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Many metabolic bone diseases arise as a result excessive osteoclastic bone resorption, which has motivated efforts to identify new molecular targets that can inhibit the formation or activity of these bone-resorbing cells. Mounting evidence indicates that the transcription factor Runx1 acts as a transcriptional repressor of osteoclast formation. Prior studies using a conditional knockout approach suggested that Runx1 in osteoclast precursors acts as an inhibitor of osteoclastogenesis; however, the effects of upregulation of Runx1 on osteoclast formation remain unknown. In this study, we investigated the skeletal effects of conditional overexpression of Runx1 in preosteoclasts by crossing novel Runx1 gain-of-function mice (Rosa26-LSL-Runx1) with LysM-Cre transgenic mice. We observed a sex-dependent effect whereby overexpression of Runx1 in female mice increased trabecular bone microarchitectural indices and improved torsion biomechanical properties. These effects were likely mediated by delayed osteoclastogenesis and decreased bone resorption. Transcriptomics analyses during osteoclastogenesis revealed a distinct transcriptomic profile in the Runx1-overexpressing cells, with enrichment of genes related to redox signaling, apoptosis, osteoclast differentiation, and bone remodeling. These data further confirm the antiosteoclastogenic activities of Runx1 and provide new insight into the molecular targets that may mediate these effects.

Background: Graft placement is a modifiable and often discussed surgical factor in anterior cruciate ligament (ACL) reconstruction (ACLR). However, the sensitivity of functional knee mechanics to variability in graft placement is not well understood. Purpose: To (1) investigate the relationship of ACL graft tunnel location and graft angle with tibiofemoral kinematics in patients with ACLR, (2) compare experimentally measured relationships with those observed with a computational model to assess the predictive capabilities of the model, and (3) use the computational model to determine the effect of varying ACL graft tunnel placement on tibiofemoral joint mechanics during walking. Study Design: Controlled laboratory study. Methods: Eighteen participants who had undergone ACLR were tested. Bilateral ACL footprint location and graft angle were assessed using magnetic resonance imaging (MRI). Bilateral knee laxity was assessed at the completion of rehabilitation. Dynamic MRI was used to measure tibiofemoral kinematics and cartilage contact during active knee flexion-extension. Additionally, a total of 500 virtual ACLR models were created from a nominal computational knee model by varying ACL footprint locations, graft stiffness, and initial tension. Laxity tests, active knee extension, and walking were simulated with each virtual ACLR model. Linear regressions were performed between internal knee mechanics and ACL graft tunnel locations and angles for the patients with ACLR and the virtual ACLR models. Results: Static and dynamic MRI revealed that a more vertical graft in the sagittal plane was significantly related ( P < .05) to a greater laxity compliance index ( R2 = 0.40) and greater anterior tibial translation and internal tibial rotation during active knee extension ( R2 = 0.22 and 0.23, respectively). Similarly, knee extension simulations with the virtual ACLR models revealed that a more vertical graft led to greater laxity compliance index, anterior translation, and internal rotation ( R2 = 0.56, 0.26, and 0.13). These effects extended to simulations of walking, with a more vertical ACL graft inducing greater anterior tibial translation, ACL loading, and posterior migration of contact on the tibial plateaus. Conclusion: This study provides clinical evidence from patients who underwent ACLR and from complementary modeling that functional postoperative knee mechanics are sensitive to graft tunnel locations and graft angle. Of the factors studied, the sagittal angle of the ACL was particularly influential on knee mechanics. Clinical Relevance: Early-onset osteoarthritis from altered cartilage loading after ACLR is common. This study shows that postoperative cartilage loading is sensitive to graft angle. Therefore, variability in graft tunnel placement resulting in small deviations from the anatomic ACL angle might contribute to the elevated risk of osteoarthritis after ACLR.

