Technology Behind Cell Therapy Augmentation of Fracture Healing: Concentrated Bone Marrow Aspirate.

With an aging population, and an anticipated increase in overall fracture incidence, a sound understanding of bone healing and how technology can optimize this process is crucial. Concentrated bone marrow aspirate (cBMA) is a technology that capitalizes on skeletal stem and progenitor cells (SSPCs) to enhance the regenerative capacity of bone. This overview highlights the science behind cBMA, discusses the role of SSPCs in bone homeostasis and fracture repair, and briefly details the clinical evidence supporting the use of cBMA in fracture healing. Despite promising early clinical results, a lack of standardization in harvest and processing techniques, coupled with patient variability, presents challenges in optimizing the use of cBMA. However, cBMA remains an emerging technology that may certainly play a crucial role in the future of fracture healing augmentation.

Increased ß2-adrenergic signaling promotes fracture healing through callus neovascularization in mice.

Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the ß2-adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene-related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

A novel surgical method for treating fractures of the middle third of the clavicle.

BACKGROUND: The clavicle is recognized as the bone most vulnerable to fractures. Moreover, approximately 80% of fractures occur in the middle third of the clavicle. Conservative treatment is associated with a higher rate of nonunion, while surgical treatment of fracture via internal fixation may have a variety of postoperative complications. Therefore, to improve patient satisfaction and reduce the complications related to internal fixation techniques, we modified the surgical approach to external fixation. OBJECTIVE: The purpose of this study was to assess the modified intervention's prospects for clinical application. METHODS: A total of 36 patients with middle clavicle fractures were treated with screw-rod external fixation between April 2015 and October 2019. We observed the operative time, intraoperative blood loss, length of hospital stay, and fracture healing time. The patients were followed up regularly, and the clinical efficacy of the modified intervention was evaluated. Finally, the patients' shoulder function was assessed based on the disabilities of the arm, shoulder, and hand (DASH) score. RESULTS: For the screw-rod external fixation, the mean operative time was found to be 48.6 ± 6.8 min, the intraoperative blood loss was 30.6 ± 17.2 mL, the length of hospital stay was 4.5 ± 1.5 days, and the fracture healing time was 2.8 ± 0.4 months. Eventually, all the patients healed well, with the combined "excellent" and "good" rate of shoulder function being assessed to be as high as 94.44%. Furthermore, the DASH scores were all less than 10, with the average score being 4.65 ± 3.34. CONCLUSIONS: The screw-rod external fixation technique offers the advantages of convenience, reliability, and good aesthetics, suggesting that it could be used as an alternative treatment method for fractures of the middle third of the clavicle.

Dnmt3b ablation affects fracture repair process by regulating apoptosis.

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 (Dnmt3bGli1ER) mice to operated tibia fracture. Fracture callus tissues of Dnmt3bGli1ER 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 Dnmt3bGli1ER mice much less than control mice. Dnmt3bGli1ER 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 Dnmt3bGli1ER 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.

Conservative treatment of fragility fracture of the pelvis: A retrospective study.

BACKGROUND: Although an increasing number of studies have reported the usefulness of early minimally invasive surgery (MIS) or fragility fracture of the pelvis (FFP), MIS is difficult to perform in every hospital, partly because of equipment problems. Moreover, different opinions exist on FFP treatment methods and the indication for surgery is usually determined by the fracture type. Since our hospital follows a conservative approach as the basic treatment, this study examined the outcomes of such an FFP approach. HYPOTHESIS: FFP outcomes are influenced by the fracture type and walking ability before the injury. PATIENTS AND METHODS: We investigated the bone fusion rate, bone fusion duration, unloading duration, walking ability trends, and outcomes in 76 patients with FFP treated conservatively at our hospital. RESULTS: The union rate, mean period until union, and follow-up period were 93.4%, 3.3 months, and 14.3 months, respectively. Walking ability significantly decreased from 5.1 points before the injury to 4.4 points during the last follow-up (p<0.01). The average unloading period was 12.8 days, and FFPs showed a high bone fusion rate, even with conservative treatment. DISCUSSION: Most patients eventually returned to their pre-injury status despite slightly decreased walking ability. Given the invasive nature of surgery, the indications for surgery should be carefully assessed after considering the risk-benefit ratio. LEVEL OF EVIDENCE: III; retrospective study.

