadiene and a blowing agent via frontal ring-opening metathesis polymerization (FROMP). The materials are characterized using microcomputed tomography (micro-CT) and an image analysis protocol to quantify the morphological characteristics. The cellular structure, porosity, and hardness of the foams change with blowing agent, concentration, and resin viscosity. Moreover, a full factorial combination of variables is used to correlate each parameter with the structure of the obtained foams. The results demonstrate the controlled production of foams with specific morphologies using the simple and efficient method of frontal polymerization.

Physical activity induced adaptation can increase proximal femur strength under loading from a fall onto the greater trochanter.

Physical activity enhances proximal femur bone mass, but it remains unclear whether the benefits translate into an enhanced ability to resist fracture related loading. We recently used baseball pitchers as a within-subject controlled model to demonstrate physical activity induced proximal femur adaptation in regions associated with weight bearing and increased strength under single-leg stance loading. However, there was no measurable benefit to resisting common injurious loading (e.g. a fall onto the greater trochanter). A lack of power and a small physical activity effect size may have contributed to the latter null finding. Softball pitchers represent an alternative within-subject controlled model to explore adaptation of the proximal femur to physical activity, exhibiting greater dominant-to-nondominant (D-to-ND) leg differences than baseball pitchers. The current study used quantitative computed tomography, statistical parametric mapping, and subject-specific finite element (FE) modeling to explore adaptation of the proximal femur to physical activity in female softball pitchers (n = 25). Female cross-country runners (n = 15) were included as symmetrically loaded controls, showing very limited D-to-ND leg differences. Softball pitchers had D-to-ND leg differences in proximal femur, femoral neck, and trochanteric volumetric bone mineral density and content, and femoral neck volume. Voxel-based morphometry analyses and cortical bone mapping showed D-to-ND leg differences within a large region connecting the superior femoral head, inferior femoral neck and medial intertrochanteric region, and within the greater trochanter. FE modeling revealed pitchers had 19.4% (95%CI, 15.0 to 23.9%) and 4.9% (95%CI, 1.7 to 8.2%) D-to-ND leg differences in predicted ultimate strength under single-leg stance loading and a fall onto the greater trochanter, respectively. These data affirm the spatial and strength adaptation of the proximal femur to weight bearing directed loading and demonstrate that the changes can also have benefits, albeit smaller, on resisting loads associated with a sideways fall onto the greater trochanter.

Effect of fatigue loading and rest on impact strength of rat ulna.

Stress fracture is a common injury among athletes and military personnel and is associated with fatigue-initiated damage and impact loading. The recovery of bending strength has been shown to be a function of the rest days allowed after fatigue loading in rodents and the aim of this study was to investigate if similar results would occur under impact conditions. In this study, cyclic axial compression load was applied in vivo on the right forelimbs while left forelimbs served as controls. Two rest groups were used: one day of rest and seven days of rest. Afterwards, all ulnae were scanned using micro-Computed Tomography followed by impact testing. The micro-CT scan confirmed the formation of woven bone on loaded ulnae after seven days rest. The peak impact force was 37.5% higher in the control (mean = 174.96 ± 33.25 N) specimens compared to the loaded bones (mean = 130.34 ± 22.37 N). Fourier-transformed infrared spectroscopy analyses suggested no significant change of chemical composition in the cortical region between the loaded and control ulnae, but woven bone region had lower carbonate and amide I content than contralateral controls (p < 0.05). We find that cyclic fatigue loading had a negative effect on bone's impact response. Bones that experienced fatigue loading became less stiff, weaker, and more prone to fracture when subjected to impact. The formation of woven bone after seven days of rest did not restore the stiffness upon impact and confirm that rest time is crucial to the recovery of fatigue damage.

Replication of the tensile behavior of knee ligaments using architected acrylic yarn.

