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Tissue engineering (TE) combines cells and biomaterials to treat orthopedic pathologies. Maturation of de novo tissue is highly dependent on local mechanical environments. Mechanical stimulation influences stem cell differentiation, however, the role of various mechanical loads remains unclear. While bioreactors simplify the complexity of the human body, the potential combination of mechanical loads that can be applied make it difficult to assess how different factors interact. Human bone marrow-derived mesenchymal stromal cells were seeded within a fibrin-polyurethane scaffold and exposed to joint-mimicking motion. We applied a full factorial design of experiment to investigate the effect that the interaction between different mechanical loading parameters has on biological markers. Additionally, we employed planned contrasts to analyze differences between loading protocols and a linear mixed model with donor as random effect. Our approach enables screening of multiple mechanical loading combinations and identification of significant interactions that could not have been studied using classical mechanobiology studies. This is useful to screen the effect of various loading protocols and could also be used for TE experiments with small sample sizes and further combinatorial medication studies., Scientific Reports, 12 (1), ISSN:2045-2322

Background: This work evaluates the feasibility, development, and validation of a machine learning pipeline that includes all tasks from MRI input to the segmentation and grading of the intervertebral discs in the lumbar spine, offering multiple different radiological gradings of degeneration as quantitative objective output. Methods: The pipelines’ performance was analysed on 1′000 T2-weighted sagittal MRI. Binary outputs were assessed with the harmonic mean of precision and recall (DSC) and the area under the precision-recall curve (AUC-PR). Multi-class output scores were averaged and complemented by the Top-2 categorical accuracy. The processing success rate was evaluated on 10′053 unlabelled MRI scans of lumbar spines. Results: The midsagittal plane selection achieved an DSC of 74,80% ± 2,99% and an AUC-PR score of 81.71% ± 2.72% (96.91% Top-2 categorical accuracy). The segmentation network obtained a DSC of 91.80% ± 0.44%. The Pfirrmann grading of intervertebral discs in the midsagittal plane was classified with a DSC of 64.08% ± 3.29% and an AUC-PR score of 68.25% ± 6.00% (91.65% Top-2 categorical accuracy). Disc herniations achieved a DSC of 61.57% ± 3.39% and an AUC-PR score of 66.86% ± 5.03%. The cranial endplate defects reached a DSC of 49.76% ± 3.45% and 52.36% ± 1.98% AUC-PR (slightly superior predictions of caudal endplate defect). The binary classifications for the caudal Schmorl’s nodes obtained a DSC of 91.58% ± 2.25% with an AUC-PR metric of 96.69% ± 1.58% (similar performance for cranial Schmorl’s nodes). Spondylolisthesis was classified with a DSC of 89.03% ± 2.42% and an AUC-PR score of 95.98% ± 1.82%. Annular Fissures were predicted with a DSC of 78.09% ± 7.21% and an AUC-PR score of 86.31% ± 7.45%. Intervertebral disc classifications in the parasagittal plane achieved an equivalent performance. The pipeline successfully processed 98.53% of the provided sagittal MRI scans. Conclusions: The present deep learning framework has the potential to aid the quantitative evaluation of spinal MRI for an array of clinically established grading systems., Computer Methods and Programs in Biomedicine Update, 2

Augmented reality (AR)-based surgical navigation may offer new possibilities for safe and accurate surgical execution of complex osteotomies. In this study we investigated the feasibility of navigating the periacetabular osteotomy of Ganz (PAO), known as one of the most complex orthopedic interventions, on two cadaveric pelves under realistic operating room conditions. Preoperative planning was conducted on computed tomography (CT)-reconstructed 3D models using an in-house developed software, which allowed creating cutting plane objects for planning of the osteotomies and reorientation of the acetabular fragment. An AR application was developed comprising point-based registration, motion compensation and guidance for osteotomies as well as fragment reorientation. Navigation accuracy was evaluated on CT-reconstructed 3D models, resulting in an error of 10.8 mm for osteotomy starting points and 5.4° for osteotomy directions. The reorientation errors were 6.7°, 7.0° and 0.9° for the x-, y- and z-axis, respectively. Average postoperative error of LCE angle was 4.5°. Our study demonstrated that the AR-based execution of complex osteotomies is feasible. Fragment realignment navigation needs further improvement, although it is more accurate than the state of the art in PAO surgery., Applied Sciences, 11 (3), ISSN:2076-3417

Computer aided orthopedic surgery suffers from low clinical adoption, despite increased accuracy and patient safety. This can partly be attributed to cumbersome and often radiation intensive registration methods. Emerging RGB-D sensors combined with artificial intelligence data-driven methods have the potential to streamline these procedures. However, developing such methods requires vast amount of data. To this end, a multi-modal approach that enables acquisition of large clinical data, tailored to pedicle screw placement, using RGB-D sensors and a co-calibrated high-end optical tracking system was developed. The resulting dataset comprises RGB-D recordings of pedicle screw placement along with individually tracked ground truth poses and shapes of spine levels L1–L5 from ten cadaveric specimens. Besides a detailed description of our setup, quantitative and qualitative outcome measures are provided. We found a mean target registration error of 1.5 mm. The median deviation between measured and ground truth bone surface was 2.4 mm. In addition, a surgeon rated the overall alignment based on 10% random samples as 5.8 on a scale from 1 to 6. Generation of labeled RGB-D data for orthopedic interventions with satisfactory accuracy is feasible, and its publication shall promote future development of data-driven artificial intelligence methods for fast and reliable intraoperative registration., Journal of Imaging, 7 (9), ISSN:2313-433X