The spatial heterogeneity in trabecular bone density within the vertebral centrum is associated with vertebral strength and could explain why volumetric bone mineral density (vBMD) exhibits low sensitivity in identifying fracture risk. This study evaluated whether the heterogeneity and spatial distribution of trabecular vBMD are associated with prevalent vertebral fracture. We examined the volumetric quantitative computed tomography (QCT) scans of the L3 vertebra in 148 participants in the Framingham Heart Study Multidetector CT study. Of these individuals, 37 were identified as cases of prevalent fracture, and 111 were controls, matched on sex and age with three controls per case. vBMD was calculated within 5-mm contiguous cubic regions of the centrum. Two measures of heterogeneity were calculated: (i) interquartile range (IQR); and (ii) quartile coefficient of variation (QCV). Ratios in the spatial distributions of the trabecular vBMD were also calculated: anterior/posterior, central/outer, superior/mid-transverse, and inferior/mid-transverse. Heterogeneity and spatial distributions were compared between cases and controls using Wilcoxon rank sum tests and t tests and tested for association with prevalent fractures with conditional logistic regressions independent of integral vBMD. Prevalent fracture cases had lower mean ± SD integral vBMD (134 ± 38 versus165 ± 42 mg/cm3 , p < .001), higher QCV (0.22 ± 0.13 versus 0.17 ± 0.09, p = .003), and lower anterior/posterior rBMD (0.65 ± 0.13 versus 0.78 ± 0.16, p < .001) than controls. QCV was positively associated with increased odds of prevalent fracture (OR 1.61; 95% CI, 1.04 to 2.49; p = .034), but this association was not independent of integral vBMD (p = .598). Increased anterior/posterior trabecular vBMD ratio was associated with decreased odds of prevalent fracture independent of integral vBMD (OR 0.38; 95% CI, 0.20 to 0.71; p = .003). In conclusion, increased trabecular vBMD in the anterior versus posterior centrum, but not trabecular vBMD heterogeneity, was associated with decreased risk of prevalent fracture independent of integral vBMD. Regional measurements of trabecular vBMD could aid in determining the risk and underlying mechanisms of vertebral fracture. © 2019 American Society for Bone and Mineral Research.

Significance: Changes in interstitial fluid clearance are implicated in many diseases. Using near-infrared (NIR) imaging with properly sized tracers could enhance our understanding of how venous and lymphatic drainage are involved in disease progression or enhance drug delivery strategies. Aim: We investigated multichromatic NIR imaging with multiple tracers to assess in vivo microvascular clearance kinetics and pathways in different tissue spaces. Approach: We used a chemically inert IR Dye 800CW (D800) to target venous capillaries and a purified conjugate of IR dye 680RD with 40 kDa PEG (P40D680) to target lymphatic capillaries in vivo. Optical imaging settings were validated and tuned in vitro using tissue phantoms. We investigated multichromatic NIR imaging’s utility in two in vivo tissue beds: the mouse tail and rat knee joint. We then tested the ability of the approach to detect interstitial fluid perturbations due to exercise. Results: In an in vitro simulated tissue environment, free dye and PEG mixture allowed for simultaneous detection without interference. In the mouse tail, co-injected NIR tracers cleared from the interstitial space via distinct routes, suggestive of lymphatic and venous uptake mechanisms. In the rat knee, we determined that exercise after injection transiently increased lymphatic drainage as measured by lower normalized intensity immediately after exercise, whereas exercise pre-injection exhibited a transient delay in clearance from the joint. Conclusions: NIR imaging enables simultaneous imaging of lymphatic and venous-mediated fluid clearance with great sensitivity and can be used to measure temporal changes in clearance rates and pathways.

SignificanceChanges in interstitial fluid clearance are implicated in many diseases. Using NIR imaging with properly sized tracers could enhance our understanding of how venous and lymphatic drainage are involved in disease progression or enhance drug delivery strategies.AimWe investigated multichromatic NIR imaging with multiple tracers to assess in vivo microvascular clearance kinetics and pathways in different tissue spaces.ApproachWe used a chemically inert IR Dye 800CW (free dye) to target venous capillaries and a purified conjugate of IR Dye 680RD with a 40 kDa PEG (PEG) to target lymphatic capillaries in vivo. Optical imaging settings were validated and tuned in vitro using tissue phantoms. We investigated multichromatic NIR imaging’s utility in two in vivo tissue beds – the mouse tail and rat knee joint. We then tested the ability of the approach to detect interstitial fluid perturbations due to exercise.ResultsIn an in vitro simulated tissue environment, free dye and PEG mixture allowed for simultaneous detection without interference. Co-injected NIR tracers cleared from the interstitial space via distinct routes allowed assessment lymphatic and venous uptake in the mouse tail. We determined that exercise after injection transiently increased lymphatic drainage as measured by lower normalized intensity immediately after exercise, while exercise pre-injection exhibited a transient delay in clearance from the jointConclusionsNIR imaging enables of simultaneous imaging of lymphatic and venous-mediated fluid clearance with great sensitivity and can be used to measure transient changes in clearance rates and pathways.

