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.

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.

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.

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.

Biomechanical evaluation of CAD/CAM magnesium miniplates as a fixation strategy for the treatment of segmental mandibular reconstruction with a fibula free flap.

Titanium patient-specific (CAD/CAM) plates are frequently used in mandibular reconstruction. However, titanium is a very stiff, non-degradable material which also induces artifacts in the imaging. Although magnesium has been proposed as a potential material alternative, the biomechanical conditions in the reconstructed mandible under magnesium CAD/CAM plate fixation are unknown. This study aimed to evaluate the primary fixation stability and potential of magnesium CAD/CAM miniplates. The biomechanical environment in a one segmental mandibular reconstruction with fibula free flap induced by a combination of a short posterior titanium CAD/CAM reconstruction plate and two anterior CAD/CAM miniplates of titanium and/or magnesium was evaluated, using computer modeling approaches. Output parameters were the strains in the healing regions and the stresses in the plates. Mechanical strains increased locally under magnesium fixation. Two plate-protective constellations for magnesium plates were identified: (1) pairing one magnesium miniplate with a parallel titanium miniplate and (2) pairing anterior magnesium miniplates with a posterior titanium reconstruction plate. Due to their degradability and reduced stiffness in comparison to titanium, magnesium plates could be beneficial for bone healing. Magnesium miniplates can be paired with titanium plates to ensure a non-occurrence of plate failure.

Quantifying bone healing after mandibular displacement in orthognathic surgery.

Impaired bony healing following bilateral sagittal split osteotomy (BSSO) is a major unmet medical need for affected patients, and rare occurrences can hinder the identification of underlying risk factors. We hypothesised that osseous union following BSSO can be quantified using volumetric analysis, and we aimed to identify the risk factors for impaired bone healing. The percentage change in bony volume was measured in orthognathic patients following BSSO using two consecutive postoperative cone-beam computed tomography scans. Patients' characteristics and treatment parameters were documented, and correlation and regression analyses of these variables performed. Thirty-six patients (23 men and 13 women) with a mean (SD) age of 33.28 (11.86) years were included. The gap site (lingual versus buccal) (p < 0.01) had a significant impact on the change in volume. Age (p = 0.06) showed a trend towards significance. Initial width of the osteotomy gap, sex, and indication for surgery did not influence osseous healing. Increased age at surgery and the side of the buccal osteotomy are independent risk factors for impaired osseous healing following BSSO.

Improved weight bearing during gait at 6 weeks post-surgery with an angle stable locking system after distal tibial fracture.

BACKGROUND: Functional recovery after intramedullary nailing of distal tibial fractures can be monitored using ipsilateral vertical ground reaction forces (vGRF), giving insight into recovery of patients' gait symmetry. Previous work compared patient cohorts to healthy controls, but it remains unclear if these metrics can identify treatment-based differences in return to function post-surgery. RESEARCH QUESTION: Is treatment of a distal tibial fracture with intramedullary nailing with an angle stable locking system (ASLS) associated with higher ipsilateral vGRF and improved symmetry compared to conventional intramedullary nailing at an early time point? METHODS: Thirty-nine patients treated with ASLS intramedullary nailing were retrospectively compared to thirty-nine patients with conventional locking. vGRFs were collected at 1, 6, 12, 26, and 52 weeks post-surgery during standing and gait. Discrete metrics of ipsilateral vGRF (maximal force, impulse) and asymmetry were compared between treatments at each time point. Time-scale comparisons of ipsilateral vGRF and lower limb asymmetry were additionally performed for gait trials. Mann-Whitney Test or a two-way analysis of variance tested discrete comparisons; statistical non-parametric mapping tested time-scale data between treatment groups. RESULTS: During gait, ASLS-treated patients applied more load on the operated limb (17-38% stance, p = 0.015) and consequently loaded limbs more symmetrically (8-37% stance, p = 0.008) during the loading response at 6 weeks post-surgery compared to conventional IM treatment. Discrete measures of symmetry at the same time point identified treatment-based differences in maximal force (p = 0.039) and impulse (p = 0.012), with ASLS-treated patients exhibiting more symmetry. No differences were identified in gait trials at later time points nor from all standing trials. SIGNIFICANCE: During the initial loading response of gait, increased ipsilateral vGRF and improved weightbearing symmetry were identified in ASLS patients at 6 weeks post-surgery compared to conventional IM nailing. Early and objective metrics of dynamic movement are suggested to identify treatment-based differences in functional recovery.

