Aims. Several previously identified patient-, injury-, and treatment-related factors are associated with the development of nonunion in distal femur fractures. However, the predictive value of these factors is not well defined. We aimed to assess the predictive ability of previously identified risk factors in the development of nonunion leading to secondary surgery in distal femur fractures. Methods. We conducted a retrospective cohort study of adult patients with traumatic distal femur fracture treated with lateral locking plate between 2009 and 2018. The patients who underwent secondary surgery due to fracture healing problem or plate failure were considered having nonunion. Background knowledge of risk factors of distal femur fracture nonunion based on previous literature was used to form an initial set of variables. A logistic regression model was used with previously identified patient- and injury-related variables (age, sex, BMI, diabetes, smoking, periprosthetic fracture, open fracture, trauma energy, fracture zone length, fracture comminution, medial side comminution) in the first analysis and with treatment-related variables (different surgeon-controlled factors, e.g. plate length, screw placement, and proximal fixation) in the second analysis to predict the nonunion leading to secondary surgery in distal femur fractures. Results. We were able to include 299 fractures in 291 patients. Altogether, 31/299 fractures (10%) developed nonunion. In the first analysis, pseudo-R. 2. was 0.27 and area under the receiver operating characteristic curve (AUC) was 0.81. BMI was the most important variable in the prediction. In the second analysis, pseudo-R. 2. was 0.06 and AUC was 0.67. Plate length was the most important variable in the prediction. Conclusion. The model including patient- and injury-related factors had moderate fit and predictive ability in the prediction of distal femur fracture nonunion leading to secondary surgery. BMI was the most important variable in prediction of nonunion. Surgeon-controlled factors had a minor role in prediction of nonunion. Cite this article: Bone Jt Open 2023;4(8):584–593

Aims. This observational cross-sectional study aimed to answer the following questions: 1) how has nonunion incidence developed from 2009 to 2019 in a nationwide cohort; 2) what is the age and sex distribution of nonunions for distinct anatomical nonunion localizations; and 3) how high were the costs for surgical nonunion treatment in a level 1 trauma centre in Germany?. Methods. Data consisting of annual International Classification of Diseases (ICD)-10 diagnosis codes from German medical institutions from 2009 to 2019, provided by the Federal Statistical Office of Germany (Destatis), were analyzed. Nonunion incidence was calculated for anatomical localization, sex, and age groups. Incidence rate ratios (IRRs) were determined and compared with a two-sample z-test. Diagnosis-related group (DRG)-reimbursement and length of hospital stay were retrospectively retrieved for each anatomical localization, considering 210 patients. Results. In 2019, a total of 11,840 nonunion cases (17.4/100,000 inhabitants) were treated. In comparison to 2018, the incidence of nonunion increased by 3% (IRR 1.03, 95% confidence interval (CI) 0.53 to 1.99, p = 0.935). The incidence was higher for male cases (IRR female/male: 0.79, 95% CI 0.76 to 0.82, p = 0.484). Most nonunions occurred at the pelvic and hip region (3.6/100,000 inhabitants, 95% CI 3.5 to 3.8), followed by the ankle and foot as well as the hand (2.9/100,000 inhabitants each). Mean estimated DRG reimbursement for in-hospital treatment of nonunions was highest for nonunions at the pelvic and hip region (€8,319 (SD 2,410), p < 0.001). Conclusion. Despite attempts to improve fracture treatment in recent years, nonunions remain a problem for orthopaedic and trauma surgery, with a stable incidence throughout the last decade. Cite this article: Bone Joint Res 2022;11(8):541–547

