Tibial Load Research Articles

Evaluation of a novel robotic testing method for stability and kinematics of total knee arthroplasty.

This work developed a novel preclinical test of total knee replacements (TKRs) in order to explain TKR instability linked to patient dissatisfaction. It was hypothesized that stability tests on the isolated moving prostheses would provide novel comparative data on the stability and kinematics among TKR designs. Three TKR designs, DePuy Synthes Attune MS, Stryker Triathlon and Zimmer Biomet Persona MC, were assessed using a robotic arm while flexing-extending 0-140°. Tests imposed 710 N body weight combined with three tibial loads: no anterior-posterior (AP) force, 90 N anterior or 90 N posterior force. Other load effects were minimized and the kinematics was recorded. Each implant was tested six times to investigate the repeatability of the method. Data were analysed using statistical parametric mapping with one-way analysis of variance (ANOVA). If significance was found (p < 0.05), post hoc t tests with Bonferroni correction were used to contrast groups. Significant differences were found throughout flexion-extension. Femoral rollback, AP stability, coupled internal-external rotation and AP position (roll-back) were all influenced by implant design. AP stability of the TKRs reduced with flexion reaching Attune 15 mm, Persona 13 mm and Triathlon 21 mm at 140° flexion. Tractive rolling significantly affected kinematics in the less congruent Triathlon design, with 6 mm different paths between flexion and extension motion (p < 0.05 across 5-100°). Paradoxical anterior femoral sliding in early flexion (0-40°) occurred in Persona and Triathlon designs. The novel testing technique provides, for the first time, comparative data on the inherent stability and kinematics of the TKR implants themselves across the arc of flexion-extension, independent of variables including soft tissue behaviour and surgical technique. The data show how much each prosthesis can contribute to the stability and motion of the implanted knee. Similar data from a wider range of designs will enable more informed decisions regarding implant design choice, aiming to reduce the prevalence of TKR instability in patients. Controlled laboratory study.

Computationally derived endosteal strain and strain gradients correlate with increased bone formation in an axially loaded murine tibia model

Osteoporosis is a common metabolic bone disorder characterized by low bone mass and microstructural degradation of bone tissue due to a derailed bone remodeling process. A deeper understanding of the mechanobiological phenomena that modulate the bone remodeling response to mechanical loading in a healthy bone is crucial to develop treatments. Rodent models have provided invaluable insight into the mechanobiological mechanisms regulating bone adaptation in response to dynamic mechanic stimuli. This study sheds light on these aspects by means of assessing the mechanical environment of the cortical and cancellous tissue to in vivo dynamic compressive loading within the mouse tibia using microCT-based finite element model in combination with diaphyseal strain gauge measures. Additionally, this work describes the relation between the mid-diaphyseal strains and strain gradients from the finite element analysis and bone formation measures from time-lapse in vivo tibial loading with a fluorochrome-derived histomorphometry analysis. The mouse tibial loading model demonstrated that cancellous strains were lower than those in the midshaft cortical bone. Sensitivity analyses demonstrated that the material property of cortical bone was the most significant model parameter. The computationally-modeled strains and strain gradients correlated significantly to the histologically-measured bone formation thickness at the mid-diaphyseal cross-section of the mouse tibia.

Bone mechanical properties were altered in a mouse model of multiple myeloma bone disease

Multiple myeloma bone disease (MMBD) is characterized by the growth of malignant plasma cells in bone marrow, leading to an imbalance in bone (re)modeling favoring excessive resorption. Loss of bone mass and altered microstructure characterize MMBD in humans and preclinical animal models, although, no study to date has examined bone composition or material properties. We hypothesized that MMBD alters bone composition, mineral crystal properties and mechanical properties in the MOPC315.BM.Luc model after intra-tibial injection of myeloma cells and three weeks of daily in vivo tibial loading. Decreased cortical bone elastic modulus and hardness measured by nanoindentation of tibiae were observed in MM-injected mice compared to PBS-injected mice, whereas cortical bone composition, mineral crystal properties measured by Fourier-transform infrared imaging or small angle X-ray scattering, respectively remained unchanged. However, MM-injected mice had thinner cancellous bone mineral particles compared to PBS-injected mice. Mechanical loading did not lead to altered cortical bone composition, mineral structure, or mechanical properties in the context of MM. Unexpectedly, we observed the intra-tibial injection itself altered the material composition of bone, manifested by increased matrix mineralization and crystal size of the hydroxyapatite crystals in the bone matrix. In conclusion, our data suggest that mechanical stimuli can be used as an adjuvant bone anabolic therapy in patients with MMBD to rebuild bone with unaltered composition and mineral structure to reduce subsequent fracture risk.

Osteocyte Sptbn1 Deficiency Alters Cell Survival and Mechanotransduction Following Formation of Plasma Membrane Disruptions (PMD) from Mechanical Loading.