Current strategies for regeneration of large bone fractures yield limited clinical success mainly due to poor integration and healing. Multidisciplinary approaches in design and development of functional tissue engineered scaffolds are required to overcome these translational challenges. Here, a new generation of hyperelastic bone (HB) implants, loaded with superparamagnetic iron oxide nanoparticles (SPIONs), are 3D bioprinted and their regenerative effect on large non-healing bone fractures is studied. Scaffolds are bioprinted with the geometry that closely correspond to that of the bone defect, using an osteoconductive, highly elastic, surgically friendly bioink mainly composed of hydroxyapatite. Incorporation of SPIONs into HB bioink results in enhanced bacteriostatic properties of bone grafts while exhibiting no cytotoxicity. In vitro culture of mouse embryonic cells and human osteoblast-like cells remain viable and functional up to 14 days on printed HB scaffolds. Implantation of damage-specific bioprinted constructs into a rat model of femoral bone defect demonstrates significant regenerative effect over the 2-week time course. While no infection, immune rejection, or fibrotic encapsulation is observed, HB grafts show rapid integration with host tissue, ossification, and growth of new bone. These results suggest a great translational potential for 3D bioprinted HB scaffolds, laden with functional nanoparticles, for hard tissue engineering applications.

Purpose: Mechanical loading of bone defects through rehabilitation is a promising approach to stimulate repair and reduce nonunion risk; however, little is known about how therapeutic mechanical stimuli modulate early-stage repair before mineralized bone formation. The objective of this study was to investigate the early effects of osteogenic loading on cytokine expression and angiogenesis during the first 3 weeks of BMP-2 mediated segmental bone defect repair. Materials and Methods: A rat model of BMP-2 mediated bone defect repair was subjected to an osteogenic mechanical loading protocol using ambulatory rehabilitation and a compliant, load-sharing fixator with an integrated implantable strain sensor. The effect of fixator load-sharing on local tissue strain, angiogenesis, and cytokine expression was evaluated. Results: Using sensor readings for local measurements of boundary conditions, finite element simulations showed strain became amplified in remaining soft tissue regions between 1 and 3 weeks (Week 3: load-sharing: ���1.89 �� 0.35% and load-shielded: ���1.38 �� 0.35% vs. Week 1: load-sharing: ���1.54 �� 0.17%; load-shielded: ���0.76 �� 0.06%). Multivariate analysis of cytokine arrays revealed that load-sharing significantly altered expression profiles in the defect tissue at 2 weeks compared to load-shielded defects. Specifically, loading reduced VEGF (p = 0.052) and increased CXCL5 (LIX) levels. Subsequently, vascular volume in loaded defects was reduced relative to load-shielded defects but similar to intact bone at 3 weeks. Endochondral bone repair was also observed histologically in loaded defects at 3 weeks. Conclusions: Together, these results demonstrate that moderate ambulatory strains previously shown to stimulate bone regeneration significantly alter early angiogenic and cytokine signaling and may promote endochondral ossification.

Mechanical loads exerted on the skeleton during activities such as walking are important regulators of bone repair, but dynamic biomechanical signals are difficult to measure inside the body. The inability to measure the mechanical environment in injured tissues is a significant barrier to developing integrative regenerative and rehabilitative strategies that can accelerate recovery from fracture, segmental bone loss, and spinal fusion. Here we engineered an implantable strain sensor platform and longitudinally measured strain across a bone defect in real-time throughout rehabilitation. The results showed that load-sharing permitted by a load-sharing fixator initially delivered a two-fold increase in deformation magnitude, subsequently increased mineralized bridging by nearly three-fold, and increased bone formation by over 60%. These data implicate a critical role for early mechanical cues on the long term healing response as strain cycle magnitude at 1 week (before appreciable healing occurred) had a significant positive correlation with the long-term bone regeneration outcomes. Furthermore, we found that sensor readings correlated with the status of healing, suggesting a role for strain sensing as an X-ray-free healing assessment platform. Therefore, non-invasive strain measurements may possess diagnostic potential to evaluate bone repair and reduce clinical reliance on current radiation-emitting imaging methods. Together, this study demonstrates a promising framework to quantitatively develop and exploit mechanical rehabilitation strategies that enhance bone repair.

