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The first set of data refers to Insulin-like Growth Factor-1 (IGF-1) protein incorporation via emulsion electrospinning into a DegraPolⓇ random fiber mesh and its characterization. Specifically, the fiber thickness was assessed and compared to pure DegraPolⓇ fibers without IGF-1 (control). Furthermore, the mechanical properties of these meshes were assessed and data on ultimate tensile stress, Young's modulus and ultimate fracture strain are presented for ring specimen and rectangular pieces taken from electrospun tubes in the transverse direction as well as rectangular pieces taken in the axial direction of the electrospun tube. Moreover, the static and the dynamic water contact angles were determined.The second set of data represents morphological aspects, such as the cytoskeletal aspect ratio (i.e. length of the cell divided by its width) for rabbit Achilles tenocytes stimulated in vitro with 1, 10, and 100 ng/mL IGF-1 supplementation compared to the corresponding cell culture without IGF-1 (control). Furthermore, qPCR was performed and collagen I, ki67 and tenomodulin gene expression data are presented for rabbit Achilles tenocytes in vitro with 0.1, 1 and 10 ng/mL IGF-1 supplementation, respectively, as well as with a supplementation of released IGF-1 from the DegraPol mesh (concentration was 1 ng/mL).

As one major problem after tendon rupture repair, surgeons are confronted with fibrotic adhesion formation of the healing tendon to the surrounding tissue. Although early active motion is recommended during rehabilitation, adhesions may lead to joint stiffness and a restricted range of motion. One viable option to counteract adhesion formation is to add a thin elastic tube that is placed over the conventionally sutured repair site. Such a tube reduces adhesion formation because it acts as a physical barrier. Additionally, such barriers can be optimized by adding a biolubricant.We here present adhesion data of rabbit Achilles tendons that were fully transsected, repaired with a 4-strand suture and received a) no implant; b) an electrospun DegraPol tube and c) a bi-layered tube with one electrospun DegraPol layer and one high molecular weight hyaluronic acid (HA)/polyethylene oxide (PEO) electrospun layer. Based on Picrosirius red stained tendon cross-sections three weeks post-operation, the percentage of adhesion data is presented. Moreover, mechanical data of the implant materials are presented as a further dataset, with the following readouts: fracture strain [%], ultimate tensile stress [MPa] and Young's modulus [MPa]. They are presented in axial and transverse stretching directions, respectively.The adhesion data can be reused for comparison to other implant materials, drugs or anti-adhesive strategies that are applied in similar pre-clinical models like the rabbit Achilles tendon model. The mechanical data of the implant materials offer the possibility to compare electrospun meshes based on other polymers to the materials used here or for computational models of such materials.

Introduction: Tendon injures rank as the second most common hand injuries, and unsatisfactory repair can significantly impact a patient's everyday life. Over the years, various suture techniques have been studied in the pursuit of finding the optimal repair method. The ideal tendon repair should achieve maximum strength, while being easy to perform and minimizing tissue trauma. This study aims to compare the mechanical properties of the cross-locked U-Tang 4-strand suture to its unmodified version, the U-Tang 4-strand suture, to assess which technique offers greater repair strength. Methods: Sixteen Achilles tendons from New Zealand White rabbits were randomly assigned to one of two suture technique groups; an original U-Tang 4-strand suture or a cross-locked U-Tang 4-strand suture, both performed using a 4-0 Supramid thread. The specimens were tested in uniaxial tension after a preconditioning phase. Cross-sectional area, load until failure, gap formation, stiffness, elastic modulus, and failure stress were determined. Results: The standard U-Tang 4-strand suture withstood a maximum force of 25.48 ± 6.06 N, while the cross-locked version endured 33.90 ± 6.09 N. This indicates that the modified version demonstrated significantly greater strength (p = 0.021). The elastic modulus of the cross-locked U-Tang 4-strand suture (0.02 ± 0.003 MPa) was significantly higher than that of the original version (0.01 ± 0.006 MPa) (p = 0.028). No significant differences were observed regarding the cross-sectional area, load at 2 mm gap formation, stiffness and failure stress. Conclusion: Employing the cross-locked U-Tang 4-strand suture results in a significantly greater maximum force and elastic modulus compared to the original U-Tang 4-strand suture, utilizing the same thread and number of strands and knots. Therefore, the cross-locking version provides an alternative for achieving more stable initial repair strength.