Knee ligament injury diagnosis is achieved by a comparison between the laxity levels sensed by a clinician in the injured and healthy limb. This is a difficult-to-learn task that requires hands-on practice to achieve proficiency. The inclusion of a physical knee simulator with biomechanically realistic passive components such as knee ligaments could provide consistent training for medical students and lead to improved care for knee injury patients. In this study, we developed a material construct that is both adaptable to a physical knee model and capable of replicating the non-linear mechanical behavior of knee ligaments with the use of helically arranged acrylic yarn. The microstructure of four different types of acrylic yarn were measured and then tested under uniaxial tension. While the fiber twist angle was similar amongst the four yarn types (range = 17.9-18.8°), one yarn was distinct with a low ply twist angle (15.2 ± 1.6°) and high packing fraction (Φ=0.32±0.08). These microstructural differences yielded a lower toe length and higher stiffness and best corresponded to ligament mechanical behavior. We then made looped-yarn constructs to modulate the sample's toe length and stiffness. We found that the load-displacement curve of the construct can be tuned by changing the loop length and loop number of the looped-yarn constructs, matching the load-displacement curve of specific knee ligaments. This study shows how spun yarn can be used to replicate the mechanical behavior of knee ligaments, creating synthetic ligament constructs that could enable the construction of biomechanically realistic joints.

Fluoroquinolone exposure in utero did not affect articular cartilage of resulting foals.

BACKGROUND: Recent studies have shown that fluoroquinolones, specifically, enrofloxacin and its active metabolite (ciprofloxacin), cross the equine placenta without causing gross or histological lesions in the first and third trimester fetuses or resulting foal. However, it is possible that in utero exposure to fluoroquinolones may cause subtle lesions not detectable by standard means; thus, a more in-depth assessment of potential toxicity is warranted. OBJECTIVES: To use quantitative magnetic resonance imaging (qMRI), biomechanical testing, and chondrocyte gene expression to evaluate the limbs of foals exposed to enrofloxacin during the third trimester of pregnancy. STUDY DESIGN: In vivo and control terminal experiment. METHODS: Healthy mares at 280 days gestation were assigned into three groups: untreated (n = 5), recommended therapeutic (7.5 mg/kg enrofloxacin, PO, SID, n = 6) or supratherapeutic (15 mg/kg, PO, SID, n = 6) doses for 14 days. Mares carried and delivered to term and nursed their foals for ~30 days. Two additional healthy foals born from untreated mares were treated post-natally with enrofloxacin (10 mg/kg PO, SID, for 5 days). By 30 days, foal stifles, hocks, elbows, and shoulders were radiographed, foals were subjected to euthanasia, and foal limbs were analysed by quantitative MRI, structural MRI, biomechanical testing and chondrocyte gene expression. RESULTS: Osteochondral lesions were detected with both radiography and structural MRI in foals from both enrofloxacin-treated and untreated mares. Severe cartilage erosions, synovitis and joint capsular thickening were identified in foals treated with enrofloxacin post-natally. Median cartilage T2 relaxation times differed between joints but did not differ between treatment groups. MAIN LIMITATIONS: A small sample size was assessed and there was no long-term follow-up. CONCLUSION: While further research is needed to address long-term foal outcomes, no differences were seen in advanced imaging, biomechanical testing or gene expression by 30 days of age, suggesting that enrofloxacin may be a safe and useful antibiotic for select bacterial infections in pregnant mares.

Biomechanical properties of canine staphylectomies closed with barbed or smooth suture.

OBJECTIVE: To compare the duration of closure and biomechanical properties of staphylectomies closed with absorbable bidirectional barbed suture or smooth monofilament suture in a simple continuous or interrupted pattern STUDY DESIGN: Ex vivo study SAMPLE POPULATION: Soft palates (n = 60) harvested from mesaticephalic canine cadavers METHODS: One centimeter of tissue was excised from the caudal border of each soft palate, and the oral and nasopharyngeal mucosal surfaces were apposed with 2-0 bidirectional Quill Monoderm knotless closure device barbed suture (Q), 3-0 Monocryl in a simple continuous (MC) pattern, or 3-0 Monocryl in a simple interrupted (MI) pattern (n = 20 per group). Duration of closure was compared between groups. Tissues were tested under tension to failure, and mode of failure data were collected by video capture. RESULTS: Closure time was longer for MI closures than for Q and MC closures, with means of 259.9, 215.4, and 196.7 seconds, respectively (P < .0001). No difference was detected in yield force, force to first tissue rupture, maximum force, and energy required for yield and maximum force between groups. Energy to yield was 190.0, 167.8, and 188.95 N-mm for MI, Q, and MC closures, respectively. CONCLUSION: Biomechanical properties of staphylectomies closed with barbed or smooth sutures did not differ in this cadaveric model. CLINICAL SIGNIFICANCE: Barbed suture can be considered as an alternative for closure of canine staphylectomies. These results provide evidence to justify additional research to evaluate clinical outcomes in dogs undergoing staphylectomy.