We and others have shown that application of high-level mechanical loading promotes the formation of transient plasma membrane disruptions (PMD) which initiate mechanotransduction. We hypothesized that increasing osteocyte cell membrane fragility, by disrupting the cytoskeleton-associated protein β2-spectrin (Sptbn1), could alter osteocytic responses and bone adaptation to loading in a PMD-related fashion. In MLO-Y4 cells, treatment with the spectrin-disrupting agent diamide or knockdown of Sptbn1 via siRNA increased the number of PMD formed by fluid shear stress. Primary osteocytes from an osteocyte-targeted DMP1-Cre Sptbn1 conditional knockout (CKO) model mimicked trends seen with diamide and siRNA treatment and suggested the creation of larger PMD, which repaired more slowly, for a given level of stimulus. Post-wounding cell survival was impaired in all three models, and calcium signaling responses from the wounded osteocyte were mildly altered in Sptbn1 CKO cultures. Although Sptbn1 CKO mice did not demonstrate an altered skeletal phenotype as compared to WT littermates under baseline conditions, they showed a blunted increase in cortical thickness when subjected to an osteogenic tibial loading protocol as well as evidence of increased osteocyte death (increased lacunar vacancy) in the loaded limb after 2weeks of loading. The impaired post-wounding cell viability and impaired bone adaptation seen with Sptbn1 disruption support the existence of an important role for Sptbn1, and PMD formation, in osteocyte mechanotransduction and bone adaptation to mechanical loading.

Combined PCL instabilities cannot be identified using posterior stress radiographs in external or internal rotation: A cadaveric study.

Posterior stress radiography is recommended to identify isolated or combined posterior cruciate ligament (PCL) deficiencies. The posterior drawer in internal (IR) or external rotation (ER) helps to differentiate between these combined instabilities. The purpose of this study was to evaluate posterior stress radiography (PSR) in isolated and combined PCL deficiency with IR and ER compared to PSR in neutral rotation (NR) for diagnosing combined PCL instabilities. Six paired fresh-frozen human cadaveric legs (n = 12) were mounted in a Telos device for PSR. The tibia was rotated using an attached foot apparatus capable of rotating the foot 30° internally and externally. A posterior tibial load of 15 kp (147.1 N) was applied to the tibial tubercle at 90° knee flexion, and a lateral radiograph was obtained. This was repeated with the foot in 30° IR and ER. The PCL, posterolateral complex (PLC), and posteromedial complex (PMC) were sectioned in six knees, while the PMC was sectioned before the PLC in the other six knees. Posterior tibial displacement (PTD) was measured radiographically. Statistical analysis was performed using a two-way ANOVA and a mixed model with Bonferroni correction, and the significance was set at p < 0.05. Furthermore, intra- and interobserver reliability was determined. Cutting the PCL significantly increased the radiographic PTD by 9.8 ± 1.8 mm (side-to-side difference compared to the intact state of the knee, n = 12; p < 0.001). This further increased to 12.2 ± 2.3 mm (n = 6; p < 0.01) with an additional PLC deficiency and to 15.4 ± 3.4 mm (n = 6; p < 0.05) with an additional PMC deficiency. A combined PLC and PMC deficiency resulted in an increase of the PTD to 15.9 ± 4.5 mm (n = 12; p < 0.01). In the PCL/PLC deficient state, ER did not demonstrate a higher PTD, compared to the NR and IR posterior drawer. In the PCL/PMC deficient state in IR, PTD was 1.6 ± 0.7 mm (p < 0.01) higher compared to NR and 3.2 ± 1.9 mm (p < 0.05) higher compared to ER. We showed excellent intra- and interobserver reliability (0.987-0.997). Combined PCL instabilities resulted in a significant increase in posterior tibial displacement in posterior stress radiographs. However, PSR in IR or ER was unable to differentiate between these combined instabilities. Based on our data, additional stress radiographs in rotation are unlikely to provide any diagnostic benefit in the clinical setting. There is no level of evidence as this study was an experimental laboratory study.

Tibial acceleration alone is not a valid surrogate measure of tibial load in response to stride length manipulation

PurposeThis study aimed to evaluate the relationship between peak tibial acceleration and peak ankle joint contact forces in response to stride length manipulation during level-ground running. MethodsTwenty-seven physically active participants ran 10 trials at preferred speed in each of 5 stride length conditions: preferred, ±5 %, and ±10 % of preferred stride length. Motion capture, force platform, and tibial acceleration data were directly measured, and ankle joint contact forces were estimated using an inverse-dynamics-based static optimization routine. ResultsIn general, peak axial tibial accelerations (p < 0.001) as well as axial (p < 0.001) and resultant (p < 0.001) ankle joint contact forces increased with stride length. When averaged within the 10 strides of each stride condition, moderate positive correlations were observed between peak axial acceleration and joint contact force (r = 0.49) as well as peak resultant acceleration and joint contact force (r = 0.51). However, 37% of participants illustrated either no relationship or negative correlations. Only weak correlations across participants existed between peak axial acceleration and joint contact force (r = 0.12) as well as peak resultant acceleration and ankle joint contact force (r = 0.18) when examined on a step-by-step basis. ConclusionThese results suggest that tibial acceleration should not be used as a surrogate for ankle joint contact force on a step-by-step basis in response to stride length manipulations during level-ground running. A 10-step averaged tibial acceleration metric may be useful for some runners, but an initial laboratory assessment would be required to identify these individuals.