Latest Progress of LIPUS in Fracture Healing: A Mini-Review.

The use of low-intensity pulsed ultrasound (LIPUS) for promoting fracture healing has been Food and Drug Administration (FDA)-approved since 1994 due to largely its non-thermal effects of sound flow sound radiation force and so on. Numerous clinical and animal studies have shown that LIPUS can accelerate the healing of fresh fractures, nonunions, and delayed unions in pulse mode regardless of LIPUS devices or circumstantial factors. Rare clinical studies show limitations of LIPUS for treating fractures with intramedullary nail fixation or low patient compliance. The biological effect is achieved by regulating various cellular behaviors involving mesenchymal stem/stromal cells (MSCs), osteoblasts, chondrocytes, and osteoclasts and with dose dependency on LIPUS intensity and time. Specifically, LIPUS promotes the osteogenic differentiation of MSCs through the ROCK-Cot/Tpl2-MEK-ERK signaling. Osteoblasts, in turn, respond to the mechanical signal of LIPUS through integrin, angiotensin type 1 (AT1), and PIEZO1 mechano-receptors, leading to the production of inflammatory factors such as COX-2, MCP-1, and MIP-1ß fracture repair. LIPUS also induces CCN2 expression in chondrocytes thereby coordinating bone regeneration. Finally, LIPUS suppresses osteoclast differentiation and gene expression by interfering with the ERK/c-Fos/NFATc1 cascade. This mini-review revisits the known effects and mechanisms of LIPUS on bone fracture healing and strengthens the need for further investigation into the underlying mechanisms.

Treatment of Severely Shortened or Comminuted Clavicular Fractures in Older Adolescent Athletes.

BACKGROUND: Recent evidence suggests that for completely displaced midshaft clavicular fractures, surgery offers no clear benefit over nonoperative treatment in a general adolescent population from 10 to 18 years of age. However, the comparative outcomes of comminuted and/or severely shortened clavicular fractures specifically in older adolescent athletes have not been explored in a focused, methodologically rigorous fashion. HYPOTHESIS: The study hypothesis was that outcomes would be superior in older adolescent athletes who underwent operative treatment compared with nonoperative treatment for comminuted and/or severely shortened clavicular fractures. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A level 2, multicenter, prospective cohort study investigating the outcomes of midshaft fractures in adolescents between 2013 and 2017 was filtered to analyze the subcohorts of athletes 14 to 18 years of age with either fracture comminution or fracture shortening of ≥25 mm or both. Patient characteristics, injury mechanisms, fracture characteristics, and treatments were compared. Complications, rates, timing of return to sports (RTS), and patient-reported outcomes (PROs) were analyzed. RESULTS: The 2 treatment groups, which included 136 older adolescent athletes (69 nonoperative, 67 operative), showed similar distributions of primary sport type, competition level, comminution, shortening, and 2-year PRO response rate (n = 99; 73%). The operative group demonstrated 3 mm-greater mean superior displacement, which was therefore statistically controlled for as a confounder in the comparative PRO analysis. No 2-year differences in nonunion, delayed union, symptomatic malunion, refracture, clinically significant complications, or rates of RTS were detected between treatment groups. The difference in timing of RTS (operative, 10.3 weeks; nonoperative, 13.5 weeks) was statistically significant. After controlling for the minor difference in superior displacement, regression analysis and matched comparison cohorts demonstrated no differences between the nonoperative and operative groups in mean or dichotomized PRO scores. CONCLUSION: In this prospective, multicenter cohort study investigating older adolescent athletes with comminuted and/or severely shortened clavicular fractures, contrary to the study hypothesis, there were no differences in complications, RTS, or PROs between nonoperatively and operatively treated patients at 2 years. Comparably excellent outcomes of severe clavicular fractures in adolescent athletes can be achieved with nonoperative treatment.

