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BMC Musculoskeletal Disorders Feb 2024Previous studies have shown that DNA methyltransferase 3b (Dnmt3b) is the only Dnmt responsive to fracture repair and Dnmt3b ablation in Prx1-positive stem cells and...
PURPOSE
Previous studies have shown that DNA methyltransferase 3b (Dnmt3b) is the only Dnmt responsive to fracture repair and Dnmt3b ablation in Prx1-positive stem cells and chondrocyte cells both delayed fracture repair. Our study aims to explore the influence of Dnmt3b ablation in Gli1-positive stem cells in fracture healing mice and the underlying mechanism.
METHODS
We generated Gli1-CreERT2; Dnmt3bflox/flox (Dnmt3b) mice to operated tibia fracture. Fracture callus tissues of Dnmt3b mice and control mice were collected and analyzed by X-ray, micro-CT, biomechanical testing, histopathology and TUNEL assay.
RESULTS
The cartilaginous callus significantly decrease in ablation of Dnmt3b in Gli1-positive stem cells during fracture repair. The chondrogenic and osteogenic indicators (Sox9 and Runx2) in the fracture healing tissues in Dnmt3b mice much less than control mice. Dnmt3b mice led to delayed bone callus remodeling and decreased biomechanical properties of the newly formed bone during fracture repair. Both the expressions of Caspase-3 and Caspase-8 were upregulated in Dnmt3b mice as well as the expressions of BCL-2.
CONCLUSIONS
Our study provides an evidence that Dnmt3b ablation Gli1-positive stem cells can affect fracture healing and lead to poor fracture healing by regulating apoptosis to decrease chondrocyte hypertrophic maturation.
Topics: Animals; Mice; Apoptosis; Bony Callus; Fracture Healing; Tibial Fractures; Zinc Finger Protein GLI1
PubMed: 38413962
DOI: 10.1186/s12891-024-07283-7 -
Bone Reports Mar 2024The prevalence of diabetes mellitus has exhibited a notable surge in recent years, thereby augmenting the susceptibility to fractures and impeding the process of...
Research on the morphological structure of partial fracture healing process in diabetic mice based on synchrotron radiation phase-contrast imaging computed tomography and deep learning.
The prevalence of diabetes mellitus has exhibited a notable surge in recent years, thereby augmenting the susceptibility to fractures and impeding the process of fracture healing. The primary objective of this investigation is to employ synchrotron radiation phase-contrast imaging computed tomography (SR-PCI-CT) to examine the morphological and structural attributes of different types of callus in a murine model of diabetic partial fractures. Additionally, a deep learning image segmentation model was utilized to facilitate both qualitative and quantitative analysis of callus during various time intervals. A total of forty male Kunming mice, aged five weeks, were randomly allocated into two groups, each consisting of twenty mice, namely, simple fracture group (SF) and diabetic fracture group (DF). Mice in DF group were intraperitoneally injected 60 mg/kg 1 % streptozotocin(STZ) solution for 5 consecutive days, and the standard for modeling was that the fasting blood glucose level was ≥11.1 mmol /l one week after the last injection of STZ. The right tibias of all mice were observed to have oblique fractures that did not traverse the entire bone. At three, seven, ten and fourteen days after the fracture occurred, the fractured tibias were extracted for SR-PCI-CT imaging and histological analysis. Furthermore, a deep learning image segmentation model was devised to automatically detect, categorize and quantitatively examine different types of callus. Image J software was utilized to measure the grayscale values of different types of callus and perform quantitative analysis. The findings demonstrated that:1)SR-PCI-CT imaging effectively depicted the morphological attributes of different types of callus of fracture healing. The grayscale values of different types of callus were significantly different( < 0.01).2)In comparison to the SF group, the DF group exhibited a significant reduction in the total amount of callus during the same period ( < 0.01). Additionally, the peak of cartilage callus in the hypertrophic phase was delayed.3)Histology provides the basis for training algorithms for deep learning image segmentation models. The deep-learning image segmentation models achieved accuracies of 0.69, 0.81 and 0.733 for reserve/proliferative cartilage, hypertrophic cartilage and mineralized cartilage, respectively, in the test set. The corresponding Dice values were 0.72, 0.83 and 0.76, respectively. In summary, SR-PCI-CT images are close to the histological level, and a variety of cartilage can be identified on synchrotron radiation CT images compared with histological examination, while artificial intelligence image segmentation model can realize automatic analysis and data generation through deep learning, and further determine the objectivity and accuracy of SR-PCI-CT in identifying various cartilage tissues. Therefore, this imaging technique combined with deep learning image segmentation model can effectively evaluate the effect of diabetes on the morphological and structural changes of callus during fracture healing in mice.