Abstract3D preoperative planning for high tibial osteotomies (HTO) has increasingly replaced 2D planning but is complex, time-consuming and therefore expensive. Several interdependent clinical objectives and constraints have to be considered, which often requires multiple rounds of revisions between surgeons and biomedical engineers. We therefore developed an automated preoperative planning pipeline, which takes imaging data as an input to generate a ready-to-use, patient-specific planning solution. Deep-learning based segmentation and landmark localization was used to enable the fully automated 3D lower limb deformity assessment. A 2D-3D registration algorithm allowed the transformation of the 3D bone models into the weight-bearing state. Finally, an optimization framework was implemented to generate ready-to use preoperative plannings in a fully automated fashion, using a genetic algorithm to solve the multi-objective optimization (MOO) problem based on several clinical requirements and constraints. The entire pipeline was evaluated on a large clinical dataset of 53 patient cases who previously underwent a medial opening-wedge HTO. The pipeline was used to automatically generate preoperative solutions for these patients. Five experts blindly compared the automatically generated solutions to the previously generated manual plannings. The overall mean rating for the algorithm-generated solutions was better than for the manual solutions. In 90% of all comparisons, they were considered to be equally good or better than the manual solution. The combined use of deep learning approaches, registration methods and MOO can reliably produce ready-to-use preoperative solutions that significantly reduce human workload and related health costs.

Introduction: The mechanical properties of skeletal muscle are indicative of its capacity to perform physical work, state of disease, or risk of injury. Ultrasound shear wave elastography conducts a quantitative analysis of a tissue’s shear stiffness, but current implementations only provide two-dimensional measurements with limited spatial extent. We propose and assess a framework to overcome this inherent limitation by acquiring numerous and contiguous measurements while tracking the probe position to create a volumetric scan of the muscle. This volume reconstruction is then mapped into a parameterized representation in reference to geometric and anatomical properties of the muscle. Such an approach allows to quantify regional differences in muscle stiffness to be identified across the entire muscle volume assessed, which could be linked to functional implications.Methods: We performed shear wave elastography measurements on the vastus lateralis (VL) and the biceps femoris long head (BFlh) muscle of 16 healthy volunteers. We assessed test-retest reliability, explored the potential of the proposed framework in aggregating measurements of multiple subjects, and studied the acute effects of muscular contraction on the regional shear wave velocity post-measured at rest.Results: The proposed approach yielded moderate to good reliability (ICC between 0.578 and 0.801). Aggregation of multiple subject measurements revealed considerable but consistent regional variations in shear wave velocity. As a result of muscle contraction, the shear wave velocity was elevated in various regions of the muscle; showing pre-to-post regional differences for the radial assessement of VL and longitudinally for BFlh. Post-contraction shear wave velocity was associated with maximum eccentric hamstring strength produced during six Nordic hamstring exercise repetitions.Discussion and Conclusion: The presented approach provides reliable, spatially resolved representations of skeletal muscle shear wave velocity and is capable of detecting changes in three-dimensional shear wave velocity patterns, such as those induced by muscle contraction. The observed systematic inter-subject variations in shear wave velocity throughout skeletal muscle additionally underline the necessity of accurate spatial referencing of measurements. Short high-effort exercise bouts increase muscle shear wave velocity. Further studies should investigate the potential of shear wave elastography in predicting the muscle’s capacity to perform work.

