Use of Fibrin Glue as a Surgical Adjunct in Bone Grafting of Fracture Non-unions.

Introduction: Non-union of long bones is a common challenge in the treatment of fractures. Bone grafting is commonly used to treat atrophic non-union, but mechanical displacement of the graft may occur, resulting in delay or failure of treatment. Fibrin glue has demonstrated positive results in management of bone defects in neurosurgery and oromaxillary facial surgery, however, there has yet to be any study on its use in long bone fractures. Materials and Methods: We conducted a prospective randomised controlled trial at a single tertiary centre involving adult patients with long bone fractures that had undergone non-union and requiring bone grafting only. Autologous iliac crest bone graft was applied to the debrided non-union site, with additional fibrin glue applied for the intervention arm. Patients were followed-up with serial radiographs until clinical and radiographical union. Results: Ten patients (3 male, 7 female), of mean age 41.7 (19 - 63) were recruited over five years, with one drop out. Eight out of nine fractures united after treatment. One patient underwent hypertrophic non-union requiring re-fixation and bone grafting. There was no difference in the time to union for patients in the fibrin glue group (19.5 weeks) versus the control group (18.75 weeks) (p=0.86). There were no complications sustained from usage of fibrin glue. Conclusion: Fibrin glue appears to be a safe adjunct for treatment of non-union of long bone fractures across varying fracture sites by holding the bone graft in place despite not demonstrating a faster time to union.

Does cessation of combustible cigarette and heated tobacco product smoking immediately following a fracture benefit fracture healing? In vivo and in vitro validation.

Combustible cigarette and heated tobacco products (HTPs), the two most frequently used tobacco products, negatively affect bone healing. However, whether smoking cessation following fracture benefits bone healing is unclear. Therefore, this study investigated the effect of smoking cessation immediately after surgery on reduced fracture healing induced by smoking. Smoking combustible cigarettes and heated tobacco products generates cigarette smoking extracts (CSE) (extracts from combustible cigarettes [cCSE] and from HTPs [hCSE], respectively). In vivo, CSEs were injected intraperitoneally into rat models for 3 weeks before femoral midshaft osteotomy and fixation. The rats were then divided into CSE continuation and cessation groups postoperatively. Micro-computed tomography (µCT) and biomechanical analyses were performed 6 weeks postoperatively to assess bone union at the fracture site. In vivo study showed µCT assessment also revealed significantly higher cortical bone mineral density (p = 0.013) and content (p = 0.013), and a higher bone union score (p = 0.046) at the fracture site in the cCSE cessation group than in the cCSE continuation group. Biomechanical assessment revealed that elasticity at the fracture site was significantly higher in the cCSE cessation group than in the cCSE continuation group (p = 0.041). These findings provide that smoking cessation, particularly of combustible cigarette, immediately after a fracture accelerates bone fracture healing and increases mechanical strength at the fracture site.

Salidroside: A Promising Agent in Bone Metabolism Modulation.

Rhodiola rosea, a long-lived herbaceous plant from the Crassulaceae group, contains the active compound salidroside, recognized as an adaptogen with significant therapeutic potential for bone metabolism. Salidroside promotes osteoblast proliferation and differentiation by activating critical signaling pathways, including bone morphogenetic protein-2 and adenosine monophosphate-activated protein kinase, essential for bone formation and growth. It enhances osteogenic activity by increasing alkaline phosphatase activity and mineralization markers, while upregulating key regulatory proteins including runt-related transcription factor 2 and osterix. Additionally, salidroside facilitates angiogenesis via the hypoxia-inducible factor 1-alpha and vascular endothelial growth factor pathway, crucial for coupling bone development with vascular support. Its antioxidant properties offer protection against bone loss by reducing oxidative stress and promoting osteogenic differentiation through the nuclear factor erythroid 2-related factor 2 pathway. Salidroside has the capability to counteract the negative effects of glucocorticoids on bone cells and prevents steroid-induced osteonecrosis. Additionally, it exhibits multifaceted anti-inflammatory actions, notably through the inhibition of tumor necrosis factor-alpha and interleukin-6 expression, while enhancing the expression of interleukin-10. This publication presents a comprehensive review of the literature on the impact of salidroside on various aspects of bone tissue metabolism, emphasizing its potential role in the prevention and treatment of osteoporosis and other diseases affecting bone physiology.

