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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.

Abstract 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.

IntroductionOpen reduction and fixation are the standard of care for treating mandibular fractures and usually lead to successful healing. However, complications such as delayed healing, non-union, and infection can compromise patient outcomes and increase healthcare costs. The initial inflammatory response, particularly the response involving specific CD8+ T cell subpopulations, is thought to play a critical role in healing long bone fractures. In this study, we investigated the role of these immune cell profiles in patients with impaired healing of mandibular fractures.Materials and methodsIn this prospective study, we included patients with mandibular fractures surgically treated at Charité – Universitätsmedizin Berlin, Germany, between September 2020 and December 2022. We used follow-up imaging and clinical assessment to evaluate bone healing. In addition, we analyzed immune cell profiles using flow cytometry and quantified cytokine levels using electrochemiluminescence-based multiplex immunoassays in preoperative blood samples.ResultsOut of the 55 patients enrolled, 38 met the inclusion criteria (30 men and 8 women; mean age 32.18 years). Radiographic evaluation revealed 31 cases of normal healing and 7 cases of incomplete consolidation, including 1 case of non-union. Patients with impaired healing exhibited increased levels of terminally differentiated effector memory CD8+ T cells (TEMRA) and a higher TEMRA to regulatory T cell (Treg) ratio, compared with those with normal healing.ConclusionsOur analysis of mandibular fracture cases confirms our initial hypothesis derived from long bone fracture healing: monitoring the TEMRA to Treg ratio in preoperative blood can be an early indicator of patients at risk of impaired bone healing. Radiologic follow-up enabled us to detect healing complications that might not be detected by clinical assessment only. This study highlights the potential of individual immune profiles to predict successful healing and may form the basis for future strategies to manage healing complications.

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 ​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.

Abstract 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-β 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.

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.

IntroductionCaloric 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.MethodsYoung 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.ResultsCR 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.DiscussionOur 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.

Abstract Background The vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigated whether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA. Methods Sixteen- to 18-month-old αCGRP-deficient mice (αCGRP−/− aged) were compared to, first, age-matched wild type (WTaged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP−/− CTRL) and non-OA WT animals (WTCTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and µ-computed tomography. Results WTaged mice exhibited elevated αCGRP serum levels compared to young WTCTRL animals. Marked signs of OA-induced cartilage destruction were seen in WTaged animals, while αCGRP−/− aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WTaged but not in αCGRP−/− aged mice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA. Conclusions Similar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.

Abstract 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.

With the implementation of the new MDR 2017/745 by the European Parliament, more robust clinical and pre-clinical data will be required due to a more stringent approval process. The EFORT Implant and Patient Safety Initiative WG1 ‘Introduction of Innovation’, combined knowledge of orthopaedic surgeons, research institutes, orthopaedic device manufacturers, patient representatives and regulatory authorities to develop a comprehensive set of recommendations for the introduction of innovations in joint arthroplasty within the boundaries of MDR 2017/745. Recommendations have been developed to address key questions about pre-clinical and clinical requirements for the introduction of new implants and implant-related instrumentation with the participation of a steering group, invited by the EFORT Board in dialogue with representatives from European National Societies and Speciality Societies. Different degrees of novelty and innovation were described and agreed on in relation to when surgeons can start, using implants and implant-related instrumentation routinely. Before any clinical phase of a new implant, following the pre-market clinical investigation or the equivalent device PMCF pathway, it is a common understanding that all appropriate pre-clinical testing (regulatory mandatory and evident state of the art) – which has to be considered for a specific device – has been successfully completed. Once manufacturers receive the CE mark for a medical device, it can be used in patients routinely when a clinical investigation has been conducted to demonstrate the conformity of devices according to MDR Article 62 or full equivalence for the technical, biological and clinical characteristics has been demonstrated (MDR, Annex XIV, Part A, 3.) and a PMCF study has been initiated.

Abstract Pulmonary hypertension worsens outcome in left heart disease. Stiffening of the pulmonary artery may drive this pathology by increasing right ventricular dysfunction and lung vascular remodeling. Here we show increased stiffness of pulmonary arteries from patients with left heart disease that correlates with impaired pulmonary hemodynamics. Extracellular matrix remodeling in the pulmonary arterial wall, manifested by dysregulated genes implicated in elastin degradation, precedes the onset of pulmonary hypertension. The resulting degradation of elastic fibers is paralleled by an accumulation of fibrillar collagens. Pentagalloyl glucose preserves arterial elastic fibers from elastolysis, reduces inflammation and collagen accumulation, improves pulmonary artery biomechanics, and normalizes right ventricular and pulmonary hemodynamics in a rat model of pulmonary hypertension due to left heart disease. Thus, targeting extracellular matrix remodeling may present a therapeutic approach for pulmonary hypertension due to left heart disease.

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.

Metabolites are demonstrated to be critical regulators of fracture healing. Succinate is found to promote vascularization and ossification, highlighting that metabolites have the potential to be used therapeutically to promote fracture healing.

Abstract Objective Platelet-rich plasma (PRP) therapy is increasingly popular to treat musculoskeletal diseases, including tendinopathies and osteoarthritis (OA). To date, it remains unclear to which extent PRP compositions are determined by the immune cell and cytokine profile of individuals or by the preparation method. To investigate this, we compared leukocyte and cytokine distributions of different PRP products to donor blood samples and assessed the effect of pro-inflammatory cytokines on chondrocytes. Design For each of three PRP preparations (ACP®, Angel™, and nSTRIDE® APS), products were derived using whole blood samples from twelve healthy donors. The cellular composition of PRP products was analyzed by flow cytometry using DURAClone antibody panels (DURAClone IM Phenotyping Basic and DURAClone IM T Cell Subsets). The MESO QuickPlex SQ 120 system was used to assess cytokine profiles (V-PLEX Proinflammatory Panel 1 Human Kit, Meso Scale Discovery). Primary human chondrocyte 2D and 3D in vitro cultures were exposed to recombinant IFN-γ and TNF-α. Proliferation and chondrogenic differentiation were quantitatively assessed. Results All three PRP products showed elevated portions of leukocytes compared to baseline levels in donor blood. Furthermore, the pro-inflammatory cytokines IFN-γ and TNF-α were significantly increased in nSTRIDE® APS samples compared to donor blood and other PRP products. The characteristics of all other cytokines and immune cells from the donor blood, including pro-inflammatory T cell subsets, were maintained in all PRP products. Chondrocyte proliferation was impaired by IFN-γ and enhanced by TNF-α treatment. Differentiation and cartilage formation were compromised upon treatment with both cytokines, resulting in altered messenger ribonucleic acid (mRNA) expression of collagen type 1A1 (COL1A1), COL2A1, and aggrecan (ACAN) as well as reduced proteoglycan content. Conclusions Individuals with elevated levels of cells with pro-inflammatory properties maintain these in the final PRP products. The concentration of pro-inflammatory cytokines strongly varies between PRP products. These observations may help to unravel the previously described heterogeneous response to PRP in OA therapy, especially as IFN-γ and TNF-α impacted primary chondrocyte proliferation and their characteristic gene expression profile. Both the individual’s immune profile and the concentration method appear to impact the final PRP product. Trial registration This study was prospectively registered in the Deutsches Register Klinischer Studien (DRKS) on 4 November 2021 (registration number DRKS00026175).

