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In attempting to develop non-invasive image based measures for the determination of the biomechanical integrity of healing fractures, traditional μCT based measurements have been limited. This study presents the development and evaluation of a tool for assessment of fracture callus mechanical properties through determination of the geometric characteristics of the fracture callus, specifically along the surface of failure identified during destructive mechanical testing. Fractures were created in tibias of ten male mice and subjected to μCT imaging and biomechanical torsion testing. Failure surface analysis, along with previously described image based measures was calculated using the μCT image data, and correlated with mechanical strength and stiffness. Three-dimensional measures along the surface of failure, specifically the surface area and torsional rigidity of bone, were shown to be significantly correlating with mechanical strength and stiffness. It was also shown that surface area of bone along the failure surface exhibits stronger correlations with both strength and stiffness than measures of average and minimum torsional rigidity of the entire callus. Failure surfaces observed in this study were generally oriented at 45° to the long axis of the bone, and were not contained exclusively within the callus. This work represents a proof of concept study, and shows the potential utility of failure surface analysis in the assessment of fracture callus stability.

Background This study was performed to compare the operative clinical outcomes of helical plating, intramedullary nailing (IMN), and long straight lateral plating in the treatment of humeral shaft fractures extending into the proximal humerus, as well as to identify the optimal fixation strategy for managing such injuries. Methods In total, 81 patients with humeral shaft fractures extending into the proximal humerus were divided into three groups based on treatment strategy: helical plating (Group A, n  = 16), IMN (Group B, n  = 12), and long straight lateral plating (Group C, n  = 53). Preoperative demographic data and imaging were collected from the medical records. Operative time, blood transfusion, bone reduction quality, bone healing rate, and incidence of complications were recorded. Clinical evaluation included the Constant–Murley score for shoulder function, the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire for upper limb function, the visual analogue scale (VAS) for pain, and assessments of shoulder stiffness or instability and patient satisfaction. Results Compared with Groups A and C, patients in Group B had a longer operative time and lower blood transfusion requirements. More than 80% of patients in each group achieved bone reduction quality rated as “better than good.” There were no significant differences among the three groups in operative time, blood transfusion, or shaft angulation. Bone healing rates were 100%, 91.7%, and 94.3% in Groups A, B, and C, respectively. Mean shoulder flexion was 155.0°, 130.0°, and 150.0°, respectively. Functional outcomes, including the Constant–Murley score, DASH score, VAS score, and patient satisfaction, were significantly better in Group A than in Groups B and C. No complications occurred in Group A. One patient in Group B developed nonunion. In Group C, complications were observed in five patients (9.4%). Conclusion In the treatment of humeral shaft fractures extending into the proximal humerus, helical plating was associated with a higher bone union rate, better functional outcomes, and a lower postoperative complication rate compared with IMN or long straight lateral locking plates. Outcomes after nailing and long straight lateral plating were similar.

Carpal navicular fractures are the most common carpal fractures. This study intends to explore the specific mechanism of Zoledronic Acid (ZA) in carpal navicular fracture healing via long non-coding RNA (lncRNA) growth arrest specificity 5 (GAS5) to mediate microRNA (miR)-29a-3p. A fractured rat model was constructed. Two weeks later, a subcutaneous injection of systemic ZA was implemented, and an injection of plasmid vectors interfered with GAS5 or miR-29a-3p expression was performed on the fracture site. Osteocalcin (OCN) and bone morphogenetic protein-2 (BMP-2) were determined, as well as serum levels of alkaline phosphatase (ALP), osteopontin (OPN) and osteoprotegerin (OPG) and bone mineral density. MC3T3-E1 cells were transfected with plasmid vectors interfering with GAS5 or miR-29a-3p, and cell proliferation and apoptosis were analyzed. GAS5 and miR-29a-3p expression in fractured rats was tested, together with their binding relationship. ZA promoted OCN and BMP-2 expression, increased bone mineral density and serum levels of ALP, OPN and OPG in fractured rats. GAS5 was upregulated and miR-29a-3p was down-regulated in fractured rats. Downregulation of GAS5 or upregulation of miR-29a-3p further promoted bone healing in fractured rats. GAS5 targets miR-29a-3p, and down-regulation of miR-29a-3p can reverse the effect of down-regulation of GAS5 on bone healing in fractured rats. ZA promoted the proliferation of MC3T3-E1 cells and inhibited apoptosis by regulating the GAS5/miR-29a-3p axis. ZA regulates miR-29a-3p expression by down-regulating GAS5 to promote carpal navicular fracture healing, promote MC3T3-E1 cell proliferation, and inhibit cell apoptosis.