Aims. The primary aim of this study was to identify independent predictors associated with nonunion and delayed union of tibial diaphyseal fractures treated with intramedullary nailing. The secondary aim was to assess the Radiological Union Scale for Tibial fractures (RUST) score as an early predictor of tibial fracture nonunion. Methods. A consecutive series of 647 patients who underwent intramedullary nailing for tibial diaphyseal fractures were identified from a trauma database. Demographic data, comorbidities, smoking status, alcohol consumption, use of non-steroidal anti-inflammatory drugs (NSAIDs), and steroid use were documented. Details regarding mechanism of injury, fracture classification, complications, and further surgery were recorded. Nonunion was defined as the requirement for revision surgery to achieve union. Delayed union was defined as a RUST score < 10 at six months postoperatively. Results. There were 41 nonunions (6.3%), of which 13 were infected (31.7%), and 77 delayed unions (11.9%). There were 127 open fractures (19.6%). Adjusting for confounding variables, NSAID use (odds ratio (OR) 3.50; p = 0.042), superficial infection (OR 3.00; p = 0.026), open fractures (OR 5.44; p < 0.001), and high-energy mechanism (OR 2.51; p = 0.040) were independently associated with nonunion. Smoking (OR 1.76; p = 0.034), open fracture (OR 2.82; p = 0.001), and high-energy mechanism (OR 1.81; p = 0.030) were independent predictors associated with delayed union. The RUST score at six-week follow-up was highly predictive of nonunion (sensitivity and specificity of 75%). Conclusion. NSAID use, high-energy mechanisms, open fractures, and superficial infection were independently associated with nonunion in patients with tibial diaphyseal fractures treated with intramedullary nailing. The six-week RUST score may be useful in identifying patients at risk of nonunion. Cite this article: Bone Jt Open 2021;2(4):227–235

Objectives. A successful outcome following treatment of nonunion requires the correct identification of all of the underlying cause(s) and addressing them appropriately. The aim of this study was to assess the distribution and frequency of causative factors in a consecutive cohort of nonunion patients in order to optimise the management strategy for individual patients presenting with nonunion. Methods. Causes of the nonunion were divided into four categories: mechanical; infection; dead bone with a gap; and host. Prospective and retrospective data of 100 consecutive patients who had undergone surgery for long bone fracture nonunion were analysed. Results. A total of 31% of patients had a single attributable cause, 55% had two causes, 14% had three causes and 1% had all four. Of those (31%) with only a single attributable cause, half were due to a mechanical factor and a quarter had dead bone with a gap. Mechanical causation was found in 59% of all patients, dead bone and a gap was present in 47%, host factors in 43% and infection was a causative factor in 38% of patients. In all, three of 58 patients (5%) thought to be aseptic and two of nine (22%) suspected of possible infection were found to be infected. A total of 100% of previously treated patients no longer considered to have ongoing infection, had multiple positive microbiology results. Conclusion. Two thirds of patients had multiple contributing factors for their nonunion and 5% had entirely unexpected infection. This study highlights the importance of identifying all of the aetiological factors and routinely testing tissue for infection in treating nonunion. It raises key points regarding the inadequacy of a purely radiographic nonunion classification system and the variety of different definitions for atrophic nonunion in the current mainstream classifications used for nonunion. Cite this article: L. Mills, J. Tsang, G. Hopper, G. Keenan, A. H. R. W. Simpson. The multifactorial aetiology of fracture nonunion and the importance of searching for latent infection. Bone Joint Res 2016;5:512–519. DOI: 10.1302/2046-3758.510.BJR-2016-0138

Background. Femoral neck nonunion is a challenging problem. If it is not treated properly, it will be ended with a catastrophe because the victims are younger and active patients and missing hip joint will result in a handicapped like person. If the head is viable, the best treatment is valgus osteotomy. In the original technique, site of nonunion was not explored but in our technique, there is exploration and cleaning of nonunion site and after reduction of fragments, fixation and subtrochanteric osteotomy were done. Materials and methods. Patients with established nonunion of femoral neck fracture entered in study. Inclusion criteria's were age under 60 years old, spherical head of femur without changing the density of it and femoral neck nonunion at least 6 months after fracture. Nonunion site was freshed and any hard ware was removed and head was reduced as possible and subtrochanteric valgus osteotomy to 150 degree was done and fixed with angle blade plate. Bone graft was not used. Patients were studied one year monthly for signs of union of fracture site and signs of avascular necrosis of femoral head. Results. 29 patients were entered in study. 21 male and 8 female with the mean age of 33 years(18 to 55). 19 had Garden type 4 and 7 garden type 3 and the rest 3 had garden type2 at first. Fracture of fixation device were seen in 15 patients. After average 4 months (3 to 5.5) 27 of them showed union of fracture site but in 7 cases, because of some collapse in fracture site, tip of hard ware entered the joint and in 2 cases avascular necrosis of head appeared. Discussion. Exploration of nonunion has some advantages. At first, in some cases removing of broken implants would be necessary for proper insertion of new device. Second, better reduction of fracture site may improve fixation and biomechanics. Third, it seems that in these cases there were through union but in the original method, there were metaplasia of fibrous tissue in the fracture site nonunion