BackgroundAge and sex are prominent risk factors for heart failure and determinants of structural and functional changes of the heart. Cardiac fibroblasts (cFB) are beyond their task as extracellular matrix-producing cells further recognized as inflammation-supporting cells. The present study aimed to evaluate the impact of sex and age on the inflammatory potential of cFB and its impact on the cardiosplenic axis and cardiac fibrosis.MaterialsLeft ventricles (LV) of 3- and 12-months old male and female C57BL/6J mice were harvested for immunohistochemistry, immunofluorescence and cFB outgrowth culture and the spleen for flow cytometry. LV-derived cFB and respective supernatants were characterized.ResultsLV-derived cFB from 3-months old male mice exhibited a higher inflammatory capacity, as indicated by a higher gene expression of CC-chemokine ligand (CCL) 2, and CCL7 compared to cFB derived from 3-months old female mice. The resulting higher CCL2/chemokine C-X3-C motif ligand (Cx3CL1) and CCL7/Cx3CL1 protein ratio in cell culture supernatants of 3-months old male vs. female cFB was reflected by a higher migration of Ly6Chigh monocytes towards supernatant from 3-months old male vs. female cFB. In vivo a lower ratio of splenic pro-inflammatory Ly6Chigh to anti-inflammatory Ly6Clow monocytes was found in 3-months old male vs. female mice, suggesting a higher attraction of Ly6Chigh compared to Ly6Clow monocytes towards the heart in male vs. female mice. In agreement, the percentage of pro-inflammatory CD68+ CD206− macrophages was higher in the LV of male vs. female mice at this age, whereas the percentage of anti-inflammatory CD68+ CD206+ macrophages was higher in the LV of 3-months old female mice compared to age-matched male animals. In parallel, the percentage of splenic TGF-β+ cells was higher in both 3- and 12-months old female vs. male mice, as further reflected by the higher pro-fibrotic potential of female vs. male splenocytes at both ages. In addition, female mice displayed a higher total LV collagen content compared to age-matched male mice, whereby collagen content of female cFB was higher compared to male cFB at the age of 12-months.ConclusionAge- and sex-dependent differences in cardiac fibrosis and inflammation are related to age- and sex-dependent variations in the inflammatory properties of cardiac fibroblasts.

Sprouting angiogenesis plays a key role during bone regeneration. For example, insufficient early revascularization of the injured site can lead to delayed or non-healing. During sprouting, endothelial cells are known to be mechano-sensitive and respond to local mechanical stimuli. Endothelial cells interact and communicate mechanically with their surroundings, such as outer-vascular stromal cells, through cell-induced traction forces. In addition, external physiological loads act at the healing site, resulting in tissue deformations and impacting cellular arrangements. How these two distinct mechanical cues (cell-induced and external) impact angiogenesis and sprout patterning in early bone healing remains however largely unknown. Therefore, the aim of this study was to investigate the relative role of externally applied and cell-induced mechanical signals in driving sprout patterning at the onset of bone healing. To investigate cellular self-organisation in early bone healing, an in silico model accounting for the mechano-regulation of sprouting angiogenesis and stromal cell organization was developed. Computer model predictions were compared to in vivo experiments of a mouse osteotomy model stabilized with a rigid or a semirigid fixation system. We found that the magnitude and orientation of principal strains within the healing region can explain experimentally observed sprout patterning, under both fixation conditions. Furthermore, upon simulating the selective inhibition of either cell-induced or externally applied mechanical cues, external mechanical signals appear to overrule the mechanical communication acting on a cell-cell interaction level. Such findings illustrate the relevance of external mechanical signals over the local cell-mediated mechanical cues and could be used in the design of fracture treatment strategies for bone regeneration.

ABSTRACT Bone has the fascinating ability to self‐regenerate. However, under certain conditions, such as type 2 diabetes mellitus (T2DM), this ability is impaired. T2DM is a chronic metabolic disease known by the presence of elevated blood glucose levels that is associated with reduced bone regeneration capability, high fracture risk, and eventual non‐union risk after a fracture. Several mechanical and biological factors relevant to bone regeneration have been shown to be affected in a diabetic environment. However, whether impaired bone regeneration in T2DM can be explained due to mechanical or biological alterations remains unknown. To elucidate the relevance of either one, the aim of this study was to investigate the relative contribution of T2DM‐related alterations on either cellular activity or mechanical stimuli driving bone regeneration. A previously validated in silico computer modeling approach that was capable of explaining bone regeneration in uneventful conditions of healing was further developed to investigate bone regeneration in T2DM. Aspects analyzed included the presence of mesenchymal stromal cells (MSCs), cellular migration, proliferation, differentiation, apoptosis, and cellular mechanosensitivity. To further verify the computer model findings against in vivo data, an experimental setup was replicated, in which regeneration was compared in healthy and diabetic after a rat femur bone osteotomy stabilized with plate fixation. We found that mechanical alterations had little effect on the reduced bone regeneration in T2DM and that alterations in MSC proliferation, MSC migration, and osteoblast differentiation had the highest effect. In silico predictions of regenerated bone in T2DM matched qualitatively and quantitatively those from ex vivo μCT at 12 weeks post‐surgery when reduced cellular activities reported in previous in vitro and in vivo studies were included in the model. The presented findings here could have clinical implications in the treatment of bone fractures in patients with T2DM. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Introduction: Mechanical loading is known to determine the course of bone fracture healing. We hypothesise that lower limb long bone loading differs with knee flexion angle during walking and frontal knee alignment, which affects fracture healing success.Materials and methods: Using our musculoskeletal in silico modelling constrained against in vivo data from patients with instrumented knee implants allowed us to assess internal loads in femur and tibia. These internal forces were associated with the clinical outcome of fracture healing in a relevant cohort of 178 extra-articular femur and tibia fractures in patients using a retrospective approach.Results: Mean peak forces differed with femoral compression (1,330–1,936 N at mid-shaft) amounting to about half of tibial compression (2,299–5,224 N). Mean peak bending moments in the frontal plane were greater in the femur (71–130 Nm) than in the tibia (from 26 to 43 Nm), each increasing proximally. Bending in the sagittal plane showed smaller mean peak bending moments in the femur (−38 to 43 Nm) reaching substantially higher values in the tibia (−63 to −175 Nm) with a peak proximally. Peak torsional moments had opposite directions for the femur (−13 to −40 Nm) versus tibia (15–48 Nm) with an increase towards the proximal end in both. Femoral fractures showed significantly lower scores in the modified Radiological Union Scale for Tibia (mRUST) at last follow-up (p < 0.001) compared to tibial fractures. Specifically, compression (r = 0.304), sagittal bending (r = 0.259), and frontal bending (r = −0.318) showed strong associations (p < 0.001) to mRUST at last follow-up. This was not the case for age, body weight, or localisation alone.Discussion: This study showed that moments in femur and tibia tend to decrease towards their distal ends. Tibial load components were influenced by knee flexion angle, especially at push-off, while static frontal alignment played a smaller role. Our results indicate that femur and tibia are loaded differently and thus require adapted fracture fixation considering load components rather than just overall load level.