Finite element simulations of smart fracture plates capable of cyclic shortening and lengthening: which stroke for which fracture?

Introduction: Bone healing can be improved by axial micromovement, as has been shown in animals and human patients with external fixators. In the development of smart fracture plates, the ideal amount of stroke for different fracture types in the different healing stages is currently unknown. It was hypothesized that the resulting strain in the fracture gap of a simple tibial shaft fracture does not vary with the amount of axial stroke in the plate, the fracture gap size, and the fracture angle. Methods: With finite element simulations based on body donation computed tomography data, the second invariant of the deviatoric strain tensor (J2), strain energy density, hydrostatic strain, octahedral shear strain, and percentage of the fracture gap in the "perfect healing window" were computed for different gap sizes (1-3 mm), angles (5°-60°), and plate stroke levels (0.05-0.60 mm) in three healing stages. Multiple linear regression analyses were performed. Results: Findings showed that an active fracture plate should deliver an axial stroke in the range of 0.10-0.45 mm. Different optimal stroke values were found for each healing phase, namely, 0.10-0.25 mm for the first, 0.10 mm for the second, and 0.35-0.45 mm for the third healing phase, depending on the fracture gap size and less on the fracture angle. J2, hydrostatic strain, octahedral shear strain and the strain energy density correlated with the fracture gap size and angle (all p < 0.001). The influence of the fracture gap size and angle on the variability (adjusted R2) in several outcome measures in the fracture gap was shown to vary throughout healing. The contribution to the variability of the percentage of the fracture gap in the perfect healing window was greatest during the second healing phase. For J2, strain energy density, hydrostatic strain, and octahedral shear strain, the fracture gap size showed the greatest contribution in the third fracture healing phase, while the influence of fracture angle was independent of the healing phase. Discussion: The present findings are relevant for implant development and to design clinical studies that aim to accelerate fracture healing using axial micromovement.

Enhanced recovery after surgery speeds up healing for hip fracture patients.

OBJECTIVE: To investigate the effects of enhanced recovery after surgery (ERAS) on the perioperative healing and stress response in patients with hip fractures. METHODS: A retrospective analysis was conducted on the medical records of 86 patients with hip fractures admitted to the Affiliated Hospital of Southwest Medical University between January 2022 and August 2023. Among them, 48 patients in the research group received ERAS, while 38 patients in the control group received conventional nursing. Hip joint function, pain levels, stress response, fracture healing time, incidence of complications, and nursing satisfaction were compared between the two groups. RESULTS: After nursing, the Harris scores notably increased in both groups, with the research group showing notably higher scores compared to the control group (P<0.05). The levels of cortisol and epinephrine, as well as the visual analog scale scores significantly decreased in both groups, with the research group showing significantly lower levels (P<0.05). In addition, the research group experienced significantly shorter fracture healing time (P<0.05), higher nursing satisfaction (P=0.014), and lower incidence of complications (P=0.028). Logistic regression analysis revealed that age, underlying diseases, nursing method, emotional disorders, and timing of surgery were independent factors influencing the post-nursing outcomes. CONCLUSION: The ERAS mode can effectively alleviate pain, improve hip joint function, reduce fracture healing time and complications, mitigate stress response, and accelerate postoperative recovery in patients with hip fractures. It is worthy of application and promotion in clinical practice.

Long non-coding TRPM2-AS regulates fracture healing by targeting miR-545-3p/Bmp2.

