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Background Muscle atrophy causes difficulty in resuming daily activities after a fracture. Because transcutaneous carbon dioxide (CO2) application has previously upregulated oxygen pressure in the local tissue, thereby demonstrating its potential in preventing muscle atrophy, here we investigated effects of CO2 application on muscle atrophy after femoral shaft fracture. Methods Thirty fracture model rats were produced and randomly divided into a no treatment (control group) and treatment (CO2 group) groups. After treatment, the soleus muscle was dissected at post-fracture days 0, 14, and 21. Evaluations were performed by measuring muscle weight and performing histological examination and gene expression analysis. Results Muscle weight was significantly higher in the CO2 group than in the control group. Histological analysis revealed that the muscle fiber cross-sectional area was reduced in both groups. Nevertheless, the extent of atrophy was lesser in the CO2 group. Muscle fibers in the control group tended to change into fast muscle fibers. Vascular staining revealed that more capillary vessels surrounded the muscle fibers in the CO2 group than in the control group. Messenger RNA (mRNA) analysis revealed that the CO2 group had a significantly enhanced expression of genes that were related to muscle synthesis. Conclusion Transcutaneous CO2 application may be a novel therapeutic strategy for preventing skeletal muscle atrophy after fracture.

The use of induced pluripotent stem cells (iPSCs) shows potential in bone regenerative strategies. In this study, we investigated whether implantation of chondrogenically differentiated iPSC-derived mesenchymal stem cells (iMSCs) can lead to successful bone regeneration in nude mice with bone defects. Two human iPSC clones (201B7 and 454E2) were used. After generating iMSCs, chondrogenic differentiation was achieved by three-dimensional pellet culture. Thereafter, a 2-mm defect was created in the radius of nude mice, and chondrogenically differentiated iMSC pellets were transplanted in the defect. Microcomputed tomography imaging was performed 8 weeks posttransplantation to assess bone regeneration. All (100%) radii in the 201B7 cell-derived pellet transplantation group and 7 of 10 (70%) radii in the 454E2 cell-derived pellet transplantation group showed bone union. In contrast, 2 of 11 radii (18%) in the control group showed bone union. Thus, the experimental groups showed significantly higher bone union rates than the control group (

Purpose This study investigated whether Escherichia coli-derived bone morphogenetic protein (BMP)-2 (E-BMP-2) adsorbed onto β-tricalcium phosphate (β-TCP) granules can induce bone regeneration in critical-size femoral segmental defects in rabbits. Methods Bone defects 20 mm in size and stabilized with an external fixator were created in the femur of New Zealand white rabbits, which were divided into BMP-2 and control groups. E-BMP-2-loaded β-TCP granules were implanted into defects of the BMP-2 group, whereas defects in the controls were implanted with β-TCP granules alone. At 12 and 24 weeks after surgery, radiographs were obtained of the femurs and histological and biomechanical assessments of the defect area were performed. Bone regeneration was quantified using micro-computed tomography at 24 weeks. Results Radiographic and histologic analyses revealed bone regeneration in the BMP-2 group but not the control group; no fracturing of newly formed bone occurred when the external fixator was removed at 12 weeks. At 24 weeks, tissue mineral density, the ratio of bone volume to total volume, and volumetric bone mineral density of the callus were higher in the BMP-2 group than in control animals. In the former, ultimate stress, extrinsic stiffness, and failure energy measurements for the femurs were higher at 24 weeks than at 12 weeks. Conclusion E-BMP-2-loaded β-TCP granules can effectively promote bone regeneration in long bone defects.

Case We describe the case of a 38-year-old woman, a yoga instructor, who had pain in the right shoulder and scapular region of 4 months' duration while performing yoga. Radiography and computed tomography diagnosed delayed union of a first rib stress fracture. The delayed union of stress fracture of the first rib was successfully treated with the limiting of yoga activity and low-intensity pulsed ultrasound (LIPUS). Conclusions Physicians should be aware that even yoga posing can cause stress fractures of the first rib. LIPUS therapy may be effective for delayed union in addition to rest.