Play During Growth: the Effect of Sports on Bone Adaptation.

PURPOSE OF REVIEW: The development of exercise interventions for bone health requires an understanding of normative growth trends. Here, we summarize changes in bone during growth and the effect of participating in sports on structural and compositional measures in different bones in males and females. RECENT FINDINGS: Growing females and males have similar normalized density and bone area fraction until age 16, after which males continue increasing at a faster rate than females. All metrics for both sexes tend to plateau or decline in the early 20s. Areal BMD measures indicate significant heterogeneity in adaptation to sport between regions of the body. High-resolution CT data indicate changes in structure are more readily apparent than changes in density. While adaptation to sport is spatially heterogeneous, participation in weight-bearing activities that involve dynamic muscle contractions tends to result in increased bone adaptation.

Tough and tunable scaffold-hydrogel composite biomaterial for soft-to-hard musculoskeletal tissue interfaces.

Tendon inserts into bone via a fibrocartilaginous interface (enthesis) that reduces mechanical strain and tissue failure. Despite this toughening mechanism, tears occur because of acute (overload) or degradative (aging) processes. Surgically fixating torn tendon into bone results in the formation of a scar tissue interface with inferior biomechanical properties. Progress toward enthesis regeneration requires biomaterial approaches to protect cells from high levels of interfacial strain. We report an innovative tissue reinforcement strategy: a stratified scaffold containing osseous and tendinous tissue compartments attached through a continuous polyethylene glycol (PEG) hydrogel interface. Tuning the gelation kinetics of the hydrogel modulates integration with the flanking compartments and yields biomechanical performance advantages. Notably, the hydrogel interface reduces formation of strain concentrations between tissue compartments in conventional stratified biomaterials that can have deleterious biological effects. This design of mechanically robust stratified composite biomaterials may be appropriate for a broad range of tendon and ligament-to-bone insertions.

The relationship between tibiofemoral geometry and musculoskeletal function during normal activity.

BACKGROUND: The effect of tibiofemoral geometry on musculoskeletal function is important to movement biomechanics. RESEARCH QUESTION: We hypothesised that tibiofemoral geometry determines tibiofemoral motion and musculoskeletal function. We then aimed at 1) modelling tibiofemoral motion during normal activity as a function of tibiofemoral geometry in healthy adults; and 2) quantifying the effect of tibiofemoral geometry on musculoskeletal function. METHODS: We used motion data for six activity types and CT images of the knee from 12 healthy adults. Geometrical variation of the tibia and femoral articular surfaces were measured in the CT images. The geometry-based tibiofemoral motion was calculated by fitting a parallel mechanism to geometrical variation in the cohort. Matched musculoskeletal models embedding the geometry-based tibiofemoral joint motion and a common generic tibiofemoral motion of reference were generated and used to calculate joint angles, net joint moments, muscle and joint forces for the six activities analysed. The tibiofemoral model was validated against bi-planar fluoroscopy measurements for walking for all the six planes of motion. The effect of tibiofemoral geometry on musculoskeletal function was the difference between the geometry-based model and the model of reference. RESULTS: The geometry-based tibiofemoral motion described the pattern and the variation during walking for all six motion components, except the pattern of anterior tibial translation. Tibiofemoral geometry had moderate effect on cohort-averages of musculoskeletal function (R2 = 0.60-1), although its effect was high in specific instances of the model, outputs and activities analysed, reaching 2.94 BW for the ankle reaction force during stair descent. In conclusion, tibiofemoral geometry is a major determinant of tibiofemoral motion during walking. SIGNIFICANCE: Geometrical variations of the tibiofemoral joint are important for studying musculoskeletal function during normal activity in specific individuals but not for studying cohort averages of musculoskeletal function. This finding expands current knowledge of movement biomechanics.