Mitigating aging and doxorubicin induced bone loss in mature mice via mechanobiology based treatments

Aging leads to a reduced anabolic response to mechanical stimuli and a loss of bone mass and structural integrity. Chemotherapy agents such as doxorubicin exacerbate the degeneration of aging skeleton and further subject older cancer patients to a higher fracture risk. To alleviate this clinical problem, we proposed and tested a novel mechanobiology-based therapy. Building upon prior findings that i) Yoda1, the Piezo1 agonist, promoted bone growth in young adult mice and suppressed bone resorption markers in aged mice, and ii) moderate tibial loading protected bone from breast cancer-induced osteolysis, we hypothesized that combined Yoda1 and moderate loading would improve the structural integrity of adult and aged skeletons in vivo and protect bones from deterioration after chemotherapy. We first examined the effects of 4-week Yoda1 (dose 5 mg/kg, 5 times/week) and moderate tibial loading (4.5 N peak load, 4 Hz, 300 cycles for 5 days/week), individually and combined, on mature mice (∼50 weeks of age). Combined Yoda1 and loading was found to mitigate age-associated cortical and trabecular bone loss better than individual interventions. As expected, the non-treated controls experienced an average drop of cortical polar moment of inertia (Ct.pMOI) by −4.3 % over four weeks and the bone deterioration occurred in the majority (64 %) of the samples. Relative to no treatment, loading alone, Yoda1 alone, and combined Yoda1 and loading increased Ct.pMOI by +7.3 %, +9.5 %, +12.0 % and increased the % of samples with positive Ct.pMOI changes by +32 %, +26 %, and +43 %, respectively, suggesting an additive protection of aging-related bone loss for the combined therapy. We further tested if the treatment efficacy was preserved in mature mice following two weeks (six injections) of doxorubicin at the dose of 2.5 or 5 mg/kg. As expected, doxorubicin increased osteocyte apoptosis, altered bone remodeling, and impaired bone structure. However, the effects induced by DOX were too severe to be rescued by Yoda1 and loading, alone or combined, although loading and Yoda1 individually, or combined, increased the number of mice showing positive responsiveness by 0 %, +15 %, and +29 % relative to no intervention after doxorubicin exposure. Overall, this study supported the potentials and challenges of the Yoda1-based strategy in mitigating the detrimental skeletal effects caused by aging and doxorubicin.

Weightbearing Computed Tomography Can Accurately Detect Subtle Lisfranc Injury.

Early detection of Lisfranc injury is critical for improving clinical outcomes, but diagnosing subtle injury can be difficult. Weightbearing computed tomography (WBCT) allows evaluation of such injuries in 3 dimensions (3D) under physiologic load. This study aimed to assess the utility of 1-, 2-, and 3-dimensional measurements on WBCT to diagnose subtle injury in isolated ligamentous Lisfranc injuries. Ten cadaveric specimens underwent WBCT evaluation of the Lisfranc joint complex in the intact state and subsequently with sequential sectioning of the dorsal Lisfranc ligament and interosseous Lisfranc ligament (IOL) to create subtle Lisfranc injury, and finally after transectioning of plantar Lisfranc ligament (PLL) to create the injury conditions for complete ligamentous Lisfranc injury. Measurements under static vertical tibial load of 80 kg were performed on WBCT images including (1) Lisfranc joint (medial cuneiform-base of second metatarsal) volume, (2) Lisfranc joint area, (3) C1-C2 intercuneiform area, (4) C1-M2 distance, (5) C1-C2 distance, (6) M1-M2 intermetatarsal distance, (7) first tarsometatarsal (TMT1) alignment, (8) second tarsometatarsal (TMT2) alignment, (9) TMT1 dorsal step-off distance, and (10) TMT2 dorsal step-off distance. In the subtle Lisfranc injury state, Lisfranc joint volume and area, C1-M2 distance, and M1-M2 distance measurements on WBCT significantly increased, when compared with the intact state (P values .001 to .014). Additionally, Lisfranc joint volume and area, C1-M2 distance, M1-M2 distance, TMT2 alignment, and TMT2 dorsal step-off measurements were increased in the complete Lisfranc injury state. Of all measurements, C1-M2 distance had the largest area under the curve (AUC) of 0.96 (sensitivity = 90%; specificity = 90%), followed by Lisfranc volume (AUC = 0.90; sensitivity = 80%; specificity = 80%) and Lisfranc area (AUC = 0.89; sensitivity = 80%; specificity = 100%). In a cadaveric model we found that WBCT scan can increase the diagnostic accuracy for subtle Lisfranc injury. Among the measurements, C1-M2 distance exhibited the highest level of accuracy. The 2D joint area and 3D joint volume also proved to be accurate, with 3D volume measurements of the Lisfranc joint displaying the most significant absolute difference between the intact state and increasing severity of Lisfranc injury. These findings suggest that 2D joint area and 3D joint volume may have potential as supplementary measurements to more accurately diagnose subtle Lisfranc injuries. WBCT may help surgeons detect subtle Lisfranc injuries.

