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Impairment of the human neuromusculoskeletal system can lead to significant mobility limitations and decreased quality of life. Computational models that accurately represent the musculoskeletal systems of individual patients could be used to explore different treatment options and ultimately to optimize clinical outcome. The most significant barrier to model-based treatment design is validation of model-based estimates of in vivo contact and muscle forces. This paper introduces an annual “Grand Challenge Competition to Predict In Vivo Knee Loads” based on a series of comprehensive publicly available in vivo data sets for evaluating musculoskeletal model predictions of contact and muscle forces in the knee. The data sets come from patients implanted with force-measuring tibial prostheses. Following a historical review of musculoskeletal modeling methods used for estimating knee muscle and contact forces, we describe the first two data sets used for the first two competitions and summarize four subsequent data sets to be used for future competitions. These data sets include tibial contact force, video motion, ground reaction, muscle EMG, muscle strength, static and dynamic imaging, and implant geometry data. Competition participants create musculoskeletal models to predict tibial contact forces without having access to the corresponding in vivo measurements, which are not released until after each year’s competition submissions. These blinded predictions provide an unbiased evaluation of the capabilities and limitations of musculoskeletal modeling methods. The paper concludes with a discussion of how these unique data sets can be used by the musculoskeletal modeling research community to improve the estimation of in vivo muscle and contact forces and ultimately to help make musculoskeletal models clinically useful.

SUMMARY Human pluripotent stem cells (hPSCs) are potential sources of cells for modeling disease and development, drug discovery, and regenerative medicine. However, it is important to identify factors that may impact the utility of hPSCs for these applications. In an unbiased analysis of 205 hPSC and 130 somatic samples, we identified hPSC-specific epigenetic and transcriptional aberrations in genes subject to X chromosome inactivation (XCI) and genomic imprinting, which were not corrected during directed differentiation. We also found that specific tissue types were distinguished by unique patterns of DNA hypomethylation, which were recapitulated by DNA demethylation during in vitro directed differentiation. Our results suggest that verification of baseline epigenetic status is critical for hPSC-based disease models in which the observed phenotype depends on proper XCI or imprinting, and that tissue-specific DNA methylation patterns can be accurately modeled during directed differentiation of hPSCs, even in the presence of variations in XCI or imprinting.

Current cartilage tissue engineering strategies cannot as yet fabricate new tissue that is indistinguishable from native cartilage with respect to zonal organization, extracellular matrix composition, and mechanical properties. Integration of implants with surrounding native tissues is crucial for long-term stability and enhanced functionality. In this study, we developed a bioprinting system with simultaneous photopolymerization capable for three-dimensional (3D) cartilage tissue engineering. Poly(ethylene glycol) dimethacrylate (PEGDMA) with human chondrocytes were printed to repair defects in osteochondral plugs (3D biopaper) in layer-by-layer assembly. Compressive modulus of printed PEGDMA was 395.73±80.40 kPa, which was close to the range of the properties of native human articular cartilage. Printed human chondrocytes maintained the initially deposited positions due to simultaneous photopolymerization of surrounded biomaterial scaffold, which is ideal in precise cell distribution for anatomic cartilage engineering. Viability of printed human chondrocytes increased 26% in simultaneous polymerization than polymerized after printing. Printed cartilage implant attached firmly with surrounding tissue and greater proteoglycan deposition was observed at the interface of implant and native cartilage in Safranin-O staining. This is consistent with the enhanced interface failure strength during the culture assessed by push-out testing. Printed cartilage in 3D biopaper had elevated glycosaminoglycan (GAG) content comparing to that without biopaper when normalized to DNA. These observations were consistent with gene expression results. This study indicates the importance of direct cartilage repair and promising anatomic cartilage engineering using 3D bioprinting technology.

ABSTRACT:The external knee adduction torque has been proposed as a surrogate measure for medial compartment load during gait. However, a direct link between these two quantities has not been demonstrated using in vivo measurement of medial compartment load. This study uses in vivo data collected from a single subject with an instrumented knee implant to evaluate this link. The subject performed five different overground gait motions (normal, fast, slow, wide, and toe-out) with simultaneous collection of instrumented implant, video motion, and ground reaction data. For each trial, the knee adduction torque was measured externally while the total axial force applied to the tibial insert was measured internally. Based on data collected from the same subject performing treadmill gait under fluoroscopic motion analysis, a regression equation was developed to calculate medial contact force from the implant load cell measurements. Correlation analyses were performed for the stance phase and entire gait cycle to quantify the relationship between the knee adduction torque and both the medial contact force and the medial to total contact force ratio. When the entire gait cycle was analyzed, R 2 for medial contact force was 0.77 when all gait trials were analyzed together and between 0.69 and 0.93 when each gait trial was analyzed separately (p < 0.001 in all cases). For medial to total force ratio, R 2 was 0.69 for all trials together and between 0.54 and 0.90 for each trial separately (p < 0.001 in all cases). When only the stance phase was analyzed, R 2 values were slightly lower. These results support the hypothesis that the knee adduction torque is highly correlated with medial compartment contact force and medial to total force ratio during gait. ß