Mechanical loads exerted on the skeleton during activities such as walking are important regulators of bone repair, but dynamic biomechanical signals are difficult to measure inside the body. The inability to measure the mechanical environment in injured tissues is a significant barrier to developing integrative regenerative and rehabilitative strategies that can accelerate recovery from fracture, segmental bone loss, and spinal fusion. Here we engineered an implantable strain sensor platform and measured strain across a bone defect in real-time throughout rehabilitation. We used the sensor to longitudinally quantify mechanical cues imparted by a load-sharing fixation plate that significantly enhanced bone regeneration in rats. We found that sensor readings correlated with the status of healing, suggesting a potential role for strain sensing as an X-ray-free healing assessment platform. This study demonstrates a promising approach to quantitatively develop and exploit mechanical rehabilitation strategies that enhance bone repair.

The accepted mechanism explaining the accelerated growth following periosteal resection is that the periosteum serves as a mechanical restraint to restrict physeal growth. To test the veracity of this mechanism we first utilized Second Harmonic Generation (SHG) imaging to measure differences of periosteal fiber alignment at various strains. Additionally, we measured changes in periosteal growth factor transcription. Next we utilized SHG imaging to assess the alignment of the periosteal fibers on the bone both before and after periosteal resection. Based on the currently accepted mechanism, we hypothesized that the periosteal fibers adjacent to the physis should be more aligned (under tension) during growth and become less aligned (more relaxed) following metaphyseal periosteal resection. In addition, we measured the changes in periosteal micro- and macro-scale mechanics.30 seven-week old New Zealand White rabbits were sacrificed. The periosteum was imaged on the bone at five regions using SHG imaging. One centimeter periosteal resections were then performed at the proximal tibial metaphyses. The resected periosteal strips were stretched to different strains in a materials testing system (MTS), fixed, and imaged using SHG microscopy. Collagen fiber alignment at each strain was then determined computationally using CurveAlign. In addition, periosteal strips underwent biomechanical testing in both circumferential and axial directions to determine modulus, failure stress, and failure strain. Relative mRNA expression of growth factors: TGFβ-1, -2, -3, Ihh, PTHrP, Gli, and Patched were measured following loading of the periosteal strips at physiological strains in a bioreactor. The periosteum adjacent to the physis of six tibiae was imaged on the bone, before and after, metaphyseal periosteal resection, and fiber alignment was computed. One-way ANOVA statistics were performed on all data.Imaging of the periosteum at different regions of the bone demonstrated complex regional differences in fiber orientation. Increasing periosteal strain on the resected strips increased periosteal fiber alignment (p0.0001). The only exception to this pattern was the 10% strain on the tibial periosteum, which may indicate fiber rupture at this non-physiologic strain. Periosteal fiber alignment adjacent to the resection became less aligned while those adjacent to the physes remained relatively unchanged before and after periosteal resection. Increasing periosteal strain on the resected strips increased periosteal fiber alignment (p0.0001). The only exception to this pattern was the 10% strain on the tibial periosteum, which may indicate fiber rupture (and consequent retraction) at this non-physiologic strain. Increasing periosteal strain revealed a significant increase in relative mRNA expression for Ihh, PTHrP, Gli, and Patched, respectively.Periosteal fibers adjacent to the growth plate do not appear under tension in the growing limb, and the alignments of these fibers remain unchanged following periosteal resection.The results of this study call into question the long-accepted role of the periosteum acting as a simple mechanical tether restricting growth at the physis.