Introduction: This work aimed to develop a novel multipurpose device for guided knee flexion-extension, both passively using a motorized pneumatic system and actively (muscle-driven) with the joint unloaded or loaded during dynamic MRI. Secondary objectives were to characterize the participant experience during device use, and present preliminary dynamic MRI data to demonstrate the different device capabilities. Material and methods: Self-reported outcomes were used to characterize the pain, physical exertion and discomfort levels experienced by 10 healthy male participants during four different active knee motion and loading protocols using the novel device. Knee angular data were recorded during the protocols to determine the maximum knee range of motion achievable. Dynamic MRI was acquired for three healthy volunteers during passive, unloaded knee motion using 2D Cartesian TSE, 2D radial GRE and 3D UTE sequences; and during active, unloaded and loaded knee motion using 2D radial GRE imaging. Because of the different MRI sequences used, spatial resolution was inherently lower for active knee motion than for passive motion acquisitions. Results: Depending on the protocol, some participants reported slight pain, mild discomfort and varying levels of physical exertion. On average, participants achieved ∼40° of knee flexion; loaded conditions can create knee moments up to 27 Nm. High quality imaging data were obtained during different motion and loading conditions. Dynamic 3D data allowed to retrospectively extract arbitrarily oriented slices. Conclusion: A novel multipurpose device for guided, physiologically relevant knee motion and loading during dynamic MRI was developed. Device use was well tolerated and suitable for acquiring high quality images during different motion and loading conditions. Different bone positions between loaded and unloaded conditions were likely due to out-of-plane motion, particularly because image registration was not performed. Ultimately, this device could be used to advance our understanding of physiological and pathological joint mechanics.

Abstract Passive translational tibiofemoral laxity has been extensively examined in posterior cruciate ligament (PCL) insufficient patients and belongs to the standard clinical assessment. However, objective measurements of passive rotational knee laxity, as well as range of tibiofemoral motion during active movements, are both not well understood. None of these are currently quantified in clinical evaluations of patients with PCL insufficiency. The objective of this study was to quantify passive translational and rotational knee laxity as well as range of anterior–posterior and rotational tibiofemoral motion during level walking in a PCL insufficient patient cohort as a basis for any later clinical evaluation and therapy. The laxity of 9 patient knees with isolated PCL insufficiency or additionally posterolateral corner (PLC) insufficiency (8 males, 1 female, age 36.78 ± 7.46 years) were analysed and compared to the contralateral (CL) knees. A rotometer device with a C-arm fluoroscope was used to assess the passive tibiofemoral rotational laxity while stress radiography was used to evaluate passive translational tibiofemoral laxity. Functional gait analysis was used to examine the range of anterior–posterior and rotational tibiofemoral motion during level walking. Passive translational laxity was significantly increased in PCL insufficient knees in comparison to the CL sides (15.5 ± 5.9 mm vs. 3.7 ± 1.9 mm, p

Abstract Particles released from cobalt-chromium-molybdenum (CoCrMo) alloys are considered common elicitors of chronic inflammatory adverse effects. There is a lack of data demonstrating particle numbers, size distribution and elemental composition of bone marrow resident particles which would allow for implementation of clinically relevant test strategies in bone marrow models at different degrees of exposure. The aim of this study was to investigate metal particle exposure in human periprosthetic bone marrow of three types of arthroplasty implants. Periprosthetic bone marrow sections from eight patients exposed to CoCrMo particles were analyzed via spatially resolved and synchrotron-based nanoscopic X-ray fluorescence imaging. These analyses revealed lognormal particle size distribution patterns predominantly towards the nanoscale. Analyses of particle numbers and normalization to bone marrow volume and bone marrow cell number indicated particle concentrations of up to 1 × 1011 particles/ml bone marrow or 2 × 104 particles/bone marrow cell, respectively. Analyses of elemental ratios of CoCrMo particles showed that particularly the particles’ Co content depends on particle size. The obtained data point towards Co release from arthroprosthetic particles in the course of dealloying and degradation processes of larger particles within periprosthetic bone marrow. This is the first study providing data based on metal particle analyses to be used for future in vitro and in vivo studies of possible toxic effects in human bone marrow following exposure to arthroprosthetic CoCrMo particles of different concentration, size, and elemental composition. Graphical abstract

So far, tendon regeneration has mainly been analyzed independent from its adjacent tissues. However, the subacromial bursa in particular appears to influence the local inflammatory milieu in the shoulder. The resolution of local inflammation in the shoulder tissues is essential for tendon regeneration, and specialized pro-resolving mediators (SPMs) play a key role in regulating the resolution of inflammation. Here, we aimed to understand the influence of the bursa on disease-associated processes in neighboring tendon healing. Bursa tissue and bursa-derived cells from patients with intact, moderate and severe rotator cuff disease were investigated for the presence of pro-resolving and inflammatory mediators, as well as their effect on tenocytes and sensitivity to mechanical loading by altering SPM signaling mediators in bursa cells. SPM signal mediators were present in the bursae and altered depending on the severity of rotator cuff disease. SPMs were particularly released from the bursal tissue of patients with rotator cuff disease, and the addition of bursa-released factors to IL-1β-challenged tenocytes improved tenocyte characteristics. In addition, mechanical loading modulated pro-resolving processes in bursa cells. In particular, pathological high loading (8% strain) increased the expression and secretion of SPM signaling mediators. Overall, this study confirms the importance of bursae in regulating inflammatory processes in adjacent rotator cuff tendons.

Background: The healing of a bone injury is a highly complex process involving a multitude of different tissue and cell types, including immune cells, which play a major role in the initiation and progression of bone regeneration. Methods: We histologically analyzed the spatio-temporal occurrence of cells of the innate immune system (macrophages), the adaptive immune system (B and T lymphocytes), and bone cells (osteoblasts and osteoclasts) in the fracture area of a femoral osteotomy over the healing time. This study was performed in a bone osteotomy gap mouse model. We also investigated two key challenges of successful bone regeneration: hypoxia and revascularization. Results: Macrophages were present in and around the fracture gap throughout the entire healing period. The switch from initially pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype coincided with the revascularization as well as the appearance of osteoblasts in the fracture area. This indicates that M2 macrophages are necessary for the restoration of vessels and that they also play an orchestrating role in osteoblastogenesis during bone healing. The presence of adaptive immune cells throughout the healing process emphasizes their essential role for regenerative processes that exceeds a mere pathogen defense. B and T cells co-localize consistently with bone cells throughout the healing process, consolidating their crucial role in guiding bone formation. These histological data provide, for the first time, comprehensive information about the complex interrelationships of the cellular network during the entire bone healing process in one standardized set up. With this, an overall picture of the spatio-temporal interplay of cellular key players in a bone healing scenario has been created. Conclusions: A spatio-temporal distribution of immune cells, bone cells, and factors driving bone healing at time points that are decisive for this process—especially during the initial steps of inflammation and revascularization, as well as the soft and hard callus phases—has been visualized. The results show that the bone healing cascade does not consist of five distinct, consecutive phases but is a rather complex interrelated and continuous process of events, especially at the onset of healing.