Diameter of Quadrupled Semitendinosus Autograft in Primary Anterior Cruciate Ligament Reconstruction Did Not Impact Early Revision Rate or Functional Outcome in a Large Cohort of Patients

To determine whether the diameter of the quadrupled semitendinosus tendon (ST) graft in primary anterior cruciate ligament reconstruction (ACLR) is related to the risk of revision ACLR within 2 years of primary ACLR, postoperative knee laxity and patient reported knee outcome. Furthermore, to investigate whether smaller graft than estimated is related to revision ACLR. Patients who underwent primary ACLR with a quadrupled ST autograft at our institution, from January 2005 to December 2017 were identified. Data from the Swedish National Knee Ligament Registry (SNKLR) were collected up to two years or until revision surgery was registered within two years after primary ACLR. Knee laxity was assessed, pre-operatively and at 6-months follow up using the KT-1000 arthrometer (134 N anterior tibial load). The Knee injury and Osteoarthritis Outcome Score (KOOS) were collected preoperatively and at two years postoperatively from SNKLR. Based on anthropometric measurements (body height and weight) and sex the estimated quadrupled ST graft diameter was calculated. A total of 4,519 patients who underwent ACLR with a quadrupled ST autograft were included. The mean graft diameter was 8.3 mm± 0.7 mm; 8.0 mm± 0.6 mm for women and 8.6 mm ± 0.7 mm for men. The quadrupled ST graft diameter was not significantly correlated to revision ACLR. There was no significant difference in the ST graft diameter regarding post-operative knee laxity. The correlations between ST graft diameter and KOOS were weak, except for the "Sport and Recreation" subscale (P=.012). The quadrupled ST graft diameter was not significantly related to the need for early revision ACLR nor was related to postoperative knee laxity or patient reported outcome except for the KOOS "Sport and Recreation" subscale. Smaller ST graft than estimated was not a risk factor for revision ACLR. The outcome after ACLR is multifactorial and ST graft diameter is of no significant importance.

The 45° and 60°of sagittal femoral tunnel placement in anterior cruciate ligament reconstruction provide similar knee stability.

The aim of the present study was to compare 45° and 60°of sagittal femoral tunnel angles in terms of anterior tibial translation (ATT), valgus angleand graft in situ force following anterior cruciate ligament reconstruction (ACLR). Ten porcine knees were subjected to the following loading conditions: (1) 89 N anterior tibial load at 35° (full extension), 60° and 90° of knee flexionand (2) 5 N m valgus tibial moment at 35° and 45° of knee flexion. ATTand graft in situ force of the intact anterior cruciate ligament (ACL) and ACLR were collected using a robotic universal force/moment sensor (UFS) testing system for (1) ACL intact, (2) ACL-deficient (ACLD) and (3) two different ACLR using different sagittal femoral tunnel angles (coronal 45°/sagittal 45° and coronal 45°/sagittal 60°). During the anterior tibial load, the femoral tunnel angle of ACLR knees at coronal 45°/sagittal 45° and 60° had significantly higher ATT than that of the ACL-intact knees at 60° of knee flexion (p < 0.05). The femoral tunnel angle of ACLR knees at coronal 45°/sagittal 60° had significantly lower graft in situ force than that of the ACL-intact knees at 60° and 90° of knee flexion (p < 0.05). During the valgus tibial moment, the femoral tunnel angle of ACLR knees at coronal 45°/sagittal 45° and 60° had significantly lower graft in situ force than that of the ACL-intact knees at all knee flexions (p < 0.05). The femoral tunnel angle of ACLR knees at coronal 45°/sagittal 45° provided similar ATT, valgus angleand graft in situ force to that of ACLR knees at coronal 45°/sagittal 60°. Therefore, both femoral tunnel angles could be used in ACLR, as the sagittal femoral tunnel angle does not appear to be relevant in post-operative knee stability. Not applicable.