Structural muscle changes, including muscle atrophy and fatty infiltration, follow rotator cuff tendon tear and are associated with a high repair failure rate. Despite extensive research efforts, no pharmacological therapy is available to successfully prevent both muscle atrophy and fatty infiltration after tenotomy of tendomuscular unit without surgical repair. Poly(ADP-ribose) polymerases (PARPs) are identified as a key transcription factors involved in the maintenance of cellular homeostasis. PARP inhibitors have been shown to influence muscle degeneration, including mitochondrial hemostasis, oxidative stress, inflammation and metabolic activity, and reduced degenerative changes in a knockout mouse model. Tenotomized infraspinatus were assessed for muscle degeneration for 16 weeks using a Swiss Alpine sheep model (n = 6). All sheep received daily oral administration of 0.5 mg Talazoparib. Due to animal ethics, the treatment group was compared with three different controls from prior studies of our institution. To mitigate potential batch heterogeneity, PARP-I was evaluated in comparison with three distinct control groups (n = 6 per control group) using the same protocol without treatment. The control sheep were treated with an identical study protocol without Talazoparib treatment. Muscle atrophy and fatty infiltration were evaluated at 0, 6 and 16 weeks post-tenotomy using DIXON-MRI. The controls and PARP-I showed a significant (control p < 0.001, PARP-I p = 0.01) decrease in muscle volume after 6 weeks. However, significantly less (p = 0.01) atrophy was observed in PARP-I after 6 weeks (control 1: 76.6 ± 8.7%; control 2: 80.3 ± 9.3%, control 3: 73.8 ± 6.7% vs. PARP-I: 90.8 ± 5.1% of the original volume) and 16 weeks (control 1: 75.7 ± 9.9; control 2: 74.2 ± 5.6%; control 3: 75.3 ± 7.4% vs. PARP-I 93.3 ± 10.6% of the original volume). All experimental groups exhibited a statistically significant (p < 0.001) augmentation in fatty infiltration following a 16-week period when compared to the initial timepoint. However, the PARP-I showed significantly less fatty infiltration (p < 0.003) compared to all controls (control 1: 55.6 ± 6.7%, control 2: 53.4 ± 9.4%, control 3: 52.0 ± 12.8% vs. PARP-I: 33.5 ± 8.4%). Finally, a significantly (p < 0.04) higher proportion and size of fast myosin heavy chain-II fiber type was observed in the treatment group. This study shows that PARP-inhibition with Talazoparib inhibits the progression of both muscle atrophy and fatty infiltration over 16 weeks in retracted sheep musculotendinous units.

Abstract 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.

Abstract Purpose Intraoperative hinge fractures in distal femur osteotomies represent a risk factor for loss of alignment and non‐union. Using finite element analysis, the goal of this study was to investigate the influence of different hinge widths and osteotomy corrections on hinge fractures in medial closed‐wedge and lateral open‐wedge distal femur osteotomies. Methods The hinge was located at the proximal margin of adductor tubercle for biplanar lateral open‐wedge and at the upper border of the lateral femoral condyle for biplanar medial closed‐wedge distal femur osteotomies, corresponding to optimal hinge positions described in literature. Different hinge widths (5, 7.5, 10 mm) were created and the osteotomy correction was opened/closed by 5, 7.5 and 10 mm. Tensile and compressive strain of the hinge was determined in a finite element analysis and compared to the ultimate strain of cortical bone to assess the hinge fracture risk. Results Doubling the correction from 5 to 10 mm increased mean tensile and compressive strain by 50% for lateral open‐wedge and 48% for medial closed‐wedge osteotomies. A hinge width of 10 mm versus 5 mm showed increased strain in the hinge region of 61% for lateral open‐wedge and 32% for medial closed‐wedge osteotomies. Medial closed‐wedge recorded a higher fracture risk compared to lateral open‐wedge osteotomies due to a larger hinge cross‐section area (60–67%) for all tested configurations. In case of a 5 mm hinge, medial closed‐wedge recorded 71% higher strain in the hinge region compared to lateral open‐wedge osteotomies. Conclusion Due to morphological features of the medial femoral condyle, finite element analysis suggests that lateral‐open wedge osteotomies are the preferable option if larger corrections are intended, as a thicker hinge can remain without an increased hinge fracture risk.

