Advanced therapies in orthopaedics.

Advanced therapies are expected to play a crucial role in supporting repair after injury, halting the degeneration of musculoskeletal tissue to enable and promote physical activity. Despite advancements, the progress in developing advanced therapies in orthopaedics lags behind specialties like oncology, since innovative regenerative treatment strategies fall short of their expectations in musculoskeletal clinical trials. Researchers should focus on understanding the mechanism of action behind the investigated target before conducting clinical trials. Strategic research networks are needed that not only enhance scientific exchange among like-minded researchers but need to include early on commercial views, companies and venture perspectives, regulatory insights and reimbursement perspectives. Only in such collaborations essential roadblocks towards clinical trials and go-to-patients be overcome.

The Global Evolution and Impact of Systems Biology and Artificial Intelligence in Stem Cell Research and Therapeutics Development: A Scoping Review.

Advanced bioinformatics analysis, such as systems biology (SysBio) and artificial intelligence (AI) approaches, including machine learning (ML) and deep learning (DL), is increasingly present in stem cell (SC) research. An approximate timeline on these developments and their global impact is still lacking. We conducted a scoping review on the contribution of SysBio and AI analysis to SC research and therapy development based on literature published in PubMed between 2000 and 2024. We identified an 8-10-fold increase in research output related to all three search terms between 2000 and 2021, with a 10-fold increase in AI-related production since 2010. Use of SysBio and AI still predominates in preclinical basic research with increasing use in clinically oriented translational medicine since 2010. SysBio- and AI-related research was found all over the globe, with SysBio output led by the United States (US, n=1487), United Kingdom (UK, n=1094), Germany (n=355), The Netherlands (n=339), Russia (n=215), and France (n=149), while for AI-related research the US (n=853) and UK (n=258) take a strong lead, followed by Switzerland (n=69), The Netherlands (n=37), and Germany (n=19). The US and UK are most active in SCs publications related to AI/ML and AI/DL. The prominent use of SysBio in ESC research was recently overtaken by prominent use of AI in iPSC and MSC research. This study reveals the global evolution and growing intersection between AI, SysBio, and SC research over the past two decades, with substantial growth in all three fields and exponential increases in AI-related research in the past decade.

The design of a sample rapid magnetic resonance imaging (MRI) acquisition protocol supporting assessment of multiple articular tissues and pathologies in knee osteoarthritis.

Objective: This expert opinion paper proposes a design for a state-of-the-art magnetic resonance image (MRI) acquisition protocol for knee osteoarthritis clinical trials in early and advanced disease. Semi-quantitative and quantitative imaging endpoints are supported, partly amendable to automated analysis. Several (peri-) articular tissues and pathologies are covered, including synovitis. Method: A PubMed literature search was conducted, with focus on the past 5 years. Further, osteoarthritis imaging experts provided input. Specific MRI sequences, orientations, spatial resolutions and parameter settings were identified to align with study goals. We strived for implementation on standard clinical scanner hardware, with a net acquisition time ≤30 â€‹min. Results: Short- and long-term longitudinal MRIs should be obtained at ≥1.5T, if possible without hardware changes during the study. We suggest a series of gradient- and spin-echo-sequences, supporting MOAKS, quantitative analysis of cartilage morphology and T2, and non-contrast-enhanced depiction of synovitis. These sequences should be properly aligned and positioned using localizer images. One of the sequences may be repeated in each participant (re-test), optimally at baseline and follow-up, to estimate within-study precision. All images should be checked for quality and protocol-adherence as soon as possible after acquisition. Alternative approaches are suggested that expand on the structural endpoints presented. Conclusions: We aim to bridge the gap between technical MRI acquisition guides and the wealth of imaging literature, proposing a balance between image acquisition efficiency (time), safety, and technical/methodological diversity. This approach may entertain scientific innovation on tissue structure and composition assessment in clinical trials on disease modification of knee osteoarthritis.

Marked differences between continuous long-term and clinical snapshot examinations: is the current standard of back pain diagnostics outdated?