Background MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate gene expression. There is increasing evidence that some miRNAs are involved in the pathology of diabetes mellitus (DM) and its complications. We hypothesized that the functions of certain miRNAs and the changes in their patterns of expression may contribute to the pathogenesis of impaired fractures due to DM. Methods In this study, 108 male Sprague–Dawley rats were divided into DM and control groups. DM rats were created by a single intravenous injection of streptozotocin. Closed transverse femoral shaft fractures were created in both groups. On post-fracture days 5, 7, 11, 14, 21, and 28, miRNA was extracted from the newly generated tissue at the fracture site. Microarray analysis was conducted with miRNA samples from each group on post-fracture days 5 and 11. The microarray findings were validated by real-time polymerase chain reaction (PCR) analysis at each time point. Results Microarray analysis revealed that, on days 5 and 11, 368 and 207 miRNAs, respectively, were upregulated in the DM group, compared with the control group. The top four miRNAs on day 5 were miR-339-3p, miR451-5p, miR-532-5p, and miR-551b-3p. The top four miRNAs on day 11 were miR-221-3p, miR376a-3p, miR-379-3p, and miR-379-5p. Among these miRNAs, miR-221-3p, miR-339-3p, miR-376a-3p, miR-379-5p, and miR-451-5p were validated by real-time PCR analysis. Furthermore, PCR analysis revealed that these five miRNAs were differentially expressed with dynamic expression patterns during fracture healing in the DM group, compared with the control group. Conclusions Our findings will aid in understanding the pathology of impaired fracture healing in DM and may support the development of molecular therapies using miRNAs for the treatment of impaired fracture healing in patients with DM.

ObjectivesDiabetes mellitus (DM) is known to impair fracture healing. Increasing evidence suggests that some microRNA (miRNA) is involved in the pathophysiology of diabetes and its complications. We hypothesized that the functions of miRNA and changes to their patterns of expression may be implicated in the pathogenesis of impaired fracture healing in DM.MethodsClosed transverse fractures were created in the femurs of 116 rats, with half assigned to the DM group and half assigned to the control group. Rats with DM were induced by a single intraperitoneal injection of streptozotocin. At post-fracture days five, seven, 11, 14, 21, and 28, miRNA was extracted from the newly generated tissue at the fracture site. Microarray analysis was performed with miRNA samples from each group on post-fracture days five and 11. For further analysis, real-time polymerase chain reaction (PCR) analysis was performed at each timepoint.ResultsMicroarray analysis showed that there were 14 miRNAs at day five and 17 miRNAs at day 11, with a greater than twofold change in the DM group compared with the control group. Among these types of miRNA, five were selected based on a comparative and extended literature review. Real-time PCR analysis revealed that five types of miRNA (miR-140-3p, miR-140-5p, miR-181a-1-3p, miR-210-3p, and miR-222-3p) were differentially expressed with changing patterns of expression during fracture healing in diabetic rats compared with controls.ConclusionsOur findings provide information to further understand the pathology of impaired fracture healing in a diabetic rat model. These results may allow the potential development of molecular therapy using miRNA for the treatment of impaired fracture healing in patients with DM. Cite this article: S. Takahara, S. Y. Lee, T. Iwakura, K. Oe, T. Fukui, E. Okumachi, T. Waki, M. Arakura, Y. Sakai, K. Nishida, R. Kuroda, T. Niikura. Altered expression of microRNA during fracture healing in diabetic rats. Bone Joint Res 2018;7:139–147. DOI: 10.1302/2046-3758.72.BJR-2017-0082.R1.

Highlights • We performed osteosynthesis with a single locking plate in a patient with osteopetrosis. • Union was delayed, and plate breakage occurred along with nonunion of the fracture. • We then used double locking plates and attained stronger internal fixation with complete fracture healing., Introduction Osteopetrosis is a skeletal disorder characterized by increased osteodensity and a remodeling defect. The fragility of dense sclerotic bones may lead to an increased incidence of fractures. Although internal fixation can be performed, technical challenges may be experienced because of the increased bone density. Complications such as delayed union, nonunion, or implant failure may occur postoperatively. Presentation of case We describe a patient with autosomal-dominant osteopetrosis type 2 who suffered a shaft fracture below a plate of his right femur. We performed osteosynthesis with a single locking plate. Union was delayed, and plate breakage occurred along with nonunion of the fracture. The nonunion was addressed using double locking plates, which secured fixation and allowed complete fracture healing. Discussion There were three reasons of nonunion in our case. First, we left gaps between the fragments. Second, we used mainly cerclage wires, rather than screws, for plate fixation, which led to inadequate stability. Third, the patient was large (height 167 cm, weight 93.1 kg), so the single plate provided insufficient fixing force. We then used double locking plates and attained stronger internal fixation with complete fracture healing. Conclusion Double plating with locking plates may be an effective treatment option for femoral fractures in patients with osteopetrosis.