The pre-metastatic niche (PMN) is a tumor-driven microenvironment in distant organs that can foster and support the survival and growth of disseminated tumor cells. This facilitates the establishment of secondary lesions that eventually form overt metastasis, the main cause of cancer-related death. In recent years, tumor-derived extracellular-vesicles (EVs) have emerged as potentially key drivers of the PMN. The role of the PMN in osteosarcoma metastasis is poorly understood and the potential contribution of osteosarcoma cell-derived EVs to PMN formation has not been investigated so far. Here, we characterize pulmonary PMN development using the spontaneously metastasizing 143-B xenograft osteosarcoma mouse model. We demonstrate the accumulation of CD11b+ myeloid cells in the pre-metastatic lungs of tumor-bearing mice. We also establish that highly metastatic 143-B and poorly metastatic SAOS-2 osteosarcoma cell-derived EV education in naïve mice can recapitulate the recruitment of myeloid cells to the lungs. Surprisingly, despite EV-induced myeloid cell infiltration in the pre-metastatic lungs, 143-B and SAOS-2 EVs do not contribute towards the 143-B metastatic burden in the context of both spontaneous as well as experimental metastasis in severe-combined immunodeficient (SCID) mice. Taken together, OS-derived EVs alone may not be able to form a functional PMN, and may perhaps require a combination of tumor-secreted factors along with EVs to do so. Additionally, our study gives a valuable insight into the PMN complexity by providing the transcriptomic signature of the premetastatic lungs in an osteosarcoma xenograft model for the first time. In conclusion, identification of regulators of cellular and molecular changes in the pre-metastatic lungs might lead to the development of a combination therapies in the future that interrupt PMN formation and combat osteosarcoma metastasis., Cancers, 12 (11), ISSN:2072-6694

We introduce a new approach for a continuous loop tendon-graft preparation, benchmarking it against established graft preparation techniques widely used in conjunction with non-adjustable interference screw fixation. A four-strand bovine tendon graft was prepared using the following graft preparation techniques: standard graft using the baseball stitch technique (M-tech group); continuous loop graft using the GraftLinkTM technique (Arthrex-tech group); continuous loop graft using the Kessler anastomosis technique (Kessler-tech group); and continuous loop graft using a Double-Z anastomosis technique (Double Z-tech group). Each group of eight specimens underwent cyclic loading followed by a load-to-failure test. The M–technique yielded a smaller graft diameter (8.4 ± 0.5 mm) compared to the statistically equivalent diameters of the three continuous loop techniques (8.9 ± 0.6 mm of Arthrex-tech group, 9.1 ± 0.4 mm of Kessler-tech group and 9.2 ± 0.6 mm of Double Z-Tech group). The continuous loop grafts formed by the Double Z-Technique showed outstanding performance among the tested techniques in terms of ultimate failure load (982 ± 121 N) and cyclic elongation (3.7 ± 1.0 mm). There was no significant difference between the four groups in cyclic stiffness. Of the assessed techniques, the Arthrex technique resulted in the lowest ultimate elongation (2.0 ± 0.7 mm), followed by the Double Z-tech (4.5 ± 1.8 mm), the M-tech (5.2 ± 3.9 mm), and the Kessler-tech (5.3 ± 2.4 mm). The Arthrex-tech group (5.98 ± 0.38 min) displayed the shortest graft preparation time, followed by the M-Tech (7.94 ± 0.58 min), Kessler-tech (9.03 ± 0.39 min) and Double Z-Tech (13.29 ± 1.14 min). Double Z-Tech can improve the construct of continuous loop tendon graft with regard to mechanical performance., Scientific Reports, 10 (1), ISSN:2045-2322

Ligament injuries occur frequently, substantially hindering routine daily activities and sports participation in patients. Surgical reconstruction using autogenous or allogeneic tissues is the gold standard treatment for ligament injuries. Although surgeons routinely perform ligament reconstructions, the integrity of these reconstructions largely depends on adequate biological healing of the interface between the ligament graft and the bone. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would lead to significantly improved ligament graft integration. To test this hypothesis, an anterior cruciate ligament reconstruction procedure was performed in Yucatan mini-pigs. A collagen scaffold was implanted in the reconstruction sites to facilitate recruitment of endogenous mesenchymal stem cells. Ultrasound-mediated reporter gene delivery successfully transfected 40% of cells recruited to the reconstruction sites. When BMP-6 encoding DNA was delivered, BMP-6 expression in the reconstruction sites was significantly enhanced. Micro-computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to significantly enhanced osteointegration in all animals 8 weeks after surgery. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchymal progenitor cells can effectively improve ligament reconstruction in large animals, thereby addressing a major unmet orthopedic need and offering new possibilities for translation to the clinical setting., Molecular Therapy, 26 (7), ISSN:1525-0016, ISSN:1525-0024