Current clinical examination of low back pain (LBP) patients primarily relies on static clinical examinations, which rarely represent the dynamic postures patients adopt during daily activities. To gain an overview on the dynamic kinematics-kinetics changes over a day, the lumbar back kinematics of asymptomatic individuals and LBP patients were measured over 24 h, and the passively resisted bending and torsional moments were estimated. 208 asymptomatic subjects (115 females) and 116 LBP patients (71 females) were analysed. Compared to static upright standing, the mean lumbar lordosis of asymptomatic subjects drops significantly by 21° during everyday life (p < 0.01). Maximum bending moments of 44.0-50.6 Nm were estimated at the L2-L3. LBP patients showed significantly lower (p < 0.01) lumbar flattening during daily life of about 16°. Maximum bending moments of 27-52 Nm were found at the L3-L4. The initial static upright lumbar lordosis was significantly lower in LBP population (by 6°) resulting in almost similar average lumbar shapes during daily activities in both groups. The torsional movements were with 2.2° greatest in L1-L2 independent of sex (p = 0.19) and LBP (p = 0.54) with moments of 6-16 Nm. The lumbar profile and associated internal moments during daily life differ substantially from those recorded during clinical examinations. LBP patients demonstrates significantly lower lordosis at the snapshot assessment and significantly lower movement variations and internal moments during daily life. Only the dynamic long-term assessments unravelled a less flexed posture in LBP population. Apparently, such a reduced dynamic flexed posture indicates a compensatory habit for pain relief.

Temporal regulation of BMP2 growth factor signaling in response to mechanical loading is linked to cytoskeletal and focal adhesion remodeling.

Biophysical cues have the ability to enhance cellular signaling response to Bone Morphogenetic Proteins, an essential growth factor during bone development and regeneration. Yet, therapeutic application of Bone Morphogenetic Protein 2 (BMP2) is restricted due to uncontrolled side effects. An understanding of the temporal characteristics of mechanically regulated signaling events and underlying mechanism is lacking. Using a 3D bioreactor system in combination with a soft macroporous biomaterial substrate, we mimic the in vivo environment that BMP2 is acting in. We show that the intensity and duration of BMP2 signaling increases with increasing loading frequency in synchrony with the number and size of focal adhesions. Long-term mechanical stimulation increases the expression of BMP receptor type 1B, specific integrin subtypes and integrin clustering. Together, this triggered a short-lived mechanical echo that enhanced BMP2 signaling even when BMP2 is administered directly after mechanical stimulation, but not when it is applied after a resting period of ≥30 min. Interfering with cytoskeletal remodeling hinders focal adhesion remodeling verifying its critical role in shifting cells into a state of high BMP2 responsiveness. The design of biomaterials that exploit this potential locally at the site of injury will help to overcome current limitations of clinical growth factor treatment.

Titanium versus plasma electrolytic oxidation surface-modified magnesium miniplates in a forehead secondary fracture healing model in sheep.

Magnesium as a biodegradable material offers promising results in recent studies of different maxillo-facial fracture models. To overcome adverse effects caused by the fast corrosion of pure magnesium in fluid surroundings, various alloys, and surface modifications are tested in animal models. In specified cases, magnesium screws already appeared for clinical use in maxillofacial surgery. The present study aims to compare the bone healing outcome in a non-load-bearing fracture scenario of the forehead in sheep when fixed with standard-sized WE43 magnesium fixation plates and screws with plasma electrolytic oxidation (PEO) surface modification in contrast to titanium osteosynthesis. Surgery was performed on 24 merino mix sheep. The plates and screws were explanted en-bloc with the surrounding tissue after four and twelve weeks. The outcome of bone healing was investigated with micro-computed tomography, histological, immunohistological, and fluorescence analysis. There was no significant difference between groups concerning the bone volume, bone volume/ total volume, and newly formed bone in volumetric and histological analysis at both times of investigation. The fluorescence analysis revealed a significantly lower signal in the magnesium group after one week, although there was no difference in the number of osteoclasts per mm2. The magnesium group had significantly fewer vessels per mm2 in the healing tissue. In conclusion, the non-inferiority of WE43-based magnesium implants with PEO surface modification was verified concerning fracture healing under non-load-bearing conditions in a defect model. STATEMENT OF SIGNIFICANCE: Titanium implants, the current gold standard of fracture fixation, can lead to adverse effects linked to the implant material and often require surgical removal. Therefore, degradable metals like the magnesium alloy WE43 with plasma electrolytic oxidation (PEO) surface modification gained interest. Yet, miniplates of this alloy with PEO surface modification have not been examined in a fracture defect model of the facial skeleton in a large animal model. This study shows, for the first time, the non-inferiority of magnesium miniplates compared to titanium miniplates. In radiological and histological analysis, bone healing was undisturbed. Magnesium miniplates can reduce the number of interventions for implant removal, thus reducing the risk for the patient and minimizing the costs.