BackgroundClinicians have very limited options to improve fracture repair. Therefore, it is critical to develop a new clinically available therapeutic option to assist fracture repair biologically. We previously reported that the topical cutaneous application of carbon dioxide (CO2) via a CO2absorption-enhancing hydrogel accelerates fracture repair in rats by increasing blood flow and angiogenesis and promoting endochondral ossification. The aim of this study was to assess the safety and efficacy of CO2therapy in patients with fractures.MethodsPatients with fractures of the femur and tibia were prospectively enrolled into this study with ethical approval and informed consent. The CO2absorption-enhancing hydrogel was applied to the fractured lower limbs of patients, and then 100% CO2was administered daily into a sealed space for 20 min over 4 weeks postoperatively. Safety was assessed based on vital signs, blood parameters, adverse events, and arterial and expired gas analyses. As the efficacy outcome, blood flow at the level of the fracture site and at a site 5 cm from the fracture in the affected limb was measured using a laser Doppler blood flow meter.ResultsNineteen patients were subjected to complete analysis. No adverse events were observed. Arterial and expired gas analyses revealed no adverse systemic effects including hypercapnia. The mean ratio of blood flow 20 min after CO2therapy compared with the pre-treatment level increased by approximately 2-fold in a time-dependent manner.ConclusionsThe findings of the present study revealed that CO2therapy is safe to apply to human patients and that it can enhance blood flow in the fractured limbs.Trial registrationThis study has been registered in the UMIN Clinical Trials Registry (Registration number:UMIN000013641, Date of registration: July 1, 2014).

Introduction Medial clavicle fractures are rare injuries. Symptomatic nonunion arises up to 8% of medial clavicle fractures when treated conservatively. Presentation of case A 53-year-old man sustained a left medial clavicle fracture and was treated conservatively at another hospital. Nine months after his initial injury, he was referred to our institution. We diagnosed pseudarthrosis of the medial clavicle. We performed open reduction and internal fixation using an inverted distal clavicle locking plate. At the 1-year follow-up, radiographs showed bone union. Discussion This is the first reported case of medial clavicle pseudarthrosis treated with an inverted distal clavicle anatomical locking plate. There are several advantages in using this plate. Conclusion This method is a good treatment option.

Background The treatment of established orthopaedic infection is challenging. While the main focus of treatment is wide surgical debridement, systemic and local antibiotic administration are important adjuvant therapies. Several reports have described the clinical use of antibiotic-impregnated calcium phosphate cement (CPC) to provide local antibiotic therapy for bone infections. However, these were all individual case reports, and no case series have been reported. We report a case series treated by a single surgeon using antibiotic-impregnated CPC as part of a comprehensive treatment plan in patients with established orthopaedic infection. Methods We enrolled 13 consecutive patients with osteomyelitis ( n = 6) or infected non-union ( n = 7). Implantation of antibiotic-impregnated CPC was performed to provide local antibiotic therapy as part of a comprehensive treatment plan that also included wide surgical debridement, systemic antibiotic therapy, and subsequent second-stage reconstruction surgery. We investigated the rate of successful infection eradication and systemic/local complications. The concentration of antibiotics in the surgical drainage fluids, blood, and recovered CPC (via elution into a phosphate-buffered saline bath) were measured. Results The mean follow-up period after surgery was 50.4 (range, 27–73) months. There were no cases of infection recurrence during follow-up. No systemic toxicity or local complications from the implantation of antibiotic-impregnated CPC were observed. The vancomycin concentration in the fluid from surgical drainage ( n = 6) was 527.1 ± 363.9 μg/mL on postoperative day 1 and 224.5 ± 198.4 μg/mL on postoperative day 2. In patients who did not receive systemic vancomycin therapy ( n = 3), the maximum serum vancomycin level was In vitro vancomycin elution was observed from the CPC that was surgically retrieved ( n = 2). Conclusions Implantation of antibiotic-impregnated CPC is an option to provide local antibiotic therapy as part of a comprehensive treatment plan.

Introduction Nonunion is a challenging problem that may occur after certain bone fractures. The treatment of nonunion is closely related to its type. To develop an effective treatment strategy for each type of nonunion, biological analysis of nonunion tissue is essential. Pseudoarthrosis is a distinct pathologic entity of nonunion. To understand the pathology of pseudoarthrosis, we investigated the cellular properties of pseudoarthrosis tissue-derived cells (PCs) in vitro. Patients and methods PCs were isolated from four patients with pseudoarthrosis and cultured. Cells were evaluated for cell-surface protein expression by using flow cytometry. Osteogenic differentiation capacity was assessed by using Alizarin Red S staining, alkaline phosphatase (ALP) activity assay, and reverse transcription polymerase chain reaction (RT-PCR) after osteogenic induction. Chondrogenic differentiation capacity was assessed via Safranin O staining and RT-PCR after chondrogenic induction. Results PCs were consistently positive for the mesenchymal stem cell-related markers CD29, CD44, CD105, and CD166, but were negative for the haematopoietic-lineage markers CD31, CD34, CD45, and CD133. Alizarin Red S staining revealed that PCs formed a mineralised matrix that was rich in calcium deposits after osteogenic induction. ALP activity under osteogenic conditions was significantly higher than that under control conditions. Gene expression of ALP, Runx2, osterix, osteocalcin, and bone sialoprotein was observed in PCs cultured under osteogenic conditions. Induced pellets were negatively stained by Safranin O staining. Gene expression of aggrecan, collagen II, collagen X, SOX5, and SOX9 was not observed. Conclusion We have shown for the first time the properties of cells in patients with pseudoarthrosis. Our results indicated that osteogenic cells existed in the pseudoarthrosis tissue. This study might provide insights into understanding the pathology of pseudoarthrosis and improving the treatment for pseudoarthrosis.