Clinical effect of nice knot-assisted minimally invasive titanium elastic nail fixation to treat Robinson 2B midshaft clavicular fracture.

BACKGROUND: The treatment of completely displaced midshaft clavicle fractures is still controversial, especially Robinson 2B fractures. Titanium elastic nail (TEN) fixation is a good option for simple fractures, but no reports exist on its use in complex fractures. This study aimed to present a surgical method using the Nice knot-assisted TEN fixation to treat Robinson 2B midshaft clavicular fractures. METHODS: A retrospective analysis of 29 patients who underwent fixation with TEN and had a 1-year postoperative follow-up between 2016 and 2020 was performed. The fractures were classified as Robinson type 2B1 in 17 cases and type 2B2 in 12 cases. Length of the incision, postoperative shoulder function Disability of Arm Shoulder and Hand (DASH) score and Constant score, complications rate, and second surgical incision length were recorded. RESULTS: The length of the incision was 2-6 cm (average 3.7 cm). All incisions healed by first intention, and no infection or nerve injury occurred. The Constant score was 92-100 (average 96) and the DASH score was 0-6.2 (mean, 2.64). TEN bending and hypertrophic nonunion occurred in one case (3.4%) and implant irritation occurred in four cases (13.8%) Fixation implants were removed at 12-26 months (mean, 14.6 months) after surgery, and the length of the second incision was 1-2.5 cm (average 1.3 cm). CONCLUSIONS: Intramedullary fixation by TEN is approved as a suitable surgical technique in clavicular fracture treatment. Nice knot-assisted fixation provides multifragmentary fracture stabilization, contributing to good fracture healing. Surgeons should consider this technique in treating Robinson 2B midshaft clavicular fractures. TRIAL REGISTRATION: Retrospectively registered. This study was approved by the Ethics Committee of Wuxi Ninth People's Hospital (LW20220021).

[Research progress on mechanism of traumatic brain injury promoting fracture healing].

Objective: To summarize the research progress on the mechanism related to traumatic brain injury (TBI) to promote fracture healing, and to provide theoretical basis for clinical treatment of fracture non-union. Methods: The research literature on TBI to promote fracture healing at home and abroad was reviewed, the role of TBI in fracture healing was summarized from three aspects of nerves, body fluids, and immunity, to explore new ideas for the treatment of fracture non-union. Results: Numerous studies have shown that fracture healing is faster in patients with fracture combined with TBI than in patients with simple fracture. It is found that the expression of various cytokines and hormones in the body fluids of patients with fracture and TBI is significantly higher than that of patients with simple fracture, and the neurofactors released by the nervous system reaches the fracture site through the damaged blood-brain barrier, and the chemotaxis and aggregation of inflammatory cells and inflammatory factors at the fracture end of patients with combined TBI also differs significantly from those of patients with simple fracture. A complex network of humoral, neural, and immunomodulatory networks together promote regeneration of blood vessels at the fracture site, osteoblasts differentiation, and inhibition of osteoclasts activity. Conclusion: TBI promotes fracture healing through a complex network of neural, humoral, and immunomodulatory, and can treat fracture non-union by intervening in the perifracture microenvironment.

Intramedullary implant stability affects patterns of fracture healing in mice with morphologically different bone phenotypes.