Titanium vs PEO Surface-Modified Magnesium Plate Fixation in a Mandible Bone Healing Model in Sheep.

Titanium plates are the current gold standard for fracture fixation of the mandible. Magnesium alloys such as WE43 are suitable biodegradable alternatives due to their high biocompatibility and elasticity modulus close to those of cortical bone. By surface modification, the reagibility of magnesium and thus hydrogen gas accumulation per time are further reduced, bringing plate fixation with magnesium closer to clinical application. This study aimed to compare bone healing in a monocortical mandibular fracture model in sheep with a human-standard size, magnesium-based, plasma electrolytic-oxidation (PEO) surface modified miniplate fixation system following 4 and 12 weeks. Bone healing was analyzed using micro-computed tomography and histological analysis with Movat's pentachrome and Giemsa staining. For evaluation of the tissue's osteogenic activity, polychrome fluorescent labeling was performed, and vascularization was analyzed using immunohistochemical staining for alpha-smooth muscle actin. Bone density and bone mineralization did not differ significantly between titanium and magnesium (BV/TV: T1: 8.74 ± 2.30%, M1: 6.83 ± 2.89%, p = 0.589 and T2: 71.99 ± 3.13%, M2: 68.58 ± 3.74%, p = 0.394; MinB: T1: 26.16 ± 9.21%, M1: 22.15 ± 7.99%, p = 0.818 and T2: 77.56 ± 3.61%, M2: 79.06 ± 4.46%, p = 0.699). After 12 weeks, minor differences were observed regarding bone microstructure, osteogenic activity, and vascularization. There was significance with regard to bone microstructure (TrTh: T2: 0.08 ± 0.01 mm, M2: 0.06 ± 0.01 mm; p = 0.041). Nevertheless, these differences did not interfere with bone healing. In this study, adequate bone healing was observed in both groups. Only after 12 weeks were some differences detected with larger trabecular spacing and more vessel density in magnesium vs titanium plates. However, a longer observational time with full resorption of the implants should be targeted in future investigations.

Clinical validation of fully automated laminar knee cartilage transverse relaxation time (T2) analysis in anterior cruciate ligament (ACL)-injured knees- on behalf of the osteoarthritis (OA)-Bio consortium.

Background: Magnetic resonance imaging (MRI) cartilage transverse relaxation time (T2) reflects cartilage composition, mechanical properties, and early osteoarthritis (OA). T2 analysis requires cartilage segmentation. In this study, we clinically validate fully automated T2 analysis at 1.5 Tesla (T) in anterior cruciate ligament (ACL)-injured and healthy knees. Methods: We studied 71 participants: 20 ACL-injured patients with, and 22 without dynamic knee instability, 13 with surgical reconstruction, and 16 healthy controls. Sagittal multi-echo-spin-echo (MESE) MRIs were acquired at baseline and 1-year follow-up. Femorotibial cartilage was segmented manually; a convolutional neural network (CNN) algorithm was trained on MRI data from the same scanner. Results: Dice similarity coefficients (DSCs) of automated versus manual segmentation in the 71 participants were 0.83 (femora) and 0.89 (tibiae). Deep femorotibial T2 was similar between automated (45.7±2.6 ms) and manual (45.7±2.7 ms) segmentation (P=0.828), whereas superficial layer T2 was slightly overestimated by automated analysis (53.2±2.2 vs. 52.1±2.1 ms for manual; P<0.001). T2 correlations were r=0.91-0.99 for deep and r=0.86-0.97 for superficial layers across regions. The only statistically significant T2 increase over 1 year was observed in the deep layer of the lateral femur [standardized response mean (SRM) =0.58 for automated vs. 0.52 for manual analysis; P<0.001]. There was no relevant difference in baseline/longitudinal T2 values/changes between the ACL-injured groups and healthy participants, with either segmentation method. Conclusions: This clinical validation study suggests that automated cartilage T2 analysis from MESE at 1.5T is technically feasible and accurate. More efficient 3D sequences and longer observation intervals may be required to detect the impact of ACL injury induced joint instability on cartilage composition (T2).