Highlights • Non-union of displaced femoral neck fractures in young adults remains a difficult problem. • Low-intensity pulsed ultrasound (LIPUS) significantly promotes bone healing. • LIPUS treatment is a useful approach for ununited displaced femoral neck fractures., Introduction Delayed union and non-union of displaced femoral neck fractures remains a difficult clinical problem for orthopaedic surgeons. In the physiologically young patient, every effort should be made to preserve the native hip joint. We present two cases of ununited femoral neck fractures in young adults who were successfully treated with low-intensity pulsed ultrasound (LIPUS) and showed satisfactory results. Presentation of case 1 A 41-year-old woman was involved in a motor vehicle crash and was diagnosed with displaced femoral neck fracture. Eleven months after internal fixation, a computed tomography (CT) scan revealed the presence of non-union of the femoral neck. LIPUS treatment was therefore initiated. After eight months, the fracture was completely consolidated. Presentation of case 2 A 39-year-old man was involved in a cycling accident and was diagnosed with displaced femoral neck fracture. Thirteen weeks after internal fixation, a CT scan revealed delayed union of the femoral neck. LIPUS treatment was therefore initiated. After six months, the fracture was completely consolidated. Conclusion We suggest use of LIPUS as a possible treatment approach for delayed union and non-union of displaced femoral neck fractures in young patients before considering further surgical intervention.

Purpose. To evaluate the rate of venous thromboembolism (VTE) after complex lower-limb fracture surgery without pharmacological prophylaxis. Methods. Between July 2005 and April 2009, 11 men and 6 women (mean age, 45 years) underwent temporary external fixation followed by internal fixation for a total of 3 femoral and 20 tibial fractures. Patients were screened for VTE using contrast-enhanced computed tomography (CT) when the D-dimer value was beyond normal range. Between May 2009 and December 2012, 18 men and 4 women (mean age, 45 years) underwent temporary external fixation followed by internal fixation for a total of 8 femoral and 20 tibial fractures. Patients were routinely screened for deep vein thrombosis (DVT) using ultrasonography and for pulmonary embolism (PE) using contrast-enhanced CT (in high-risk patients with multiple injuries or pelvic and acetabular fractures). In both groups, pharmacological prophylaxis was not used; only mechanical prophylaxis was used. Results. The 2 groups were comparable in terms of age, sex, and proportion of bilateral external fixation, open fracture, and associated injury, except that the duration of external fixation was longer in the early group (29.8±28.0 vs. 11.6±4.0 days, p=0.001). Of the 17 patients in the early group, 5 developed VTEs (3 DVTs and 2 PEs) at a mean of 13.6 (range, 6–20) days after injury; 2 of whom developed VTE during the external fixation period. Of the 22 patients in the later period, 10 developed VTEs (10 DVTs and 4 PEs) at a mean of 13 (range, 5–33) days after injury; 7 of whom developed VTE during the external fixation period. Conclusion. The rate of VTE was high in patients undergoing complex lower-limb fracture surgery without pharmacological prophylaxis.

An unicondylar fracture of the femur is uncommon and of the medial condyle more so. Open reduction and internal fixation of these fractures is most commonly performed with screws or plate and screws. Secure bone fixation is compromised by osteoporosis in elderly patients; additional measures may be required. We report the case of an elderly osteoporotic patient with a medial condyle fracture nonunion treated successfully through retrograde intramedullary nailing. A 78-year-old osteoporotic woman suffered medial condyle fracture of the femur 9 months before visiting our hospital. She had been treated conservatively, and the fracture demonstrated a complete nonunion with gross instability. The edge fragments appeared sclerotic, and the nonunion site was accompanied by a bony defect. Although fixation by a plate and screw is the standard method for the treatment of such fracture, we judged that stability would be difficult to achieve with this method due to the accompanying bony defect and osteoporosis. Thus, we performed open reduction and fixation by retrograde intramedullary nailing with the use of “condyle screw and nut” system, followed by bone grafting. Bony union was successfully obtained. The stability and range of motion of the knee were recovered, and the patient regained the ability to walk. We suggest the unique application of retrograde intramedullary nailing with condyle screw and nut for the treatment of specific, complex cases of femoral medial condyle fracture.