Almost all prior mouse fracture healing models have used needles or K-wires for fixation, unwittingly providing inadequate mechanical stability during the healing process. Our contention is that the reported outcomes have predominantly reflected this instability, rather than the impact of diverse biological conditions, pharmacologic interventions, exogenous growth factors, or genetic considerations. This important issue becomes obvious upon a critical review of the literature. Therefore, the primary aim of this study was to demonstrate the significance of mouse-specific implants designed to provide both axial and torsional stability (Screw and IM Nail) compared to conventional pins (Needle and K-wires), even when used in mice with differently sized marrow canals and diverse genetic backgrounds. B6 (large medullary canal), DBA, and C3H (smaller medullary canals) mice were employed, all of which have different bone morphologies. Closed femoral fractures were created and stabilized with intramedullary implants that provide different mechanical conditions during the healing process. The most important finding of this study was that appropriately designed mouse-specific implants, providing both axial and torsional stability, had the greatest influence on bone healing outcomes regardless of the different bone morphologies encountered. For instance, unstable implants in the B6 strain (largest medullary canal) resulted in significantly greater callus, with a fracture region mainly comprising trabecular bone along with the presence of cartilage 28 days after surgery. The DBA and C3H strains (with smaller medullary canals) instead formed significantly less callus, and only had a small amount of intracortical trabeculation remaining. Moreover, with more stable fracture fixation a higher BV/TV was observed and cortices were largely restored to their original dimensions and structure, indicating an accelerated healing and remodeling process. These observations reveal that the diaphyseal cortical thickness, influenced by the genetic background of each strain, played a pivotal role in determining the amount of bone formation in response to the fracture. These findings are highly important, indicating the rate and type of tissue formed is a direct result of mechanical instability, and this most likely would mask the true contribution of the tested genes, genetic backgrounds, or various therapeutic agents administered during the bone healing process.

What Is the Likelihood of Union and Frequency of Complications After Parallel Plating and Supplemental Bone Grafting for Resistant Distal Femoral Nonunions?