OBJECTIVE: Delayed fracture healing increases the suffering of patients. An in-depth investigation of the pathogenesis of delayed fracture healing may offer new direction for the prevention and treatment. METHODS: The study included 63 normal healing tibial fractures and 58 delayed healing tibial fractures patients. Long non-coding RNA (lncRNA)TRPM2-AS, microRNA-545-3p (miR-545-3p), bone morphogenetic protein 2 (Bmp2) mRNA and osteogenic differentiation markers, including runt-related transcription factor 2 (Runx2), osteocalcin (Ocn), and alkaline phosphatase (Alp) mRNA expression were determined by Real-time quantitative reverse transcription-polymerase chain reaction in serum and MC3T3-E1 cells. The prediction potential of TRPM2-AS in delayed healing fracture patients was verified by receiver operating characteristic curves. The binding relationship of TRPM2-AS/miR-545-3p/Bmp2 was evaluated by dual luciferase reporter gene assay. Cell proliferation and apoptosis were detected by CCK-8 and flow cytometry. RESULTS: TRPM2-AS was remarkably down-regulated in patients with delayed fracture healing and could better predict the fracture healing status. TRPM2-AS downregulation inhibited osteogenic markers mRNA expression, restrained proliferation, and promoted apoptosis of MC3T3-E1 cells (p < 0.05). In delayed fracture healing, miR-545-3p was dramatically up-regulated and was negatively regulated by TRPM2-AS. Reducing miR-545-3p eliminate the negative effect of TRPM2-AS down-regulation on osteoblast proliferation and differentiation (p < 0.05). miR-545-3p targets Bmp2, which plays a positive role in osteoblast differentiation (p < 0.05). CONCLUSION: This study found that TRPM2-AS has the potential to be a diagnostic marker for delayed fracture healing and revealed that the TRPM2-AS/miR-545-3p/Bmp2 axis affects fracture healing by regulating osteoblast.

Adaptive Image Segmentation Reveals Substantial Cortical Bone Remodeling During Early Fracture Repair.

The goal of this study was to develop an image analysis algorithm for quantifying the effects of remodeling on cortical bone during early fracture healing. An adaptive thresholding technique with boundary curvature and tortuosity control was developed to automatically identify the endocortical and pericortical boundaries in the presence of high-gradient bone mineral density (BMD) near the healing zone. The algorithm successfully segmented more than 47,000 microCT images from 12 healing ovine osteotomies and intact contralateral tibiae. Resampling techniques were used to achieve data dimensionality reduction on the segmented images, allowing characterization of radial and axial distributions of cortical BMD. Local (transverse slice) and total (whole bone) remodeling scores were produced. These surrogate measures of cortical remodeling derived from BMD revealed that cortical changes were detectable throughout the region covered by callus and that the localized loss of cortical BMD was highest near the osteotomy. Total remodeling score was moderately and significantly correlated with callus volume and mineral composition (r > 0.64, p < 0.05), suggesting that the cortex may be a source of mineral needed to build callus.

Inflammatory response toward a Mg-based metallic biomaterial implanted in a rat femur fracture model.

