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Frontiers in Surgery 2024Delayed union and non-union of fractures continue to be a major problem in trauma and orthopedic surgery. These cases are challenging for the surgeon. In addition, these... (Review)
Review
Delayed union and non-union of fractures continue to be a major problem in trauma and orthopedic surgery. These cases are challenging for the surgeon. In addition, these patients suffer from multiple surgeries, pain and disability. Furthermore, these cases are a major burden on healthcare systems. The scientific community widely agrees that the stability of fixation plays a crucial role in determining the outcome of osteosynthesis. The extent of stabilization affects factors like fracture gap strain and fluid flow, which, in turn, influence the regenerative processes positively or negatively. Nonetheless, a growing body of literature suggests that during the fracture healing process, there exists a critical time frame where intervention can stimulate the bone's return to its original form and function. This article provides a summary of existing evidence in the literature regarding the impact of different levels of fixation stability on the strain experienced by newly forming tissues. We will also discuss the timing and nature of this "window of opportunity" and explore how current knowledge is driving the development of new technologies with design enhancements rooted in mechanobiological principles.
PubMed: 38756355
DOI: 10.3389/fsurg.2024.1376441 -
PloS One 2024First metatarsophalangeal joint arthrodesis is a typical medical treatment performed in cases of arthritis or joint deformity. The gold standard for this procedure is... (Comparative Study)
Comparative Study
Comparative analysis of mechanical conditions in bone union following first metatarsophalangeal joint arthrodesis with varied locking plate positions: A finite element analysis.
BACKGROUND
First metatarsophalangeal joint arthrodesis is a typical medical treatment performed in cases of arthritis or joint deformity. The gold standard for this procedure is arthrodesis stabilisation with the dorsally positioned plate. However, according to the authors' previous studies, medially positioned plate provides greater bending stiffness. It is worth to compare the mechanical conditions for bone formation in the fracture callus for both placements of the locking plate.
METHODS
Two finite element models of the first metatarsophalangeal joint with the dorsally and medially positioned plate were defined in the Abaqus software to simulate differentiation of the fracture callus. A simplified load application, i.e. one single step per each day and the diffusion of the mesenchymal stem cells into the fracture region were assumed in an iterative hardening process. The changes of the mesenchymal stem cells into different phenotypes during the callus stiffening were governed by the octahedral shear strain and interstitial fluid velocity according to Prendergast mechanoregulation theory. Basing on the obtained results the progress of the cartilage and bone tissues formation and their distribution within the callus were compared between two models.
FINDINGS
The obtained results suggest that after 6 weeks of simulation the healing progress is in general comparable for both plates. However, earlier closing of external callus was observed for the medially positioned plate which had greater vertical bending stiffness. This process enables faster internal callus hardening and promotes symmetrical bridging.
Topics: Finite Element Analysis; Arthrodesis; Bone Plates; Humans; Metatarsophalangeal Joint; Biomechanical Phenomena; Bony Callus; Fracture Healing
PubMed: 38753866
DOI: 10.1371/journal.pone.0303752 -
The Journal of Clinical Investigation May 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 were key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings established contextual roles of p21+ vs p16+ senescent/senescent-like cells that may be leveraged for therapeutic opportunities.
PubMed: 38753433
DOI: 10.1172/JCI179834 -
BMC Musculoskeletal Disorders May 2024External fixation is widely used in the treatment of traumatic fractures; however, orthopedic surgeons encounter challenges in deciding the optimal time for fixator...
BACKGROUND
External fixation is widely used in the treatment of traumatic fractures; however, orthopedic surgeons encounter challenges in deciding the optimal time for fixator removal. The axial load-share ratio (LS) of the fixator is a quantitative index to evaluate the stiffness of callus healing. This paper introduces an innovative method for measuring the LS and assesses the method's feasibility and efficacy. Based on a novel hexapod LS-measurement system, the proposed method is to improve the convenience and precision of measuring LS in vivo, hence facilitating the safe removal of external fixators.