Background The pathogenesis of osteoarthritis following anterior cruciate ligament (ACL) reconstruction is currently unknown. The study purpose was to leverage recent advances in quantitative and dynamic MRI to test the hypothesis that abnormal joint mechanics within four years of reconstruction is accompanied by evidence of early compositional changes in cartilage. Methods Static MR imaging was performed bilaterally on eleven subjects with an ACL reconstruction (1–4 years post-surgery) and on twelve healthy subjects to obtain tibial cartilage thickness maps. Quantitative imaging (mcDESPOT) was performed unilaterally on all subjects to assess the fraction of bound water in the tibial plateau cartilage. Finally, volumetric dynamic imaging was performed to assess cartilage contact patterns during an active knee flexion–extension task. A repeated-measures ANOVA was used to test for the effects of surgical reconstruction and location on cartilage thickness, bound water fractions, and contact across the medial and lateral tibia plateaus. Findings No significant differences in cartilage thickness were found between groups. However, there was a significant reduction in the fraction of water bound by proteoglycan in the ACL reconstructed knees, most notably along the anterior portion of the medial plateau and the weight-bearing lateral plateau. During movement, reconstructed knees exhibited greater contact along the medial spine in the medial plateau and along the posterior aspect of the lateral plateau, when compared with their healthy contralateral knees and healthy controls. Interpretation This study provides evidence that abnormal mechanics in anterior cruciate ligament reconstructed knees are present coincidently with early biomarkers of cartilage degeneration.

The distribution of bone tissue within the vertebra can modulate vertebral strength independently of average density and may change with age and disc degeneration. Our results show that the age-associated decrease in bone density is spatially non-uniform and associated with disc health, suggesting a mechanistic interplay between disc and vertebra. While the decline of bone mineral density (BMD) in the aging spine is well established, the extent to which age influences BMD distribution within the vertebra is less clear. Measures of regional BMD (rBMD) may improve predictions of vertebral strength and suggest how vertebrae might adapt with intervertebral disc degeneration. Thus, we aimed to assess how rBMD values were associated with age, sex, and disc height loss (DHL). We measured rBMD in the L3 vertebra of 377 participants from the Framingham Heart Study (41–83 years, 181 M/196 F). Integral (Int.BMD) and trabecular BMD (Tb.BMD) were measured from QCT images. rBMD ratios (anterior/posterior, superior/mid-transverse, inferior/mid-transverse, and central/outer) were calculated from the centrum. A radiologist assigned a DHL severity score to adjacent intervertebral discs (L2–L3 and L3–L4). Int.BMD and Tb.BMD were both associated with age, though the decrease across age was greater in women (Int.BMD, − 2.6 mg/cm3 per year; Tb.BMD, − 2.6 mg/cm3 per year) than men (Int.BMD, − 0.5 mg/cm3 per year; Tb.BMD, − 1.2 mg/cm3 per year). The central/outer (− 0.027/decade) and superior/mid-transverse (− 0.018/decade) rBMD ratios were negatively associated with age, with similar trends in men and women. Higher Int.BMD or Tb.BMD was associated with increased odds of DHL after adjusting for age and sex. Low central/outer ratio and high anterior/poster and superior/mid-transverse ratios were also associated with increased odds of DHL. Our results indicate that the distribution of bone within the L3 vertebra is different across age, but not between sexes, and is associated with disc degeneration.

Background Abnormal knee mechanics may contribute to early cartilage degeneration following anterior cruciate ligament reconstruction. Anterior cruciate ligament graft geometry has previously been linked to abnormal tibiofemoral kinematics, suggesting this parameter may be important in restoring normative cartilage loading. However, the relationship between graft geometry and cartilage contact is unknown. Methods Static MR images were collected and segmented for eighteen subjects to obtain bone, cartilage, and anterior cruciate ligament geometries for their reconstructed and contralateral knees. The footprint locations and orientation of the anterior cruciate ligament were calculated. Volumetric, dynamic MR imaging was also performed to measure tibiofemoral kinematics, cartilage contact location, and contact sliding velocity while subjects performed loaded knee flexion-extension. Multiple linear regression was used to determine the relationship between non-anatomic graft geometry and asymmetric knee mechanics. Findings Non-anatomic graft geometry was related to asymmetric knee mechanics, with the sagittal plane graft angle being the best predictor of asymmetry. A more vertical sagittal graft angle was associated with greater anterior tibial translation (β = 0.11 mm deg , P = 0.049, R2 = 0.22), internal tibial rotation (β = 0.27 deg deg , P = 0.042, R2 = 0.23), and adduction angle (β = 0.15 deg deg , P = 0.013, R2 = 0.44) at peak knee flexion. A non-anatomic sagittal graft orientation was also linked to asymmetries in tibial contact location and sliding velocity on the medial (β = −4.2 mm s deg , P = 0.002, R2 = 0.58) and lateral tibial plateaus (β = 5.7 mm s deg , P = 0.006, R2 = 0.54). Interpretation This study provides evidence that non-anatomic graft geometry is linked to asymmetric knee mechanics, suggesting that restoring native anterior cruciate ligament geometry may be important to mitigate the risk of early cartilage degeneration in these patients.