Abstract Purpose Primary glenohumeral osteoarthritis is commonly associated with static posterior subluxation of the humeral head. Scapulae with static/dynamic posterior instability feature a superiorly and horizontally oriented acromion. We investigated whether the acromion acts as a restraint to posterior humeral translation. Methods Five three‐dimensional (3D) printed scapula models were biomechanically tested. A statistical shape mean model (SSMM) of the normal scapula of 40 asymptomatic shoulders was fabricated. Next, a SSMM of scapular anatomy associated with posterior subluxation was generated using data of 20 scapulae (“B1”). This model was then used to generate three models of surgical correction: glenoid version, acromial orientation, and acromial and glenoid orientation. With the joint axially loaded (100N) and the humerus stabilized, an anterior translation force was applied to the scapula in 35°, 60° and 75° of glenohumeral flexion. Translation (mm) was measured. Results In the normal scapula, the humerus translates significantly less to contact with the acromion compared to all other configurations (p

Intervertebral discs are microstructurally complex spinal tissues that add greatly to the flexibility and mechanical strength of the human spine. Attempting to provide an adjustable basis for capturing a wide range of mechanical characteristics and to better address known challenges of numerical modeling of the disc, we present a robust finite-element-based model formulation for spinal segments in a hyperelastic framework using tetrahedral elements. We evaluate the model stability and accuracy using numerical simulations, with particular attention to the degenerated intervertebral discs and their likely skewed and narrowed geometry. To this end, 1) annulus fibrosus is modeled as a fiber-reinforced Mooney-Rivlin type solid for numerical analysis. 2) An adaptive state-variable dependent explicit time step is proposed and utilized here as a computationally efficient alternative to theoretical estimates. 3) Tetrahedral-element-based FE models for spinal segments under various loading conditions are evaluated for their use in robust numerical simulations. For flexion, extension, lateral bending, and axial rotation load cases, numerical simulations reveal that a suitable framework based on tetrahedral elements can provide greater stability and flexibility concerning geometrical meshing over commonly employed hexahedral-element-based ones for representation and study of spinal segments in various stages of degeneration.

Abstract Tendon extracellular matrix (ECM) mechanical unloading results in tissue degradation and breakdown, with niche-dependent cellular stress directing proteolytic degradation of tendon. Here, we show that the extracellular-signal regulated kinase (ERK) pathway is central in tendon degradation of load-deprived tissue explants. We show that ERK 1/2 are highly phosphorylated in mechanically unloaded tendon fascicles in a vascular niche-dependent manner. Pharmacological inhibition of ERK 1/2 abolishes the induction of ECM catabolic gene expression (MMPs) and fully prevents loss of mechanical properties. Moreover, ERK 1/2 inhibition in unloaded tendon fascicles suppresses features of pathological tissue remodeling such as collagen type 3 matrix switch and the induction of the pro-fibrotic cytokine interleukin 11. This work demonstrates ERK signaling as a central checkpoint to trigger tendon matrix degradation and remodeling using load-deprived tissue explants.