OBJECTIVE The aim of this study was to report the clinical results of atypical femoral fractures (AFFs) treated with low-intensity pulsed ultrasound (LIPUS). MATERIALS AND METHODS The data on AFFs that were surgically treated in our hospital from 2010 to 2016 was retrospectively analyzed. AFF was diagnosed based on the criteria defined by the second report of an ASBMR task force. RESULTS Seven fractures in 6 cases were included in this study. Two fractures were referred to us as being nonunion. Five fractures were subtrochanteric fractures and 2 fractures were shaft fractures. Five fresh AFFs were fixed with an intramedullary nail and 2 nonunion fractures were fixed with plates. LIPUS was used in 6 fractures. Bone union was achieved in 5 fractures with the average time to union being 17 months (5-29). In 4 out of the 6 fractures treated with LIPUS, bone union was achieved after 14 months on average. In the other 2 LIPUS-treated fractures, bone union was not achieved even at 1 year after surgery. DISCUSSION It is known that AFF healing tends to be very slow. Some case reports indicate that AFF healing might be accelerated by LIPUS. In the current series, the subtrochanteric fracture that was not treated with LIPUS healed at 29 months after surgery, which was much longer than the average time to union in the 5 fractures that were treated with LIPUS. Although our number of cases is small, LIPUS may be a potentially useful tool for accelerating AFF repair.

Purpose Diabetes mellitus (DM) is known to impair fracture healing. The purpose of this study was to elucidate and compare the gene expression patterns and localization of stromal cell-derived factor 1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) during fracture healing of the femur in rats with and without DM. Methods Closed transverse fractures were created in the femurs of rats equally divided into a DM group and control group; DM was induced by streptozotocin. At post-fracture days five, seven, 11, 14, 21 and 28, total RNA was extracted from the fracture callus and mRNA expression levels of SDF-1 and CXCR4 were measured by real-time polymerase chain reaction. Localization of SDF-1 and CXCR4 proteins at the fracture site was determined by immunohistochemistry at days 21 and 28. Results SDF-1 expression was significantly lower in the DM group than in the healthy group on days 21 and 28, and showed a significant difference between days 14 and 21 in the healthy group. There was no significant difference in CXCR4 expression levels between the healthy and DM groups at any time point. On day 21 immunoreactivity of SDF-1 and CXCR4 was detected at the fracture site of the healthy group but no immunoreactivity was observed in the DM group. On day 28, immunoreactivity of SDF-1 and CXCR4 was detected at the fracture site in both groups. Conclusion Gene expression and localization of SDF-1 and CXCR4 was altered during fracture healing, which may contribute to the impaired fracture healing in DM.

Background: We previously demonstrated that topical cutaneous application of CO2, by means of a hydrogel in which the CO2 readily dissolves, increases blood flow and oxygen dissociation from hemoglobin in the soft tissues surrounding bone. In the present study, we utilized a rat fracture model to test the hypothesis that application of this treatment to fractured limbs would accelerate fracture repair. Methods: A closed femoral shaft fracture was created in each rat. Topical cutaneous application of CO2 by means of a hydrogel was performed five times a week for up to four weeks in the CO2/hydrogel group (n = 60). Sham treatments were performed in the control group (n = 60). Radiographic, histological, immunohistochemical, laser Doppler perfusion imaging, real-time polymerase chain reaction, and biomechanical assessments were performed. Results: Radiographic fracture union was evident at week 3 in twelve (86%) of fourteen animals in the CO2/hydrogel group compared with five (36%) of fourteen in the control group (p < 0.05; 95% CI [confidence interval] for the difference in union rate, 2.26% to 99.64%). Histological assessment revealed promotion of endochondral ossification in the CO2/hydrogel group. Immunohistochemical assessment at week 2 showed significantly greater capillary density in the CO2/hydrogel group (p < 0.05; 95% CI for the difference, 161 to 258 per mm2). Laser Doppler perfusion imaging demonstrated that the blood flow in the fractured limb was significantly greater at weeks 2 and 3 in the CO2/hydrogel group (p < 0.05; 95% CI for the difference, 8.4% to 22.4% and 6.7% to 19.0%, respectively). Gene expression of chondrogenic, osteogenic, and angiogenic markers was significantly greater in the CO2/hydrogel group at several time points. Ultimate stress, extrinsic stiffness, and failure energy (relative to the contralateral limb) were significantly greater in the CO2/hydrogel group at week 3 (p < 0.05; 95% CI for the difference, 24.8% to 67.5%, 4.0 % to 22.7%, and 9.6% to 58.8%, respectively). There were no significant differences between the groups with respect to any outcome measure at week 4. Conclusions: Topical cutaneous application of CO2 by means of a hydrogel accelerated fracture repair in association with the promotion of angiogenesis, blood flow, and endochondral ossification. Clinical Relevance: Topical cutaneous application of CO2 by this method is a novel and potentially useful therapy for accelerating fracture repair.