BACKGROUND: Management of resistant distal femur nonunions is challenging because patients not only have disability from an unhealed fracture, but also often have a shortened femur, stiff knee, deformities, and bone defects to address during revision surgery. Dual plating of the distal femur in such a setting can maintain stability that allows the nonunion to heal while also addressing bone defects and correcting deformities simultaneously. Dual-plating techniques that have been described lack standardization with regard to the size and type of medial-side implants and configuration of the dual-plate construct. QUESTIONS/PURPOSES: (1) What proportion of patients achieve radiologic evidence of union after parallel plating of resistant distal femoral nonunions? (2) What improvements in function are achieved with this approach, as assessed by improvements in femoral length discrepancy, knee flexion, and patient-reported outcome scores? (3) What complications are associated with the technique? METHODS: Between 2017 and 2020, the senior author of this study treated 38 patients with resistant distal femoral nonunions, defined here as nonunions that persisted for more than 12 months since the injury despite a minimum of two previous internal fixation procedures. During the study period, our preferred technique for treating aseptic, resistant distal femoral nonunions was to use dual plates in a parallel configuration augmented with autografts. Of 38 patients, three patients with active signs of infection who underwent resection and reconstruction using bone transport techniques and two patients older than 65 years with deficient distal femur bone stock who underwent endoprosthetic reconstruction were excluded. Of the 33 included patients, 67% (22 of 33) were male. The median age was 40 years (range 20 to 67 years). Nonunion was articular and metaphyseal in 13 patients and metaphyseal only in 20 patients. Our surgical approach was to remove existing implants, perform intraoperative culturing to rule out infection, debride the nonunion, correct the deformity, perform intra-articular and extra-articular lysis of adhesions with quadriceps release, and apply fixation using medial and lateral fixed-angle anatomic locked implants positioned in a parallel configuration. Every attempt to improve length was undertaken, and the defects were filled with autografts. A total of 97% of patients were followed until union occurred (one of 33 was lost to follow-up before union was documented), and 79% (26 of 33) were assessed for functional outcomes at a minimum of 2 years (median 38 months [range 25 to 60 months]) after excluding patients lost to follow-up and those in whom union did not occur after parallel plating. Union was defined as evidence of central trabecular bridging on AP radiographs and posterior cortical bridging on lateral radiographs. These radiologic criteria were defined to overcome difficulties in assessing radiologic healing in patients with lateral and medial plates. With parallel plating, bridging trabecular bone along the posterior cortex on lateral radiographs and the central region on AP radiographs is visualized and can be appreciated and interpreted as evidence of healing in two orthogonal planes. Preoperative and follow-up clinical assessment of knee ROM, the extent of femoral length correction based on calibrated femoral radiographs before and after surgery, and the evaluation of improvement in lower limb function based on the preoperative and follow-up differences in responses to the lower extremity functional scale (LEFS) were studied (the LEFS is scored from 0 to 80, with higher scores representing better function). Complications and secondary surgical procedures to address them were abstracted from a longitudinally maintained trauma database. RESULTS: Sixty-seven percent (22 of 33) of nonunions showed radiologic healing by 24 weeks, and another 24% (eight of 33) healed by 36 weeks. Six percent (two of 33) did not unite, and one patient was lost to follow-up before union was documented. In the 79% (26 of 33) of patients available for final functional outcome assessment, the median femoral shortening had improved from 2.4 cm (range 0 to 4 cm) to 1.1 cm (range 0 to 2.3 cm; p < 0.001), and the median knee ROM had improved from 70° (range 20° to 110°) to 100° (range 50° to 130°; p = 0.002) after surgery. The median LEFS score improved to 63 (range 41 to 78) compared with 22 (range 15 to 33; p < 0.001) before surgery. Serious complications, including major thromboembolic events, iliac graft site infection, knee stiffness (flexion < 60°), and medial plate impingement necessitating removal, were seen in 30% (10 of 33) of patients. Secondary surgical interventions were performed in 24% (eight of 33) of patients to address procedure-related complications. CONCLUSION: Based on our findings, a high likelihood of union and improvements in knee and lower limb function can be expected with parallel plating of resistant distal femur nonunions using anatomic locked plates. However, the increased frequency of complications observed in our study suggests the need for improvements in dual-plating techniques and to explore possible alternative fixation methods through larger multicenter comparative studies. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Lateral minimally invasive plate osteosynthesis (MIPO) with long PHILOS for proximal metaphyseal-diaphyseal humeral fracture: surgical techniques and a clinical series.

The minimally invasive plate osteosynthesis (MIPO) for proximal metaphyseal-diaphyseal humeral fracture is an effective alternative treatment with satisfactory outcomes. In this study, we described the surgical techniques and clinical results using MIPO via a lateral approach and long PHILOS plate fixation in 23 patients. All fractures were successfully united within a mean union time of 13.5 weeks (range 9-18). There was no iatrogenic radial nerve palsy. The deltoid power was grade 5 in all patients, except for 2 patients who had associated brachial plexus injury and gunshot injury at the deltoid muscle. The mean Constant-Murley score was 85.6 (range 16-98) and DASH score was 12.1 (range 1.7-85). Based on these findings, the lateral MIPO with long PHILOS plate fixation could be an alternative for the proximal metaphyseal-diaphyseal fractures of the humeral shaft.

Bone-Targeted Nanoparticle Drug Delivery System-Mediated Macrophage Modulation for Enhanced Fracture Healing.