Competitive alpine skiers are exposed to enormous forces acting on their bodies–particularly on the knee joint and hence the patellar tendon - during both the off-season preparation and in-season competition phases. However, factors influencing patellar tendon adaptation and regional pattern differences between alpine skiers and healthy controls are not yet fully understood, but are essential for deriving effective screening approaches and preventative countermeasures. Thirty elite competitive alpine skiers, all members of the Swiss Alpine Ski Team, and 38 healthy age-matched controls were recruited. A set of two-dimensional shear wave elastography measurements of the PT was acquired and projected into three-dimensional space yielding a volumetric representation of the shear wave velocity profile of the patellar tendon. Multivariate linear models served to quantify differences between the two cohorts and effects of other confounding variables with respect to regional shear wave velocity. A significant (p < 0.001) intergroup difference was found between skiers (mean ± SD = 10.4 ± 1.32 m/s) and controls (mean ± SD = 8.9 ± 1.59 m/s). A significant sex difference was found within skiers (p = 0.024), but no such difference was found in the control group (p = 0.842). Regional SWV pattern alterations between skiers and controls were found for the distal region when compared to the mid-portion (p = 0.023). Competitive alpine skiers exhibit higher SWV in all PT regions than healthy controls, potentially caused by long-term adaptations to heavy tendon loading. The presence of sex-specific differences in PT SWV in skiers but not in controls indicates that sex effects have load-dependent dimensions. Alterations in regional SWV patterns between skiers and controls suggest that patellar tendon adaptation is region specific. In addition to the implementation of 3D SWE, deeper insights into long-term tendon adaptation and normative values for the purpose of preventative screening are provided.

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.

Musculoskeletal modeling is a well-established method in spine biomechanics and generally employed for investigations concerning both the healthy and the pathological spine. It commonly involves inverse kinematics and optimization of muscle activity and provides detailed insight into joint loading. The aim of the present work was to develop and validate a procedure for the automatized generation of semi-subject-specific multi-rigid body models with an articulated lumbar spine. Individualization of the models was achieved with a novel approach incorporating information from annotated EOS images. The size and alignment of bony structures, as well as specific body weight distribution along the spine segments, were accurately reproduced in the 3D models. To ensure the pipeline’s robustness, models based on 145 EOS images of subjects with various weight distributions and spinopelvic parameters were generated. For validation, we performed kinematics-dependent and segment-dependent comparisons of the average joint loads obtained for our cohort with the outcome of various published in vivo and in situ studies. Overall, our results agreed well with literature data. The here described method is a promising tool for studying a variety of clinical questions, ranging from the evaluation of the effects of alignment variation on joint loading to the assessment of possible pathomechanisms involved in adjacent segment disease.

Adolescent idiopathic scoliosis (AIS) is the most common spine disorder affecting children worldwide, yet little is known about the pathogenesis of this disorder. Here, we demonstrate that genetic regulation of structural components of the axial skeleton, the intervertebral discs, and dense connective tissues (i.e., ligaments and tendons) is essential for the maintenance of spinal alignment. We show that the adhesion G protein-coupled receptor ADGRG6, previously implicated in human AIS association studies, is required in these tissues to maintain typical spine alignment in mice. Furthermore, we show that ADGRG6 regulates biomechanical properties of tendon and stimulates CREB signaling governing gene expression in cartilaginous tissues of the spine. Treatment with a cAMP agonist could mirror aspects of receptor function in culture, thus defining core pathways for regulating these axial cartilaginous and connective tissues. As ADGRG6 is a key gene involved in human AIS, these findings open up novel therapeutic opportunities for human scoliosis.

