Atrophic Nonunion Research Articles

Nonunion of Vascularized Fibula With Shortening and Multiplanar Deformity in a 6 Years Old Managed Simultaneously With Hexapod Circular External Fixator

The hexapod circular external fixator is considered a major upgrade to the classic Ilizarov ring fixators, which made it easier to manage complex deformities. Surgeons now, using it, can manage deformities in all three planes simultaneously without the need for frame modifications. We present a case report that shows the versatile nature of the hexapod circular fixator in a 6-year-old female patient who presented with multiple problems seen in a single bone, namely, two types nonunion at two different sites of a vascularized fibula graft of the leg (hypertrophic nonunion at the proximal site and atrophic nonunion at the distal site) with varus, procurvatum, and internal rotation deformities as well as 3-cm shortening. She underwent vascularized fibular graft surgery to treat osteomyelitis of the tibia 2 years prior. A hexapod circular fixator was applied which would statically stabilize the lower nonunion site (augmented with bone marrow injection at that site) and corrected the deformities and shortening through distraction at the proximal hypertrophic nonunion site in one surgical procedure. The case demonstrates the versatility of the hexapod circular fixator in treating complex orthopaedic situations, maintaining a minimally invasive approach while allowing full weight-bearing.

The role of AKR1B10 in osteogenic differentiation of mesenchymal stem cells and atrophic nonunion

Atrophic nonunion is a chronic disease without effective medications. Here, high-throughput mRNA sequencing was used to explore the novel targets in atrophic nonunion. AKR1B10, a member of aldo-keto reductase family 1, is upregulated in atrophic nonunion tissues. There are currently no studies to reveal the role of AKR1B10 in atrophic nonunion. We used rat bone marrow-derived mesenchymal stem cells (BMSCs) to explore the effect of AKR1B10 on the osteogenic differentiation and autophagy. In vivo, we implanted collagen sponges loaded with LV-shAKR1B10-transduced BMSCs into rat fractured femurs to explore the role of AKR1B10 in fracture healing. The results showed that AKR1B10 reduced the activity of ALP, suppressed the expression of COL1A1, RUNX2 and OCN, and inhibited calcification deposition in osteogenically differentiated BMSCs. AKR1B10 reduced the expression of LC3II, decreased the number of autophagosomes, and promoted the expression of p62. In addition, the promoting effect of AKR1B10 knockdown on osteogenic differentiation of BMSCs was attenuated by 3-MA treatment. Implantation of collagen sponges found that knockdown of AKR1B10 promoted bone fracture healing. In conclusion, AKR1B10 inhibited the osteogenic differentiation and autophagy, and delayed the bone fracture healing. These results provide a new perspective on revealing the role of AKR1B10 in nonunion and may also provide a new therapeutic target for the treatment of nonunion.

Prognostic factors of extracorporeal shockwave therapy in the treatment of nonunion in long bones: a retrospective study.

Nonunion of long bone fractures is a significant complication following surgical fixation, with an incidence ranging from 5% to 10%. Surgical intervention is the standard treatment for nonunions, but it may come with potential complications. Nonoperative approaches, such as Extracorporeal Shockwave Therapy (ESWT), have been advocated as alternatives. The retrospective study, conducted between January 2004 and January 2018, 91 patients who underwent ESWT for tibia or femur nonunions were included. Nonunion was defined based on radiographic criteria and clinical symptoms. The nonunion morphology was categorized as hypertrophic, oligotrophic, or atrophic. ESWT was administered using the OssaTron device in a single treatment session. Bony union was defined as the presence of bridging callus over fracture site with more than three-fourths of the circumference in both planes within the 12-month postoperative period. The study included 91 patients, with an overall union rate of 62.6%. Higher healing rate was observed in trophic nonunion(69.9%) than atrophic nonunion(33.3%). Multivariate analysis identified the number of surgeries, maximum fracture gap, and atrophic nonunion as independent factors influencing the risk of fracture nonunion after ESWT. ROC curves were generated for these factors, providing more than one surgical interventions, and fracture gap greater than 3.94mm as negative predictors of ESWT for long bone nonunions. The study's primary findings suggest that ESWT is effective in achieving bony union for nonunions in long bones(62.6%). Despite the overall positive results, the study highlights that atrophic nonunions, larger fracture gaps more than 3.94mm, and multiple surgeries are associated with poorer outcomes.