METHODS
A novel hexapod system is introduced, including its composition, theoretical model, and method for LS measurement. We conducted a retrospective study on 82 patients with tibial fractures treated by the Taylor Spatial Frame in our hospital from September 2018 to June 2020, of which 35 took LS measurements with our novel method (Group I), and 47 were with the traditional method (Group II). The external fixator was removed when the measurement outcome (LS < 10%) was consistent with the surgeon's diagnosis based on the clinical and radiological assessment (bone union achieved).
RESULTS
No significant difference was found in the fracture healing time (mean 25.3 weeks vs. 24.9 weeks, P > 0.05), frame-wearing duration (mean 25.5 weeks vs. 25.8 weeks, P > 0.05), or LS measurement frequency (mean 1.1 times vs. 1.2 times, P > 0.05). The measurement system installation time in Group I was significantly shorter compared to Group II (mean 14.8 min vs. 81.3 min, P < 0.001). The LS value of the first measurement in Group I was lower than that of Group II (mean 5.1% vs. 6.9%, P = 0.011). In Group I, the refracture rate was 0, but in Group II it was 4.3% (2/47, P > 0.05).
CONCLUSION
The novel hexapod LS-measurement system and involved method demonstrated enhanced convenience and precision in measuring the LS of the external fixator in vivo. The LS measurement indicates the callus stiffness of fracture healing, and is applicable to evaluate the safety of removing the fixator. Consequently, it is highly recommended for widespread adoption in clinical practice.
Topics: Humans; External Fixators; Female; Tibial Fractures; Male; Retrospective Studies; Adult; Fracture Healing; Middle Aged; Fracture Fixation; Device Removal; Weight-Bearing; Young Adult; Aged; Feasibility Studies; Equipment Design
PubMed: 38724941
DOI: 10.1186/s12891-024-07440-y -
Journal of Clinical Medicine Apr 2024: Fracture healing is a very complex and well-orchestrated regenerative process involving many cell types and molecular pathways. Despite the high efficiency of this... (Review)
Review
: Fracture healing is a very complex and well-orchestrated regenerative process involving many cell types and molecular pathways. Despite the high efficiency of this process, unsatisfying healing outcomes, such as non-union, occur for approximately 5-10% of long bone fractures. Although there is an obvious need to identify markers to monitor the healing process and to predict a potential failure in callus formation to heal the fracture, circulating bone turnover markers' (BTMs) utility as biomarkers in association with radiographic and clinical examination still lacks evidence so far. : A systematic review on the association between BTMs changes and fracture healing in long bone non-union was performed following PRISMA guidelines. The research papers were identified via the PubMed, Cochrane, Cinahl, Web of Science, Scopus, and Embase databases. Studies in which the failure of fracture healing was associated with osteoporosis or genetic disorders were not included. : A total of 172 studies were collected and, given the inclusion criteria, 14 manuscripts were included in this review. Changes in circulating BTMs levels were detected during the healing process and across groups (healed vs. non-union patients and healthy vs. patients with non-union). However, we found high heterogeneity in patients' characteristics (fracture site, gender, and age) and in sample scheduling, which made it impossible to perform a meta-analysis. : Clinical findings and radiographic features remain the two important components of non-union diagnosis so far. We suggest improving blood sample standardization and clinical data collection in future research to lay the foundations for the effective use of BTMs as tools for diagnosing non-union.
PubMed: 38673606
DOI: 10.3390/jcm13082333 -
Theranostics 2024Mechanical forces are indispensable for bone healing, disruption of which is recognized as a contributing cause to nonunion or delayed union. However, the underlying...
Mechanical forces are indispensable for bone healing, disruption of which is recognized as a contributing cause to nonunion or delayed union. However, the underlying mechanism of mechanical regulation of fracture healing is elusive. We used the lineage-tracing mouse model, conditional knockout depletion mouse model, hindlimb unloading model and single-cell RNA sequencing to analyze the crucial roles of mechanosensitive protein polycystin-1 (PC1, ) promotes periosteal stem/progenitor cells (PSPCs) osteochondral differentiation in fracture healing. Our results showed that cathepsin ()-positive PSPCs are fracture-responsive and mechanosensitive and can differentiate into osteoblasts and chondrocytes during fracture repair. We found that polycystin-1 declines markedly in PSPCs with mechanical unloading while increasing in response to mechanical stimulus. Mice with conditional depletion of in PSPCs show impaired osteochondrogenesis, reduced cortical bone formation, delayed fracture healing, and diminished responsiveness to mechanical unloading. Mechanistically, PC1 facilitates nuclear translocation of transcriptional coactivator TAZ via PC1 C-terminal tail cleavage, enhancing osteochondral differentiation potential of PSPCs. Pharmacological intervention of the PC1-TAZ axis and promotion of TAZ nuclear translocation using Zinc01442821 enhances fracture healing and alleviates delayed union or nonunion induced by mechanical unloading. Our study reveals that PSPCs within the callus can sense mechanical forces through the PC1-TAZ axis, targeting which represents great therapeutic potential for delayed fracture union or nonunion.