Background: Total knee arthroplasty (TKA) is a highly effective treatment for severe knee osteoarthritis that is increasingly performed in younger, more active patients. As postoperative muscular impairments may negatively affect surgical outcomes and implant longevity, functional muscle recovery gains increasing importance in meeting future patient demands. This study aimed to assess the status of periarticular muscles in the long-term follow-up after TKA and to evaluate its impact on in vivo tibio-femoral joint loads.Methods: A case series was created, with eight patients with knee osteoarthritis. All subjects received an instrumented knee implant in unilateral TKA. Native computed tomography scans, acquired pre and postoperatively, were used to evaluate distal muscle volumes and fatty infiltration. In vivo tibio-femoral joint loads were measured telemetrically during standing, walking, stair climbing and chair rising and were correlated to muscle status.Results: Postoperatively a reduction in fatty infiltration across all periarticular muscles was pronounced. High average peak loads acted in the tibio-femoral joint ranging from 264% during stand-to-sit activities up to 341% body weight (BW) during stair descent. Fatty infiltration of the m. quadriceps femoris and hamstrings were associated with increased tibio-femoral joint contact forces during walking (r = 0.542; 0.412 and 0.766).Conclusion: The findings suggest that a fatty infiltration of periarticular muscles may lead to increased tibio-femoral joint contact forces. However, we only observed weak correlations between these parameters. Improvements in functional mobility and the restoration of a pain-free joint likely explain the observed postoperative reductions in fatty infiltration. Perioperative rehabilitation approaches targeting residual impairments in muscle quality could, contribute to reduced tibio-femoral joint loads and improved long-term outcomes of TKA. However, it has to be pointed out that the study included a small number of patients, which may limit its validity.

Abstract Background Quadriceps tendon ruptures (QTRs) are rare but debilitating injuries, often associated with chronic metabolic conditions or long‐term steroid treatment. While the surgical treatment for acute QTRs is described thoroughly, no common strategy exists for the often frustrating treatment of chronic, reoccurring QTRs. The pro‐angiogenic and immunomodulatory properties of placenta‐derived adherent mesenchymal stromal‐like (PLX‐PAD) cells have been described to protect musculoskeletal tissues from inflammation and catabolic cytokine migration, yet little is known about the regenerative potential of PLX‐PAD cells in repetitively damaged tendon tissue. Case We report the case of an 80‐year‐old male patient with a chronic three‐time QTR of his right knee. The quadriceps tendon was reconstructed applying a conventional suture anchor repair procedure combined with a synthetic mesh augmentation and additional intramuscular and intratendineous PLX‐PAD cell injections as an individualized treatment approach. No adverse events were reported, and excellent radiological and functional outcomes with a passive range of motion of 0/0/120° knee extension‐flexion were observed at the 12 month follow‐up. Gait analysis confirmed restoration of joint motion, including gait speed, deficit in step length, and knee extensor muscle strength (pre‐surgery: 0.98 m/s, 40 cm, 42.4 ± 12.4 N; 9 months post‐surgery: 1.07 m/s, 0 cm, 10.4 ± 18.9 N) as well as hyperextension throughout stance and late swing phases (pre‐surgery: −11.2 ± 0.9°; 9 months post‐surgery: −2.7 ± 1.6°). Postoperative lymphocyte and cytokine analyses from the patient's peripheral blood serum suggested a systemic short‐term immunoregulatory reaction with postoperatively increased interleukin (IL)‐6 (pre‐surgery: 0.79 pg/mL; day 1: 139.97 pg/mL; day 5: 5.58 pg/mL; 9 months: 1.76 pg/mL) and IL‐10 (pre‐surgery: 0.9 pg/mL; day 1: 1.21 pg/ mL; day 5: 0.3 pg/mL; 9 months: 0.34 pg/mL) levels that decreased again over time. Conclusions Herein, we demonstrate a successfully treated chronic QTR with a synergistic surgical and biological reconstructive treatment approach. This local add‐on treatment with PLX‐PAD cells may be considered in specific cases of chronic QTRs, not susceptible to traditional suture anchor procedures and which exhibit a high risk of treatment failure. Further scientific engagement is warranted to explore underlying immunomodulatory mechanisms of action behind PLX‐PAD cell treatment for tendon injuries.

Patients suffering from musculoskeletal diseases must cope with a diminished quality of life and an increased burden on medical expenses. The interaction of immune cells and mesenchymal stromal cells during bone regeneration is one of the key requirements for the restoration of skeletal integrity. While stromal cells of the osteo-chondral lineage support bone regeneration, an excessive accumulation of cells of the adipogenic lineage is thought to promote low-grade inflammation and impair bone regeneration. Increasing evidence indicates that pro-inflammatory signaling from adipocytes is responsible for various chronic musculoskeletal diseases. This review aims to summarize the features of bone marrow adipocytes by phenotype, function, secretory features, metabolic properties and their impact on bone formation. In detail, the master regulator of adipogenesis and prominent diabetes drug target, peroxisome proliferator-activated receptor γ (PPARG), will be debated as a potential therapeutic approach to enhance bone regeneration. We will explore the possibilities of using clinically established PPARG agonists, the thiazolidinediones (TZDs), as a treatment strategy to guide the induction of a pro-regenerative, metabolically active bone marrow adipose tissue. The impact of this PPARG induced bone marrow adipose tissue type on providing the necessary metabolites to sustain osteogenic-as well as beneficial immune cells during bone fracture healing will be highlighted.

Due to their advantages in applicability, patient-specific (CAD/CAM) reconstruction plates are increasingly used in fibula free flap mandible reconstruction. In addition, recently, CAD/CAM miniplates, with further advantages in postoperative management, have been introduced. However, biomechanical conditions induced by CAD/CAM systems remain partially unknown. This study aimed to evaluate the primary fixation stability of CAD/CAM fixators. For a patient-specific scenario, the biomechanical conditions induced in a one segmental fibula free flap stabilized using either a CAD/CAM reconstruction plate or CAD/CAM miniplates were determined using finite element analysis. The main output parameters were the strains between intersegmental bone surfaces and stresses in the fixation systems due to different biting scenarios. CAD/CAM miniplates resulted in higher mechanical strains in the mesial interosseous gap, whereas CAD/CAM reconstruction plate fixation resulted in higher strains in the distal interosseous gap. For all investigated fixation systems, stresses in the fixation systems were below the material yield stress and thus material failure would not be expected. While the use of CAD/CAM miniplates resulted in strain values considered adequate to promote bone healing in the mesial interosseous gap, in the distal interosseous gap CAD/CAM reconstruction plate fixation might result in more beneficial tissue straining. A mechanical failure of the fixation systems would not be expected.