Technologically advanced running shoes reduce oxygen cost and cumulative tibial loading per kilometer in recreational female and male runners

Technologically advanced running shoes (TARS) improve performance compared to classical running shoes (CRS). Improved race performance has been attributed to metabolic savings in male runners, but it remains unclear if these same benefits are experienced among females and in recreational runners. The mechanisms behind these benefits are still not fully understood despite the need for optimisation, and their influence on injury mechanisms has not been explored. Here we combined biomechanical, physiological, and modelling approaches to analyse joint mechanics, oxygen uptake, and tibial load in nineteen male and female recreational runners running with CRS and TARS at their individual lactate threshold speed (12.4 ± 1.9 km/h). Oxygen uptake was 3.0 ± 1.5% lower in TARS than in CRS. Ankle dorsiflexion, joint moment and joint power were reduced in TARS compared to CRS at various phases of stance including midstance, while knee joint mechanics were mostly similar throughout. There were no significant differences for tibial bending moment during the stance phase but cumulative tibial damage per kilometre was 12 ± 9% lower in TARS compared to CRS. Our results suggest that running with TARS reduces oxygen cost in recreational female and male runners, which may partly be explained by differences in lower limb joint mechanics. The lower cumulative tibial bone load with TARS may allow runners to run longer distances in this type of shoe compared to CRS.

Advancing Exoskeleton Development: Validation of a Robotic Surrogate to Measure Tibial Strain.

Bone stress injuries are prevalent among athletes and military recruits and can significantly compromise training schedules. The development of an ankle-foot orthosis to reduce tibial load and enable a faster return to activity will require new device testing methodologies capable of capturing the contribution of muscular force on tibial strain. Thus, an actuated robotic surrogate leg was developed to explore how tibial strain changes with different ankle-foot orthosis conditions. The purpose of this work was to assess the reliability, scalability, and behavior of the surrogate. A dual actuation system consisting of a Bowden cable and a vertical load applied to the femur via a material testing system, replicated the action-reaction of the Achilles-soleus complex. Maximum and minimum principal strain, maximum shear strain, and axial strain were measured by instrumented strain gauges at five locations on the tibia. Strains were highly repeatable across tests but did not consistently match in vivo data when scaled. However, the stiffness of the ankle-foot orthosis strut did not systematically affect tibial load, which is consistent with in vivo findings. Future work will involve improving the scalability of the results to match in vivo data and using the surrogate to inform exoskeletal designs for bone stress injuries.

Bone Mechanical Loading Reduces Heart Rate and Increases Heart Rate Variability via the Autonomic Nervous System in Anesthetized Mice

Mechanical loading of bone creates interstitial fluid flow and shear stress within the bone lacunocanalicular system, leading to alterations of bone size and mass. Bone plays an important role as an endocrine organ, releasing endocrine signaling molecules that impact systemic physiology. Further, the central and peripheral nervous systems regulate bone mass in response to strain through alterations in autonomic tone. This suggests the potential for interplay between bone and other organs via endocrine signaling and autonomic innervation. In this study, our group investigated this potential interplay by focusing on bone and heart. We hypothesized that mechanical bone loading of mice in vivo would result in altered cardiac function. To test this hypothesis, we performed acute in vivo mechanical loading on right leg tibias of anesthetized TOPGAL and CD-1 mice. Tibias underwent compressive cyclic loading (a sine wave) that modulates between -0.3N and -9.0N for 300 cycles at 2 Hz. Cardiac function was monitored with lead II electrocardiogram (ECG) data, heart rate (HR), and heart rate variability (HRV). Immediate, transient reduction in resting HR (0.93 ± 0.013 fold change from baseline, n=6-7, p&lt;0.01 compared to control) was achieved during tibial loading in 6-month-old male and female mice, with concurrent increase in HRV (1.24 ± 0.11 fold change from baseline, n=6-7, p&lt;0.01). Both HR and HRV returned to baseline levels upon completion of the loading process. ECG measurements, QRS and corrected QT (QTc), were not found to be altered (p&gt;0.05) during loading and 30 minutes following loading. In further studies, 1N-2N did not produce a decrease in HR, while 3N (0.92 ± 0.077 fold change from baseline, n=12, p&lt;0.05) and 9N (0.93 ± 0.061 fold change from baseline, n=13, p&lt;0.05) decreased HR. There was decreased magnitude and responsiveness with aging to 11 months old at 3N and 9N (p&gt;0.05), suggesting the response may weaken with age. The immediate, transient nature of the changes to resting HR and HRV suggest a neural mechanism for this response. To test this mechanism, we inhibited local neuronal afferent activity by injecting lidocaine (2.5mg/kg) near the tibia prior to loading. In doing so, the decrease in HR during loading was significantly diminished (vehicle 0.90 ± 0.060 vs. lidocaine 0.97 ± 0.042 fold change from baseline, n=7-8, p&lt;0.05). To test the efferent arm of the response, mice were injected with the parasympathetic, muscarinic acetylcholine receptor antagonist atropine (2mg/kg), or the sympathetic, β1/β2 receptor antagonist propranolol (10mg/kg). Propranolol significantly inhibited the HR decrease during loading (vehicle 0.88 ± 0.095 vs. propranolol 0.98 ± 0.026 fold change from baseline, n=7-8, p&lt;0.05), while atropine did not (n=8-11, p&gt;0.05). These findings suggest that reductions in sympathetic tone on the heart during bone loading led to the decrease in HR. In conclusion, this study uncovered a reflexive neural connection between bone and heart that is affected by age and mediated by afferent neurons in the tibia and alterations in efferent sympathetic tone to the heart. These findings provide new knowledge that builds on the current science of bone remodeling and its regulation. This study was funded by HRSA Medical Student Education Grant T99HP39202 and NIH P01AG039355. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Combining raloxifene and mechanical loading improves bone composition and mechanical properties in a murine model of chronic kidney disease (CKD)