Teriparatide and Atrophic Nonunion

Teriparatide and Atrophic Nonunion

Clavicle Shaft Non-Unions-Do We Even Need Bone Grafts?

Background: The surgical treatment of bony non-unions is traditionally performed with additional bone grafts when atrophic and/or stronger implants when hypertrophic. In the case of the clavicle shaft, however, in our experience, a more controversial method where no additional bone graft is needed leads to equally good consolidation rates, independent of the non-union morphology. This method requires the meticulous anatomical reconstruction of the initial fracture and fixation according to the AO principle of relative stability. Methods: A retrospective review following the STROBE guidelines was performed on a consecutive cohort of all patients who received surgical treatment of a midshaft clavicle non-union at the Medical Center of the University of Freiburg between January 2003 and December 2023. Patients were identified using a retrospective systematical query in the Hospital Information System (HIS) using the International Statistical Classification of Diseases and Related Health Problems Version 10 (ICD-10) codes of the German Diagnosis Related Groups (G-DRG). Two groups were formed to compare the consolidation rates of patients who received additional bone grafting from the iliac crest with those of patients who did not. A 3.5 mm reconstruction LCP plate was used in all patients. Consolidation rates were evaluated using follow-up radiographs and outcomes after material removal with a mean follow-up of 31.5 ± 44.3 months (range 0-196). Results: Final data included 50 patients, predominantly male (29:21); age: 46.0 ± 13.0 years, BMI 26.1 ± 3.7. Autologous bone grafts from the iliac crest were used in 38.0% (n = 19), while no bone addition was used in 62.0% (n = 30). Six patients were lost to follow-up. Radiological consolidation was documented after a mean of 15.1 ± 8.0 months for the remaining 44 patients. Consolidation rates were 94.4% (n = 17) in patients for whom additional bone grafting was used and 96.2% (n = 25) in patients for whom no graft was used. There was no relevant difference in the percentage of atrophic or hypertrophic non-unions between both groups (p = 0.2425). Differences between groups in the rate of consolidation were not significant (p = 0.7890). The complication rate was low, with 4.5% (n = 2). Conclusions: Independent of the non-union morphology, non-unions of the clavicle midshaft can be treated successfully with 3.5 mm locking reconstruction plates without the use of additional bone grafting in most cases.

A REVIEW OF ANIMAL MODELS FOR BONE FRACTURE NONUNION AND THEIR ROLE IN STUDYING BIOLOGICAL THERAPY EFFICACY

The bone healing impairment, such as non-union fractures after injuries of long bones, lead to loss of working capacity and result in significant financial costs, which emphasizes the socioeconomic significance of the problem. However, it is not known which method of modeling the non-union bone fractures is more optimal for further research into the effectiveness of biological therapy aimed at treating bone healing impairment. For a detailed study of methods of non-union fracture treatment of, it is necessary to determine the developed animal models. The objective was to analyze the existing animal models of fracture nonunion in long bones in vivo and to consider the possibility of their further use to evaluate the effectiveness of the use of modern biotechnologies for the in the management of fracture nonunion. It was found that the majority of developed animal models of atrophic long bone non-union were created using small animals, namely rats, mice, and rabbits. A more common method of modeling bone non-union is performing an osteotomy with the formation of a defect of different widths between the bone fragments and subsequent removal of the periosteum proximal and distal to the osteotomy site; damage to the endosteum or removal of bone marrow. Also, in such animal models, researchers use a silicone spacer, a polysulfone plate, or a latex-silicone foil to physically prevent fracture union. In these animal models, studies using mesenchymal stromal cells, platelet-rich plasma or bone morphogenetic protein-2 (BMP-2) have already been conducted for the management of non-union bone fractures. At the same time, the clinical results of the application of various biological therapies are ambiguous, which determines the conduct of further experimental studies, in particular, in vivo. However, there are disagreements about which in vivo modeling methods give a reproducible result and prevent bone union, which determines the need for further analysis of existing modeling tools for conducting research in this direction.