The immune system plays an important role in fracture healing, by modulating the pro-inflammatory and anti-inflammatory responses occurring instantly upon injury. An imbalance in these responses can lead to adverse outcomes, such as non-union of fractures. Implants are used to support and stabilize complex fractures. Biodegradable metallic implants offer the potential to avoid a second surgery for implant removal, unlike non-degradable implants. However, considering our dynamic immune system it is important to conduct in-depth studies on the immune response to these implants in living systems. In this study, we investigated the immune response to Mg and Mg-10Gd in vivo in a rat femur fracture model with external fixation. In vivo imaging using liposomal formulations was used to monitor the fluorescence-related inflammation over time. We combine ex vivo methods with our in vivo study to evaluate and understand the systemic and local effects of the implants on the immune response. We observed no significant local or systemic effects in the Mg-10Gd implanted group compared to the SHAM and Mg implanted groups over time. Our findings suggest that Mg-10Gd is a more compatible implant material than Mg, with no adverse effects observed in the early phase of fracture healing during our 4-week study. STATEMENT OF SIGNIFICANCE: Degradable metallic implants in form of Mg and Mg-10Gd intramedullary pins were assessed in a rat femur fracture model, alongside a non-implanted SHAM group with special respect to the potential to induce an inflammatory response. This pre-clinical study combines innovative non-invasive in vivo imaging techniques associated with multimodal, ex vivo cellular and molecular analytics. The study contributes to the development and evaluation of degradable biometals and their clinical application potential. The study results indicate that Mg-10Gd did not exhibit any significant harmful effects compared to the SHAM and Mg groups.

Therapeutic Potential of Platelet-Rich Plasma in Fracture Healing: A Comprehensive Review.

Fracture healing is a dynamic process essential for the restoration of bone integrity and function. However, factors such as patient age, comorbidities, and the severity of the fracture can impede this process, leading to delayed healing or nonunion. Platelet-rich plasma (PRP) has emerged as a promising therapeutic option for enhancing fracture healing. PRP is an autologous blood product containing a concentrated mixture of platelets, growth factors, and cytokines known to promote tissue regeneration and repair. This comprehensive review provides an overview of the fracture healing process, emphasizing the importance of timely and efficient bone repair. We discuss the mechanisms underlying the purported efficacy of PRP in fracture healing, drawing upon both preclinical and clinical evidence. Preclinical studies in animal models have demonstrated the ability of PRP to accelerate fracture healing, stimulate osteogenesis, and enhance bone regeneration. Clinical studies have yielded mixed results, with some reporting positive outcomes in terms of accelerated healing and improved functional outcomes, while others have shown no significant benefits over standard treatments. Factors influencing the efficacy of PRP, such as timing of administration, PRP concentration, and patient-specific variables, are also examined. Furthermore, safety considerations and potential adverse effects associated with PRP therapy are discussed. Despite the promising preclinical findings, challenges remain in standardizing PRP formulations, optimizing administration protocols, and addressing unanswered questions regarding its long-term efficacy and safety. This review aims to provide insights into the therapeutic potential of PRP in fracture healing, informing future research directions and guiding clinical practice.

Bone Fracture Healing under the Intervention of a Stretchable Ultrasound Array.

Ultrasound treatment has been recognized as an effective and noninvasive approach to promote fracture healing. However, traditional rigid ultrasound probe is bulky, requiring cumbersome manual operations and inducing unfavorable side effects when functioning, which precludes the wide application of ultrasound in bone fracture healing. Here, we report a stretchable ultrasound array for bone fracture healing, which features high-performance 1-3 piezoelectric composites as transducers, stretchable multilayered serpentine metal films in a bridge-island pattern as electrical interconnects, soft elastomeric membranes as encapsulations, and polydimethylsiloxane (PDMS) with low curing agent ratio as adhesive layers. The resulting ultrasound array offers the benefits of large stretchability for easy skin integration and effective affecting region for simple skin alignment with good electromechanical performance. Experimental investigations of the stretchable ultrasound array on the delayed union model in femoral shafts of rats show that the callus growth is more active in the second week of treatment and the fracture site is completely osseous healed in the sixth week of treatment. Various bone quality indicators (e.g., bone modulus, bone mineral density, bone tissue/total tissue volume, and trabecular bone thickness) could be enhanced with the intervention of a stretchable ultrasound array. Histological and immunohistochemical examinations indicate that ultrasound promotes osteoblast differentiation, bone formation, and remodeling by promoting the expression of osteopontin (OPN) and runt-related transcription factor 2 (RUNX2). This work provides an effective tool for bone fracture healing in a simple and convenient manner and creates engineering opportunities for applying ultrasound in medical applications.