IntroductionPatients with chronic kidney disease (CKD) are at an alarming risk of fracture compared to age and sex-matched non-CKD individuals. Clinical and preclinical data highlight two key factors in CKD-induced skeletal fragility: cortical porosity and reduced matrix-level properties including bone hydration. Thus, strategies are needed to address these concerns to improve mechanical properties and ultimately lower fracture risk in CKD. We sought to evaluate the singular and combined effects of mechanical and pharmacological interventions on modulating porosity, bone hydration, and mechanical properties in CKD. MethodsSixteen-week-old male C57BL/6J mice underwent a 10-week CKD induction period via a 0.2 % adenine-laced casein-based diet (n = 48) or remained as non-CKD littermate controls (Con, n = 48). Following disease induction (26 weeks of age), n = 7 CKD and n = 7 Con were sacrificed (baseline cohort) to confirm a steady-state CKD state was achieved prior to the initiation of treatment. At 27 weeks of age, all remaining mice underwent right tibial loading to a maximum tensile strain of 2050 μƐ 3× a week for five weeks with the contralateral limb as a non-loaded control. Half of the mice (equal number CKD and Con) received subcutaneous injections of 0.5 mg/kg raloxifene (RAL) 5× a week, and the other half remained untreated (UN). Mice were sacrificed at 31 weeks of age. Serum biochemistries were performed, and bi-lateral tibiae were assessed for microarchitecture, whole bone and tissue level mechanical properties, and composition including bone hydration. ResultsRegardless of intervention, BUN and PTH were higher in CKD animals throughout the study. In CKD, the combined effects of loading and RAL were quantified as lower cortical porosity and improved mechanical, material, and compositional properties, including higher matrix-bound water. Loading was generally responsible for positive impacts in cortical geometry and structural mechanical properties, while RAL treatment improved some trabecular outcomes and material-level mechanical properties and was responsible for improvements in several compositional parameters. While control animals responded positively to loading, their bones were less impacted by the RAL treatment, showing no deformation, toughness, or bound water improvements which were all evident in CKD. Serum PTH levels were negatively correlated with matrix-bound water. DiscussionAn effective treatment program to improve fracture risk in CKD ideally focuses on the cortical bone and considers both cortical porosity and matrix properties. Loading-induced bone formation and mechanical improvements were observed across groups, and in the CKD cohort, this included lower cortical porosity. This study highlights that RAL treatment superimposed on active bone formation may be ideal for reducing skeletal complications in CKD by forming new bone with enhanced matrix properties.

432 Ligament Engagement and In-Situ Force During Multiplanar Loading of the Medial Knee Ligaments

OBJECTIVES/GOALS: Load sharing across the arc of knee flexion of the medial knee ligaments (MKLs) is not well understood. The goal of this research is to characterize ligament engagement and in-situ force within the deep and superficial medial collateral ligament (dMCL, sMCL) and the posterior oblique ligament (POL) in response to externally applied multiplanar loads. METHODS/STUDY POPULATION: Ten human cadaveric knees, 5 male and 5 female, age 32±7 (25-42) [mean±SD (range min-max)] years, were mounted to a force sensor and a 6-degree-of-freedom robotic arm. Knee kinematics, before and after serial dissection of the sMCL, dMCL, and POL, were recorded from 0-30 degrees during applied isolated external rotation, valgus angulation, and anterior tibial moments, and the force (Newtons, N) borne by each structure was measured via the principle of superposition. Loads in the dMCL, sMCL, and POL will be compared across each knee and at each flexion angle with paired t-tests and repeated-measures analysis of variance with Tukey post hoc testing. Ten knees will provide &gt;99% power to detect differences of 5N ± 3% at p=0.05, which is considered the threshold for clinically meaningful force differences. RESULTS/ANTICIPATED RESULTS: Our anticipated results include characterization of the means and standard deviations of the in-situ forces within the dMCL, sMCL, and POL in response to externally applied valgus angulation, tibial external rotation, and anterior-directed tibial loading at 0, 15, and 30 degrees of knee flexion. Our statistical analysis will determine if there are clinically meaningful differences (5N ± 3%) in the loads within each ligament at different knee flexion angles and will also provide data regarding differential relative ligament engagement for each applied force scenario, which is an indication of the percentage of contribution that each structure contributes to knee stability during application of forces and torques to the knee. DISCUSSION/SIGNIFICANCE: Data on ligament engagement and in-situ forces will help clinicians better diagnose potentially injured ligaments when they observe pathological knee laxity in an injured patient. Our results will also inform future computer modeling studies on injury mechanisms, individual anatomical variability, and surgical planning.