Single trauma injuries or isolated fractures are often manageable and generally heal without complications. In contrast, high-energy trauma results in multi/poly-trauma injury patterns presenting imbalanced pro- and anti- inflammatory responses often leading to immune dysfunction. These injuries often exhibit delayed healing, leading to fibrosis of injury sites and delayed healing of fractures depending on the intensity of the compounding traumas. Immune dysfunction is accompanied by a temporal shift in the innate and adaptive immune cells distribution, triggered by the overwhelming release of an arsenal of inflammatory mediators such as complements, cytokines and damage associated molecular patterns (DAMPs) from necrotic cells. Recent studies have implicated this dysregulated inflammation in the poor prognosis of polytraumatic injuries, however, interventions focusing on immunomodulating inflammatory cellular composition and activation, if administered incorrectly, can result in immune suppression and unintended outcomes. Immunomodulation therapy is promising but should be conducted with consideration for the spatial and temporal distribution of the immune cells during impaired healing. This review describes the current state of knowledge in the spatiotemporal distribution patterns of immune cells at various stages during musculoskeletal wound healing, with a focus on recent advances in the field of Osteoimmunology, a study of the interface between the immune and skeletal systems, in long bone fractures. The goals of this review are to (1) discuss wound and fracture healing processes of normal and delayed healing in skeletal muscles and long bones; (2) provide a balanced perspective on temporal distributions of immune cells and skeletal cells during healing; and (3) highlight recent therapeutic interventions used to improve fracture healing. This review is intended to promote an understanding of the importance of inflammation during normal and delayed wound and fracture healing. Knowledge gained will be instrumental in developing novel immunomodulatory approaches for impaired healing.

Infection associated with osteosynthesis material (IOM) is one of the most feared and challenging complications of trauma surgery and can cause significant functional loss, requiring multiple interventions and excessive consumption of antimicrobials. Evidence is needed about the best surgical procedure and the duration of antibiotic treatment according to the age of the implant or onset of infection symptoms, as it considers the biofilm formation and the state of fracture healing. There were not clinical trials evaluating the optimal duration of antibiotic therapy in IOM when implant is retained. Because there are antibiotics that have proven to be effective for the treatment of infection associated to implant, mainly in PJI, these antibiotics could be used in these infections. Investigating whether shorter duration of treatment is a priority in infectious diseases, as a way to reduce the exposure to antibiotics and help in controlling antimicrobial resistance and avoiding unnecessary adverse events and cost. We aim to describe the hypothesis, objectives, design, variables and procedures for a pragmatic randomized controlled trial comparing different durations of antibiotic treatment in IOM after long bone fractures treated with debridement and implant retention. This is a multicenter, open-label, non-inferiority, randomized, controlled, pragmatic phase 3 trial, comparing different durations of antibiotic treatment in IOM after long bone fractures treated with debridement and implant retention. Patients with microbiologically confirmed IOM will be included. Eligible patients are those older than 14 years, with early IOM (up to 2 weeks after the implant surgery) and delayed IOM (between 3 and 10 weeks after the implant surgery) with stabilized fracture and absence of bone exposure who sign the informed consent. Randomization will be 1:1 to receive a short-term antibiotic treatment (8 weeks in early IOM and 12 weeks in delayed IOM) or a long-term antibiotic treatment (12 weeks in early IOM or until fracture healing or implant removal in delayed IOM). The antibiotic treatment will be that used in routine practice by the specialist in infectious diseases. The primary outcome is the composited variable \"cure\" that includes clinical cure, radiological healing, and definitive soft tissue coverage, which will be evaluated in the test of cure at 12 months after the end of antibiotic therapy. Adverse events, resistance development during therapy and functional status will be collected. A total of 364 patients are needed to show a 10% non-inferiority margin, with 80% power and 5% one-sided significance level. If the hypothesis of non-inferiority of short vs. long antibiotic treatments is demonstrated, and the efficacy of antibiotics with less ecological impact in long treatments, the impact on reduction of bacterial resistance, toxicity and health costs will be observed. This trial is registered at ClinicalTrials.gov (NCT05294796) on Jan 26th 2022 and at the European Union Drug Regulating Authorities Clinical Trials (EUDRACT) (2021-003914-38) on Jul 16th 2021. The Sponsor Study Code is DURATIOM.