Topics: Animals; Fracture Healing; Mice; Cell Differentiation; TRPP Cation Channels; Chondrocytes; Stem Cells; Osteogenesis; Mice, Knockout; Chondrogenesis; Periosteum; Osteoblasts; Disease Models, Animal; Male; Adaptor Proteins, Signal Transducing
PubMed: 38646641
DOI: 10.7150/thno.93269 -
Journal of ISAKOS : Joint Disorders &... Apr 2024Stress fractures, a common overuse injury in physically active individuals, present a significant challenge for athletes and military personnel. Patients who sustain...
Stress fractures, a common overuse injury in physically active individuals, present a significant challenge for athletes and military personnel. Patients who sustain stress fractures have demanding training regimes, where periods of rest and immobilisation have unacceptable negative consequences on sport goals and finances. Aside from being an overuse injury, there are various contributing risk factors that put certain individuals at risk of a stress fracture. The main two being nutritional deficiencies and hormonal variations which have significant effects on bone metabolism and turnover. Historically, treatment of stress fractures focused on conservative strategies such as rest and immobilisation. Calcium and vitamin D deficiencies have been closely linked to stress fractures and so over time supplementation has also played a role in treatment. With the introduction of biologics into orthopaedics, newer treatment strategies have been applied accelerate fracture healing and perhaps improve fracture callus quality. If such therapies can reduce, time spent away from sport and activity, it would be ideal for treating stress fractures. This article aims to offers insights into the evolving landscape of stress fracture management. It investigates the pre-clinical evidence and available published clinical applications. Though fracture healing is well understood, the role of biologics for fracture healing is still indeterminate. Available literature for the use of biologics therapies in stress fractures is restricted and most reports have used biologics as a supplement to surgical fixation in subjects in studies that lack control groups. Randomised control trials have been proposed and registered by a few groups with results awaited. Assessing individuals for risk factors, addressing hormonal imbalances and nutritional deficiencies seem an effective approach to addressing the burden of stress fractures. We await better designed trials and studies to accurately determine the clinical benefit of adding biologics to management of these injuries.
PubMed: 38631518
DOI: 10.1016/j.jisako.2024.04.008 -
International Journal of Molecular... Mar 2024Fracture healing is a complex series of events that requires a local inflammatory reaction to initiate the reparative process. This inflammatory reaction is important...
Fracture healing is a complex series of events that requires a local inflammatory reaction to initiate the reparative process. This inflammatory reaction is important for stimulating the migration and proliferation of mesenchymal progenitor cells from the periosteum and surrounding tissues to form the cartilaginous and bony calluses. The proinflammatory cytokine interleukin (IL)-17 family has gained attention for its potential regenerative effects; however, the requirement of IL-17 signaling within mesenchymal progenitor cells for normal secondary fracture healing remains unknown. The conditional knockout of IL-17 receptor a () in mesenchymal progenitor cells was achieved by crossing mice with mice to generate ; mice. At 3 months of age, mice underwent experimental unilateral mid-diaphyseal femoral fractures and healing was assessed by micro-computed tomography (µCT) and histomorphometric analyses. The effects of IL-17RA signaling on the osteogenic differentiation of fracture-activated periosteal cells was investigated in vitro. Examination of the intact skeleton revealed that the conditional knockout of decreased the femoral cortical porosity but did not affect any femoral trabecular microarchitectural indices. After unilateral femoral fractures, conditional knockout impacted the cartilage and bone composition of the fracture callus that was most evident early in the healing process (day 7 and 14 post-fracture). Furthermore, the in vitro treatment of fracture-activated periosteal cells with IL-17A inhibited osteogenesis. This study suggests that IL-17RA signaling within + mesenchymal progenitor cells can influence the early stages of endochondral ossification during fracture healing.