A Comparative Biomechanical Study of Alternative Medial Collateral Ligament Reconstruction Techniques

Background: There is little evidence of the biomechanical performance of medial collateral ligament (MCL) reconstructions for restoring stability to the MCL-deficient knee regarding valgus, external rotation (ER), and anteromedial rotatory instability (AMRI). Hypothesis: A short isometric reconstruction will better restore stability than a longer superficial MCL (sMCL) reconstruction, and an additional deep MCL (dMCL) graft will better control ER and AMRI than single-strand reconstructions. Study Design: Controlled laboratory study. Methods: Nine cadaveric human knees were tested in a kinematics rig that allowed tibial loading while the knee was flexed-extended 0° to 100°. Optical markers were placed on the femur and tibia and displacements were measured using a stereo camera system. The knee was tested intact, and then after MCL (sMCL + dMCL) transection, and loaded in anterior tibial translation (ATT), ER, varus-valgus, and combined ATT + ER (AMRI loading). Five different isometric MCL reconstructions were tested: isolated long sMCL, a short construct, each with and without dMCL addition, and isolated dMCL reconstruction, using an 8 mm–wide synthetic graft. Results: MCL deficiency caused an increase in ER of 4° at 0° of flexion (P = .271) up to 14° at 100° of flexion (P = .002), and valgus laxity increased by 5° to 8° between 0° and 100° of flexion (P < .024 at 0°-90°). ATT did not increase significantly in isolated MCL deficiency (P > .999). All 5 reconstructions restored native stability across the arc of flexion apart from the isolated long sMCL, which demonstrated residual ER instability (P≤ .047 vs other reconstructions). Conclusion: All tested techniques apart from the isolated long sMCL graft are satisfactory in the context of restoring the valgus, ER, and AMRI stability to the MCL-deficient knee in a cadaveric model. Clinical Relevance: Contemporary MCL reconstruction techniques fail to control ER and therefore AMRI as they use a long sMCL graft and do not address the dMCL. This study compares 5 MCL reconstruction techniques. Both long and short isometric constructs other than the long sMCL achieved native stability in valgus and ER/AMRI. Double-strand reconstructions (sMCL + dMCL) tended to provide more stability. This study shows which reconstructions demonstrate the best biomechanical performance, informs surgical reconstruction techniques for AMRI, and questions the efficacy of current popular techniques.

Anterior cruciate ligament injury should not be considered a contraindication for medial unicompartmental knee arthroplasty: Finite element analysis.

The research objective of this study is to use finite element analysis to investigate the impact of anterior cruciate ligament (ACL) injury on medial unicompartmental knee arthroplasty (UKA) and explore whether patients with ACL injuries can undergo UKA. Based on the morphology of the ACL, models of ACL with diameters ranging from 1 to 10mm are created. Finite element models of UKA include ACL absence and ACLs with different diameters. After creating a complete finite element model and validating it, four different types of loads are applied to the knee joint. Statistical analysis is conducted to assess the stress variations in the knee joint structure. A total of 11 finite element models of UKA were established. Regarding the stress on the ACL, as the diameter of the ACL increased, when a vertical load of 750N was applied to the femur, combined with an anterior tibial load of 105N, the stress on the ACL increased from 2.61 MPa to 4.62 MPa, representing a 77.05% increase. Regarding the equivalent stress on the polyethylene gasket, a notable high stress change was observed. The stress on the gasket remained between 12.68 MPa and 14.33 MPa in all models. the stress on the gasket demonstrated a decreasing trend. The equivalent stress in the lateral meniscus and lateral femoral cartilage decreases, reducing from the maximum stress of 4.71 MPa to 2.61 MPa, with a mean value of 3.73 MPa. This represents a reduction of 44.72%, and the statistical significance is (P < 0.05). However, under the other three loads, there was no significant statistical significance (P > 0.05). This study suggests that the integrity of the ACL plays a protective role in performing medial UKA. However, this protective effect is limited when performing medial UKA. When the knee joint only has varying degrees of ACL injury, even ACL rupture, and the remaining structures of the knee joint are intact with anterior-posterior stability in the knee joint, it should not be considered a contraindication for medial UKA.