Background Delayed healing is a common postoperative complication among fractured patients, imposing an additional financial burden. This research examined the clinical relationship between CRNDE and delayed fracture healing (DFH) and the potential regulatory mechanisms underlying fracture improvement. Methods qRT-PCR was utilized to assess the expression of CRNDE and miR-29a-3p in serum and cellular samples, and to evaluate the expression of genes associated with osteogenic differentiation. The diagnostic and predictive significance of serum CRNDE was analyzed using ROC analysis and logistic regression. Additionally, an hFOB 1.19 osteogenic differentiation model was established. The CCK-8 assay and flow cytometry techniques were used to investigate the effects of silencing CRNDE, as well as the concurrent inhibition of both CRNDE and miR-29a-3p, on the proliferation and apoptosis of hFOB 1.19 cells. Results CRNDE was down-regulated, while miR-29a-3p was up-regulated in DFH patients. The serum CRNDE could effectively identify DFH patients and predict the DFH occurrence. In the hFOB 1.19 osteogenic differentiation model, silencing CRNDE led to a significant decrease in the expression of osteogenic differentiation markers, a reduction in the proliferation activity of hFOB 1.19 cells, and an increase in apoptosis. There was a negative regulatory interaction between CRNDE and miR-29a-3p. Concurrently inhibiting the expression of both CRNDE and miR-29a-3p could effectively restore the functional activity of hFOB 1.19 cells. Conclusion Serum CRNDE holds potential as a biomarker for the diagnosis and prediction of DFH. The sponging effect of CRNDE on miR-29a-3p could ameliorate fracture healing.

Background Fracture healing is a complex biological process involving precisely coordinated phases of inflammation, cartilage formation, vascularization, and bone remodeling. Growing evidence suggests that non-coding RNAs play crucial regulatory roles in bone metabolism. Objective This study systematically investigated the role and molecular mechanisms of lncRNA GABARAPL2 (lnc_GABARAPL2) in fracture healing through integrated bioinformatics analysis, clinical validation, and functional experiments, with the goal of identifying novel biomarkers and therapeutic targets for impaired fracture healing. Methods Lnc_GABARAPL2, miR-302a-3p, RUNX2 and OCN mRNA expression levels were quantified by RT-qPCR. Osteogenic differentiation was assessed through Western blot (Collagen I) and spectrophotometric ALP activity measurement and alizarin red S-based mineralization assay. In vitro, lnc_GABARAPL2 expression was modulated in hBMSCs via siRNA knockdown and overexpression vectors, with target interaction validated by dual-luciferase reporter assay. Cell proliferation (CCK-8) and apoptosis (flow cytometry) were assessed. Statistical methods included t-tests, ANOVA, and ROC curve analysis. Results Lnc_GABARAPL2 expression was significantly elevated in non-union patients and demonstrated excellent predictive performance. Multivariate regression analysis confirmed lnc_GABARAPL2 as an independent predictor of non-union. Functional studies revealed that lnc_GABARAPL2 impaired osteogenic differentiation by suppressing ALP activity and reducing expression of key osteogenic markers RUNX2 and Collagen I, while modulating bone marrow mesenchymal stem cell proliferation and apoptosis through targeting miR-302a-3p. Conclusion These findings establish that lnc_GABARAPL2 may as a regulator of fracture healing and a promising predictive biomarker for non-union and targeting miR-302a-3p to modulate bone marrow mesenchymal stem cell functions, providing new insights for the development of RNA-based therapeutic strategies for impaired bone repair.