Volumetric evaluation of osteotomy gap following mandibular bilateral sagittal split osteotomy using a novel semi-automated approach: a pilot study.

OBJECTIVES: To establish an analysis pipeline for the volumetric evaluation of the osteotomy site after bilateral sagittal split osteotomy (BSSO). PATIENTS AND METHODS: Cone-beam computed tomography (CBCT) was performed before, directly after BSSO, and 6-12 months after surgery. Image segmentations of each osteotomy gap data set were performed manually by four physicians and were compared to a semi-automatic segmentation approach. RESULTS: Five patients with a total of ten osteotomy gaps were included. The mean interclass correlation coefficient (ICC) of individual patients was 0.782 and the standard deviation 0.080 when using the manual segmentation approach. However, the mean ICC of the evaluation of anatomical sites and time points separately was 0.214, suggesting a large range of deviation within the manual segmentation of each rater. The standard deviation was 0.355, further highlighting the extent of the variation. In contrast, the semi-automatic approach had a mean ICC of 0.491 and a standard deviation of 0.365, which suggests a relatively higher agreement among the operators compared to the manual segmentation approach. Furthermore, the volume of the osteotomy gap in the semi-automatic approach showed the same tendency in every site as the manual segmentation approach, but with less deviation. CONCLUSION: The semi-automatic approach developed in the present study proved to be valid as a standardised method with high repeatability. Such image analysis methods could help to quantify the progression of bone healing after BSSO and beyond, eventually facilitating the earlier identification of patients with retarded healing.

Caloric restriction reduces trabecular bone loss during aging and improves bone marrow adipocyte endocrine function in male mice.

Introduction: Caloric restriction (CR) is a nutritional intervention that increases life expectancy while lowering the risk for cardio-metabolic disease. Its effects on bone health, however, remain controversial. For instance, CR has been linked to increased accumulation of bone marrow adipose tissue (BMAT) in long bones, a process thought to elicit detrimental effects on bone. Qualitative differences have been reported in BMAT in relation to its specific anatomical localization, subdividing it into physiological and potentially pathological BMAT. We here examine the local impact of CR on bone composition, microstructure and its endocrine profile in the context of aging. Methods: Young and aged male C57Bl6J mice were subjected to CR for 8 weeks and were compared to age-matched littermates with free food access. We assessed bone microstructure and BMAT by micro-CT, bone fatty acid and transcriptomic profiles, and bone healing. Results: CR increased tibial BMAT accumulation and adipogenic gene expression. CR also resulted in elevated fatty acid desaturation in the proximal and mid-shaft regions of the tibia, thus more closely resembling the biochemical lipid profile of the distally located, physiological BMAT. In aged mice, CR attenuated trabecular bone loss, suggesting that CR may revert some aspects of age-related bone dysfunction. Cortical bone, however, was decreased in young mice on CR and remained reduced in aged mice, irrespective of dietary intervention. No negative effects of CR on bone regeneration were evident in either young or aged mice. Discussion: Our findings indicate that the timing of CR is critical and may exert detrimental effects on bone biology if administered during a phase of active skeletal growth. Conversely, CR exerts positive effects on trabecular bone structure in the context of aging, which occurs despite substantial accumulation of BMAT. These data suggest that the endocrine profile of BMAT, rather than its fatty acid composition, contributes to healthy bone maintenance in aged mice.