Aim. Treatment algorithms for fracture-related nonunion depend on the presence or absence of bacterial infection. However, the manifestation of septic nonunion varies. Low-grade infections, unlike manifest infections, lack clinical signs of infection and present similarly to aseptic nonunion. The clinical importance of low-grade infection in nonunion is not entirely clear. Therefore, the aim of this study was to evaluate the clinical relevance of low-grade infection in the development and management of femoral or tibial nonunion. Method. A prospective, multicenter clinical study enrolled patients with nonunion and regular healed fractures. Preoperatively, complete blood count without differential, C-reactive protein (CRP), and procalcitonin were obtained, clinical signs of infection were recorded, and a suspected septic or aseptic diagnosis was made based on history and clinical examination. During surgical nonunion revision or routine implant removal, tissue samples were collected for microbiology and histopathology, and osteosynthesis material for sonication. Nonunion patients were followed for 12 months. Definitive diagnosis of “septic” or “aseptic” nonunion was made according to diagnostic criteria for fracture-related infection, considering the results of any further revision surgery during follow-up. Results. 34 patients with regular healed fractures were included. 62 nonunion patients were diagnosed as aseptic, 22 with manifest, and 23 with low-grade infection. The positive predictive value was 88% and the negative predictive value 72% for the suspected diagnosis. The nonunion groups had significantly higher CRP levels than the regular healer group. Differentiation between septic and aseptic nonunion based on blood values was not possible. Low-grade infection demonstrated less frequently histopathologic signs of infection than manifest infection (22% vs. 50%, p=0.048), with 15% of regular healers having histopathologic signs of infection. Cutibacterium acnes was less present in manifest compared to low-grade infection (p=0.042). Healing rates for septic nonunion involving C. acnes were significantly lower for manifest infection (20%) than for low-grade infection (100%, p=0.002). Patients with low-grade infection were treated with systemic antibiotics less frequently than patients with manifest infection (p=0.026), with no significant difference in healing rate (83% vs. 64%), which was slightly lower for low-grade infection than for aseptic nonunion (90%). Conclusions. Low-grade infections play a significant role in nonunion development and are difficult to diagnose preoperatively due to the lack of clinical signs of infection and unremarkable blood counts. However, our results imply that for low-grade infections, antibiotic therapy may not always be mandatory to heal the nonunion. This study was supported by the German Social Accident Insurance (FF-FR0276)

To develop a reliable and effective radiological score to assess the healing of isolated ulnar shaft fractures (IUSF), the Radiographic Union Score for Ulna fractures (RUSU). Initially, 20 patients with radiographs six weeks following a non-operatively managed ulnar shaft fracture were selected and scored by three blinded observers. After intraclass correlation (ICC) analysis, a second group of 54 patients with radiographs six weeks after injury (18 who developed a nonunion and 36 who united) were scored by the same observers. In the initial study, interobserver and intraobserver ICC were 0.89 and 0.93, respectively. In the validation study the interobserver ICC was 0.85. The median score for patients who united was significantly higher than those who developed a nonunion (11 vs 7, p<0.001). A ROC curve demonstrated that a RUSU ≤8 had a sensitivity of 88.9% and specificity of 86.1% in identifying patients at risk of nonunion. Patients with a RUSU ≤8 (n = 21) were more likely to develop a nonunion (n = 16/21) than those with a RUSU ≥9 (n = 2/33; OR 49.6, 95% CI 8.6–284.7). Based on a PPV of 76%, if all patients with a RUSU ≤8 underwent fixation at 6-weeks, the number of procedures needed to avoid one nonunion would be 1.3. The RUSU shows good interobserver and intraobserver reliability and is effective in identifying patients at risk of nonunion six weeks after fracture. This tool requires external validation but may enhance the management of patients with isolated ulnar shaft fractures