Despite decades of progress, developing minimally invasive bone-specific drug delivery systems (DDS) to improve fracture healing remains a significant clinical challenge. To address this critical therapeutic need, nanoparticle (NP) DDS comprised of poly(styrene-alt-maleic anhydride)-b-poly(styrene) (PSMA-b-PS) functionalized with a peptide that targets tartrate-resistant acid phosphatase (TRAP) and achieves preferential fracture accumulation has been developed. The delivery of AR28, a glycogen synthase kinase-3 beta (GSK3ß) inhibitor, via the TRAP binding peptide-NP (TBP-NP) expedites fracture healing. Interestingly, however, NPs are predominantly taken up by fracture-associated macrophages rather than cells typically associated with fracture healing. Therefore, the underlying mechanism of healing via TBP-NP is comprehensively investigated herein. TBP-NPAR28 promotes M2 macrophage polarization and enhances osteogenesis in preosteoblast-macrophage co-cultures in vitro. Longitudinal analysis of TBP-NPAR28 -mediated fracture healing reveals distinct spatial distributions of M2 macrophages, an increased M2/M1 ratio, and upregulation of anti-inflammatory and downregulated pro-inflammatory genes compared to controls. This work demonstrates the underlying therapeutic mechanism of bone-targeted NP DDS, which leverages macrophages as druggable targets and modulates M2 macrophage polarization to enhance fracture healing, highlighting the therapeutic benefit of this approach for fractures and bone-associated diseases.

Preparation of Novel Sea Cucumber Intestinal Peptides to Promote Tibial Fracture Healing in Mice by Inducing Differentiation of Hypertrophic Chondrocytes to the Osteoblast Lineage.

SCOPE: Hypertrophic chondrocytes have a decisive regulatory role in the process of fracture healing, and the fate of hypertrophic chondrocytes is not only apoptosis. However, the mechanism of sea cucumber (Stichopus japonicus) intestinal peptide (SCIP) on fracture promotion is still unclear. This study aims to investigate the effect of sea cucumber intestinal peptide on the differentiation fate of hypertrophic chondrocytes in a mouse tibial fracture model. METHODS AND RESULTS: Mice are subjected to open fractures of the right tibia to establish a tibial fracture model. The results exhibit that the SCIP intervention significantly promotes the mineralization of cartilage callus, decreases the expression of the hypertrophic chondrocyte marker Col X, and increases the expression of the osteoblast marker Col I. Mechanically, SCIP promotes tibial fracture healing by promoting histone acetylation and inhibiting histone methylation, thereby upregulating pluripotent transcription factors induced the differentiation of hypertrophic chondrocytes to the osteoblast lineage in a manner distinct from classical endochondral ossification. CONCLUSION: This study is the first to report that SCIP can promote tibial fracture healing in mice by inducing the differentiation of hypertrophic chondrocytes to the osteoblast lineage. SCIP may be considered raw material for developing nutraceuticals to promote fracture healing.

Moderate static magnetic field promotes fracture healing and regulates iron metabolism in mice.

BACKGROUND: Fractures are the most common orthopedic diseases. It is known that static magnetic fields (SMFs) can contribute to the maintenance of bone health. However, the effect and mechanism of SMFs on fracture is still unclear. This study is aim to investigate the effect of moderate static magnetic fields (MMFs) on bone structure and metabolism during fracture healing. METHODS: Eight-week-old male C57BL/6J mice were subjected to a unilateral open transverse tibial fracture, and following treatment under geomagnetic field (GMF) or MMF. The micro-computed tomography (Micro-CT) and three-point bending were employed to evaluate the microarchitecture and mechanical properties. Endochondral ossification and bone remodeling were evaluated by bone histomorphometric and serum biochemical assay. In addition, the atomic absorption spectroscopy and ELISA were utilized to examine the influence of MMF exposure on iron metabolism in mice. RESULTS: MMF exposure increased bone mineral density (BMD), bone volume per tissue volume (BV/TV), mechanical properties, and proportion of mineralized bone matrix of the callus during fracture healing. MMF exposure reduced the proportion of cartilage in the callus area during fracture healing. Meanwhile, MMF exposure increased the number of osteoblasts in callus on the 14th day, and reduced the number of osteoclasts on the 28th day of fracture healing. Furthermore, MMF exposure increased PINP and OCN levels, and reduced the TRAP-5b and ß-CTX levels in serum. It was also observed that MMF exposure reduced the iron content in the liver and callus, as well as serum ferritin levels while elevating the serum hepcidin concentration. CONCLUSIONS: MMF exposure could accelerate fracture healing via promote the endochondral ossification and bone formation while regulating systemic iron metabolism during fracture healing. This study suggests that MMF may have the potential to become a form of physical therapy for fractures.