Osteosynthesis of periprosthetic femoral fractures around hip arthroplasties is challenging, and locking plate fixation has been found to be a reasonable treatment. However, there is a paucity of evidence of the extent to which patients recover their activities of daily living (ADL). The purpose of this study was to study the clinical results, particularly recovery of ADL, radiological results, and potential complications arising from the use of locking plate fixation for periprosthetic femoral fractures around hip arthroplasties. We conducted a retrospective, multi-center study. Patients with periprosthetic femoral fractures around hip arthroplasties who were treated by osteosynthesis with use of locking plates and who underwent follow-up for at least 6 months postoperatively were enrolled in the study. For each patient, recovery of ADL, in terms of social and ambulatory recovery and Parker mobility score, were compared before fracture and at last follow-up. Postoperative complications were investigated. Bony union, loss of reduction, and malunion were assessed radiologically. Thirty-two patients were enrolled in this study. Mean follow-up was 25.1 months. For 84.4, 68.8, and 53.1 % of patients, respectively, social status, ambulation, and Parker mobility score at last follow-up were determined to be equal to that before the fracture. Bony union was observed for 30 patients within the follow-up period. Four patients had not achieved bony union 6 months postoperatively. There was no loss of reduction, malunion, or implant breakage, and no infection. For one patient each, partial pullout of the locking screws and a supracondylar fracture at the plate end were observed, and additional surgery was required. Our results reveal that locking plate fixation provided sufficient stability for satisfactory recovery of ADL for most elderly patients with periprosthetic femoral fractures around hip arthroplasties.

Background: Currently, an algorithmic approach for deciding treatment options according to the Vancouver classification is wide ly used for treatment of periprosthetic femoral fractures after hip arthroplasty. However, this treatment algorithm based on the Vancouver classification lacks consideration of patient physiology and surgeon’s experience (judgment), which are also important for deciding treatment options. The purpose of this study was to assess the treatment results and discuss the treatment options using a case series. Methods: Eighteen consecutive cases with periprosthetic femoral fractures after total hip arthroplasty and hemiarthroplasty were retrospectively reviewed. A locking compression plate system was used for osteosynthesis during the study period. The fracture type was determined by the Vancouver classification. The treatment algorithm based on the Vancouver classification was gener ally applied, but was modified in some cases according to the surgeon’s judgment. The reasons for modification of the treatment algorithm were investigated. Mobility status, ambulatory status, and social status were assessed before the fracture and at the latest follow-up. Radiological results including bony union and stem stability were also evaluated. Results: Thirteen cases were treated by osteosynthesis, two by revision arthroplasty and three by conservative treatment. Four cases of type B2 fractures with a loose stem, in which revision arthroplasty is recommended according to the Vancouver classification, were treated by other options. Of these, three were treated by osteosynthesis and one was treated conservatively. The reasons why the three cases were treated by osteosynthesis were technical difficulty associated with performance of revision arthroplasty owing to severe central migration of an Austin-Moore implant in one case and subsequent severe hip contracture and low activity in two cases. The reasons for the conservative treatment in the remaining case were low activity, low-grade pain, previous wiring around the fracture and light weight. All patients obtained primary bony union and almost fully regained their prior activities. Conclusions: We suggest reaching a decision regarding treatment methods of periprosthetic femoral fractures by following the algorithmic approach of the Vancouver classification in addition to the assessment of each patient’s hip joint pathology, physical status and activity, especially for type B2 fractures. The customized treatments demonstrated favorable overall results.

The authors describe a tactile surgical navigation system using custom 3-dimensional (3D) models of the bony pelvis for complex acetabular fracture surgery. The bone area of interest was extracted from the Digital Imaging and Communications in Medicine (DICOM) data of computed tomography scans. A standard triangulated language file was used to create 3D models of the bony pelvis by layered manufacturing using a 3D printer and non-cytotoxic, sterilizable, acrylic-based photopolymers. No infections and no toxic or other adverse events were observed. The models were useful for preoperative assessment, planning, and simulation; intraoperative assessment; obtaining informed consent; and education. [ Orthopedics . 2014; 37(4):237–242.]

Low intensity pulsed ultrasound (LIPUS) stimulation is a clinically established treatment method used to accelerate long bone fracture healing; however, this method is currently not applied to mandibular fractures. In this study, we investigated the effects of LIPUS on human mandibular fracture haematoma-derived cells (MHCs) in order to explore the possibility of applying LIPUS treatment to mandibular fractures. MHCs were isolated from five patients. The cells were divided into two groups: (1) LIPUS (+) group: MHCs cultured in osteogenic medium with LIPUS treatment; and (2) LIPUS (−) group: MHCs cultured in osteogenic medium without LIPUS treatment. The osteogenic differentiation potential and proliferation of the MHCs were compared between the two groups. The waveform used was equal to the wave conditions of a clinical fracture healing system. The gene expression levels of ALP, OC, Runx2, OSX, OPN, and PTH-R1 and mineralization were increased in the LIPUS (+) group compared to the LIPUS (−) group. There were no significant differences in cell proliferation between the two groups. These findings demonstrate the significant effects of LIPUS on the osteogenic differentiation of MHCs. This study provides significant evidence for the potential usefulness of the clinical application of LIPUS to accelerate mandibular fracture healing.