PubMed: 38390284
DOI: 10.1016/j.bonr.2024.101743 -
Journal of Orthopaedic Trauma May 2024The purposes of this study were to assess clinical and radiographic outcomes following plate-assisted bone segment transport (PABST) in large bone defects of the lower...
OBJECTIVES
The purposes of this study were to assess clinical and radiographic outcomes following plate-assisted bone segment transport (PABST) in large bone defects of the lower extremities.
DESIGN
Retrospective study of prospectively collected data.
SETTING
Level-1 trauma center located in Germany.
PATIENT SELECTION CRITERIA
Patients who underwent PABST and were at least 1 year postoperatively were included.
OUTCOME MEASURES AND COMPARISONS
Demographic data were collected. Radiographic apparent bone gap (RABG), time to consolidation, time to full weight-bearing, and consolidation index were calculated. Numeric rating scale, lower extremity functional scale (LEFS), and complications were assessed.
RESULTS
Fifteen patients [13 male; mean age 51 years (range, 20-75)] underwent PABST and had follow-up at a mean of 29.1 months. The tibia was affected in 8 and the femur in 7 patients. Preoperative RABG was 60 mm [interquartile range (IQR): 40-125], and bone defects were caused by septic nonunions in 73% of patients. Fourteen patients (93%) demonstrated consolidated transport callus at 7.3 months [95% confidence interval (95% CI), 6-8.5], and 9 patients (60%) demonstrated complete consolidation of both docking site and transport callus at 11.5 months (95% CI, 7.3-15.3). Postoperative RABG was 0.1 mm (IQR: 0-0.8), and consolidation index was 1.9 months/cm (95% CI, 1.3-2.5). All patients achieved full weight-bearing at 8.7 months (IQR: 6.5-10.3). LEFS was 42 (95% CI, 34-50), and numeric rating scale was 3 (95% CI, 2-4). Patients treated for tibial defects had a significantly higher consolidation rate compared with patients treated for femoral defects ( P = 0.040).
CONCLUSIONS
PABST demonstrated high consolidation of transport callus with few complications. Although full weight-bearing was achieved in all patients, complete consolidation of the docking site was only present in 60% of cases.
LEVEL OF EVIDENCE
Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Topics: Humans; Male; Middle Aged; Tibia; Retrospective Studies; Treatment Outcome; Femur; Lower Extremity; Tibial Fractures
PubMed: 38381977
DOI: 10.1097/BOT.0000000000002784 -
Proceedings of the Institution of... Mar 2024Locking compression plates (LCPs) have become a widely used option for treating femur bone fractures. However, the optimal screw configuration with combi-holes remains a...
Locking compression plates (LCPs) have become a widely used option for treating femur bone fractures. However, the optimal screw configuration with combi-holes remains a subject of debate. The study aims to create a time-dependent finite element (FE) model to assess the impacts of different screw configurations on LCP fixation stiffness and healing efficiency across four healing stages during a complete fracture healing process. To simulate the healing process, we integrated a time-dependent callus formation mechanism into a FE model of the LCP with combi-holes. Three screw configuration parameters, namely working length, screw number, and screw position, were investigated. Increasing the working length negatively affected axial stiffness and healing efficiency ( < 0.001), while screw number or position had no significant impact ( > 0.01). The time-dependent model displayed a moderate correlation with the conventional time-independent model for axial stiffness and healing efficiency (ρ ≥ 0.733, ≤ 0.025). The highest healing efficiency (95.2%) was observed in screw configuration C125 during the 4-8-week period. The results provide insights into managing fractures using LCPs with combi-holes over an extended duration. Under axial compressive loading conditions, the use of the C125 screw configuration can enhance callus formation during the 4-12-week period for transverse fractures. When employing the C12345 configuration, it becomes crucial to avoid overconstraint during the 4-8-week period.
Topics: Humans; Fracture Healing; Fracture Fixation, Internal; Biomechanical Phenomena; Bone Plates; Bone Screws; Femoral Fractures
PubMed: 38372206
DOI: 10.1177/09544119241229157 -
BioRxiv : the Preprint Server For... Feb 2024Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they...
Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of p21+ cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, p21+ neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while p21+ OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell-like OCH subset that was p21+ and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells are key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings establish contextual roles of p21+ p16+ senescent/senescent-like cells that may be leveraged for therapeutic opportunities.