Aim. Differentiation of infected (INF) nonunion from aseptic (AS) nonunion is crucial for the choice of intra- and postoperative treatment. Preoperative diagnosis of infected nonunion is challenging, especially in case of low-grade infection lacking clinical signs of infection. Standard blood markers such as C-reactive protein or leucocyte count do not aid in preoperative diagnosis. Proteomic profiling has shown promising results for differentiation of numerous chronic disease states, and in this study was applied to preoperative blood samples of patients with nonunion in an attempt to identify potential biomarkers. Method. This prospective multicenter study enrolled patients undergoing revision surgery of femur or tibia nonunion. Patients with implant removal after regular fracture healing (HEAL) were included as a control-group. Preoperative blood samples, intraoperative tissue samples, sonication of osteosynthesis material and 1-year-follow-up questionnaire were taken. Nonunion patients were grouped into INF or AS after assessing bacterial culture and histopathology of retrieved samples. Diagnosis of infection followed the fracture related infection consensus group criteria, with additional consideration of healing one year after revision surgery. Targeted proteomics was used to investigate a predefined panel of 45 cytokines in preoperative blood samples. Statistical differences were calculated with Kruskal Wallis and Dunn's post hoc test. Cytokines with less than 80% of samples being above the lower limit of detection range (LLDR) were excluded for this study. Results. We recruited 62 AS, 43 INF and 32 HEAL patients. Patients in the two nonunion groups (INF and AS) did not differ concerning smoking, diabetes or initial open or closed fracture. Thirty-two cytokines were above LLDR in >80% of patients. INF patients showed a significant difference in expression of 8 cytokines compared to AS, with greatest differences observed for Macrophage Colony Stimulating Factor 1 (MCSF-1) and Hepatocyte Growth Factor (HGF) (p<0.01). In comparing AS with HEAL patients, 9 cytokines displayed significant differences, including interleukin (IL)-6, Vascular Endothelial Growth Factor A (VEGFA), Matrix Metalloproteinase 1 (MMP-1). Comparison of INF with HEAL patients revealed significantly different expression of 20 cytokines, including. IL-6, IL-18, VEGFA or MMP-1. Conclusions. Our study revealed differences in plasma cytokine profile of blood samples from INF and AS patients. Although no single biomarker is sufficient to differentiate these patients preoperatively in isolation, future multivariant analysis of this cytokine data in combination with clinical characteristics may provide valuable diagnostic insights. Funded by German Social Accident Insurance (FF-FR 0276) and AO Trauma (AR2021_04)

Aim. Failed consolidation (nonunion) after foot and ankle arthrodesis is a major complication, which can lead to additional revision arthrodesis with increased risk of morbidity. Multiple factors can contribute to developing a nonunion, including a low-grade infection. The aim of this study was to investigate the rate of unsuspected low-grade infection in revision arthrodesis for nonunions after foot and ankle arthrodesis. We also analyzed the outcome of unsuspected low-grade infections. Method. We conducted a retrospective study in The Sint Maartenskliniek, The Netherlands. All patients who underwent revision arthrodesis for assumed aseptic nonunion after foot and ankle arthrodesis between January 2020 and July 2021 were included. Patients were excluded if <5 tissue samples were obtained during revision arthrodesis or if they were treated for infection after the index arthrodesis. For the included patients, at least 5 tissue samples for culture were taken during the revision arthrodesis. The causative microorganisms, antibiotic susceptibility and treatment were assessed. An unsuspected infection was defined as ≥2 positive cultures with phenotypical identical microorganisms. Success was defined as union on imaging during clinical follow-up, without signs of persistent infection after finishing the antibiotic treatment. Results. In total 91 revision arthrodesis due to nonunion were performed. The mean duration between index and revision arthrodesis was 571 days. In 14 patients, an unexpected infection was diagnosed. The most frequent causative bacteria identified were Cutibacterium acnes (n=10) and Staphylococcus spps. (n=5). One infection was caused by a Gram-negative bacilli (Acinetobacter spps.). Two infections were polymicrobial. Of the 14 infections, 12 were treated with antibiotics for 12 weeks, 1 for 6 weeks and 1 was not treated. After one-year follow-up, the success rate was 86% and in one patient re-surgery was performed for a non-infectious reason. Conclusions. In 18% of the revisions for nonunion after foot and ankle arthrodesis, an unexpected low- grade infection was the cause of the nonunion. Nonunion occurring after foot and ankle arthrodesis is a severe complication, leading to additional revision arthrodesis. Low-grade infection should be considered as possible explanation of the nonunion, despite the lack of local inflammatory signs. As 18% of the nonunions were unexpectedly caused by low-grade infection, we strongly recommend obtaining at least 5 tissue samples for culture during revision arthrodesis. The outcome of unexpected infection as cause of nonunion is good, when treated with targeted antibiotics for 12 weeks