Case Studies of a Simulation Workflow to Improve Bone Healing Assessment in Impending Non-Unions.

Background: The healing potential of a fracture is determined by mechanical and biological factors. Simulation-based workflows can help assess these factors to assist in predicting non-unions. The aim of this study was the introduction of two use cases for a novel patient-specific simulation workflow based on clinically available information. Methods: The used software is an extension of the "Ulm Bone Healing model" and was applied in two cases with non-union development after fracture fixation to show its principal feasibility. The clinical and radiographic information, starting from initial treatment, were used to feed the simulation process. Results: The simulation predicted non-union development and axial deviation in a mechanically driven non-union. In the case of a biological non-union, a slow, incomplete healing course was correctly identified. However, the time offset in callus bridging was discordant between the simulation and the distinctly slower healing response in the clinical case. Conclusions: The simulation workflow presented in the two clinical use cases allowed for the identification of fractures at risk for impending non-union immediately after the initial fixation based on available clinical and radiographic information. Further validation in a large non-union cohort is needed to increase the model's precision, especially in biologically challenging cases, and show its validity as a screening instrument.

Anti-Microbial Drug Metronidazole Promotes Fracture Healing: Enhancement in the Bone Regenerative Efficacy of the Drug by a Biodegradable Sustained-Release In Situ Gel Formulation.

Nitroimidazoles comprise a class of broad-spectrum anti-microbial drugs with efficacy against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. Among these drugs, metronidazole (MTZ) is commonly used with other antibiotics to prevent infection in open fractures. However, the effect of MTZ on bone remains understudied. In this paper, we evaluated six nitroimidazole drugs for their impact on osteoblast differentiation and identified MTZ as having the highest osteogenic effect. MTZ enhanced bone regeneration at the femur osteotomy site in osteopenic ovariectomized (OVX) rats at the human equivalent dose. Moreover, in OVX rats, MTZ significantly improved bone mass and strength and improved microarchitecture compared to the vehicle-treated rats, which was likely achieved by an osteogenic mechanism attributed to the stimulation of the Wnt pathway in osteoblasts. To mitigate the reported neurological and genotoxic effects of MTZ, we designed an injectable sustained-release in situ gel formulation of the drug that improved fracture healing efficacy by 3.5-fold compared to oral administration. This enhanced potency was achieved through a significant increase in the circulating half-life and bioavailability of MTZ. We conclude that MTZ exhibits osteogenic effects, further accentuated by our sustained-release delivery system, which holds promise for enhancing bone regeneration in open fractures.

Finite element solution of coupled multiphysics reaction-diffusion equations for fracture healing in hard biological tissues.

This study proposes a computational framework to investigate the multi-stage process of fracture healing in hard tissues, e.g., long bone, based on the mathematical Bailon-Plaza and Van der Meulen formulation. The goal is to explore the influence of critical biological factors by employing the finite element method for more realistic configurations. The model integrates a set of variables, including cell densities, growth factors, and extracellular matrix contents, managed by a coupled system of partial differential equations. A weak finite element formulation is introduced to enhance the numerical robustness for coarser mesh grids, complex geometries, and more accurate boundary conditions. This formulation is less sensitive to mesh quality and converges smoothly with mesh refinement, exhibiting superior numerical stability compared to previously available strong-form solutions. The model accurately reproduces various stages of healing, including soft cartilage callus formation, endochondral and intramembranous ossification, and hard bony callus development for various sizes of fracture gap. Model predictions align with the existing research and are logically coherent with the available experimental data. The developed multiphysics simulation clarifies the coordination of cellular dynamics, extracellular matrix alterations, and signaling growth factors during fracture healing.

Oral dehydroepiandrosterone supplementation enhances osteoporotic fracture healing in the OVX rats.