PubMed: 38370844
DOI: 10.1101/2024.02.01.578420 -
Current Osteoporosis Reports Feb 2024Fractures are a prominent form of traumatic injury and shall continue to be for the foreseeable future. While the inflammatory response and the cells of the bone marrow... (Review)
Review
PURPOSE OF REVIEW
Fractures are a prominent form of traumatic injury and shall continue to be for the foreseeable future. While the inflammatory response and the cells of the bone marrow microenvironment play significant roles in fracture healing, the nervous system is also an important player in regulating bone healing.
RECENT FINDINGS
Considerable evidence demonstrates a role for nervous system regulation of fracture healing in a setting of traumatic injury to the brain. Although many of the impacts of the nervous system on fracture healing are positive, pain mediated by the nervous system can have detrimental effects on mobilization and quality of life. Understanding the role the nervous system plays in fracture healing is vital to understanding fracture healing as a whole and improving quality of life post-injury. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.
Topics: Humans; Fracture Healing; Artificial Intelligence; Quality of Life; Bony Callus; Fractures, Bone
PubMed: 38294715
DOI: 10.1007/s11914-023-00850-2 -
Frontiers in Bioengineering and... 2023Impaired fracture healing, specifically non-union, has been found to occur up to 14% in tibial shaft fractures. The current standard of care to treat non-union often...
Impaired fracture healing, specifically non-union, has been found to occur up to 14% in tibial shaft fractures. The current standard of care to treat non-union often requires additional surgeries which can result in long recovery times. Injectable-based therapies to accelerate fracture healing have the potential to mitigate the need for additional surgeries. Gene therapies have recently undergone significant advancements due to developments in nanotechnology, which improve mRNA stability while reducing immunogenicity. In this study, we tested the efficacy of mineral coated microparticles (MCM) and fluoride-doped MCM (FMCM) to effectively deliver firefly luciferase (FLuc) mRNA lipoplexes (LPX) to the fracture site. Here, adult mice underwent a tibia fracture and stabilization method and all treatments were locally injected into the fracture. Level of osteogenesis and amount of bone formation were assessed using gene expression and histomorphometry respectively. Localized and systemic inflammation were measured through gene expression, histopathology scoring and measuring C-reactive protein (CRP) in the serum. Lastly, daily IVIS images were taken to track and measure transfection over time. MCM-LPX-FLuc and FMCM-LPX-FLuc were not found to cause any cytotoxic effects when tested . When measuring the osteogenic potential of each mineral composition, FMCM-LPX-FLuc trended higher in osteogenic markers through qRT-PCR than the other groups tested in a murine fracture and stabilization model. Despite FMCM-LPX-FLuc showing slightly elevated and levels in the fracture callus, inflammation scoring of the fracture callus did not result in any differences. Additionally, an acute systemic inflammatory response was not observed in any of the samples tested. The concentration of MCM-LPX-FLuc and FMCM-LPX-FLuc that was used in the murine fracture model did not stimulate bone when analyzed through stereological principles. Transfection efficacy and kinetics of delivery platforms revealed that FMCM-LPX-FLuc prolongs the luciferase signal both and . These data together reveal that FMCM-LPX-FLuc could serve as a promising mRNA delivery platform for fracture healing applications.
PubMed: 38264578
DOI: 10.3389/fbioe.2023.1295313 -
A Novel Method to Fix Paediatric Mandibular Fracture using 2-0 Polyglactin Suture: A Technical Note.African Journal of Paediatric Surgery :... Jan 2024Reduction and stabilisation of fractures at the earliest is valuable in the paediatric age groups. This novel technique focuses on stabilisation of the fracture...
BACKGROUND
Reduction and stabilisation of fractures at the earliest is valuable in the paediatric age groups. This novel technique focuses on stabilisation of the fracture fragments using vicryl, which has an added advantage to conventional plating and wiring. This study aimed on a novel cost-effective technique of stabilising the paediatric mandibular fracture using 2-0 resorbable polyglactin 910 suture with minimal trauma to tooth buds and bone and adequate stability.
TECHNIQUE
After raising a full-thickness mucoperiosteal flap, the fracture segments are identified and reduced. 1.6mm drill bit is used to make holes through the buccal cortex on either side of the fractured segment in an anteroposterior direction. The patency of holes is checked by passing a long 26-gauge wire. The proximal end of the wire is bent into a loop, a 2-0 resorbable polyglactin suture (vicryl) is passed through this loop and the loop is pressed in place to lock the suture. The wire with the attached suture is pulled through the distal end. Once the suture is secure in place, the 26G wire is cut, and the two ends of sutures are knotted and stabilised. The mucoperiosteal flap is then closed.