Objective Meniscus lesions following trauma or associated with osteoarthritis (OA) have been described, yet meniscus aging has not been systematically analyzed. The objectives of this study were to (i) establish standardized protocols for representative macroscopic and microscopic analysis, (ii) improve existing scoring systems, and (iii) apply these techniques to a large number of human menisci. Design Medial and lateral menisci from 107 human knees were obtained and cut in two different planes (triangle/crossection and transverse/horizontal) in three separate locations (mid portion, anterior and posterior horns). All sections included vascular and avascular regions and were graded for i) surface integrity, ii) cellularity, iii) matrix/fiber organization and collagen alignment, and iv) Safranin-O staining intensity. The cartilage in all knee compartments was also scored. Results The new macroscopic and microscopic grading systems showed high inter-reader and intra-reader intraclass correlation coefficients. The major age-related changes in menisci in joints with no or minimal OA included increased Safranin-O staining intensity, decreased cell density, the appearance of acellular zones, and evidence of mucoid degeneration with some loss of collagen fiber organization. The earliest meniscus changes occurred predominantly along the inner rim. Menisci from OA joints showed severe fibrocartilaginous separation of the matrix, extensive fraying, tears and calcification. Abnormal cell arrangements included decreased cellularity, diffuse hypercellularity along with cellular hypertrophy and abnormal cell clusters. In general, the anterior horns of both medial and lateral menisci were less affected by age and OA. Conclusions New standardized protocols and new validated grading systems allowed us to conduct a more systematic evaluation of changes in aging and OA menisci at a macroscopic and microscopic level. Several meniscus abnormalities appear to be specific to aging in the absence of significant OA. With aging the meniscal surface can be intact but abnormal matrix organization and cellularity was observed within the meniscal substance. The increased Safranin-O staining appears to represent a shift from fibroblastic to chondrocytic phenotype during aging and early degeneration.

With the advantages of high throughput, digital control, and highly accurate placement of cells and biomaterial scaffold to the desired 2D and 3D locations, bioprinting has great potential to develop promising approaches in translational medicine and organ replacement. The most recent advances in organ and tissue bioprinting based on the thermal inkjet printing technology are described in this review. Bioprinting has no or little side effect to the printed mammalian cells and it can conveniently combine with gene transfection or drug delivery to the ejected living systems during the precise placement for tissue construction. With layer-by-layer assembly, 3D tissues with complex structures can be printed using scanned CT or MRI images. Vascular or nerve systems can be enabled simultaneously during the organ construction with digital control. Therefore, bioprinting is the only solution to solve this critical issue in thick and complex tissues fabrication with vascular system. Collectively, bioprinting based on thermal inkjet has great potential and broad applications in tissue engineering and regenerative medicine. This review article introduces some important patents related to bioprinting living systems and the bioprinting in tissue engineering field.

Excessive contact force is believed to contribute to the development of medial compartment knee osteoarthritis. The external knee adduction moment (KAM) has been identified as a surrogate measure for medial contact force during gait, with an abnormally large peak value being linked to increased pain and rate of disease progression. This study used in vivo gait data collected from a subject with a force-measuring knee implant to assess whether KAM decreases accurately predict corresponding decreases in medial contact force. Changes in both quantities generated via gait modification were analyzed statistically relative to the subject's normal gait. The two gait modifications were a ''medial thrust'' gait involving knee medialization during stance phase and a ''walking pole'' gait involving use of bilateral walking poles. Reductions in the first (largest) peak of the KAM (32-33%) did not correspond to reductions in the first peak of the medial contact force. In contrast, reductions in the second peak and angular impulse of the KAM (15-47%) corresponded to reductions in the second peak and impulse of the medial contact force (12-42%). Calculated reductions in both KAM peaks were highly sensitive to rotation of the shank reference frame about the superior-inferior axis of the shank. Both peaks of medial contact force were best predicted by a combination of peak values of the external KAM and peak absolute values of the external knee flexion moment (R 2 ¼ 0.93). Future studies that evaluate the effectiveness of gait modifications for offloading the medial compartment of the knee should consider the combined effect of these two knee moments. ß