The treatment of large bone defects is a clinical challenge. 3D printed scaffolds are a promising treatment option for such critical-size defects. However, the design of scaffolds to treat such defects is challenging due to the large number of variables impacting bone regeneration; material stiffness, architecture or equivalent scaffold stiffness—due it specific architecture—have all been demonstrated to impact cell behavior and regeneration outcome. Computer design optimization is a powerful tool to find optimal design solutions within a large parameter space for given anatomical constraints. Following this approach, scaffold structures have been optimized to avoid mechanical failure while providing beneficial mechanical stimulation for bone formation within the scaffold pores immediately after implantation. However, due to the dynamics of the bone regeneration process, the mechanical conditions do change from immediately after surgery throughout healing, thus influencing the regeneration process. Therefore, we propose a computer framework to optimize scaffold designs that allows to promote the final bone regeneration outcome. The framework combines a previously developed and validated mechanobiological bone regeneration computer model, a surrogate model for bone healing outcome and an optimization algorithm to optimize scaffold design based on the level of regenerated bone volume. The capability of the framework is verified by optimization of a cylindrical scaffold for the treatment of a critical-size tibia defect, using a clinically relevant large animal model. The combined framework allowed to predict the long-term healing outcome. Such novel approach opens up new opportunities for sustainable strategies in scaffold designs of bone regeneration.

The treatment of large bone defects represents a major clinical challenge. 3D printed scaffolds appear as a promising strategy to support bone defect regeneration. The 3D design of such scaffolds impacts the healing path and thus defect regeneration potential. Among others, scaffold architecture has been shown to influence the healing outcome. Gyroid architecture, characterized by a zero mean surface curvature, has been discussed as a promising scaffold design for bone regeneration. However, whether gyroid scaffolds are favourable for bone regeneration in large bone defects over traditional strut-like architecture scaffolds remains unknown. Therefore, the aim of this study was to investigate whether gyroid scaffolds present advantages over more traditional strut-like scaffolds in terms of their bone regeneration potential. Validated bone defect regeneration principles were applied in an in silico modeling approach that allows to predict bone formation in defect regeneration. Towards this aim, the mechano-biological bone regeneration principles were adapted to allow simulating bone regeneration within both gyroid and strut-like scaffolds. We found that the large surface curvatures of the gyroid scaffold led to a slower tissue formation dynamic and conclusively reduced bone regeneration. The initial claim, that an overall reduced zero mean surface curvature would enhance bone formation, could not be confirmed. The here presented approach illustrates the potential of in silico tools to evaluate in pre-clinical studies scaffold designs and eventually lead to optimized architectures of 3D printed implants for bone regeneration.

Abstract The long-term success of highly effective total hip arthroplasty (THA) is mainly restricted by aseptic loosening, which is widely associated with friction between the head and cup liner. However, knowledge of the in vivo joint friction and resulting temperature increase is limited. Employing a novel combination of in vivo and in silico technologies, we analyzed the hypothesis that the intraoperatively defined implant orientation defines the individual joint roofing, friction and its associated temperature increase. A total of 38,000 in vivo activity trials from a special group of 10 subjects with instrumented THA implants with an identical material combination were analyzed and showed a significant link between implant orientation, joint kinematics, joint roofing and friction-induced temperature increase but surprisingly not with acting joint contact force magnitude. This combined in vivo and in silico analysis revealed that cup placement in relation to the stem is key to the in vivo joint friction and heating-up of THA. Thus, intraoperative placement, and not only articulating materials, should be the focus of further improvements, especially for young and more active patients.

The success of cell-free in situ tissue engineering approaches depends on an appropriate recruitment of autologous cells from neighboring tissues. This identifies cellular migration as a critical parameter for the pre-clinical characterization of biomaterials. Here, we present a new method to quantify both the extent and the spatial anisotropy of cell migration in vitro. For this purpose, a cell spheroid is used as a cell source to provide a high number of cells for cellular invasion and, at the same time, to guarantee a controlled and spatially localized contact to the material. Therefore, current limitations of assays based on 2D cell sources can be overcome. We tested the method on three biomaterials that are in clinical use for soft tissue augmentation in maxilla-facial surgery and a substrate used for 3D in vitro cell culture. The selected biomaterials were all collagen-derived, but differed in their internal architecture. The analysis of cellular isodensity profiles within the biomaterials allowed the identification of the extent and the preferential directions of migration, as well as their relation to the biomaterials and their specific pore morphologies. The higher cell density within the biomaterials resulting from the here-introduced cell spheroid assay compared to established 2D cell layer assays suggests a better representation of the in vivo situation. Consequently, the presented method is proposed to advance the pre-clinical evaluation of cell recruitment into biomaterials, possibly leading to an improved prediction of the regeneration outcome.

Abstract Loss-of-function mutations in the Sost gene lead to high bone mass phenotypes. Pharmacological inhibition of Sost/sclerostin provides a new drug strategy for treating osteoporosis. Questions remain as to how physical activity may affect bone mass under sclerostin inhibition and if that effect differs between males and females. We previously observed in female Sost knockout (KO) mice an enhanced cortical bone formation response to a moderate level of applied loading (900 με at the tibial midshaft). The purpose of the present study was to examine cortical bone adaptation to the same strain level applied to male Sost KO mice. Strain-matched in vivo compressive loading was applied to the tibiae of 10-, 26- and 52-week-old male Sost KO and littermate control (LC) mice. The effect of tibial loading on bone (re)modeling was measured by microCT, 3D time-lapse in vivo morphometry, 2D histomorphometry and gene expression analyses. As expected, Sost deficiency led to high cortical bone mass in 10- and 26-week-old male mice as a result of increased bone formation. However, the enhanced bone formation associated with Sost deficiency did not appear to diminish with skeletal maturation. An increase in bone resorption was observed with skeletal maturation in male LC and Sost KO mice. Two weeks of in vivo loading (900 με at the tibial midshaft) induced only a mild anabolic response in 10- and 26-week-old male mice, independent of Sost deficiency. A decrease in the Wnt inhibitor Dkk1 expression was observed 3 h after loading in 52-week-old Sost KO and LC mice, and an increase in Lef1 expression was observed 8 h after loading in 10-week-old Sost KO mice. The current results suggest that long-term inhibition of sclerostin in male mice does not influence the adaptive response of cortical bone to moderate levels of loading. In contrast with our previous strain-matched study in females showing enhanced bone responses with Sost ablation, these results in males indicate that the influence of Sost deficiency on the cortical bone formation response to a moderate level of loading differs between males and females. Clinical studies examining antibodies to inhibit sclerostin may need to consider that the efficacy of additional physical activity regimens may be sex dependent.