Activity-Dependent Compensation at the Hip and Ankle at 8 Years After the Reconstruction of Isolated and Combined Posterior Cruciate Ligament Injuries.

BACKGROUND: After posterior cruciate ligament reconstruction (PCLR), functional deficits at the knee can persist. It remains unclear if neighboring joints compensate for the knee during demanding activities of daily living. PURPOSE: To assess long-term alterations in lower limb mechanics in patients after PCLR. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 28 patients who had undergone single-bundle unilateral isolated or combined PCLR performed stair navigation, squat, sit-to-stand, and stand-to-sit tasks at 8.2 ± 2.2 years after surgery. Motion capture and force plates were used to collect kinematic and kinetic data. Then, 3-dimensional hip, knee, and ankle kinematic data of the reconstructed limb were compared with those of the contralateral limb using statistical parametric mapping. RESULTS: Side-to-side differences at the knee were primarily found during upward-driven movements at 8 years after surgery. The reconstructed knee exhibited lower internal rotation during the initial loading phase of stair ascent versus the contralateral knee (P = .005). During the sit-to-stand task, higher flexion angles during the midcycle (P = .017) and lower external rotation angles (P = .049) were found in the reconstructed knee; sagittal knee (P = .001) and hip (P = .016) moments were lower in the reconstructed limb than the contralateral limb. In downward-driven movements, side-to-side differences were minimal at the knee but prominent at the ankle and hip: during stair descent, the reconstructed ankle exhibited lower dorsiflexion and lower external rotation during the midcycle versus the contralateral ankle (P = .006 and P = .040, respectively). Frontal hip moments in the reconstructed limb were higher than those in the contralateral limb during the stand-to-sit task (P = .010); during squats, sagittal hip angles in the reconstructed limb were higher than those in the contralateral limb (P < .001). CONCLUSION: Patients after PCLR exhibited compensations at the hip and ankle during downward-driven movements, such as stair descent, squats, and stand-to-sit. Conversely, residual long-term side-to-side differences at the knee were detected during upward-driven movements such as stair ascent and sit-to-stand. CLINICAL RELEVANCE: After PCLR, side-to-side differences in biomechanical function were activity-dependent and occurred either at the knee or neighboring joints. When referring to the contralateral limb to assess knee function in the reconstructed limb, concentric, upward-driven movements should be prioritized. Compensations at the hip and ankle during downward-driven movements lead to biases in long-term functional assessments.

Mechanical heterogeneity in a soft biomaterial niche controls BMP2 signaling.

The extracellular matrix is known to impact cell function during regeneration by modulating growth factor signaling. However, how the mechanical properties and structure of biomaterials can be used to optimize the cellular response to growth factors is widely neglected. Here, we engineered a macroporous biomaterial to study cellular signaling in environments that mimic the mechanical stiffness but also the mechanical heterogeneity of native extracellular matrix. We found that the mechanical interaction of cells with the heterogeneous and non-linear deformation properties of soft matrices (E < 5 kPa) enhances BMP-2 growth factor signaling with high relevance for tissue regeneration. In contrast, this effect is absent in homogeneous hydrogels that are often used to study cell responses to mechanical cues. Live cell imaging and in silico finite element modeling further revealed that a subpopulation of highly active, fast migrating cells is responsible for most of the material deformation, while a second, less active population experiences this deformation as an extrinsic mechanical stimulation. At an overall low cell density, the active cell population dominates the process, suggesting that it plays a particularly important role in early tissue healing scenarios where cells invade tissue defects or implanted biomaterials. Taken together, our findings demonstrate that the mechanical heterogeneity of the natural extracellular matrix environment plays an important role in triggering regeneration by endogenously acting growth factors. This suggests the inclusion of such mechanical complexity as a design parameter in future biomaterials, in addition to established parameters such as mechanical stiffness and stress relaxation.

Increased ß2-adrenergic signaling promotes fracture healing through callus neovascularization in mice.

Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the ß2-adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene-related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

Stabilizing a Femur Osteotomy with a Plate Fixation in Ambystoma mexicanum.