Dead or alive — use of indocyanine green angiography for intraoperative assessment of bone vitality in nonunion fractures: a controlled case series of four patients

Background. Indocyanine green (ICG) fluorescence imaging is a surgical tool with increasing applications in various surgical disciplines. During nonunion resection, the assessment of bone vascularization is currently based only on the surgeon’s experience. We introduced the use of indocyanine green (ICG) angiography in orthopedics. The aims of the study: 1) to use ICG fluorescence angiography to evaluate the bone perfusion in patients with atrophic nonunion, where poor or absent ICG flow reveals avascular tissue associated with bone necrosis requiring surgical resections; 2) to describe our case series of patients operated with this technique. Methods. We used ICG angiography in patients operated for tibial nonunion resection. We administered 0.5 mg/kg of ICG powder dissolved in sterile saline at 2.5 mg/ml concentration. The time from the injection to the beginning of appreciation of the green dye was measured. Non-viable bone was resected accordingly. Patient underwent routine follow-up. We enrolled all the suitable patients operated from April 2019 to June 2021 and matched three control patients for each of them. We reviewed their medical records and noted any relevant data. Results. We enrolled 4 cases and 12 controls, all male. The mean age was 30.8±6.9 years. The mean duration from trauma to surgery was 10.5 (0.7-25.0) months. The mean duration of surgery was 190.8±40.3 min. The defect size was 4.89±2.03 cm. ICG allowed rapid visualization of bone vascularization after 25-45 sec. No adverse events were observed. The mean external fixation time was 11.8±5.0 months. The mean external fixation index was 2.69±1.10. Seven patients needed a surgical revision during treatment. Three patients underwent reintervention after frame removal. There are no statistically significant differences between cases and controls. Conclusions. The research findings of this study are limited by the small number of observations. However, this technique is safe, easy, and rapid and may contribute to intraoperative decision of how much to resect. Using ICG could objectively demonstrate bone perfusion to help surgeons to avoid massive bone defects.

Efficacy and safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) combined with autologous bone for the treatment of long bone nonunion: A report of a prospective case series

IntroductionRecombinant human Bone morphogenetic proteins have been used for the treatment of nonunions with promising results. We have been investigating both experimentally and clinically the efficacy of the rhBMP-2 with the macro / micro-porous hydroxyapatite carrier granules on the potency on the reconstruction of long bone defect. The purpose of this study was to prospectively evaluate the efficacy and safety of this specific rhBMP-2 with HA carrier granules mixed with autologous cancellous bone in patients with nonunion and bone defect resulted from the fracture related infection. Materials and MethodsThis was a retrospective review of a prospective cohort at a university hospital. Patients diagnosed with nonunion under the definition of the United States Food and Drug Administration with bone defect after long bone fractures were enrolled from January 2020 to February 2021. We included patients with atrophic and oligotrophic nonunion, and hypertrophic nonunion with malalignment that needed to be corrected. The other patient group was consisted of segmental bone defect resulted from FRI. The maximum amount of rhBMP-2 allowed in this clinical study was 6 mg and was added to autologous bone at a 1:1 ratio. Autologous bone was added to the mixture if the volume of mixed graft was insufficient to fill the bone defect. Patients were followed 3, 6, and 12 months post-operatively. Each visit, a radiograph was taken for assessment. Visual analog scale (VAS), questionnaire for quality of life (SF-12 physical component summary [PCS], mental component summary [MCS]), and weight-bearing status were collected for functional outcome assessment. Drug safety was assessed by examining BMP-2 antibodies. ResultsOf the 24 enrolled patients (mean age: 57 years), 15 (62.5 %), 2 (8.33 %), and 7 (29.17 %) presented atrophic nonunion, hypertrophic nonunion with deformity, and bone defect after fracture related infection, respectively. Thirteen patients had nonunion in the femur, 9 in the tibia, and 1 in the humerus and radius. The average amount of harvested autologous bone was 9.25 g and 4.96 mg of rhBMP-2. All 24 patients achieved union after 1-year follow up. The union rate was 95.83 % and 100 % at 6 and 12 months postoperatively, respectively. Preoperative SF-12 PCS (mean: 34.71) improved at 6 and 12 months postoperatively, respectively. Preoperative SF-12 MCS (mean: 42.89) improved 12 months postoperatively (49.13, p = 0.0338). Change of VAS was statistically significant 3 months postoperatively (p = 0.0012). No adverse effects or development of BMP-2 antibodies were observed. ConclusionBMP-2 combined with autogenous bone resulted in excellent radiographical and functional outcomes in a relatively small prospective series of patients with nonunion and bone defect, without adverse effects. Further investigations are necessary to support our finding and optimize treatment strategies in nonunion patients.