Interaction between Mesenchymal Stem Cells and Immune Cells during Bone Injury Repair.

Fractures are the most common large organ trauma in humans. The initial inflammatory response promotes bone healing during the initial post-fracture phase, but chronic and persistent inflammation due to infection or other factors does not contribute to the healing process. The precise mechanisms by which immune cells and their cytokines are regulated in bone healing remain unclear. The use of mesenchymal stem cells (MSCs) for cellular therapy of bone injuries is a novel clinical treatment approach. Bone progenitor MSCs not only differentiate into bone, but also interact with the immune system to promote the healing process. We review in vitro and in vivo studies on the role of the immune system and bone marrow MSCs in bone healing and their interactions. A deeper understanding of this paradigm may provide clues to potential therapeutic targets in the healing process, thereby improving the reliability and safety of clinical applications of MSCs to promote bone healing.

Augmentation plate without bone graft in the management of distal tibial diaphyseal non-union.

PURPOSE: The objective of this study was to assess the efficacy of augmentation plating with retaining of previous implant in situ in cases of non-united oligotrophic or atrophic aseptic distal tibial diaphyseal and metaphyseal fractures without bone grafting depending on the unified bone healing and non-union theory. METHODS: Through the period between December 2019 and December 2022, twelve patients with distal third tibial non-unions who were fixed at time of fracture either by intramedullary interlocking nails (seven cases) or by minimally invasive plate osteosynthesis (five cases) were included. Non-union was diagnosed on basis of absence of any healing progression in three months period or absence of fracture healing after six months from index surgery. All patients had oligotrophic or atrophic non-union. Augmentation plating through an anterolateral approach was done on average of 7.25 months after initial surgery (6-9 months). Circumferential exposure of the fracture site and debridement of fibrous tissue were not necessary. No bone grafting was done as no cases had major bone defect. RESULTS: All patients achieved complete radiological union with a mean time of 21.8 weeks (range 18-30 weeks) that mean full callus formation in all cortices. All patients were walking independently after three months (13weeks) from surgery and returned to work even in cases of absent complete radiological union. No cases had been complicated with wound healing problems (infection or dehiscence). One patient had incomplete ankle dorsiflexion (10°) due to tight calf muscles and one patient had paresthesia on the dorsum of the foot that was not improved at last follow up (one year after surgery). CONCLUSION: Augmentation plating is a safe and effective option for management of distal tibial diaphyseal nonunion even in cases of oligotrophic or atrophic non-union.

FOXO 1 deletion in chondrocytes rescues diabetes-impaired fracture healing by restoring angiogenesis and reducing apoptosis.