Osteoporosis easily causes delayed fracture union, even non-union. It has been demonstrated that dehydroepiandrosterone (DHEA) supplementation can increase estrogen levels and improve bone mineral density (BMD) in the elderly, while the role of DHEA on fracture healing remains unknown. This study aimed to elucidate the impact of DHEA supplementation on osteoporotic fracture healing. Seventy-two female Sprague-Dawley rats were used. Forty-eight rats received ovariectomy (OVX), and the remaining rats received a sham OVX operation (sham group). A right transverse femoral osteotomy was performed in all rats at 12 weeks post-OVX. OVX rats were randomly allocated into 2 groups (n = 24 in each group): (i) ovariectomized rats (control group) and (ii) ovariectomized rats treated with DHEA (DHEA group, 5 mg/kg/day). The DHEA supplementation was initiated on the first day post-fracture for 3, 6, and 12 weeks. Fracture healing was evaluated by radiography, histology, biomechanical analysis, and dual-energy X-ray absorptiometry (DEXA). Serum biomarkers were analyzed using enzyme-linked immunosorbent assay (ELISA). At 3 and 6 weeks, radiographs revealed reduced calluses formation and lower radiographic scores in the control group than in other groups. The sham and DHEA groups showed higher BMD and bone mineral content (BMC) at the fracture site than the control group after fracture. Histological analysis revealed the fracture callus was remodeled better in the sham and DHEA groups than in the control group. At the early phase of healing, DHEA supplementation increased osteoblast number, callus area, and cartilage area than the control group. An increased bone area was observed in the DHEA group than in the control group at the late phase of healing. Additionally, improved biomechanical characteristics were observed in both the sham and DHEA groups than those in the control group post-fracture. ELISA showed higher levels of insulin-like growth factor-1 (IGF-1) and 17ß-estradiol (E2) in the DHEA group than in the control group post-fracture. Furthermore, the DHEA group exhibited significantly elevated alkaline phosphatase (ALP) and osteocalcin (OC) levels compared to the control group at 6 and 12 weeks. The DHEA group and the control group did not exhibit a notable difference in TRAP-5b levels. The present study demonstrated that the DHEA treatment has a favorable impact on osteoporotic fracture healing by enhancing callus formation, consolidation, and strength in the OVX rats.

Bone consolidation under septic condition and hardware retention: about 69 patients.

INTRODUCTION: Management of infection on internal fixation hardware is particularly complex. The main aim of the present study was to assess bone consolidation rates under septic conditions in patients treated for bone and joint infection (BJI) with hardware retention. Secondary objectives were to determine a time limit beyond which it is unreasonable to retain hardware, and to assess risk factors for non-consolidation and functional results. The study hypothesis was that bone consolidation is possible under septic conditions without hardware exchange. MATERIAL AND METHOD: A single-center retrospective observational study was conducted on 69 patients for the period January 1, 2009 to December 31, 2019. We included all patients aged over 15 years with infection after internal fixation or fusion whose files had been discussed in the multidisciplinary team meeting during the study period. Bone healing was screened for on X-ray or CT. Study data comprised type of fracture, smoking status, time to treatment for open fracture, initial surgery time, type of hardware, interval between fixation and revision, and type of irrigation. Functional results were assessed at follow-up: walking, pain, return to work and SF12 and QuickDASH scores. RESULTS: The bone healing rate was 73.5% (50/68 patients) at a mean 24 weeks (range, 6-68 weeks). Time to revision did not significantly impact consolidation: 60% for 2 weeks (6/10 cases), 80% for 2-10 weeks (35/40 cases), and 64% for >10 weeks (9/14 cases) (p = 0.28). Smoking, longer initial surgery time and Gustilo type IIIb or IIIc were significant risks factors for non-consolidation. DISCUSSION: Bone consolidation under septic conditions with hardware retention adhering to an established medical and surgical protocol was reliable and straightforward, without extra morbidity. These findings are encouraging, and in line with the literature. We were unable to determine a time limit beyond which hardware prevented healing. LEVEL OF EVIDENCE: IV; descriptive epidemiological study.