Efficacy and safety of autologous or allogeneic mesenchymal stromal cells from adult adipose tissue expanded and combined with tricalcium phosphate biomaterial for the surgical treatment of atrophic nonunion of long bones: a phase II clinical trial

BackgroundAutologous bone grafting is the standard treatment for the surgical management of atrophic nonunion of long bones. Other solutions, such as bone marrow mesenchymal stem cells (BM-MSC) combined with phospho-calcium material, have also been used. Here we evaluate the safety and early efficacy of a novel procedure using autologous or allogenic adipose tissue mesenchymal stromal cells (AT-MSC) seeded in a patented tricalcium phosphate-based biomaterial for the treatment of bone regeneration in cases of atrophic nonunion.MethodsThis was a prospective, multicentric, open-label, phase 2 clinical trial of patients with atrophic nonunion of long bones. Biografts of autologous or allogenic AT-MSC combined with a phosphate substrate were manufactured prior to the surgical procedures. The primary efficacy was measured 6 months after surgery, but patients were followed for 12 months after surgery and a further year out of the scope of the study. All adverse events were recorded. This cohort was compared with a historical cohort of 14 cases treated by the same research team with autologous BM-MSC.ResultsA total of 12 patients with atrophic nonunion of long bones were included. The mean (SD) age was 41.2 (12.1) years and 66.7% were men. Bone healing was achieved in 10 of the 12 cases (83%) treated with the AT-MSC biografts, a percentage of healing similar (11 of the 14 cases, 79%) to that achieved in patients treated with autologous BM-MSC. Overall, two adverse events, in the same patient, were considered related to the procedure.ConclusionsThe results of this study suggest that AT-MSC biografts are safe for the treatment of bone regeneration in cases of atrophic nonunion and reach high healing rates.Trial registrationStudy registered with EUDRA-CT (2013-000930-37) and ClinicalTrials.gov (NCT02483364).

THE SU-PERIOSTEUM: IMPROVING BONE BIOLOGY USING NOVEL CHIMERIC FIBULA-PERIOSTEAL FLAP

IntroductionThe presence of pluripotent mesenchymal cells in the periosteum along with the growth factors produced or released following injury provides this tissue with an important role in bone healing. Utilising this property, vascularised periosteal flaps may increase the union rates in recalcitrant atrophic long bone non-union. The novel chimeric fibula-periosteal flap utilises the periosteum raised on an independent periosteal vessel, thus allowing the periosteum to be inset freely around the osteotomy site, improving bone biology.Materials & MethodsTen patients, with established non-union, underwent fibula-periosteal chimeric flaps (2016–2022) at the Canniesburn Plastic Surgery Unit, UK. Preoperative CT angiography was performed to identify the periosteal branches. A case-control approach was used. Patients acted as their own controls, which obviated patient specific risks for non-union. One osteotomy site was covered by the chimeric periosteal flap and one without. In two patients both the osteotomies were covered using a long periosteal flap.ResultsUnion rate of 100% (11/11) was noted with periosteal flap osteotomies, versus those without flaps at 28.6% (2/7) (p = 0.0025). Time to union was also reduced in the periosteal flaps at 8.5 months versus 16.75 months in the control group (p = 0.023). Survival curves with a hazard ratio of 4.1, equating to a 4 times higher chance of union with periosteal flaps (log-rank p = 0.0016) was observed.ConclusionsThe chimeric fibula-periosteal flap provides an option for atrophic recalcitrant non-unions where use of vascularised fibula graft alone may not provide an adequate biological environment for consolidation.