Background Bone defects may occur because of severe trauma, nonunion, infection, or tumor resection. However, treatments for bone defects are often difficult and have not been fully established yet. We previously designed an efficient system of topical cutaneous application of carbon dioxide (CO2) using a novel hydrogel, which facilitates CO2 absorption through the skin into the deep area within a limb. In this study, the effect of topical cutaneous application of CO2 on bone healing was investigated using a rat femoral defect model. Methods In this basic research study, an in vivo bone defect model, fixed with an external fixator, was created using a rat femur. The affected limb was shaved, and CO2 was applied for 20 min/day, 5 days/week. In the control animals, CO2 gas was replaced with air. Radiographic, histological, biomechanical, and genetic assessments were performed to evaluate bone healing. Results Radiographically, bone healing rate was significantly higher in the CO2 group than in the control group at 4 weeks (18.2% vs. 72.7%). The degree of bone healing scored using the histopathological Allen grading system was significantly higher in the CO2 group than in the control group at 2 weeks (1.389 ± 0.334 vs. 1.944 ± 0.375). The ultimate stress, extrinsic stiffness, and failure energy were significantly greater in the CO2 group than in the control group at 4 weeks (3.2 ± 0.8% vs. 38.1 ± 4.8%, 0.6 ± 0.3% vs. 41.5 ± 12.2%, 2.6 ± 0.8% vs. 24.7 ± 5.9%, respectively.). The volumetric bone mineral density of the callus in micro-computed tomography analysis was significantly higher in the CO2 group than in the control group at 4 weeks (180.9 ± 43.0 mg/cm3 vs. 247.9 ± 49.9 mg/cm3). Gene expression of vascular endothelial growth factor in the CO2 group was significantly greater than that in the control group at 3 weeks (0.617 ± 0.240 vs. 2.213 ± 0.387). Conclusions Topical cutaneous application of CO2 accelerated bone healing in a rat femoral defect model. CO2 application can be a novel and useful therapy for accelerating bone healing in bone defects; further research on its efficacy in humans is warranted.

Parathyroid hormone (PTH) 1-34 has been shown to accelerate fracture healing. Previously, we reported that progenitor cells with osteogenic and chondrogenic potential exist in human fracture haematoma, suggesting that the fracture haematoma-derived progenitor cells (HCs) contribute to fracture healing. However, there has been no study investigating the effect of PTH on HCs. We investigated the effect of pulsatile and continuous PTH treatment on human fracture HCs in vitro. HCs were isolated from seven patients. The HCs were divided into four groups: growth medium; control [osteogenic medium (OM) without PTH]; PTH-C (OM with continuous PTH); and PTH-P (OM with pulsatile PTH) groups. Osteogenic differentiation potential and proliferation of HCs were compared among the four groups. For chondrogenesis, the HCs were divided into two groups: control [chondrogenic medium (CM) without PTH]; and PTH-C (CM with continuous PTH) groups, and chondrogenic differentiation potential was analysed. PTH treatment did not affect cell proliferation, regardless of the mode of administration. Osteogenic activity was also not significantly affected by continuous PTH treatment but significantly inhibited by pulsatile PTH treatment. Conversely, chondrogenic differentiation was significantly inhibited by continuous PTH treatment. Our results revealed that PTH treatment on HCs, either continuous or pulsatile, does not exhibit any positive effect, and indicates that exogenous PTH administration after fracture has no effect on HCs. PTH may not have a positive effect at the fracture site during the early stage of fracture healing in which haematoma formation occurs. Copyright © 2013 John Wiley & Sons, Ltd.

OBJECTIVES Low-intensity pulsed ultrasound (US) has been shown to have positive effects on the healing of nonunions, and bone morphogenetic protein 7 (BMP-7) is known to be a strong stimulator of osteogenic differentiation. Recently, we showed that nonunion tissue contains multilineage mesenchymal progenitor cells, suggesting that nonunion tissue-derived cells may play an important role during the healing process of nonunions. In this study, we investigated whether low-intensity pulsed US promoted BMP-7-induced osteogenic differentiation of nonunion tissue-derived cells in vitro. METHODS Nonunion tissue-derived cells were isolated from 7 patients. The cells were divided into two groups: (1) BMP-7 alone, consisting of nonunion tissue-derived cells cultured in osteogenic medium containing BMP-7 without low-intensity pulsed US treatment; and (2) BMP-7 + low-intensity pulsed US, consisting of nonunion tissue-derived cells cultured in osteogenic medium containing BMP-7 with low-intensity pulsed US treatment. The osteogenic differentiation potential and proliferation of nonunion tissue-derived cells were compared between the two groups. RESULTS The alkaline phosphatase activity, gene expression levels of alkaline phosphatase and runt-related transcription factor 2, and mineralization were higher in the BMP-7 + low-intensity pulsed US group than in the BMP-7-alone group. There was no significant difference in cell proliferation between the two groups. CONCLUSIONS These findings show a significant effect of low-intensity pulsed US on the osteogenic differentiation of nonunion tissue-derived cells induced by BMP-7. This study may provide substantial evidence for the clinical combined application of BMP-7 and low-intensity pulsed US for nonunion treatment.