CONCLUSION
A novel method of stabilisation of paediatric fracture without hampering the tooth and jaw growth, especially in the financially unstable population. 2-0 polyglactin 910 suture is cost-effective, $2 US, compared to resorbable plates costing about $150 US, and easily available. Polyglactin 910 takes 40-60 days for resorption, and half-life tensile strength is 2 weeks; thus, it gives adequate stability and time for callus formation and does not damage the tooth buds or bone by cutting through them.
Topics: Humans; Child; Mandibular Fractures; Polyglactin 910; Neurosurgical Procedures; Fracture Fixation, Internal
PubMed: 38259021
DOI: 10.4103/ajps.ajps_127_22 -
Medicina (Kaunas, Lithuania) Dec 2023: Korean and traditional Chinese medicine state that pyrite is effective for fracture treatment, but supporting clinical data are limited. This systematic review aimed... (Meta-Analysis)
Meta-Analysis Review
: Korean and traditional Chinese medicine state that pyrite is effective for fracture treatment, but supporting clinical data are limited. This systematic review aimed to investigate the therapeutic role of Chinese patent medicine containing pyrite (CPMP) in clinical treatment for fractures. : Seven electronic databases were searched using the keywords "pyrite", "pyritum", and "zirantong" between inception and December 2022, yielding 29 published clinical studies. Randomized controlled trials that included CPMP were considered eligible regardless of the fracture type. Quality assessment and meta-analysis of the included RCTs were also performed. : Most studies showed high heterogeneity (I > 50%) and significant results ( < 0.05). Compared to the results of the control group, CPMP was more effective in terms of the primary outcome related to the efficacy rate, including the total effective rate, callus growth rate, bone union, and edema disappearance time (all < 0.00001) and in terms of secondary outcomes related to pain reduction, namely pain intensity and pain disappearance time, than the control group (both < 0.01). CPMP was more effective than the control group in terms of erythrocyte sedimentation rate ( < 0.01), hematocrit ( < 0.01), erythrocyte aggregation ( < 0.05), and plasma viscosity ( < 0.05). CPMP did not cause serious side effects, and the incidence of complications was significantly less than that in the control group. : CPMP may be a safe and effective alternative treatment for fractures and may be beneficial in preventing postoperative complications, reducing pain, relieving symptoms, and accelerating healing.
Topics: Humans; Fractures, Bone; Medicine, East Asian Traditional; Asian People; Pain; Iron; Sulfides
PubMed: 38256337
DOI: 10.3390/medicina60010076 -
International Journal of Molecular... Jan 2024Fracture healing in the aged is associated with a reduced healing capacity, which often results in delayed healing or non-union formation. Many factors may contribute to...
Fracture healing in the aged is associated with a reduced healing capacity, which often results in delayed healing or non-union formation. Many factors may contribute to this deterioration of bone regeneration, including a reduced 'angiogenic trauma response'. The phosphodiesterase-3 (PDE-3) inhibitor cilostazol has been shown to exert pro-angiogenic and pro-osteogenic effects in preclinical studies. Therefore, we herein analyzed in a stable closed femoral fracture model whether this compound also promotes fracture healing in aged mice. Forty-two aged CD-1 mice (age: 16-18 months) were daily treated with 30 mg/kg body weight cilostazol ( = 21) or vehicle (control, = 21) by oral gavage. At 2 and 5 weeks after fracture, the femora were analyzed by X-ray, biomechanics, micro-computed tomography (µCT), histology, immunohistochemistry, and Western blotting. These analyses revealed a significantly increased bending stiffness at 2 weeks (2.2 ± 0.4 vs. 4.3 ± 0.7 N/mm) and an enhanced bone formation at 5 weeks (4.4 ± 0.7 vs. 9.1 ± 0.7 mm) in cilostazol-treated mice when compared to controls. This was associated with a higher number of newly formed CD31-positive microvessels (3.3 ± 0.9 vs. 5.5 ± 0.7 microvessels/HPF) as well as an elevated expression of phosphoinositide-3-kinase (PI3K) (3.6 ± 0.8 vs. 17.4 ± 5.5-pixel intensity × 10) and runt-related transcription factor (RUNX)2 (6.4 ± 1.2 vs. 18.2 ± 2.7-pixel intensity × 10) within the callus tissue. These findings indicate that cilostazol accelerates fracture healing in aged mice by stimulating angiogenesis and the expression of PI3K and RUNX2. Hence, cilostazol may represent a promising compound to promote bone regeneration in geriatric patients.
Topics: Animals; Female; Male; Mice; Angiogenesis; Cilostazol; Core Binding Factor Alpha 1 Subunit; Femoral Fractures; Fracture Healing; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phosphodiesterase 3 Inhibitors; X-Ray Microtomography
PubMed: 38255829
DOI: 10.3390/ijms25020755