Introduction: Diabetes mellitus is associated with higher risks of long bone and jaw fractures. It is also associated with a higher incidence of delayed union or non-union. Our previous investigations concluded that a dominant mechanism was the premature loss of cartilage during endochondral bone formation associated with increased osteoclastic activities. We tested the hypothesis that FOXO1 plays a key role in diabetes-impaired angiogenesis and chondrocyte apoptosis. Methods: Closed fractures of the femur were induced in mice with lineage-specific FOXO1 deletion in chondrocytes. The control group consisted of mice with the FOXO1 gene present. Mice in the diabetic group were rendered diabetic by multiple streptozotocin injections, while mice in the normoglycemic group received vehicle. Specimens were collected 16 days post fracture. The samples were fixed, decalcified, and embedded in paraffin blocks for immunostaining utilizing anti cleaved caspase-3 or CD31 specific antibodies compared with matched control IgG antibody, and apoptosis by the TUNEL assay. Additionally, ATDC5 chondrocytes were examined in vitro by RT-PCR, luciferase reporter and chromatin immunoprecipitation assays. Results: Diabetic mice had ~ 50% fewer blood vessels compared to normoglycemic mice FOXO1 deletion in diabetic mice partially rescued the low number of blood vessels (p < 0.05). Additionally, diabetes increased caspase-3 positive and apoptotic chondrocytes by 50%. FOXO1 deletion in diabetic animals blocked the increase in both to levels comparable to normoglycemic animals (p < 0.05). High glucose (HG) and high advanced glycation end products (AGE) levels stimulated FOXO1 association with the caspase-3 promoter in vitro, and overexpression of FOXO1 increased caspase-3 promoter activity in luciferase reporter assays. Furthermore, we review previous mechanistic studies demonstrating that tumor necrosis factor (TNF) inhibition reverses impaired angiogenesis and reverses high levels of chondrocyte apoptosis that occur in fracture healing. Discussion: New results presented here, in combination with recent studies, provide a comprehensive overview of how diabetes, through high glucose levels, AGEs, and increased inflammation, impair the healing process by interfering with angiogenesis and stimulating chondrocyte apoptosis. FOXO1 in diabetic fractures plays a negative role by reducing new blood vessel formation and increasing chondrocyte cell death which is distinct from its role in normal fracture healing.

Fixators dynamization for delayed union and non-union of femur and tibial fractures: a review of techniques, timing and influence factors.

The optimal balance between mechanical environment and biological factors is crucial for successful bone healing, as they synergistically affect bone development. Any imbalance between these factors can lead to impaired bone healing, resulting in delayed union or non-union. To address this bone healing disorder, clinicians have adopted a technique known as "dynamization" which involves modifying the stiffness properties of the fixator. This technique facilitates the establishment of a favorable mechanical and biological environment by changing a rigid fixator to a more flexible one that promotes bone healing. However, the dynamization of fixators is selective for certain types of non-union and can result in complications or failure to heal if applied to inappropriate non-unions. This review aims to summarize the indications for dynamization, as well as introduce a novel dynamic locking plate and various techniques for dynamization of fixators (intramedullary nails, steel plates, external fixators) in femur and tibial fractures. Additionally, Factors associated with the effectiveness of dynamization are explored in response to the variation in dynamization success rates seen in clinical studies.

Elastic Stable Intramedullary Nailing Improves Fracture Healing and Mobility in Children with Femoral Fractures.

Objective: To explore the application value and safety of elastic stable intramedullary nailing (ESIN) in pediatric femoral fractures (FFs), providing more reliable safety for the treatment of FFs in the future. Methods: This study selected 60 cases of pediatric FFs who completed fracture treatment in our hospital between March 2014 and January 2023, with 32 cases undergoing ESIN fixation included in the research group (RG) and another 28 cases receiving plate internal fixation assigned to the control group (CG). The operative time (OT), intraoperative blood loss (IBL), incision length, fracture healing time, fixator removal time, weight-bearing time, and hospital length of stay (HLOS) of the two groups were counted, and the pain of the children was evaluated by the Visual Analogue Scale (VAS). The clinical efficacy and complication rate were recorded, and the hip and knee functions before and after treatment were evaluated by the Hospital for Special Surgery (HSS) score. After the completion of treatment, the child's family was surveyed about their satisfaction with the treatment. Results: The research group had less OT, IBL, and incision length, as well as shorter fracture healing time, fixator removal time, weight-bearing time, and HLOS than the control group (P < .05), with markedly lower VAS scores at 12h-48h postoperatively (P < .05). In addition, the research group demonstrated an obviously higher overall response rate (96.88%) and a lower complication rate (15.63%) than the control group (P < .05). Furthermore, HSS scores and treatment satisfaction were higher in the research group than in the control group (P < .05). Conclusions: ESIN is a highly effective treatment for pediatric femoral fractures, leading to accelerated fracture healing, improved mobility, and exhibiting high clinical application value.