Topics: Animals; Mice; Fracture Healing; Osteogenesis; X-Ray Microtomography; Mesenchymal Stem Cells; Femoral Fractures; Inflammation
PubMed: 38612562
DOI: 10.3390/ijms25073751 -
JBMR Plus May 2024Nonunion resulting from early bone resorption is common after bone transplantation surgery. In these patients, instability or osteoporosis causes hyperactive catabolism...
Nonunion resulting from early bone resorption is common after bone transplantation surgery. In these patients, instability or osteoporosis causes hyperactive catabolism relative to anabolism, leading to graft resorption instead of fusion. Systemic zoledronate administration inhibits osteoclastogenesis and is widely used to prevent osteoporosis; however, evidence on local zoledronate application is controversial due to osteoblast cytotoxicity, uncontrolled dosing regimens, and local release methods. We investigated the effects of zolendronate on osteoclastogenesis and osteogenesis and explored the corresponding signaling pathways. In vitro cytotoxicity and differentiation of MC3T3E1 cells, rat bone marrow stromal cells (BMSCs) and preosteoclasts (RAW264.7 cells) were evaluated with different zolendronate concentrations. In vivo bone regeneration ability was tested by transplanting different concentrations of zolendronate with β-tricalcium phosphate (TCP) bone substitute into rat femoral critical-sized bone defects. In vitro zolendronate concentrations below 2.5 × 10 M did not compromise viability in the three cell lines and did not promote osteogenic differentiation in MC3T3E1 cells and BMSCs. In RAW264.7 cells, zoledronate inhibited extracellular regulated protein kinases and c-Jun n-terminal kinase signaling, downregulating c-Fos and NFATc1 expression, with reduced expression of fusion-related dendritic cell‑specific transmembrane protein and osteoclast-specific Ctsk and tartrate-resistant acid phosphatase (. In vivo histological staining revealed increased osteoid formation and neovascularization and reduced fibrotic tissue with 500 μM and 2000 μM zolendronate. More osteoclasts were found in the normal saline group after 6 weeks, and sequential osteoclast formation occurred after zoledronate treatment, indicating inhibition of bone resorption during early callus formation without inhibition of late-stage bone remodeling. In vivo soaking β-TCP artificial bone with 500 μM or 2000 μM zoledronate is a promising approach for bone regeneration, with potential applications in bone transplantation.
PubMed: 38606146
DOI: 10.1093/jbmrpl/ziae031 -
Trauma Case Reports Jun 2024Atypical femoral fractures (AFFs) occur with minor trauma and are believed to be a potential complication of the prolonged use of antiresorptive agents, such as...
Atypical femoral fractures (AFFs) occur with minor trauma and are believed to be a potential complication of the prolonged use of antiresorptive agents, such as bisphosphonate and denosumab, for the treatment of bone metastasis. In comparison with typical femoral fractures, AFFs have a higher incidence of complications, including implant failure and delayed union or nonunion. This report describes the case of a 42-year-old woman who developed denosumab-associated AFF after denosumab therapy for bone metastasis from breast cancer. Surgical treatment with IMN was performed after open anatomical reduction. To reduce the risk of delayed union and nonunion, the autogenous bone graft obtained from the iliac crest was conducted. The radiograph taken 5 weeks after surgery showed callus formation. Full weight bearing was allowed 3 months after surgery. Six months postoperatively, radiographs and computed tomography images demonstrated bone union. Twelve months after surgery, the patient was able to walk easily without pain. For cancer patients with bone metastasis whose life expectancy may be limited, a decline in physical activity can be fatal. Consequently, it is crucial to avoid a decrease in activities of daily living brought about by delayed union or nonunion. In this regard, autogenous bone grafting is a viable and effective technique for the treatment of AFFs in patients with bone metastases.
PubMed: 38590922
DOI: 10.1016/j.tcr.2024.101005