Sex- and age-related differences in the inflammatory properties of cardiac fibroblasts: impact on the cardiosplenic axis and cardiac fibrosis.

Background: Age 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. Materials: Left 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. Results: LV-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-ß+ 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. Conclusion: Age- and sex-dependent differences in cardiac fibrosis and inflammation are related to age- and sex-dependent variations in the inflammatory properties of cardiac fibroblasts.

Loading of the Hip and Knee During Swimming: An in Vivo Load Study.

BACKGROUND: Swimming is commonly recommended as postoperative rehabilitation following total hip arthroplasty (THA) and total knee arthroplasty (TKA). So far, in vivo hip and knee joint loads during swimming remain undescribed. METHODS: In vivo hip and knee joint loads were measured in 6 patients who underwent THA and 5 patients who underwent TKA with instrumented joint implants. Joint loads, including the resultant joint contact force (F Res ), torsional moment around the femoral shaft axis or the tibial axis (M Tors ), bending moment at the middle of the femoral neck (M Bend ), torsional moment around the femoral neck axis (M Tne ), and medial force ratio (MFR) in the knee, were measured during breaststroke swimming at 0.5, 0.6, and 0.7 m/s and the breaststroke and crawl kicks at 0.5 and 1.0 m/s. RESULTS: The ranges of the median maximal F Res were 157% to 193% of body weight for the hip and 93% to 145% of body weight for the knee during breaststroke swimming. Greater maxima of F Res (hip and knee), M Tors (hip and knee), M Bend (hip), and M Tne (hip) were observed with higher breaststroke swimming velocities, but significance was only identified between 0.5 and 0.6 m/s in F Res (p = 0.028), M Tors (p = 0.028), and M Bend (p = 0.028) and between 0.5 and 0.7 m/s in F Res (p = 0.045) in hips. No difference was found in maximal MFR between different breaststroke swimming velocities. The maximal F Res was significantly positively correlated with the breaststroke swimming velocity (hip: r = 0.541; p < 0.05; and knee: r = 0.414; p < 0.001). The maximal F Res (hip and knee) and moments (hip) were higher in the crawl kick than in the breaststroke kick, and a significant difference was recognized in F Res Max for the hip: median, 179% versus 118% of body weight (p = 0.028) for 0.5 m/s and 166% versus 133% of body weight (p = 0.028) for 1.0 m/s. CONCLUSIONS: Swimming is a safe and low-impact activity, particularly recommended for patients who undergo THA or TKA. Hip and knee joint loads are greater with higher swimming velocities and can be influenced by swimming styles. Nevertheless, concrete suggestions to patients who undergo arthroplasty on swimming should involve individual considerations. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

The dual pro-inflammatory and bone-protective role of calcitonin gene-related peptide alpha in age-related osteoarthritis.

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.

Uterine scars after caesarean delivery: From histology to the molecular and ultrastructural level.