After tendon rupture repair, two main problems may occur: re-rupture and adhesion formation. Suitable non-murine animal models are needed to study the healing tendon in terms of biomechanical properties and extent of adhesion formation. In this study 24 New Zealand White rabbits received a full transection of the Achilles tendon 2 cm above the calcaneus, sutured with a 4-strand Becker suture. Post-surgical analysis was performed at 3, 6 and 12 weeks. In the 6-week group, animals received a cast either in a 180 deg stretched position during 6 weeks (adhesion provoking immobilization), or were re-casted with a 150 deg position after 3 weeks (adhesion inhibiting immobilization), while in the other groups (3 and 12 weeks) a 180 deg position cast was applied for 3 weeks. Adhesion extent was analyzed by histology and ultrasound. Histopathological scoring was performed according to a method by Stoll et al. (2011), and the main biomechanical properties were assessed. Histopathological scores increased as a function of time, but did not reach values of healthy tendons after 12 weeks (only around 15 out of 20 points). Adhesion provoking immobilization led to an adhesion extent of 82.7±9.7%, while adhesion inhibiting immobilization led to 31.9±9.8% after 6 weeks. Biomechanical properties increased over time, however, they did not reach full strength nor elastic modulus at 12 weeks post-operation. Furthermore, the rabbit Achilles tendon model can be modulated in terms of adhesion formation to the surrounding tissue. It clearly shows the different healing stages in terms of histopathology and offers a suitable model regarding biomechanics because it exhibits similar biomechanics as the human flexor tendons of the hand., Biology Open, 5 (9), ISSN:2046-6390

The role of intrinsic and extrinsic healing in injured tendons is still debated. In this study, we characterized cell plasticity, proliferative capacity, and migration characteristics as proxy measures of healing potential in cells derived from the peritenon (extrinsic healing) and compared these to cells from the tendon core (intrinsic healing). Both cell populations were extracted from horse superficial digital flexor tendon and characterized for tenogenic and matrix remodeling markers as well as for rates of migration and replication. Furthermore, colony-forming unit assays, multipotency assays, and real-time quantitative polymerase chain reaction analyses of markers of osteogenic and adipogenic differentiation after culture in induction media were performed. Finally, cellular capacity for differentiation towards a myofibroblastic phenotype was assessed. Our results demonstrate that both tendon- and peritenon-derived cell populations are capable of adipogenic and osteogenic differentiation, with higher expression of progenitor cell markers in peritenon cells. Cells from the peritenon also migrated faster, replicate more quickly, and show higher differentiation potential toward a myofibroblastic phenotype when compared to cells from the tendon core. Based on these data, we suggest that cells from the peritenon have substantial potential to influence tendon-healing outcome, warranting further scrutiny of their role., PLoS ONE, 9 (3), ISSN:1932-6203

Purpose Symptomatic adjacent segment disease (ASD) has been reported to occur in up to 27 % of lumbar fusion patients. A previous study identified patients at risk according to the difference of pelvic incidence and lordosis. Patients with a difference between pelvic incidence and lumbar lordosis >15° have been found to have a 20 times higher risk for ASD. Therefore, it was the aim of the present study to investigate forces acting on the adjacent segment in relation to pelvic incidence–lumbar lordosis (PILL) mismatch as a measure of spino-pelvic alignment using rigid body modeling to decipher the underlying forces as potential contributors to degeneration of the adjacent segment. Methods Sagittal configurations of 81 subjects were reconstructed in a musculoskeletal simulation environment. Lumbar spine height was normalized, and body and segmental mass properties were kept constant throughout the population to isolate the effect of sagittal alignment. A uniform forward/backward flexion movement (0°–30°–0°) was simulated for all subjects. Intervertebral joint loads at lumbar level L3–L4 and L4–L5 were determined before and after simulated fusion. Results In the unfused state, an approximately linear relationship between sagittal alignment and intervertebral loads could be established (shear: 0° flexion r = 0.36, p < 0.001, 30° flexion r = 0.48, p < 0.001; compression: 0° flexion r = 0.29, p < 0.01, 30° flexion r = 0.40, p < 0.001). Additionally, shear changes during the transition from upright to 30° flexed posture were on average 32 % higher at level L3–L4 and 14 % higher at level L4–L5 in alignments that were clinically observed to be prone to ASD. Simulated fusion affected shear forces at the level L3–L4 by 15 % (L4–L5 fusion) and 23 % (L4–S1 fusion) more for alignments at risk for ASD. Conclusion Higher adjacent segment shear forces in alignments at risk for ASD already prior to fusion provide a mechanistic explanation for the clinically observed correlation between PILL mismatch and rate of adjacent segment degeneration., European Spine Journal, 23 (7), ISSN:0940-6719, ISSN:1432-0932, ISSN:001991155

Knee Surgery, Sports Traumatology, Arthroscopy, 19 (12), ISSN:0942-2056, ISSN:1433-7347