State-of-the-art preoperative biomechanical analysis for the planning of spinal surgery not only requires the generation of three-dimensional patient-specific models but also the accurate biomechanical representation of vertebral joints. The benefits offered by computational models suitable for such purposes are still outweighed by the time and effort required for their generation, thus compromising their applicability in a clinical environment. In this work, we aim to ease the integration of computerized methods into patient-specific planning of spinal surgery. We present the first pipeline combining deep learning and finite element methods that allows a completely automated model generation of functional spine units (FSUs) of the lumbar spine for patient-specific FE simulations (FEBio). The pipeline consists of three steps: (a) multiclass segmentation of cropped 3D CT images containing lumbar vertebrae using the DenseVNet network, (b) automatic landmark-based mesh fitting of statistical shape models onto 3D semantic segmented meshes of the vertebral models, and (c) automatic generation of patient-specific FE models of lumbar segments for the simulation of flexion-extension, lateral bending, and axial rotation movements. The automatic segmentation of FSUs was evaluated against the gold standard (manual segmentation) using 10-fold cross-validation. The obtained Dice coefficient was 93.7% on average, with a mean surface distance of 0.88 mm and a mean Hausdorff distance of 11.16 mm (N = 150). Automatic generation of finite element models to simulate the range of motion (ROM) was successfully performed for five healthy and five pathological FSUs. The results of the simulations were evaluated against the literature and showed comparable ROMs in both healthy and pathological cases, including the alteration of ROM typically observed in severely degenerated FSUs. The major intent of this work is to automate the creation of anatomically accurate patient-specific models by a single pipeline allowing functional modeling of spinal motion in healthy and pathological FSUs. Our approach reduces manual efforts to a minimum and the execution of the entire pipeline including simulations takes approximately 2 h. The automation, time-efficiency and robustness level of the pipeline represents a first step toward its clinical integration.

Abstract Background Fascin-1, a prominent actin-bundling protein, is found to be upregulated in several human carcinomas. While it is accepted that Fascin-1 expression correlates with poor clinical outcome and decreased survival in various carcinomas, its role in sarcoma such as osteosarcoma (OS) remains unknown. In the present study, we evaluated the prognostic value and biological relevance of Fascin-1 in OS. Methods The correlation between Fascin-1 expression and the outcome of OS patients was determined by immunohistochemistry analysis of Fascin-1 expression in a tissue microarray of OS tissue specimens collected during primary tumor resection. To examine the effect of Fascin-1, shRNA and overexpression technology to alter Fascin-1 levels in OS cells were used in cellular assays as well as in intratibial xenograft OS models in SCID mice. Results Kaplan-Meier survival analysis of Fascin-1 expression in OS tumor specimens revealed a direct relationship between Fascin-1 expression and poor patient survival. Furthermore, overexpression of Fascin-1 in OS cells significantly increased their migratory capacity as well as the activity of the matrix metalloprotease MMP-9, known to be critical for the execution of metastasis. Finally, using relevant xenograft mouse models, orthotopic intratibial transplantation of two different OS cell lines overexpressing Fascin-1 promoted tumor growth and lung metastasis. Conclusions Collectively, our findings demonstrate for the first time that Fascin-1 has considerable potential as a novel prognostic biomarker in OS, and suggest that targeting of Fascin-1 might be a new anti-metastatic strategy in OS patient treatment.

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.

BACKGROUND:Tendinopathy is a common musculoskeletal disorder and current treatment options show limited success. Genipin is an effective collagen crosslinker with low cytotoxicity and a promising therapeutic strategy for stabilizing an intratendinous lesion. PURPOSE:This study examined the mechanical effect and delivery of intratendinous genipin injection in healthy and degenerated tendons. STUDY DESIGN:Controlled laboratory study. METHODS:Bovine superficial digital flexor tendons were randomized into four groups: Healthy control (N = 25), healthy genipin (N = 25), degenerated control (N = 45) and degenerated genipin (N = 45). Degeneration was induced by Collagenase D injection. After 24h, degenerated tendons were subsequently injected with either 0.2ml of 80mM genipin or buffer only. 24h post-treatment, samples were cyclically loaded for 500 cycles and then ramp loaded to failure. Fluorescence and absorption assays were performed to analyze genipin crosslink distribution and estimate tissue concentration after injection. RESULTS:Compared to controls, genipin treatment increased ultimate force by 19% in degenerated tendons (median control 530 N vs. 633 N; p = 0.0078). No significant differences in mechanical properties were observed in healthy tendons, while degenerated tendons showed a significant difference in ultimate stress (+23%, p = 0.049), stiffness (+27%, p = 0.037), work to failure (+42%, p = 0.009), and relative stress relaxation (-11%, p < 0.001) after genipin injection. Fluorescence and absorption were significantly higher in genipin treated tendons compared to control groups. A higher degree of crosslinking (+45%, p < 0.001) and a more localized distribution were observed in the treated healthy compared to degenerated tendons, with higher genipin tissue concentrations in healthy (7.9 mM) than in degenerated tissue (2.3 mM). CONCLUSION:Using an ex-vivo tendinopathy model, intratendinous genipin injections recovered mechanical strength to the level of healthy tendons. Measured by genipin tissue distribution, injection is an effective method for local delivery. CLINICAL RELEVANCE:This study provides a proof of concept for the use of intratendinous genipin injection in the treatment of tendinopathy. The results demonstrate that a degenerated tendon can be mechanically augmented by a clinically viable method of local genipin delivery. This warrants further in vivo studies towards the development of a clinically applicable treatment based on genipin.