Current clinical treatments of osteochondral defects in articulating joints are frequently not successful in restoring articular surfaces. Novel scaffold-based tissue engineering strategies may help to improve current treatment options and foster a true regeneration of articulating structures. A frequently desired property of scaffolds is their ability to degrade over time and allow a full restoration of tissue and function. However, it remains largely unknown how scaffold degradation influences the mechanical stability of the tissue in a defect region and, in turn, the regenerative process. Such differing goals–supporting regeneration by degrading its own structure–can hardly be analyzed for tissue engineered constructs in clinical trials and in vivo preclinical experiments. Using an in silico analysis, we investigated the degradation-induced modifications in material and architectural properties of a scaffold with strut-like architecture over the healing course and their influence on the mechanics-dependent tissue formation in osteochondral defects. The repair outcome greatly varied depending on the degradation modality, i.e. surface erosion or bulk degradation with and without autocatalysis, and of the degradation speed, i.e. faster, equal or slower than the expected repair time. Bulk degradation with autocatalysis, independently of degradation speed, caused the mechanical failure of the scaffold prior to osteochondral defect repair and was thereby deemed inappropriate for further application. On the other hand, scaffolds with strut-like architecture degrading by both surface erosion and bulk degradation with slow degradation speed resulted in comparably good repair outcomes, thereby indicating such degradation modalities as favorable for the application in osteochondral defects.

This study aimed to characterize ipsilateral loading and return to weight-bearing symmetry (WBS) in patients undergoing total hip arthroplasty (THA) during activities of daily living (ADLs) using instrumented insoles. A prospective study in 25 THA patients was performed, which included controlled pre- and postoperative follow-ups in a single rehabilitation center of an orthopedic department. Ipsilateral loading and WBS of ADLs were measured with insoles in THA patients and in a healthy control group of 25 participants. Measurements in the THA group were performed at 4 different visits: a week pre-THA, within a week post-THA, 3–6 weeks post-THA, and 6–12 weeks post-THA, whereas the healthy control group was measured once. ADLs included standing comfortably, standing evenly, walking, and sit-to-stand-to-sit (StS) transitions. All ADLs were analyzed using discrete methods, and walking included a time-scale analysis to provide temporal insights in the ipsilateral loading and WBS waveforms. THA patients only improved beyond their pre-surgery levels while standing comfortably (ipsilateral loading and WBS, p < 0.05) and during StS transitions (WBS, p < 0.05). Nevertheless, patients improved upon their ipsilateral loading and WBS deficits observed within a week post-surgery across all investigated ADLs. Ipsilateral loading and WBS of THA patients were comparable to healthy participants at 6–12 weeks post-THA, except for ipsilateral loading during walking (p < 0.05) at the initial and terminal double-leg support period of the stance phase. Taken together, insole measurements allow for the quantification of ipsilateral loading and WBS deficits during ADLs, identifying differences between pre- and postoperative periods, and differentiating THA patients from healthy participants. However, post-THA measurements that lack pre-surgery assessments may not be sensitive to identifying patient-specific improvements in ipsilateral loading and WBS. Moreover, StS transitions and earlier follow-up time points should be considered an important clinical metric of biomechanical recovery after THA.

Total hip arthroplasty (THA) is an extremely successful treatment strategy. Patient expectations, however, have increased; if not properly guided by surgeons, at present, patients expect next to pain-free restoration of the joint and a fast return to work and sports. While the revision rates after THA also increased in younger patients, knowledge on musculoskeletal loads still remains sparse, and the current recommendations on postoperative rehabilitation are based on expert opinions only. The aim of this study was to unravel biomechanical contact conditions in “working age” (60 years, 67.7 ± 8.6 years) patients during activities recommended post-THA. We hypothesized that working age patients would show substantially increased hip contact loads compared to older patients. The in vivo joint contact force (Fres) and torsion torque (Mtors), reflecting the main contact load situation, experienced during activities of daily living and sports activities were measured in a unique group of 16 patients with instrumented THA. We summarized patient activities and sports recommendations after THA mentioned within the literature using PubMed (without claim of completeness). The measurements showed that younger working age patients experienced significant (p = 0.050) increased Mtors (21.52 ± 9.11 Nm) than older retirement age patients (13.99 ± 7.89 Nm) by walking. Bowling, as a recommended low-impact sport, was associated with Fres of up to 5436 N and Mtors of up to 108 Nm in the working age group, which were higher than the Fres (5276 N) and Mtors (71 Nm) during high-impact soccer. Based on our results, age was proven to be a discriminator in joint loading, with working age patients presenting with increased loads compared to retirement age patients, already during daily activities. The current patient recommendations have led to further increased joint loadings. If THA cannot be delayed in a patient, we propose counselling patients on a carefully considered return to sports, focusing on low-impact activities, as indicated hereby. The findings from this work illustrate the need to provide critical feedback to patient expectations when returning to work and sports activities. Patients returning to more intensive sports activities should be carefully monitored and advised to avoid as much overloading as possible.

Titanium fixation devices are the gold standard for the treatment of mandibular fractures; however, they present serious limitations, such as non-degradability and generation of imaging artifacts. As an alternative, biodegradable magnesium alloys have lately drawn attention due to their biodegradability and biocompatibility. In addition, magnesium alloys offer a relatively high modulus of elasticity in comparison to biodegradable polymers, being a potential option to substitute titanium in highly loaded anatomical areas, such as the mandible. This study aimed to evaluate the biomechanical competence of magnesium alloy WE43 plates for mandibular fracture fixation in comparison to the clinical standard or even softer polymer solutions. A 3D finite element model of the human mandible was developed, and four different fracture scenarios were simulated, together with physiological post-operative loading and boundary conditions. In a systematic comparison, the material properties of titanium alloy Ti-6Al-4V, magnesium alloy WE43, and polylactic acid (PLA) were assigned to the fixation devices, and two different plate thicknesses were tested. No failure was predicted in the fixation devices for any of the tested materials. Moreover, the magnesium and titanium fixation devices induced a similar amount of strain within the healing regions. On the other hand, the PLA devices led to higher mechanical strains within the healing region. Plate thickness only slightly influenced the primary fixation stability. Therefore, magnesium alloy WE43 fixation devices seem to provide a suitable biomechanical environment to support mandibular fracture healing in the early stages of bone healing. Magnesium WE43 showed a biomechanical performance similar to clinically used titanium devices with the added advantages of biodegradability and radiopacity, and at the same time it showed a remarkably higher primary stability compared to PLA fixation devices, which appear to be too unstable, especially in the posterior and more loaded mandibular fracture cases.