Preventing Atrophic Long-Bone Nonunion: Retrospective Analysis at a Level I Trauma Center.

Background: Among the risk factors for nonunion are unchangeable patient factors such as the type of injury and comorbidities, and factors that can be influenced by the surgeon such as fracture treatment and the postoperative course. While there are numerous studies analyzing unchangeable factors, there is poor evidence for factors that can be affected by the physician. This raises the need to fill the existing knowledge gaps and lay the foundations for future prevention and in-depth treatment strategies. Therefore, the goal of this study was to illuminate knowledge about nonunion in general and uncover the possible reasons for their development; Methods: This was a retrospective analysis of 327 patients from 2015 to 2020 from a level I trauma center in Germany. Information about patient characteristics, comorbidities, alcohol and nicotine abuse, fracture classification, type of osteosynthesis, etc., was collected. Matched pair analysis was performed, and statistical testing performed specifically for atrophic long-bone nonunion; Results: The type of osteosynthesis significantly affected the development of nonunion, with plate osteosynthesis being a predictor for nonunion. The use of wire cerclage did not affect the development of nonunion, nor did the use of NSAIDs, smoking, alcohol, osteoporosis and BMI; Conclusion: Knowledge about predictors for nonunion and strategies to avoid them can benefit the medical care of patients, possibly preventing the development of nonunion.

Plate augmentation and hybrid bone grafting are effective treatments for atrophic nonunion of the femur with the original intramedullary nail retained in situ

The purpose of this study is to evaluate the efficacy of plate augmentation and hybrid bone grafting for treating atrophic nonunion of the femur with original intramedullary nail retained in situ.In this study, 36 patients with atrophic nonunion of the femur who underwent surgery using the technique of plate augmentation and a hybrid bone grafting while retaining the original intramedullary nail in situ in Xi’an Honghui Hospital from January 2019 to December 2021 were enrolled. 28 patients who met the inclusion and exclusion criteria were ultimately included in the study. These 28 patients, consisting of 20 males and 8 females with a mean age of 38 years, were evaluated based on factors such as operation time, intraoperative blood loss, the average hospitalization days. Additionally, the results and function of these patients were evaluated by union time, Wu’s scores of limb function and incidence of serious complications.All 28 patients achieved bone union at the 12 month follow-up, with an average follow-up time of 14.6 ± 4.2 months.The average operation time was 68.3 ± 11.2 min, and the average intraoperative blood loss was 140 ± 22.6 ml. Patients were hospitalized for an average of 5.8 ± 1.1 days. Full clinical and radiological bone union was achieved on average at 5.1 ± 1.9 months. The mean value of Wu's scores at the 12 month follow-up was significantly higher than before the operation. Limb function was excellent in 27 patients and good in one patient at the 12 month follow-up. However, five patients experienced the lower limb vein thrombosis, including one deep vein thrombosis and four lower limb intermuscular vein thromboses. One patient had a superficial infections of the surgical incision site, while three patients reported pain and numbness where their iliac bone graft was extracted at the 12 month follow-up. The technique of plate augmentation and hybrid bone grafting, combined with retaining the original intramedullary nail in situ has been shown to be a safe, effective, simply and standardizable practice for treating atrophic femoral nonunion with an intact original IMN fixation.