Targeting an inflammation-amplifying cell population can attenuate osteoarthritis-associated pain

BackgroundUnderstanding of pain in osteoarthritis, its genesis, and perception is still in its early stages. Identification of precise ligand-receptor pairs that transduce pain and the cells and tissues in which they reside will elucidate new therapeutic approaches for pain management. Our recent studies had identified an inflammation-amplifying (Inf-A) cell population that is expanded in human OA cartilage and is distinctive in the expression of both IL1R1 and TNF-R2 receptors and active Jnk signaling cascade.MethodsIn this study, we have tested the function of the cartilage-resident IL1R1+TNF-R2+ Inf-A cells in OA. We have identified that the IL1R1+TNF-R2+ Inf-A cells expand in aged mice as well as after anterior cruciate ligament tear upon tibia loading and OA initiation in mice. We targeted and modulated the Jnk signaling cascade in InfA through competitive inhibition of Jnk signaling in mice and human OA explants and tested the effects on joint structure and gait in mice.ResultsModulation of Jnk signaling led to attenuation of inflammatory cytokines CCL2 and CCL7 without showing any structural improvements in the joint architecture. Interestingly, Jnk inhibition and lowered CCL2 and 7 are sufficient to significantly improve the gait parameters in treated PTOA mice demonstrating reduced OA-associated pain. Consistent with the mice data, treatment with JNK inhibitor did not improve human OA cartilage explants.ConclusionThese studies demonstrate that Inf-A, an articular-cartilage resident cell population, contributes to pain in OA via secretion of CCL2 and 7 and can be targeted via inhibition of Jnk signaling.

The loading direction dramatically affects the mechanical properties of the mouse tibia.

Introduction: The in vivo tibial loading mouse model has been extensively used to evaluate bone adaptation in the tibia after mechanical loading treatment. However, there is a prevailing assumption that the load is applied axially to the tibia. The aim of this in silico study was to evaluate how much the apparent mechanical properties of the mouse tibia are affected by the loading direction, by using a validated micro-finite element (micro-FE) model of mice which have been ovariectomized and exposed to external mechanical loading over a two-week period. Methods: Longitudinal micro-computed tomography (micro-CT) images were taken of the tibiae of eleven ovariectomized mice at ages 18 and 20weeks. Six of the mice underwent a mechanical loading treatment at age 19weeks. Micro-FE models were generated, based on the segmented micro-CT images. Three models using unitary loads were linearly combined to simulate a range of loading directions, generated as a function of the angle from the inferior-superior axis (θ, 0°-30° range, 5° steps) and the angle from the anterior-posterior axis (ϕ, 0°: anterior axis, positive anticlockwise, 0°-355° range, 5° steps). The minimum principal strain was calculated and used to estimate the failure load, by linearly scaling the strain until 10% of the nodes reached the critical strain level of -14,420με. The apparent bone stiffness was calculated as the ratio between the axial applied force and the average displacement along the longitudinal direction, for the loaded nodes. Results: The results demonstrated a high sensitivity of the mouse tibia to the loading direction across all groups and time points. Higher failure loads were found for several loading directions (θ = 10°, ϕ 205°-210°) than for the nominal axial case (θ = 0°, ϕ = 0°), highlighting adaptation of the bone for loading directions far from the nominal axial one. Conclusion: These results suggest that in studies which use mouse tibia, the loading direction can significantly impact the failure load. Thus, the magnitude and direction of the applied load should be well controlled during the experiments.

Combining PTH(1-34) and mechanical loading has increased benefit to tibia bone mechanics in ovariectomised mice.

Combined treatment with PTH(1-34) and mechanical loading confers increased structural benefits to bone than monotherapies. However, it remains unclear how this longitudinal adaptation affects the bone mechanics. This study quantified the individual and combined longitudinal effects of PTH(1-34) and mechanical loading on the bone stiffness and strength evaluated in vivo with validated micro-finite element (microFE) models. C57BL/6 mice were ovariectomised at 14-week-old and treated either with injections of PTH(1-34), compressive tibia loading or both interventions concurrently. Right tibiae were in vivo microCT-scanned every 2 weeks from 14 until 24-week-old. MicroCT images were rigidly registered to reference tibia and the cortical organ level (whole bone) and tissue level (midshaft) morphometric properties and bone mineral content were quantified. MicroCT images were converted into voxel-based homogeneous, linear elastic microFE models to estimate the bone stiffness and strength. This approach allowed us for the first time to quantify the longitudinal changes in mechanical properties induced by combined treatments in a model of accelerated bone resorption. Both changes of stiffness and strength were higher with co-treatment than with individual therapies, consistent with increased benefits with the tibia bone mineral content and cortical area, properties strongly associated with the tibia mechanics. The longitudinal data shows that the two bone anabolics, both individually and combined, had persistent benefit on estimated mechanical properties, and that benefits (increased stiffness and strength) remained after treatment was withdrawn.