The axolotl (Ambystoma mexicanum) is a promising model organism for regenerative medicine due to its remarkable ability to regenerate lost or damaged organs, including limbs, brain, heart, tail, and others. Studies on axolotl shed light on cellular and molecular pathways ruling progenitor activation and tissue restoration after injury. This knowledge can be applied to facilitate the healing of regeneration-incompetent injuries, such as bone non-union. In the current protocol, the femur osteotomy stabilization using an internal plate fixation system is described. The procedure was adapted for use in aquatic animals (axolotl, Ambystoma mexicanum). ≥20 cm snout-to-tail tip axolotls with fully ossified, mouse-size comparable femurs were used, and special attention was paid to the plate positioning and fixation, as well as to the postoperative care. This surgical technique allows for standardized and stabilized bone fixation and could be useful for direct comparison to axolotl limb regeneration and analogous studies of bone healing across amphibians and mammals.

A two-way street - cellular metabolism and myofibroblast contraction.

Tissue fibrosis is characterised by the high-energy consumption associated with myofibroblast contraction. Although myofibroblast contraction relies on ATP production, the role of cellular metabolism in myofibroblast contraction has not yet been elucidated. Studies have so far only focused on myofibroblast contraction regulators, such as integrin receptors, TGF-ß and their shared transcription factor YAP/TAZ, in a fibroblast-myofibroblast transition setting. Additionally, the influence of the regulators on metabolism and vice versa have been described in this context. However, this has so far not yet been connected to myofibroblast contraction. This review focuses on the known and unknown of how cellular metabolism influences the processes leading to myofibroblast contraction and vice versa. We elucidate the signalling cascades responsible for myofibroblast contraction by looking at FMT regulators, mechanical cues, biochemical signalling, ECM properties and how they can influence and be influenced by cellular metabolism. By reviewing the existing knowledge on the link between cellular metabolism and the regulation of myofibroblast contraction, we aim to pinpoint gaps of knowledge and eventually help identify potential research targets to identify strategies that would allow switching tissue fibrosis towards tissue regeneration.

Altered knee kinematics after posterior cruciate ligament single-bundle reconstruction-a comprehensive prospective biomechanical in vivo analysis.

Purpose: Passive tibiofemoral anterior-posterior (AP) laxity has been extensively investigated after posterior cruciate ligament (PCL) single-bundle reconstruction. However, the PCL also plays an important role in providing rotational stability in the knee. Little is known in relation to the effects of PCL single-bundle reconstruction on passive tibiofemoral rotational laxity. Gait biomechanics after PCL reconstruction are even less understood. The aim of this study was a comprehensive prospective biomechanical in vivo analysis of the effect of PCL single-bundle reconstruction on passive tibiofemoral rotational laxity, passive anterior-posterior laxity, and gait pattern. Methods: Eight patients undergoing PCL single-bundle reconstruction (seven male, one female, mean age 35.6 ± 6.6 years, BMI 28.0 ± 3.6 kg/m2) were analyzed preoperatively and 6 months postoperatively. Three of the eight patients received additional posterolateral corner (PLC) reconstruction. Conventional stress radiography was used to evaluate passive translational tibiofemoral laxity. A previously established rotometer device with a C-arm fluoroscope was used to assess passive tibiofemoral rotational laxity. Functional gait analysis was used to examine knee kinematics during level walking. Results: The mean side-to-side difference (SSD) in passive posterior translation was significantly reduced postoperatively (12.1 ± 4.4 mm vs. 4.3 ± 1.8 mm; p < 0.01). A significant reduction in passive tibiofemoral rotational laxity at 90° knee flexion was observed postoperatively (27.8° ± 7.0° vs. 19.9° ± 7.5°; p = 0.02). The range of AP tibiofemoral motion during level walking was significantly reduced in the reconstructed knees when compared to the contralateral knees at 6-month follow-up (16.6 ± 2.4 mm vs. 13.5 ± 1.6 mm; p < 0.01). Conclusion: PCL single-bundle reconstruction with optional PLC reconstruction reduces increased passive tibiofemoral translational and rotational laxity in PCL insufficient knees. However, increased passive tibiofemoral translational laxity could not be fully restored and patients showed altered knee kinematics with a significantly reduced range of tibiofemoral AP translation during level walking at 6-month follow-up. The findings of this study indicate a remaining lack of restoration of biomechanics after PCL single-bundle reconstruction in the active and passive state, which could be a possible cause for joint degeneration after PCL single-bundle reconstruction.