Hypoxia preconditioning of adipose stem cell-derived exosomes loaded in gelatin methacryloyl (GelMA) promote type H angiogenesis and osteoporotic fracture repair

The challenges posed by delayed atrophic healing and nonunion stand as formidable obstacles in osteoporotic fracture treatment. The processes of type H angiogenesis and osteogenesis emerge as pivotal mechanisms during bone regeneration. Notably, the preconditioning of adipose-derived stem cell (ADSC) exosomes under hypoxic conditions has garnered attention for its potential to augment the secretion and functionality of these exosomes. In the present investigation, we embarked upon a comprehensive elucidation of the underlying mechanisms of hypo-ADSC-Exos within the milieu of osteoporotic bone regeneration. Our findings revealed that hypo-ADSC-Exos harboured a preeminent miRNA, namely, miR-21-5p, which emerged as the principal orchestrator of angiogenic effects. Through in vitro experiments, we demonstrated the capacity of hypo-ADSC-Exos to stimulate the proliferation, migration, and angiogenic potential of human umbilical vein endothelial cells (HUVECs) via the mediation of miR-21-5p. The inhibition of miR-21-5p effectively attenuated the proangiogenic effects mediated by hypo-ADSC-Exos. Mechanistically, our investigation revealed that exosomal miR-21-5p emanating from hypo-ADSCs exerts its regulatory influence by targeting sprouly1 (SPRY1) within HUVECs, thereby facilitating the activation of the PI3K/AKT signalling pathway. Notably, knockdown of SPRY1 in HUVECs was found to potentiate PI3K/AKT activation and, concomitantly, HUVEC proliferation, migration, and angiogenesis. The culminating stage of our study involved a compelling in vivo demonstration wherein GelMA loaded with hypo-ADSC-Exos was validated to substantially enhance local type H angiogenesis and concomitant bone regeneration. This enhancement was unequivocally attributed to the exosomal modulation of SPRY1. In summary, our investigation offers a pioneering perspective on the potential utility of hypo-ADSC-Exos as readily available for osteoporotic fracture treatment.Graphical

The Treatment of Periprosthetic Fracture Revision of the Humerus with “Bamboo Support” Structural Allograft Technique—Atrophic Non-Union of a Post-Operative Periprosthetic Fracture after Reverse Total Shoulder Arthroplasty: A Case Report

Periprosthetic fractures are a serious complication of joint replacement surgery. With the growing prevalence of reverse total shoulder arthroplasty (RTSA), the incidence of relatively uncommon periprosthetic humeral fractures has increased. Here, we present the unique case of a 74-year-old woman who developed atrophic non-union after plate osteosynthesis for a periprosthetic fracture associated with RTSA. Fixation failure was evident 3 months after the surgical intervention; the patient underwent a 3-month course of arm sling immobilization. However, bone resorption continued, and varus angulation of the fracture developed. In this case, surgical strategy involved the use of long proximal humerus internal locked system plate (DePuy Synthes, Paoli, PA, USA), augmented with autologous iliac bone graft and allogenic humerus structural bone graft with the “bamboo support technique”, fixed with Cable System (DePuy Synthes, Paoli, PA, USA). No reports have addressed the management of failed periprosthetic fractures using allogeneic humeral strut bone grafts. This report aims to fill the gap by presenting a novel surgical technique for the management of periprosthetic fractures associated with RTSA in case of treatment failure.

Universal Long Bone Nonunion Classification.

The management of bone union disorders is a complex problem in orthopaedics, requiring a reliable and comprehensive classification system for accurate diagnosis and treatment. Despite advances in understanding pathophysiology, diagnosis, and treatment in this area, there is no generally accepted classification system. The aim of our work was to create a comprehensive classification, which will systemize the vast majority of bone union disorders, underline their differences and form the basis for their treatment. The key criteria for nonunion evaluation and treatment were identified based on the conducted literature review: Time from the initial event (delayed union or nonunion), location, type of pathology (A, Hypertrophic; B, Normotrophic; C, Oligotrophic) and the presence of hardware. Based on these criteria the ULBNC has been developed. Atrophic nonunions were excluded from this classification as they are considered segmental bone defects with special classification. The ULBNC is based on the same principles of coding as the "gold standard" AO/OTA Fractures Classification system with alpha-numeric coding "from simple to complex." The choice of treatment method depends on the type, group, and subgroup of the nonunion as described. Universal Long Bone Nonunion Classification (ULBNC) is an alphanumeric system that describes the localization, type of pathology and morphologic characteristics of a nonunion. The use of ULBNC in practice and research will optimize and standardize the treatment of various types of bone healing disorders and eventually improve clinical outcomes. Solomin LN, Semenistyy AA, Komarov AV, et al. Universal Long Bone Nonunion Classification. Strategies Trauma Limb Reconstr 2023;18(3):169-173.