Introduction and Objective. Nonunion is incomplete healing of fracture and fracture that lacks potential to heal without further intervention. Nonunion commonly presents with persistent pain, swelling, or instability. Those symptoms affect patient quality of life. It is known that using low intensity pulsed ultrasound (LIPUS) for fresh fractures promotes healing. However, effectiveness of LIPUS for nonunion is still controversial. If LIPUS is prove to be effective for healing nonunion, it can potentially provide an alternative to surgery. In addition, we can reduce costs by treating nonunion with LIPUS than performing revision surgery. Materials and Methods. The two authors carried out a systematic search of PubMed, Ovid MEDLINE, and the Cochrane Library. Meta-analysis of healing rate in nonunion and delayed union patients who underwent LIPUS was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) instruction method using a random effects model. Results. The initial search identified 652 articles. Of these, 541 were excluded on the basis of the title because they were either a review paper or covered an unrelated topic. The abstracts of the remaining 111 articles were examined further. That review resulted in a sample of 12 articles. We performed a meta-analysis with a random effects model using Open Meta Analyst software. The result of pooled effect size of healing rate was 73.4% (95%CI: 65.3–81.6%). Due to the fact that nonunion lacks potential to heal without further intervention, we suggest that the therapeutic effect of 73.4% from LIPUS is sufficiently effective. As far as we know, there are no trials comparing the therapeutic effectiveness of surgery and LIPUS, so it cannot be said which is more advantageous. However, the healing rate of revision surgery was reported between 68–96%; therefore, our result is within that range. Thus, if surgery is difficult due to complications, we can recommend LIPUS. Conclusions. Meta-analysis of healing rate of nonunion treated by low-intensity pulsed ultrasound is 73.4%, which suggests sufficient therapeutic effectiveness. Furthermore, we can say that LIPUS may provide an alternative treatment for nonunion patients who cannot tolerate revision surgery due to complications

Aims. Though most humeral shaft fractures heal nonoperatively, up to one-third may lead to nonunion with inferior outcomes. The Radiographic Union Score for HUmeral Fractures (RUSHU) was created to identify high-risk patients for nonunion. Our study evaluated the RUSHU’s prognostic performance at six and 12 weeks in discriminating nonunion within a significantly larger cohort than before. Methods. Our study included 226 nonoperatively treated humeral shaft fractures. We evaluated the interobserver reliability and intraobserver reproducibility of RUSHU scoring using intraclass correlation coefficients (ICCs). Additionally, we determined the optimal cut-off thresholds for predicting nonunion using the receiver operating characteristic (ROC) method. Results. The RUSHU demonstrated good interobserver reliability with an ICC of 0.78 (95% CI 0.72 to 0.83) at six weeks and 0.77 (95% CI 0.71 to 0.82) at 12 weeks. Intraobserver reproducibility was good or excellent for all analyses. Area under the curve in the ROC analysis was 0.83 (95% CI 0.77 to 0.88) at six weeks and 0.89 (95% CI 0.84 to 0.93) at 12 weeks, indicating excellent discrimination. The optimal cut-off values for predicting nonunion were ≤ eight points at six weeks and ≤ nine points at 12 weeks, providing the best specificity-sensitivity trade-off. Conclusion. The RUSHU proves to be a reliable and reproducible radiological scoring system that aids in identifying patients at risk of nonunion at both six and 12 weeks post-injury during non-surgical treatment of humeral shaft fractures. The statistically optimal cut-off values for predicting nonunion are ≤ eight at six weeks and ≤ nine points at 12 weeks post-injury