From breast cancer cell homing to the onset of early bone metastasis: The role of bone (re)modeling in early lesion formation.

Breast cancer often metastasizes to bone, causing osteolytic lesions. Structural and biophysical changes are rarely studied yet are hypothesized to influence metastasis. We developed a mouse model of early bone metastasis and multimodal imaging to quantify cancer cell homing, bone (re)modeling, and onset of metastasis. Using tissue clearing and three-dimensional (3D) light sheet fluorescence microscopy, we located enhanced green fluorescent protein-positive cancer cells and small clusters in intact bones and quantified their size and spatial distribution. We detected early bone lesions using in vivo microcomputed tomography (microCT)-based time-lapse morphometry and revealed altered bone (re)modeling in the absence of detectable lesions. With a new microCT image analysis tool, we tracked the growth of early lesions over time. We showed that cancer cells home in all bone compartments, while osteolytic lesions are only detected in the metaphysis, a region of high (re)modeling. Our study suggests that higher rates of (re)modeling act as a driver of lesion formation during early metastasis.

In vivo load on knee, hip and spine during manual materials handling with two lifting techniques.

It is generally accepted that the lifting technique strongly influences physical loads within the human body and, thus, the risk of musculoskeletal disorders. However, there is a lack of knowledge regarding whether particular lifting techniques are effective in reducing loads. Hence, this retrospective study quantified (partly published) in vivo loads at joints within the human body during two typical lifting techniques, stoop lifting and squat lifting. Patients who had received instrumented implants underwent in vivo load measurements at either the knee (two patients), the hip (eight patients), or the upper lumbar spine (four patients) while lifting a 10 kg weight frontally with either straight (stoop) or bent (squat) knees. Contact forces and moments and the orientation of the contact force vector were determined and examined using the paired t test of Statistical Parametric Mapping. The two lifting techniques did not differ in terms of load magnitudes but did differ in terms of directions: (i) at the hip joint, the load vector varied significantly (p < 0.05) in the frontal and sagittal planes, (ii) at the knee joint, the load vector differed significantly (p < 0.05) in the sagittal plane (iii) while the load vector and magnitude did not differ at the upper lumbar spine (p > 0.05). Our findings indicate that the lifting technique causes changes in the orientation rather than the magnitude of lower extremity joint contact loads. Even though this quantification could only be performed in a small group of patients, the quantification of the relevance of such lifting technique recommendations will hopefully guide future recommendations towards a more scientific interpretation.

External Mechanical Stability Regulates Hematoma Vascularization in Bone Healing Rather than Endothelial YAP/TAZ Mechanotransduction.

Bone fracture healing is regulated by mechanobiological cues. Both, extracellular matrix (ECM) deposition and microvascular assembly determine the dynamics of the regenerative processes. Mechanical instability as by inter-fragmentary shear or compression is known to influence early ECM formation and wound healing. However, it remains unclear how these external cues shape subsequent ECM and microvascular network assembly. As transcriptional coactivators, the mechanotransducers yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) translate physical cues into downstream signaling events, yet their role in sprouting angiogenesis into the hematoma after injury is unknown. Using bone healing as model system for scar-free regeneration, the role of endothelial YAP/TAZ in combination with tuning the extrinsic mechanical stability via fracture fixation is investigated. Extrinsically imposed shear across the gap delayed hematoma remodeling and shaped the morphology of early collagen fiber orientations and microvascular networks, suggesting that enhanced shear increased the nutrient exchange in the hematoma. In contrast, endothelial YAP/TAZ deletion has little impact on the overall vascularization of the fracture gap, yet slightly increases the collagen fiber deposition under semi-rigid fixation. Together, these data provide novel insights into the respective roles of endothelial YAP/TAZ and extrinsic mechanical cues in orchestrating the process of bone regeneration.