Impact of Platelet-Rich Plasma and Adipose-Derived Stromal Vascular Fraction on Atrophic Non-union Fracture Healing in a Rabbit Model

Impact of Platelet-Rich Plasma and Adipose-Derived Stromal Vascular Fraction on Atrophic Non-union Fracture Healing in a Rabbit Model

Parathyroid hormone stimulates bone regeneration in an atrophic non-union model in aged mice

BackgroundNon-union formation still represents a major burden in trauma and orthopedic surgery. Moreover, aged patients are at an increased risk for bone healing failure. Parathyroid hormone (PTH) has been shown to accelerate fracture healing in young adult animals. However, there is no information whether PTH also stimulates bone regeneration in atrophic non-unions in the aged. Therefore, the aim of the present study was to analyze the effect of PTH on bone regeneration in an atrophic non-union model in aged CD-1 mice.MethodsAfter creation of a 1.8 mm segmental defect, mice femora were stabilized by pin-clip fixation. The animals were treated daily with either 200 mg/kg body weight PTH 1–34 (n = 17) or saline (control; n = 17) subcutaneously. Bone regeneration was analyzed by means of X-ray, biomechanics, micro-computed tomography (µCT) imaging as well as histological, immunohistochemical and Western blot analyses.ResultsIn PTH-treated animals bone formation was markedly improved when compared to controls. This was associated with an increased bending stiffness as well as a higher number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and CD31-positive microvessels within the callus tissue. Furthermore, PTH-treated aged animals showed a decreased inflammatory response, characterized by a lower number of MPO-positive granulocytes and CD68-positive macrophages within the bone defects when compared to controls. Additional Western blot analyses demonstrated a significantly higher expression of cyclooxygenase (COX)-2 and phosphoinositide 3-kinase (PI3K) in PTH-treated mice.ConclusionTaken together, these findings indicate that PTH is an effective pharmacological compound for the treatment of non-union formation in aged animals.

Treatment of recalcitrant femur nonunion with pedicled corticoperiosteal medial femoral condyle flap

Periosteal or osteoperiosteal medial femoral condyle (MFC) flaps may be good options for atrophic nonunion. The aim of this study was to evaluate the effectiveness and safety of pedicled MFC flap in the treatment of recalcitrant femur nonunion without bone defect. Thirteen patients (11 male and 2 female), who suffered recalcitrant femur nonunion and were treated with pedicled osteoperiosteal MFC flap between January 2014 and April 2018, were included in this study. Patient files were reviewed retrospectively. Atrophic or recalcitrant 2/3 distal femoral nonunion were the indications for this clinical procedure. Demographics and operative data, flap size, visual analog scale (VAS) score, time to union, and complications were evaluated. A total of 13 patients underwent femur nonunion treatment with MFC flap after an average of 3.4 previous surgical procedures. The median age was 34 (Q1: 32.5, Q3:43) years old. The mean flap size was 4.3 × 6.4 cm, all nonunions healed in a median 5 months (Q1: 4.5, Q3: 6). There were an intraoperative knee medial collateral ligament injury in a patient, hematoma in a patient, and seroma in two patients. The median length of the follow-up was 40 months (Q1: 30, Q3: 47). There wasn’t any additional complication in long-term follow-up. Functional outcomes were satisfactory. The median preoperative VAS score was 7 (Q1: 6, Q3: 9.5), decreasing to 1 (Q1: 0, Q3: 1) at the 6-month follow-up, and further reducing to 0 (Q1: 0, Q3: 1) at the 24-month follow-up. The nonunion period ranged from 6 to 18 months. The pedicled MFC flap is a good option for recalcitrant femur nonunion where larger vascularized flaps are not warranted. It is easy to harvest, does not require microvascular anastomosis, is effective, and offers minimal donor site morbidity.