Aims. The primary aim was to estimate the cost-effectiveness of routine operative fixation for all patients with humeral shaft fractures. The secondary aim was to estimate the health economic implications of using a Radiographic Union Score for HUmeral fractures (RUSHU) of < 8 to facilitate selective fixation for patients at risk of nonunion. Methods. From 2008 to 2017, 215 patients (mean age 57 yrs (17 to 18), 61% female (n = 130/215)) with a nonoperatively managed humeral diaphyseal fracture were retrospectively identified. Union was achieved in 77% (n = 165/215) after initial nonoperative management, with 23% (n = 50/215) uniting after surgery for nonunion. The EuroQol five-dimension three-level health index (EQ-5D-3L) was obtained via postal survey. Multiple regression was used to determine the independent influence of patient, injury, and management factors upon the EQ-5D-3L. An incremental cost-effectiveness ratio (ICER) of < £20,000 per quality-adjusted life-year (QALY) gained was considered cost-effective. Results. At a mean of 5.4 yrs (1.2 to 11.0), the mean EQ-5D-3L was 0.736 (95% confidence interval (CI) 0.697 to 0.775). Adjusted analysis demonstrated the EQ-5D-3L was inferior among patients who united after nonunion surgery (β = 0.103; p = 0.032). Offering routine fixation to all patients to reduce the rate of nonunion would be associated with increased treatment costs of £1,542/patient, but would confer a potential EQ-5D-3L benefit of 0.120/patient over the study period. The ICER of routine fixation was £12,850/QALY gained. Selective fixation based on a RUSHU < 8 at six weeks post-injury would be associated with reduced treatment costs (£415/patient), and would confer a potential EQ-5D-3L benefit of 0.335 per ‘at-risk patient’. Conclusion. Routine fixation for patients with humeral shaft fractures to reduce the rate of nonunion observed after nonoperative management appears to be a cost-effective intervention at five years post-injury. Selective fixation for patients at risk of nonunion based on their RUSHU may confer even greater cost-effectiveness, given the potential savings and improvement in health-related quality of life. Cite this article: Bone Jt Open 2022;3(7):566–572

The primary aim was to identify patient and injury factors independently associated with humeral diaphyseal fracture nonunion after non-operative management. The secondary aim was to determine the effect of management (operative/non-operative) on nonunion. Over a ten-year period, 734 humeral diaphyseal fractures (732 consecutive patients) were retrospectively identified from a trauma database. Follow-up was available for 663 fractures (662 patients; median age 57yrs [16–96], 54% female [n=359/662]) which formed the study cohort. Patient and injury characteristics were recorded. There were 523 patients (79%) managed non-operatively and 139 (21%) managed operatively. Outcome (union/nonunion) was determined from medical records and radiographs. Median follow-up was five months (1.2–74). Nonunion occurred in 22.7% of non-operatively managed injuries (n=119/524). Multivariate analysis demonstrated pre-injury NSAIDs (adjusted OR [AOR] 40.8, 95% CI 2.6–632.3; p=0.008), being underweight (BMI <18.5kg/m2; AOR 7.3, 95% CI 1.3 to 40.2; p=0.022), overweight (BMI 25–29.9kg/m2; AOR 2.5, 95% CI 1.1 to 5.9; p=0.034) and class II obesity (BMI 35–39.9kg/m2; AOR 4.5, 95% CI 1.4 to 15.5; p=0.014) were independently associated with an increased risk of nonunion. Operative fixation was independently associated with a lower risk of nonunion (2.9%, n=4/139) than non-operative management (AOR for non-operative/operative 11.0, 95% CI 2.8 to 43.6; p=0.001). Based upon these results, five patients would need to undergo operative fixation to avoid one nonunion. Pre-injury NSAIDs and BMI were independently associated with nonunion following non-operative management of a humeral diaphyseal fracture. Operative fixation was the independent factor most strongly associated with a lower risk of nonunion

Objectives. To explore the therapeutic potential of combining bone marrow-derived mesenchymal stem cells (BM-MSCs) and hydroxyapatite (HA) granules to treat nonunion of the long bone. Methods. Ten patients with an atrophic nonunion of a long bone fracture were selectively divided into two groups. Five subjects in the treatment group were treated with the combination of 15 million autologous BM-MSCs, 5g/cm. 3. (HA) granules and internal fixation. Control subjects were treated with iliac crest autograft, 5g/cm. 3. HA granules and internal fixation. The outcomes measured were post-operative pain (visual analogue scale), level of functionality (LEFS and DASH), and radiograph assessment. Results. Post-operative pain evaluation showed no significant differences between the two groups. The treatment group demonstrated faster initial radiographic and functional improvements. Statistically significant differences in functional scores were present during the first (p = 0.002), second (p = 0.005) and third (p = 0.01) month. Both groups achieved similar outcomes by the end of one-year follow-up. No immunologic or neoplastic side effects were reported. Conclusions. All cases of nonunion of a long bone presented in this study were successfully treated using autologous BM-MSCs. The combination of autologous BM-MSCs and HA granules is a safe method for treating nonunion. Patients treated with BM-MSCs had faster initial radiographic and functional improvements. By the end of 12 months, both groups had similar outcomes. Cite this article: H.D. Ismail, P. Phedy, E. Kholinne, Y. P. Djaja, Y. Kusnadi, M. Merlina, N. D. Yulisa. Mesenchymal stem cell implantation in atrophic nonunion of the long bones: A translational study. Bone Joint Res 2016;5:287–293. DOI: 10.1302/2046-3758.57.2000587