Summary: Pharmacological application of teleost calcitonin (CT) has been shown to exert chondroprotective and anti-resorptive effects in patients with rheumatoid arthritis (RA). However, the role of endogenous CT that signals through the calcitonin receptor (CTR) remains elusive. Collagen II antibody-induced arthritis (CAIA) was stimulated in wild type (WT) and CTR-deficient (Calcr−/−) mice. Animals were monitored over 10 or 48 days. Joint inflammation, cartilage degradation, and bone erosions were assessed by clinical arthritis score, histology, histomorphometry, gene expression analysis, and μ-computed tomography. CAIA was accompanied by elevated systemic CT levels and CTR expression in the articular cartilage. Inflammation, cartilage degradation, and systemic bone loss were more pronounced in Calcr−/− CAIA mice. Expression of various pro-inflammatory, bone resorption, and catabolic cartilage markers were exclusively increased in Calcr−/− CAIA mice. Endogenous CT signaling through the mammalian CTR has the potential to protect against joint inflammation, cartilage degradation, and excessive bone remodeling in experimental RA.

Low back pain (LBP) could be associated with a reduced lumbar mobility. For the evaluation of lumbar flexibility, parameters such as finger-floor distance (FFD) are historically established. However, the extent of the correlation of FFD to lumbar flexibility or other involved joint kinematics such as pelvic motion, as well as the influence of LBP, is not yet known. We conducted a prospective cross-sectional observation study with 523 participants included (167 with LBP > 12 weeks, 356 asymptomatic). LBP-participants were matched for sex, age, height, and body-mass-index with an asymptomatic control cohort, resulting in two cohorts with 120 participants each. The FFD in maximal trunk flexion was measured. The Epionics-SPINE measurement-system was used to evaluate the pelvic and lumbar Range-of-Flexion (RoF), and the correlation of FFD to pelvic- and lumbar-RoF was evaluated. In an asymptomatic sub-cohort of 12 participants, we examined the individual correlation of FFD to pelvic- and lumbar-RoF under gradual trunk flexion. Participants with LBP showed a significantly reduced pelvic-RoF (p < 0.001) and lumbar-RoF (p < 0.001) as well as an increased FFD (p < 0.001) compared to the asymptomatic control cohort. Asymptomatic participants exhibited a weak correlation of FFD to pelvic-RoF and lumbar-RoF (r < 0.500). LBP patients revealed a moderate correlation of FFD to pelvic-RoF (male: p < 0.001, r = −0.653, female: p < 0.001, r = −0.649) and sex-dependent to lumbar-RoF (male: p < 0.001, r = −0.604, female: p = 0.012, r = −0.256). In the sub-cohort of 12 participants, gradual trunk flexion showed a strong correlation of FFD to pelvic-RoF (p < 0.001, r = −0.895) but a moderate correlation to lumbar-RoF (p < 0.001, r = −0.602). The differences in FFD in an individual patient, assuming consistent hip function, may be attributed partially to the differences in lumbar flexibility. However, the absolute values of FFD do not qualify as a measure for lumbar mobility. Rather, using validated non-invasive measurement devices should be considered.

Some approaches in total knee arthroplasty aim for an oblique joint line to achieve an even medio-lateral load distribution across the condyles during the stance phase of gait. While there is much focus on the angulation of the joint line in static frontal radiographs, precise knowledge of the associated dynamic joint line orientation and the internal joint loading is limited. The aim of this study was to analyze how static alignment in frontal radiographs relates to dynamic alignment and load distribution, based on direct measurements of the internal joint loading and kinematics. A unique and novel combination of telemetrically measured in vivo knee joint loading and simultaneous internal joint kinematics derived from mobile fluoroscopy (“CAMS-Knee dataset”) was employed to access the dynamic alignment and internal joint loading in 6 TKA patients during level walking. Static alignment was measured in standard frontal postoperative radiographs while external adduction moments were computed based on ground reaction forces. Both static and dynamic parameters were analyzed to identify correlations using linear and non-linear regression. At peak loading during gait, the joint line was tilted laterally by 4°–7° compared to the static joint line in most patients. This dynamic joint line tilt did not show a strong correlation with the medial force (R2: 0.17) or with the mediolateral force distribution (pseudo R2: 0.19). However, the external adduction moment showed a strong correlation with the medial force (R2: 0.85) and with the mediolateral force distribution (pseudo R2: 0.78). Alignment measured in static radiographs has only limited predictive power for dynamic kinematics and loading, and even the dynamic orientation of the joint line is not an important factor for the medio-lateral knee load distribution. Preventive and rehabilitative measures should focus on the external knee adduction moment based on the vertical and horizontal components of the ground reaction forces.

Abstract Diseases that jeopardize the musculoskeletal system and cause chronic impairment are prevalent throughout the Western world. In Germany alone, ~1.8 million patients suffer from these diseases annually, and medical expenses have been reported to reach 34.2bn Euros. Although musculoskeletal disorders are seldom fatal, they compromise quality of life and diminish functional capacity. For example, musculoskeletal disorders incur an annual loss of over 0.8 million workforce years to the German economy. Among these diseases, traumatic skeletal muscle injuries are especially problematic because they can occur owing to a variety of causes and are very challenging to treat. In contrast to chronic muscle diseases such as dystrophy, sarcopenia, or cachexia, traumatic muscle injuries inflict damage to localized muscle groups. Although minor muscle trauma heals without severe consequences, no reliable clinical strategy exists to prevent excessive fibrosis or fatty degeneration, both of which occur after severe traumatic injury and contribute to muscle degeneration and dysfunction. Of the many proposed strategies, cell‐based approaches have shown the most promising results in numerous pre‐clinical studies and have demonstrated success in the handful of clinical trials performed so far. A number of myogenic and non‐myogenic cell types benefit muscle healing, either by directly participating in new tissue formation or by stimulating the endogenous processes of muscle repair. These cell types operate via distinct modes of action, and they demonstrate varying levels of feasibility for muscle regeneration depending, to an extent, on the muscle injury model used. While in some models the injury naturally resolves over time, other models have been developed to recapitulate the peculiarities of real‐life injuries and therefore mimic the structural and functional impairment observed in humans. Existing limitations of cell therapy approaches include issues related to autologous harvesting, expansion and sorting protocols, optimal dosage, and viability after transplantation. Several clinical trials have been performed to treat skeletal muscle injuries using myogenic progenitor cells or multipotent stromal cells, with promising outcomes. Recent improvements in our understanding of cell behaviour and the mechanistic basis for their modes of action have led to a new paradigm in cell therapies where physical, chemical, and signalling cues presented through biomaterials can instruct cells and enhance their regenerative capacity. Altogether, these studies and experiences provide a positive outlook on future opportunities towards innovative cell‐based solutions for treating traumatic muscle injuries—a so far unmet clinical need.