Suppression of DNMT2/3 by proinflammatory cytokines inhibits CtBP1/2-dependent genes to promote the occurrence of atrophic nonunion

Failure of bone healing after fracture often results in nonunion, but the underlying mechanism of nonunion pathogenesis is poorly understood. Herein, we provide evidence to clarify that the inflammatory microenvironment of atrophic nonunion (AN) mice suppresses the expression levels of DNA methyltransferases 2 (DNMT2) and 3A (DNMT3a), preventing the methylation of CpG islands on the promoters of C-terminal binding protein 1/2 (CtBP1/2) and resulting in their overexpression. Increased CtBP1/2 acts as transcriptional corepressors that, along with histone acetyltransferase p300 and Runt-related transcription factor 2 (Runx2), suppress the expression levels of six genes involved in bone healing: BGLAP (bone gamma-carboxyglutamate protein), ALPL (alkaline phosphatase), SPP1 (secreted phosphoprotein 1), COL1A1 (collagen 1a1), IBSP (integrin binding sialoprotein), and MMP13 (matrix metallopeptidase 13). We also observe a similar phenomenon in osteoblast cells treated with proinflammatory cytokines or treated with a DNMT inhibitor (5-azacytidine). Forced expression of DNMT2/3a or blockage of CtBP1/2 with their inhibitors can reverse the expression levels of BGLAP/ALPL/SPP1/COL1A1/IBSP/MMP13 in the presence of proinflammatory cytokines. Administration of CtBP1/2 inhibitors in fractured mice can prevent the incidence of AN. Thus, we demonstrate that the downregulation of bone healing genes dependent on proinflammatory cytokines/DNMT2/3a/CtBP1/2-p300-Runx2 axis signaling plays a critical role in the pathogenesis of AN. Disruption of this signaling may represent a new therapeutic strategy to prevent AN incidence after bone fracture.

Induced membrane technique versus one-stage autografting in management of atrophic nonunion of long bone in the lower limb: clinical and health burden outcomes

ObjectiveIn this study, we aimed to compare the outcomes of the two-stage induced membrane technique (IMT) and one-stage autografting in the treatment of aseptic atrophic nonunion in lower limb long bones.MethodsFrom January 2014 to January 2022, we reviewed all surgically treated long bone nonunion patients, including patients aged 18 years or older with atrophic nonunion, who were either treated with the two-stage induced membrane technique (IMT) or one-stage autografting. Outcome parameters interns of clinical, quality of life and healthcare burden were recorded and retrospectively analysed between the two treatment populations. The follow-up time was at least 1 year.ResultsIn total, 103 patients who met the criteria for aseptic atrophic nonunion were enrolled. Among them, 41 (39.8%) patients were treated with two-stage IMT, and 62 (60.2%) patients were treated with one-stage autologous bone grafting. The follow-up time was 12 to 68 months, with an average of 28.4 months. The bone healing rate was comparable in both groups (IMT: 92.7% vs. one-stage grafting: 91.9%, P = 0.089) at 12 months post-operation, and the bone healing Lane–Sandhu score was superior in the IMT group (mean: 8.68 vs. 7.81, P = 0.002). Meanwhile, the SF-12 scores of subjective physical component score (PCS) (mean: 21.36 vs. 49.64, P < 0.01) and mental health component score (MCS) (mean: 24.85 vs. 46.14, P < 0.01) significantly increased in the IMT group, as well as in the one-stage grafting group, and no statistically significant difference was found within groups. However, the total hospital stays (median: 8 days vs. 14 days, P < 0.01) and direct medical healthcare costs (median: ¥30,432 vs. ¥56,327, P < 0.05) were greater in the IMT group, while the complications (nonunion 8, infection 3, material failure 2, and donor site pain 6) were not significantly different between the two groups (17.1% vs. 19.4, P = 0.770).ConclusionThe data indicate that two-stage method of IMT serves as an alternative method in treating atrophic nonunion; however, it may not be a preferred option, in comprehensive considering patient clinical outcomes and healthcare burden. More evidence-based research is needed to further guide clinical decision-making.