Objectives. Nonunion is one of the most troublesome complications to treat in orthopaedics. Former authors believed that atrophic nonunion occurred as a result of lack of mesenchymal stem cells (MSCs). We evaluated the number and viability of MSCs in site of atrophic nonunion compared with those in iliac crest. Methods. We enrolled five patients with neglected atrophic nonunions of long bones confirmed by clinical examinations and plain radiographs into this study. As much as 10 ml bone marrow aspirate was obtained from both the nonunion site and the iliac crest and cultured for three weeks. Cell numbers were counted using a haemocytometer and vitality of the cells was determined by trypan blue staining. The cells were confirmed as MSCs by evaluating their expression marker (CD 105, CD 73, HLA-DR, CD 34, CD 45, CD 14, and CD 19). Cells number and viability were compared between the nonunion and iliac creat sites. Results. After three weeks, numbers of 6.08×10. 6. cells (. sd. 2.07) and 4.98×10. 6. cells (. sd. 1.15) were obtained from the nonunion site and the iliac crest, respectively, with viability of 87.1% (81.7% to 90.8%) and 89.8% (84.7% to 94.5%), respectively. No differences was found between the two sources of MSCs regarding cells number (p = 0.347) and viability (p = 0.175). Conclusions. Our findings showed the existence of MSCs in the site of atrophic nonunion, at a similar number and viability to those isolated from the iliac crest

Introduction. Our previous study using microarray analysis showed that Rad (Ras associated with diabetes) was highly expressed in nonunion. The purpose of this study is to investigate the gene expression and immunolocalization of Rad, and other Ras-related G proteins: Rem1 and Rem2 in fracture/nonunion site using rat experimental models. Hypothesis. We hypothesized that Rad had a significant role in nonunion formation. Materials & Methods. For standard healing model, K-wire was inserted into the femur and a closed fracture was created. Nonunion model was produced by periosteal cauterization at the fracture site. At post-fracture days 3, 7, 10, 14, 21, and 28, RNA was extracted from callus or fibrous tissue for real-time PCR. At day 14, specimens were harvested for immunohistochemistry. Results. Significant difference of Rad gene expression was not observed between standard healing fracture and nonunion at the earlier time points. In contrast, significantly higher expression in nonunion was observed at the later time points. There were no significant differences between standard healing fracture and nonunion in gene expression of Rem1 and Rem2. In immunohistochemical analysis, Rad and Rem1 were detected in the fracture site, and Rem2 was not detected. On the other hand, Rad was only detected in fibrous tissue in nonunion. Discussion & Conclusion. Our results suggest a significant role of Rad in fracture healing and nonunion formation. Rad may become a target agent for treatment of nonunion

Introduction. Many surgeons assess biological activity of fracture nonunion by the presence or absence of callus using radiograph. However, it is difficult to assess biological activity only by radiographic appearance. Bone scintigraphy reflects blood supply and bone metabolism and is possibly useful to assess biological activity in nonunion cases. Hypothesis. We hypothesized that poor callus visualization did not always mean lack of biological activity. Materials & Methods. Retrospective assessment and comparison of radiographs and Tc-99m bone scintigraphy of 44 patients with uninfected nonunion was done. Results. Uptake was observed at or around the nonunion site in all cases. Three patterns of uptake were noted; Spot type (S): intense uniform uptake, Uneven type (U): uptake with distribution from cold to hot, and Cleft type (C): decreased uptake surrounded by significant uptake on both sides. All 9 cases of hypertrophic nonunion demonstrated the S type. In 21 cases of oligotrophic nonunion, there were 12 S, 5 U and 4 C. In 3 cases of comminuted nonunion, there were 1 U and 2 C. In 5 cases of defect nonunion, there were 1 U and 4 C. In 6 cases of atrophic nonunion, there were 2 U and 4 C. Discussion & Conclusions. Our results suggest that poor callus visualization does not always mean lack of biological activity. The distribution of uptake and the cleft with decreased uptake are helpful findings to assess the necessity of bone graft or other supplementation in nonunion surgery