Ultrasound-based shear wave elastography (SWE) provides the means to quantify tissue mechanical properties in vivo and has proven valuable in detecting degenerative processes in tendons. Its current mode of use is for two-dimensional rendering measurements, which are highly position-dependent. We therefore propose an approach to create a volumetric reconstruction of the mechano-acoustic properties of a structure of interest based on optically tracking the ultrasound probe during free-hand measurement sweeps. In the current work, we aimed (1) to assess the technical feasibility of the three-dimensional mapping of unidirectional shear wave velocity (SWV), (2) to evaluate the possible artefacts associated with hand-held image acquisition, (3) to investigate the reproducibility of the proposed technique, and (4) to study the potential of this method in detecting local adaptations in a longitudinal study setting. Operative and technical feasibility as well as potential artefacts associated with hand-held image acquisition were studied on a synthetic phantom containing discrete targets of known mechanical properties. Measurement reproducibility was assessed based on inter-day and inter-reader scans of the patellar, Achilles, and supraspinatus tendon of ten healthy volunteers and was compared to traditional two-dimensional image acquisition. The potential of this method in detecting local adaptations was studied by testing the effect of short-term voluntary isometric loading history on SWV along the tendon long axis. The suggested approach was technically feasible and reproducible, with a moderate to very good reliability and a standard error of measurement in the range of 0.300–0.591 m/s for the three assessed tendons at the two test-retest modalities. We found a consistent variation in SWV along the longitudinal axis of each tendon, and isometric loading resulted in regional increases in SWV in the patellar and Achilles tendons. The proposed method outperforms traditional two-dimensional measurement with regards to reproducibility and may prove valuable in the objective assessment of pathological tendon changes.

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.

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.

Mechanical loading and inflammation interact to cause degenerative disc disease and low back pain (LBP). However, the underlying mechanosensing and mechanotransductive pathways are poorly understood. This results in untargeted pharmacological treatments that do not take the mechanical aspect of LBP into account. We investigated the role of the mechanosensitive ion channel TRPV4 in stretch-induced inflammation in human annulus fibrosus (AF) cells. The cells were cyclically stretched to 20% hyperphysiological strain. TRPV4 was either inhibited with the selective TRPV4 antagonist GSK2193874 or knocked out (KO) via CRISPR-Cas9 gene editing. The gene expression, inflammatory mediator release and MAPK pathway activation were analyzed. Hyperphysiological cyclic stretching significantly increased the IL6, IL8, and COX2 mRNA, PGE2 release, and activated p38 MAPK. The TRPV4 pharmacological inhibition significantly attenuated these effects. TRPV4 KO further prevented the stretch-induced upregulation of IL8 mRNA and reduced IL6 and IL8 release, thus supporting the inhibition data. We provide novel evidence that TRPV4 transduces hyperphysiological mechanical signals into inflammatory responses in human AF cells, possibly via p38. Additionally, we show for the first time the successful gene editing of human AF cells via CRISPR-Cas9. The pharmacological inhibition or CRISPR-based targeting of TRPV4 may constitute a potential therapeutic strategy to tackle discogenic LBP in patients with AF injury.