Interventions used to treat patellofemoral pain in runners are often designed to alter patellofemoral mechanics. This study used a computational model to investigate the influence of two interventions, step rate manipulation and quadriceps strengthening, on patellofemoral contact pressures during running. Running mechanics were analyzed using a lower extremity musculoskeletal model that included a knee with six degree-of-freedom tibiofemoral and patellofemoral joints. An elastic foundation model was used to compute articular contact pressures. The lower extremity model was scaled to anthropometric dimensions of 22 healthy adults, who ran on an instrumented treadmill at 90%, 100% and 110% of their preferred step rate. Numerical optimization was then used to predict the muscle forces, secondary tibiofemoral kinematics and all patellofemoral kinematics that would generate the measured primary hip, knee and ankle joint accelerations. Mean and peak patella contact pressures reached 5.0 and 9.7MPa during the midstance phase of running. Increasing step rate by 10% significantly reduced mean contact pressures by 10.4% and contact area by 7.4%, but had small effects on lateral patellar translation and tilt. Enhancing vastus medialis strength did not substantially affect pressure magnitudes or lateral patellar translation, but did shift contact pressure medially toward the patellar median ridge. Thus, the model suggests that step rate tends to primarily modulate the magnitude of contact pressure and contact area, while vastus medialis strengthening has the potential to alter mediolateral pressure locations. These results are relevant to consider in the design of interventions used to prevent or treat patellofemoral pain in runners.

Background: Although knees that have undergone anterior cruciate ligament reconstruction (ACLR) often exhibit normal laxity on clinical examination, abnormal kinematic patterns have been observed when the joint is dynamically loaded during whole body activity. This study investigated whether abnormal knee kinematics arise with loading under isolated dynamic movements. Hypothesis: Tibiofemoral and patellofemoral kinematics of ACLR knees will be similar to those of the contralateral uninjured control knee during passive flexion-extension, with bilateral differences emerging when an inertial load is applied. Study Design: Controlled laboratory study. Methods: The bilateral knees of 18 subjects who had undergone unilateral ACLR within the past 4 years were imaged by use of magnetic resonance imaging (MRI). Their knees were cyclically (0.5 Hz) flexed passively. Subjects then actively flexed and extended their knees against an inertial load that induced stretch-shortening quadriceps contractions, as seen during the load acceptance phase of gait. A dynamic, volumetric, MRI sequence was used to track tibiofemoral and patellofemoral kinematics through 6 degrees of freedom. A repeated-measures analysis of variance was used to compare secondary tibiofemoral and patellofemoral kinematics between ACLR and healthy contralateral knees during the passive and active extension phases of the cyclic motion. Results: Relative to the passive motion, inertial loading induced significant shifts in anterior and superior tibial translation, internal tibial rotation, and all patellofemoral degrees of freedom. As hypothesized, tibiofemoral and patellofemoral kinematics were bilaterally symmetric during the passive condition. However, inertial loading induced bilateral differences, with the ACLR knees exhibiting a significant shift toward external tibial rotation. A trend toward greater medial and anterior tibial translation was seen in the ACLR knees. Conclusion: This study demonstrates that abnormal knee kinematic patterns in ACLR knees emerge during a simple, active knee flexion-extension task that can be performed in an MRI scanner. Clinical Relevance: It is hypothesized that abnormal knee kinematics may alter cartilage loading patterns and thereby contribute to increased risk for osteoarthritis. Recent advances in quantitative MRI can be used to detect early cartilage degeneration in ACLR knees. This study demonstrates the feasibility of identifying abnormal ACLR kinematics by use of dynamic MRI, supporting the combined use of dynamic and quantitative MRI to investigate the proposed link between knee motion, cartilage contact, and early biomarkers of cartilage degeneration.