The aim of our study is to investigate the natural history of scaphoid non-union. Factors affecting the outcome of scaphoid fracture non-union surgery were assessed using data collected retrospectively from 785 cases treated at 18 centres throughout the UK. All cases had undergone this surgery before October 2014, ensuring a minimum period of 2 years between surgery and data collection from the medical records. Smoking status significantly influenced the union rate of 94 proximal pole (non-smokers = 71%, smokers = 44%, p < 0.05) but not waist (non-smokers = 73% non-unions. Type of bone graft did not affect the union rate of the 282 waist nonunions (iliac crest = 69%; non-vascular distal radius = 75% and vascularised distal radius = 70%: P=0.35), but did influence the union rate of the 98 proximal pole nonunions (iliac crest = 58%; non-vascular distal radius = 58% and vascularised distal radius = 82%: P=0.004). Time interval between fracture and non-union surgery did not affect the union rate of 121 proximal pole nonunions (3–6 months = 56%; 6–12 months = 76%; 1–2 years = 69%; 2+years = 54%: P=0.5), but did influence the union rate of 303 nonunions of the waist (3–6 months = 80%; 6–12 months = 82%; 1–2 years = 65%; 2+years = 55%: P=0.02). Non-unions of the proximal pole appear to be influenced by smoking status and bone graft type, whereas non-unions of the scaphoid are influenced by the time to non-union surgery

Aims. To evaluate if union of clavicle fractures can be predicted at six weeks post-injury by the presence of bridging callus on ultrasound. Methods. Adult patients managed nonoperatively with a displaced mid-shaft clavicle were recruited prospectively. Ultrasound evaluation of the fracture was undertaken to determine if sonographic bridging callus was present. Clinical risk factors at six weeks were used to stratify patients at high risk of nonunion with a combination of Quick Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH) ≥ 40, fracture movement on examination, or absence of callus on radiograph. Results. A total of 112 patients completed follow-up at six months with a nonunion incidence of 16.7% (n = 18/112). Sonographic bridging callus was detected in 62.5% (n = 70/112) of the cohort at six weeks post-injury. If present, union occurred in 98.6% of the fractures (n = 69/70). If absent, nonunion developed in 40.5% of cases (n = 17/42). The sensitivity to predict union with sonographic bridging callus at six weeks was 73.4% and the specificity was 94.4%. Regression analysis found that failure to detect sonographic bridging callus at six weeks was associated with older age, female sex, simple fracture pattern, smoking, and greater fracture displacement (Nagelkerke R. 2. = 0.48). Of the cohort, 30.4% (n = 34/112) had absent sonographic bridging callus in addition to one or more of the clinical risk factors at six weeks that predispose to nonunion. If one was present the nonunion rate was 35%, 60% with two, and 100% when combined with all three. Conclusion. Ultrasound combined with clinical risk factors can accurately predict fracture healing at six weeks following a displaced midshaft clavicle fracture. Cite this article: Bone Joint Res 2021;10(2):113–121

Introduction. what size of defect is optimal for creating an atrophic nonunion animal model has not been well defined. Our aim in this study was to establish a clinically relevant model of atrophic nonunion in rat femur by creation of a bone defect to research fracture healing and nonunion. Materials and methods. We used 30 male Fischer 344 rats (aged 10–11 weeks), which were equally divided into six groups. The segmental bone defects to a single femur in each rat were performed by double transverse osteotomy, and different sized defects were created by group for each group (1 mm, 2 mm, 3 mm, 4 mm, 5 mm and 6 mm). The defects were measured and maintained strictly by using an original external fixator. The periosteum for each defect was stripped both proximally and distally. Thereafter, these models were evaluated by radiology and histology. Radiographs were taken at baseline and at intervals of two weeks over a period of 8 weeks. Atrophic nonunion was defined as a lack of continuity and atrophy of both defect ends radiologically and histologically at eight weeks. Results. In the 1 mm defect group, all defects had healed. In the 2 mm group, one-fifth remained atrophic nonunion. In the 3 mm group, three-fifths had atrophic nonunion, and all of the defects of groups of 4 mm and over were atrophic nonunion. Conclusion. This study showed that we were able to predictively produce an atrophic nonunion animal model by creating defects of at least 4 mm in the Fischer 344 rat femur