The emerging role of tranexamic acid and its principal target, plasminogen, in skeletal health.

The worldwide burden of skeletal diseases such as osteoporosis, degenerative joint disease and impaired fracture healing is steadily increasing. Tranexamic acid (TXA), a plasminogen inhibitor and anti-fibrinolytic agent, is used to reduce bleeding with high effectiveness and safety in major surgical procedures. With its widespread clinical application, the effects of TXA beyond anti-fibrinolysis have been noticed and prompted renewed interest in its use. Some clinical trials have characterized the effects of TXA on reducing postoperative infection rates and regulating immune responses in patients undergoing surgery. Also, several animal studies suggest potential therapeutic effects of TXA on skeletal diseases such as osteoporosis and fracture healing. Although a direct effect of TXA on the differentiation and function of bone cells in vitro was shown, few mechanisms of action have been reported. Here, we summarize recent findings of the effects of TXA on skeletal diseases and discuss the underlying plasminogen-dependent and -independent mechanisms related to bone metabolism and the immune response. We furthermore discuss potential novel indications for TXA application as a treatment strategy for skeletal diseases.

ß-catenin mRNA encapsulated in SM-102 lipid nanoparticles enhances bone formation in a murine tibia fracture repair model.

Fractures continue to be a global economic burden as there are currently no osteoanabolic drugs approved to accelerate fracture healing. In this study, we aimed to develop an osteoanabolic therapy which activates the Wnt/ß-catenin pathway, a molecular driver of endochondral ossification. We hypothesize that using an mRNA-based therapeutic encoding ß-catenin could promote cartilage to bone transformation formation by activating the canonical Wnt signaling pathway in chondrocytes. To optimize a delivery platform built on recent advancements in liposomal technologies, two FDA-approved ionizable phospholipids, DLin-MC3-DMA (MC3) and SM-102, were used to fabricate unique ionizable lipid nanoparticle (LNP) formulations and then tested for transfection efficacy both in vitro and in a murine tibia fracture model. Using firefly luciferase mRNA as a reporter gene to track and quantify transfection, SM-102 LNPs showed enhanced transfection efficacy in vitro and prolonged transfection, minimal fracture interference and no localized inflammatory response in vivo over MC3 LNPs. The generated ß-cateninGOF mRNA encapsulated in SM-102 LNPs (SM-102-ß-cateninGOF mRNA) showed bioactivity in vitro through upregulation of downstream canonical Wnt genes, axin2 and runx2. When testing SM-102-ß-cateninGOF mRNA therapeutic in a murine tibia fracture model, histomorphometric analysis showed increased bone and decreased cartilage composition with the 45 µg concentration at 2 weeks post-fracture. µCT testing confirmed that SM-102-ß-cateninGOF mRNA promoted bone formation in vivo, revealing significantly more bone volume over total volume in the 45 µg group. Thus, we generated a novel mRNA-based therapeutic encoding a ß-catenin mRNA and optimized an SM-102-based LNP to maximize transfection efficacy with a localized delivery.

Denosumab and metatarsal fracture healing: potential benefits with delayed remodeling: a case report.

Background: Denosumab is known to enhance callus formation while delaying remodeling. However, its effects on fracture healing are scarcely reported in the literature. This case report, to the best of our knowledge, is the first to report the potential effect of denosumab on a metatarsal fracture in an older adult patient, 4 months after administration, resulting in a favorable clinical course with early weight-bearing 17 days after the fracture. Presentation of case: A 73-year-old female sustained a right-foot second metatarsal fracture due to the fall of a heavy object. She has a history of diabetes mellitus, hypertension, and osteoporosis. Prior to sustaining the fracture, she received seven doses of denosumab spaced 6 months apart, with the last dose administered 4 months earlier. Furthermore, the patient was treated with a backsplint for 6 weeks. After 17 days, follow-up radiographs showed a large callus formation, with no pain and the ability to bear weight. Subsequent radiographs revealed a large callus with delayed remodeling. Discussion: This case report suggests that denosumab remains effective for promoting rapid callus formation even 4 months after administration for osteoporosis, despite delayed remodeling. This delay did not seem to have negative effects on the clinical outcomes, as the patient achieved weight-bearing within 17 days after sustaining the fracture. Conclusion: Denosumab may positively influence fracture healing in older adults with metatarsal fractures, potentially leading to delayed remodeling. However, further studies are needed to confirm these observations.