The purpose of this study was to determine the accuracy of knee kinematics and cartilage contact measured by volumetric dynamic MRI. A motor-actuated phantom drove femoral and tibial bone segments through cyclic, 3D motion patterns. Volumetric images were continuously acquired using a 3D radially undersampled cine spoiled gradient echo sequence (SPGR-VIPR). Image data was binned based on position measured via MRI-compatible rotary encoder. High-resolution static images were segmented to create bone models. Model-based tracking was performed by optimally registering the bone models to the volumetric images at each frame of the SPGR-VIPR series. 3D tibiofemoral translations and orientations were reconstructed, and compared to kinematics obtained by tracking fiducial markers. Imaging was repeated on a healthy subject who performed cyclic knee flexion-extension. Cartilage contact for the subject was assessed by measuring the overlap between articular cartilage surfaces. Model-based tracking was able to track tibiofemoral angles and translations with precisions less than 0.8° and 0.5 mm. These precisions resulted in an uncertainty of less than 0.5 mm in cartilage contact location. Dynamic SPGR-VIPR imaging can accurately assess in vivo knee kinematics and cartilage contact during voluntary knee motion performed in a MRI scanner. This technology could facilitate the quantitative investigation of links between joint mechanics and the development of osteoarthritis.

Objectives: Osteoarthritis (OA) is common following ACL-reconstructive (ACLR) surgery (6). The cause of early OA is not understood, but theories have focused on osteochondral damage at the time of injury (2) and abnormal joint mechanics following surgical repair (7). In this study, we investigate the inter-relationship of cartilage mechanics and biomarkers of OA in both ACL-deficient (ACLD) and ACLR knees. Our approach employs a novel dynamic MR sequence to measure joint mechanics (3) and the recently developed mcDESPOT to assess regional variations in water bound to proteoglycan (PG) (5). We hypothesize that bound water will be diminished in the cartilage of ACLD knees and, after surgery, will continue to adapt in a manner that reflects altered cartilage loading. This abstract presents initial observations on a cross-section of healthy, ACLD and ACLR knees. Methods: The dominant knees of 8 healthy controls, ACLD knees of 5 patients and ACLR knees of 8 patients were imaged in a 3 T MRI scanner (Table). Controls had no history of pain, injury, or surgery to their knee. Patients had no additional ligament injury and no meniscal damage. ACLD subjects were imaged prior to reconstructive surgery. Femoral and tibial cartilage were segmented from MR images and cartilage thickness was calculated. The mcDESPOT sequence provided a fraction map of water bound to PG (Fpg). Subjects flexed their knee against an inertial load at 0.5 Hz, while a SPGR-VIPR sequence continuously acquired volumetric data. Kinematics were obtained using model tracking of the dynamic images (3). Cartilage was registered to the bone segments for all frames, and contact patterns were characterized by the proximity between surfaces. Spatial representations of tibial cartilage contact, thickness and Fpg were co-registered for each subject. Results: Our initial images suggest lower Fpg values in ACLD knees, primarily on the posterior-lateral tibia. This is also observed in ACLR knees, with additional evidence of diminished Fpg on the weight-bearing medial tibia. Contact patterns were altered in both groups. ACLD tended to exhibit increased contact on the posterior lateral tibia and anterior contact in the medial tibia. Contact differences in the ACLR knees were more subtle, but tended to show a posterior-lateral shift on the medial tibia when compared to control knees (Figure). These initial observations support our hypotheses that cartilage composition may be altered in ACLD knees and continues to adapt following ACLR. While contact in ACLR knees appears to be restored close to the healthy condition, we observed a residual shift in the medial plateau. Interestingly, this shift corresponds with a decrease in PG content not observed in ACLD knees. Loss of PG occurs early in OA, prior to any morphological changes (1, 4). Decreased PG content was also observed in ACLD and ACLR knees in the posterio-lateral tibia, consistent with observations of edema and cartilage damage following an ACL injury (2). Conclusion: Initial observations of our novel dynamic and quantitative MR images suggests altered cartilage composition due to both injury and abnormal mechanics following surgical repair.