Bone repair involves bone resorption through osteoclastogenesis and the stimulation of neovascularization and osteogenesis by endothelial progenitor cells (EPCs). However, the role of EPCs in osteoclastogenesis is unclear. In this study, we assess the effects of EPC‐derived exosomes on the migration and osteoclastic differentiation of primary mouse bone marrow‐derived macrophages (BMMs) in vitro using immunofluorescence, western blotting, RT‐PCR and Transwell assays. We also evaluated the effects of EPC‐derived exosomes on the homing and osteoclastic differentiation of transplanted BMMs in a mouse bone fracture model in vivo. We found that EPCs cultured with BMMs secreted exosomes into the medium and, compared with EPCs, exosomes had a higher expression level of LncRNA‐MALAT1. We confirmed that LncRNA‐MALAT1 directly binds to miR‐124 to negatively control miR‐124 activity. Moreover, overexpression of miR‐124 could reverse the migration and osteoclastic differentiation of BMMs induced by EPC‐derived exosomes. A dual‐luciferase reporter assay indicated that the integrin ITGB1 is the target of miR‐124. Mice treated with EPC‐derived exosome‐BMM co‐transplantations exhibited increased neovascularization at the fracture site and enhanced fracture healing compared with those treated with BMMs alone. Overall, our results suggest that EPC‐derived exosomes can promote bone repair by enhancing recruitment and differentiation of osteoclast precursors through LncRNA‐MALAT1.

Critical-size bone defects, which require large-volume tissue reconstruction, remain a clinical challenge. Bone engineering has the potential to provide new treatment concepts, yet clinical translation requires anatomically and physiologically relevant preclinical models. The ovine critical-size long-bone defect model has been validated in numerous studies as a preclinical tool for evaluating both conventional and novel bone-engineering concepts. With sufficient training and experience in large-animal studies, it is a technically feasible procedure with a high level of reproducibility when appropriate preoperative and postoperative management protocols are followed. The model can be established by following a procedure that includes the following stages: (i) preoperative planning and preparation, (ii) the surgical approach, (iii) postoperative management, and (iv) postmortem analysis. Using this model, full results for peer-reviewed publication can be attained within 2 years. In this protocol, we comprehensively describe how to establish proficiency using the preclinical model for the evaluation of a range of bone defect reconstruction options. This protocol describes how to establish an ovine critical-size, segmental bone defect model to study bone regeneration and reconstruction.

Mental traumatization is associated with long-bone growth retardation, osteoporosis and increased fracture risk. We revealed earlier that mental trauma disturbs cartilage-to-bone transition during bone growth and repair in mice. Trauma increased tyrosine hydroxylase-expressing neutrophils in bone marrow and fracture callus. Here we show that tyrosine hydroxylase expression in the fracture hematoma of patients correlates positively with acknowledged stress, depression, and pain scores as well as individual ratings of healing-impairment and pain-perception post-fracture. Moreover, mice lacking tyrosine hydroxylase in myeloid cells are protected from chronic psychosocial stress-induced disturbance of bone growth and healing. Chondrocyte-specific β2-adrenoceptor-deficient mice are also protected from stress-induced bone growth retardation. In summary, our preclinical data identify locally secreted catecholamines in concert with β2-adrenoceptor signalling in chondrocytes as mediators of negative stress effects on bone growth and repair. Given our clinical data, these mechanistic insights seem to be of strong translational relevance. Authors present both preclinical data in mice and clinical data from humans in support of the hypothesis that stress negatively affects bone growth and repair. These effects are mediated by neutrophil-derived catecholamines inhibiting cartilage-to-bone transition via β2-adrenoceptor signaling in chondrocytes.