Uterine rupture during a trial of labor after caesarean delivery (CD) is a serious complication for mother and fetus. The lack of knowledge on histological features and molecular pathways of uterine wound healing has hindered research in this area from evolving over time. We analysed collagen content and turnover in uterine scars on a histological, molecular and ultrastructural level. Therefore, tissue samples from the lower uterine segment were obtained during CD from 16 pregnant women with at least one previous CD, from 16 pregnant women without previous CD, and from 16 non-pregnant premenopausal women after hysterectomy for a benign disease. Histomorphometrical collagen quantification showed, that the collagen content of the scar area in uterine wall specimens after previous CD was significantly higher than in the unscarred myometrium of the same women and the control groups. Quantitative real-time PCR of uterine scar tissue from FFPE samples delineated by laser microdissection yielded a significantly higher COL3A1 expression and a significantly lower COL1A2/COL3A1 ratio in scarred uteri than in samples from unscarred uteri. Histological collagen content and the expression of COL1A2 and COL3A1 were positively correlated, while COL1A2/COL3A1 ratio was negatively correlated with the histological collagen content. Transmission electron microscopy revealed a destroyed myometrial ultrastructure in uterine scars with increased collagen density. We conclude that the high collagen content in uterine scars results from an ongoing overexpression of collagen I and III. This is a proof of concept to enable further analyses of specific factors that mediate uterine wound healing.

External mechanical loading overrules cell-cell mechanical communication in sprouting angiogenesis during early bone regeneration.

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.

Reduced Bone Regeneration in Rats With Type 2 Diabetes Mellitus as a Result of Impaired Stromal Cell and Osteoblast Function-A Computer Modeling Study.

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.

Lower-limb internal loading and potential consequences for fracture healing.

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.

Biomarkers for osteoarthritis: Current status and future prospects.

Osteoarthritis (OA) is the most common form of arthritis globally and a major cause of pain, physical disability, and loss of economic productivity, with currently no causal treatment available. This review article focuses on current research on OA biomarkers and the potential for using biomarkers in future clinical practice and clinical trials of investigational drugs. We discuss how biomarkers, specifically soluble ones, have a long path to go before reaching clinical standards of care. We also discuss how biomarkers can help in phenotyping and subtyping to achieve enhanced stratification and move toward better-designed clinical trials. We also describe how biomarkers can be used for molecular endotyping and for determining the clinical outcomes of investigational cell-based therapies. Biomarkers have the potential to be developed as surrogate end points in clinical trials and help private-public consortia and the biotechnology and pharmaceutical industries develop more effective and targeted personalized treatments and enhance clinical care for patients with OA.

Measuring translational research impact requires reaching beyond current metrics.

Translational impact assessment is key to selecting those biomedical research discoveries most likely to be converted into viable new products to improve human health. However, metrics for translational success are variable, are not limited to commercial success, and may not be relevant to every case or institution. Societal impact is a top translational priority in a globalized society.

Introduction of innovations in joint arthroplasty: Recommendations from the 'EFORT implant and patient safety initiative'.

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.

Elastin stabilization prevents impaired biomechanics in human pulmonary arteries and pulmonary hypertension in rats with left heart disease.

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.

Aging and injury affect nuclear shape heterogeneity in tendon.

Tissue level properties are commonly studied using histological stains assessed with qualitative scoring methods. As qualitative evaluation is typically insensitive, quantitative analysis provides additional information about pathological mechanisms, but cannot capture structural heterogeneity across cell subpopulations. However, molecular analyses of cell and nuclear behavior have identified that cell and more recently also nuclear shape are highly associated with cell function and malfunction. This study combined a Visually Aided Morpho-Phenotyping Image Recognition analysis that automatically segments cells based on their shape with an added capacity to further discriminate between cells in certain protein-rich extracellular matrix regions. We used tendon as a model system given the enormous changes in organization and cell and nuclear shape they undergo during aging and injury. Our results uncover that multiple shape modes of nuclei exist during maturity and aging in rat tendon and that distinct subgroups of cell nuclei shapes exist in proteoglycan-rich regions during aging. With injury, several immunomarkers (αSMA, CD31, CD146) were associated with more rounded shape modes. In human tendons, the cell nuclei at sites of injury were found to be more rounded relative to uninjured tissues. To conclude, the tendon tissue changes occurring during aging and injury could be associated with a variation in cell nuclear morphology and the appearance of various region-specific subpopulations. Thus, the methodologies developed allow for a deeper understanding of cell heterogeneity during tendon aging and injury and may be extended to study further clinical applications.