Comprehensive evaluation of advanced platelet-rich fibrin in common complications following sagittal split ramus osteotomy: a double-blind, split-mouth, randomized clinical trial.

The sagittal split ramus osteotomy (SSRO) carries potential risks and complications. A double-blind, split-mouth, randomized clinical trial was performed, involving 30 patients undergoing mandibular setback. Advanced platelet-rich fibrin (A-PRF) was applied to one side, and the other side served as a control. The volume of postoperative drainage over 24 h was recorded. At 1, 2, and 5 days, and 3 months postsurgery, nerve recovery was assessed using the two-point discrimination test (TPD), while pain was evaluated using a visual analogue scale (VAS pain). Facial swelling was evaluated by taking linear measurements from facial reference points at the same time intervals. In the treatment group, the 24-hour drainage volume was lower (P = 0.011), pain was better on day 5 (P = 0.011), and TPD was better on day 2 (P = 0.011), day 5 (P = 0.007), and 3 months postoperatively (P = 0.020) than in the control group. There was also less facial swelling in the treatment group when compared to the baseline of 3 months postoperative (day 1, P = 0.012; day 2, P = 0.001; day 5, P = 0.011). The difference in bone mineral density (HU) at 3 months between the treatment group (469.7 ± 134.2) and the control group (348.3 ± 127.2) was statistically significant (P = 0.011), in favour of the treatment group. A-PRF may reduce postoperative complications such as neurosensory disturbance of the inferior alveolar nerve, pain, swelling, and drainage while enhancing bone healing in the osteotomy gap following SSRO. TRIAL REGISTRATION: The study was registered with the Chinese Clinical Trial Register (ChiCTR2200064534).

Long non-coding RNA MIAT serves as a biomarker of fragility fracture and promotes fracture healing.

BACKGROUND: Fragility fracture is common in the elderly. Osteoblast differentiation is essential for bone healing and regeneration. Expression pattern of long non-coding RNA MIAT during fracture healing was examined, and its role in osteoblast differentiation was investigated. METHODS: 90 women with simple osteoporosis and 90 women with fragility fractures were included. Another 90 age-matched women were set as the control group. mRNA levels were tested using RT-qPCR. Cell viability was detected via CCK-8, and osteoblastic biomarkers, including ALP, OCN, Collagen I, and RUNX2 were tested via ELISA. The downstream miRNAs and genes targeted by MIAT were predicted by bioinformatics analysis, whose functions and pathways were annotated via GO and KEGG analysis. RESULTS: Serum MIAT was upregulated in osteoporosis women with high accuracy of diagnostic efficacy. Serum MIAT was even elevated in the fragility fracture group, but decreased in a time manner after operation. MIAT knockdown promoted osteogenic proliferation and differentiation of MC3T3-E1, but the influences were reversed by miR-181a-5p inhibitor. A total of 137 overlapping target genes of miR-181a-5p were predicted based on the miRDB, TargetScan and microT datasets, which were mainly enriched for terms related to signaling pathways regulating pluripotency of stem cells, cellular senescence, and osteoclast differentiation. CONCLUSIONS: LncRNA MIAT serves as a promising biomarker for osteoporosis, and promotes osteogenic differentiation via targeting miR-181a-5p.