Abstract Background An early detection of Osteoarthritis is urgently needed and still not possible until today. The aim of the study was to assess whether molecular biomarkers of cartilage turnover are associated with longitudinal change in knee cartilage thickness during a 2 year period in individuals with increased risk of developing knee osteoarthritis. A secondary aim was to assess whether prior knee injury or subjective patient-reported outcomes at baseline (BL) were associated with articular cartilage changes. Nineteen volleyball players (mean age 46.5 ± 4.9 years, 47% male) with a 30-year history of regular high impact training were recruited. The serum biomarkers Cpropeptide of type II procollagen (CPII), cartilage oligomeric matrix protein (COMP), collagenase generated carboxy-terminal neoepitope of type II collagen (sC2C), cartilage intermediate layer protein 2 (CILP-2), and the urine biomarkers C-telopeptide of type II collagen (CTX-II) and collagenase-generated peptide(s) of type II collagen (C2C-HUSA) were assessed at BL and at 2 year follow up (FU). Femorotibial cartilage thinning, thickening and absolute thickness change between BL and FU was evaluated from magnetic resonance imaging. Subjective clinical status at BL was evaluated by the International Knee Documentation Committee Subjective Knee Form and the Short-Form 36 Physical Component Score. Results CILP-2 was significantly higher at FU and linearly associated with the absolute cartilage thickness change during the experimental period. Prior injury was a predictor of increased absolute cartilage thickness change. Conclusion Measuring the change in the cartilage biomarker CILP-2 might be a valid and sensitive method to detect early development of knee osteoarthritis as CILP-2 appears to be related to cartilage thickness loss in certain individuals with increased risk of developing knee osteoarthritis. Prior knee injury may be predictive of increased articular cartilage thickness change.

The mechano-response of highly loaded tissues such as bones or tendons is well investigated, but knowledge regarding the mechano-responsiveness of adjacent tissues such as the subacromial bursa is missing. For a better understanding of the physiological role of the bursa as a friction-reducing structure in the joint, the study aimed to analyze whether and how bursa-derived cells respond to physiological and pathological mechanical loading. This might help to overcome some of the controversies in the field regarding the role of the bursa in the development and healing of shoulder pathologies. Cells of six donors seeded on collagen-coated silicon dishes were stimulated over 3 days for 1 or 4 h with 1, 5, or 10% strain. Orientation of the actin cytoskeleton, YAP nuclear translocation, and activation of non-muscle myosin II (NMM-II) were evaluated for 4 h stimulations to get a deeper insight into mechano-transduction processes. To investigate the potential of bursa-derived cells to adapt their matrix formation and remodeling according to mechanical loading, outcome measures included cell viability, gene expression of extracellular matrix and remodeling markers, and protein secretions. The orientation angle of the actin cytoskeleton increased toward a more perpendicular direction with increased loading and lowest variations for the 5% loading group. With 10% tension load, cells were visibly stressed, indicated by loss in actin density and slightly reduced cell viability. A significantly increased YAP nuclear translocation occurred for the 1% loading group with a similar trend for the 5% group. NMM-II activation was weak for all stimulation conditions. On the gene expression level, only the expression of TIMP2 was down-regulated in the 1 h group compared to control. On the protein level, collagen type I and MMP2 increased with higher/longer straining, respectively, whereas TIMP1 secretion was reduced, resulting in an MMP/TIMP imbalance. In conclusion, this study documents for the first time a clear mechano-responsiveness in bursa-derived cells with activation of mechano-transduction pathways and thus hint to a physiological function of mechanical loading in bursa-derived cells. This study represents the basis for further investigations, which might lead to improved treatment options of subacromial bursa-related pathologies in the future.

Mandibular fracture fixation and reconstruction are usually performed using titanium plates and screws, however, there is a need to improve current fixation techniques. Animal models represent an important step for the testing of new designs and materials. However, the validity of those preclinical models in terms of implant biomechanics remains largely unknown. In this study, we investigate the biomechanics of the sheep mandible as a preclinical model for testing the mechanical strength of fixation devices and the biomechanical environment induced on mandibular fractures. We aimed to assess the comparability of the biomechanical conditions in the sheep mandible as a preclinical model for human applications of fracture fixation devices and empower analyses of the effect of such defined mechanical conditions on bone healing outcome. We developed 3D finite element models of the human and sheep mandibles simulating physiological muscular loads and three different clenching tasks (intercuspal, incisal, and unilateral). Furthermore, we simulated fractures in the human mandibular body, sheep mandibular body, and sheep mandibular diastema fixated with clinically used titanium miniplates and screws. We compared, at the power stroke of mastication, the biomechanical environment (1) in the healthy mandibular body and (2) at the fracture sites, and (3) the mechanical solicitation of the implants as well as the mechanical conditions for bone healing in such cases. In the healthy mandibles, the sheep mandibular body showed lower mechanical strains compared to the human mandibular body. In the fractured mandibles, strains within a fracture gap in sheep were generally not comparable to humans, while similar or lower mechanical solicitation of the fixation devices was found between the human mandibular body fracture and the sheep mandibular diastema fracture scenarios. We, therefore, conclude that the mechanical environments of mandibular fractures in humans and sheep differ and our analyses suggest that the sheep mandibular bone should be carefully re-considered as a model system to study the effect of fixation devices on the healing outcome. In our analyses, the sheep mandibular diastema showed similar mechanical conditions for fracture fixation devices to those in humans.

Abstract. This manuscript summarizes presentations of a symposium on key considerations in design of biomechanical models at the 2019 Basic Science Focus Forum of the Orthopaedic Trauma Association. The first section outlines the most important characteristics of a high-quality biomechanical study. The second section considers choices associated with designing experiments using finite element modeling versus synthetic bones versus human specimens. The third section discusses appropriate selection of experimental protocols and finite element analyses. The fourth section considers the pros and cons of use of biomechanical research for implant design. Finally, the fifth section examines how results from biomechanical studies can be used when clinical evidence is lacking or contradictory. When taken together, these presentations emphasize the critical importance of biomechanical research and the need to carefully consider and optimize models when designing a biomechanical study.

A misdirected or imbalanced local immune composition is often one of the reasons for unsuccessful regeneration resulting in scarring or fibrosis. Successful healing requires a balanced initiation and a timely down-regulation of the inflammation for the re-establishment of a biologically and mechanically homeostasis. While biomaterial-based approaches to control local immune responses are emerging as potential new treatment options, the extent to which biophysical material properties themselves play a role in modulating a local immune niche response has so far been considered only occasionally. The communication loop between extracellular matrix, non-hematopoietic cells, and immune cells seems to be specifically sensitive to mechanical cues and appears to play a role in the initiation and promotion of a local inflammatory setting. In this review, we focus on the crosstalk between ECM and its mechanical triggers and how they impact immune cells and non-hematopoietic cells and their crosstalk during tissue regeneration. We realized that especially mechanosensitive receptors such as TRPV4 and PIEZO1 and the mechanosensitive transcription factor YAP/TAZ are essential to regeneration in various organ settings. This indicates novel opportunities for therapeutic approaches to improve tissue regeneration, based on the immune-mechanical principles found in bone but also lung, heart, and skin.