The study objective was to investigate the influence of coronal plane alignment and ligament properties on total knee replacement (TKR) contact loads during walking. We created a subject-specific knee model of an 83-year-old male who had an instrumented TKR. The knee model was incorporated into a lower extremity musculoskeletal model and included deformable contact, ligamentous structures, and six degrees-of-freedom (DOF) tibiofemoral and patellofemoral joints. A novel numerical optimization technique was used to simultaneously predict muscle forces, secondary knee kinematics, ligament forces, and joint contact pressures from standard gait analysis data collected on the subject. The nominal knee model predictions of medial, lateral, and total contact forces during gait agreed well with TKR measures, with root-mean-square (rms) errors of 0.23, 0.22, and 0.33 body weight (BW), respectively. Coronal plane component alignment did not affect total knee contact loads, but did alter the medial–lateral load distribution, with 4 deg varus and 4 deg valgus rotations in component alignment inducing +17% and −23% changes in the first peak medial tibiofemoral contact forces, respectively. A Monte Carlo analysis showed that uncertainties in ligament stiffness and reference strains induce ±0.2 BW uncertainty in tibiofemoral force estimates over the gait cycle. Ligament properties had substantial influence on the TKR load distributions, with the medial collateral ligament and iliotibial band (ITB) properties having the largest effects on medial and lateral compartment loading, respectively. The computational framework provides a viable approach for virtually designing TKR components, considering parametric uncertainty and predicting the effects of joint alignment and soft tissue balancing procedures on TKR function during movement.

This study investigated the use of dynamic, volumetric MRI to measure 3D skeletal motion. Ten healthy subjects were positioned on a MR-compatible knee loading device and instructed to harmonically flex and extend their knee at 0.5 Hz. The device induced active quadriceps loading with knee flexion, similar to the load acceptance phase of gait. Volumetric images were continuously acquired for 5 min using a 3D cine spoiled gradient-echo sequence in conjunction with vastly undersampled isotropic projection reconstruction. Knee angle was simultaneously monitored and used retrospectively to sort images into 60 frames over the motion cycle. High-resolution static knee images were acquired and segmented to create subject-specific models of the femur and tibia. At each time frame, bone positions and orientations were determined by automatically registering the skeletal models to the dynamic images. Three-dimensional tibiofemoral translations and rotations were consistent across healthy subjects. Internal tibia rotations of 7.8 6 3.5 were present with 35.8 6 3.8 of knee flexion, a pattern consistent with knee kinematic measures during walking. We conclude that vastly under-sampled isotropic projection reconstruction imaging is a promising approach for noninvasively measuring 3D joint kinematics, which may be useful for assessing cartilage contact and investigating the causes and treatment of joint abnormalities. Magn Reson Med 69:1310–1316, 2013. V C 2012 Wiley Periodicals, Inc.

The study objective was to construct and validate a subject-specific knee model that can simulate full six degree of freedom tibiofemoral and patellofemoral joint behavior in the context of full body movement. Segmented MR images were used to reconstruct the geometry of 14 ligament bundles and articular cartilage surfaces. The knee was incorporated into a lower extremity musculoskeletal model, which was then used to simulate laxity tests, passive knee flexion, active knee flexion, and human walking. Simulated passive and active knee kinematics were shown to be consistent with subject-specific measures obtained via dynamic MRI. Anterior tibial translation and internal tibial rotation exhibited the greatest variability when uncertainties in ligament properties were considered. When used to simulate walking, the model predicted knee kinematic patterns that differed substantially from passive joint behavior. Predictions of mean knee cartilage contact pressures during normal gait reached 6.2 and 2.8 MPa on the medial tibial plateau and patellar facets, respectively. Thus, the dynamic modeling framework can be used to simulate the interaction of soft tissue loads and cartilage contact during locomotion activities, and therefore provides a basis to simulate the effects of soft tissue injury and surgical treatment on functional knee mechanics.