The surgical standard of care for lumbar discectomy leaves the annulus fibrosus (AF) defect unrepaired, despite considerable risk for a recurrent herniation. Identification of a viable defect repair strategy has until now been elusive. The scope of this ex vivo biomechanical study was to evaluate crosslinking hydrogels as potentially promising AF defect sealants, and provide a baseline for their use in combination with collagen scaffolds that restore disc volume. This study directly compared genipin crosslinked fibrin hydrogel (FibGen) as a promising preclinical candidate against a clinically available adhesive composed of glutaraldehyde and albumin (BioGlue). Forty-two bovine coccygeal functional spine units (FSU) were randomly allocated into four groups, namely untreated (control, n = 12), repaired with either one of the tested hydrogels (BioGlue, n = 12; FibGen, n = 12), or FibGen used in combination with a collagen hydrogel scaffold (FibGen+Scaffold, n = 6). All specimens underwent a moderate mechanical testing protocol in intact, injured and repaired states. After completion of the moderate testing protocol, the samples underwent a ramp-to-failure test. Lumbar discectomy destabilized the FSU as quantified by increased torsional range of motion (28.0° (19.1, 45.1) vs. 41.39° (27.3, 84.9), p

Eukaryotic cells are densely packed with macromolecular complexes and intertwining organelles, continually transported and reshaped. Intriguingly, organelles avoid clashing and entangling with each other in such limited space. Mitochondria form extensive networks constantly remodeled by fission and fusion. Here, we show that mitochondrial fission is triggered by mechanical forces. Mechano-stimulation of mitochondria – via encounter with motile intracellular pathogens, via external pressure applied by an atomic force microscope, or via cell migration across uneven microsurfaces – results in the recruitment of the mitochondrial fission machinery, and subsequent division. We propose that MFF, owing to affinity for narrow mitochondria, acts as a membrane-bound force sensor to recruit the fission machinery to mechanically strained sites. Thus, mitochondria adapt to the environment by sensing and responding to biomechanical cues. Our findings that mechanical triggers can be coupled to biochemical responses in membrane dynamics may explain how organelles orderly cohabit in the crowded cytoplasm.

The posterior cruciate ligament (PCL) is the strongest ligament of the knee, serving as one of the major passive stabilizers of the tibio-femoral joint. However, despite a number of experimental and modelling approaches to understand the kinematics and kinetics of the ligament, the normal loading conditions of the PCL and its functional bundles are still controversially discussed.This study aimed to generate science-based evidence for understanding the functional loading of the PCL, including the anterolateral and posteromedial bundles, in the healthy knee joint through systematic review and statistical analysis of the literature.MEDLINE, EMBASE and CENTRAL.Databases were searched for articles containing any numerical strain or force data on the healthy PCL and its functional bundles. Studied activities were as follows: passive flexion, flexion under 100N and 134N posterior tibial load, walking, stair ascent and descent, body-weight squatting and forward lunge.Statistical analysis was performed on the reported load data, which was weighted according to the number of knees tested to extract average strain and force trends of the PCL and identify deviations from the norms.From the 3577 articles retrieved by the initial electronic search, only 66 met all inclusion criteria. The results obtained by aggregating data reported in the eligible studies indicate that the loading patterns of the PCL vary with activity type, knee flexion angle, but importantly also the technique used for assessment. Moreover, different fibres of the PCL exhibit different strain patterns during knee flexion, with higher strain magnitudes reported in the anterolateral bundle. While during passive flexion the posteromedial bundle is either lax or very slightly elongated, it experiences higher strain levels during forward lunge and has a synergetic relationship with the anterolateral bundle. The strain patterns obtained for virtual fibres that connect the origin and insertion of the bundles in a straight line show similar trends to those of the real bundles but with different magnitudes.This review represents what is now the best available understanding of the biomechanics of the PCL, and may help to improve programs for injury prevention, diagnosis methods as well as reconstruction and rehabilitation techniques.