To investigate the effect of the combined application of bone morphogenetic protein-7 (BMP-7) and low-intensity pulsed ultrasound (LIPUS) on human fracture hematoma-derived progenitor cells (HCs).HCs were isolated from 6 patients. The cells were then divided into 4 groups and cultured: (1) control group, HCs cultured in growth medium without LIPUS; (2) LIPUS group, HCs cultured in growth medium with LIPUS; (3) BMP-7 group, HCs cultured in osteogenic medium containing BMP-7 without LIPUS; and (4) BMP-7 + LIPUS group, HCs cultured in osteogenic medium with LIPUS. Osteogenic differentiation potential and proliferation of HCs were compared among 4 groups.Alkaline phosphatase activity, the expression of osteogenic genes, and the mineralization of HCs in BMP-7 + LIPUS group were shown to be significantly increased compared with the other groups. However, LIPUS did not affect the proliferation of HCs in the presence or absence of BMP-7.These findings demonstrated for the first time the significant effect of LIPUS on the osteogenic differentiation of HCs in the presence of BMP-7. This study may provide significant evidence for the clinical combined application of BMP-7 and LIPUS for the treatment of acute bone fractures.

The use of intramedullary nails to treat trochanteric fractures of the femur has increased with the increasing size of the elderly population. The third generation Gamma nail is currently one of the most popular devices for the treatment of trochanteric fractures. Nail breakage is a rare complication, possibly resulting from fatigue fracture of the implant. We present the first reported case of breakage of a third generation Gamma nail that was not used to treat a pathological fracture. An 83-year-old woman with an unstable trochanteric fracture of the femur was treated using a third generation Gamma nail. She was referred to our hospital 14 months postoperatively with nail breakage at the opening for the lag screw. The breakage was secondary to nonunion, which was thought to be mainly due to insufficient reduction of the fracture. The broken nail was removed, and the patient underwent cemented bipolar hemiarthroplasty. At followup 18 months later, she was mobile with a walker and asymptomatic with no complications. This case shows that inadequate operation such as insufficient reduction of the trochanteric fracture may result in nonunion and implant breakage, even when using a high-strength, well-designed implant.

Nonunion of a sacral fracture is a rare but serious clinical condition which can cause severe chronic pain, discomfort while sitting, and significant restriction of the level of activities. Fracture nonunions reportedly occur most often after nonoperative initial treatment or inappropriate operative treatment. We report a case of fracture nonunion of the sacrum and pubic rami that resulted from non-operative initial treatment, which was treated successfully using bone grafting through a posterior approach and CT-guided percutaneous iliosacral screw fixation combined with anterior external fixation. Although autologous bone grafting has been the gold standard for the treatment of pelvic fracture nonunions, little has been written describing the approach. We utilized a posterior approach for bone grafting, which could allow direct visualization of the nonunion site and preclude nerve root injury. By this procedure, we were able to obtain the healing of fracture nonunion, leading to pain relief and functional recovery.

Endurance exercise generates CO2 via aerobic metabolism; however, its role remains unclear. Exogenous CO2 by transcutaneous delivery promotes muscle fibre-type switching to increase endurance power in skeletal muscles. Here we determined the performance of rats running in activity wheels with/without transcutaneous CO2 exposure to clarify its effect on endurance exercise and recovery from muscle fatigue. Rats were randomised to control, training and CO2 groups. Endurance exercise included activity-wheel running with/without transcutaneous CO2 delivery. Running performance was measured after exercise initiation. We also analysed changes in muscle weight and muscle fibres in the tibialis anterior muscle. Running performance improved over the treatment period in the CO2 group, with a concomitant switch in muscle fibres to slow-type. The mitochondrial DNA content and capillary density in the CO2 group increased. CO2 was beneficial for performance and muscle development during endurance exercise: it may enhance recovery from fatigue and support anabolic metabolism in skeletal muscles.

Background The discovery of microRNA (miRNA) has revealed a novel type of regulatory control for gene expression. Increasing evidence suggests that miRNA regulates chondrocyte, osteoblast, and osteoclast differentiation and function, indicating miRNA as key regulators of bone formation, resorption, remodeling, and repair. We hypothesized that the functions of certain miRNAs and changes to their expression pattern may play crucial roles during the process of fracture healing. Methods Standard healing fractures and unhealing fractures produced by periosteal cauterization at the fracture site were created in femurs of seventy rats, with half assigned to the standard healing fracture group and half assigned to the nonunion group. At post-fracture days 3, 7, 10, 14, 21, and 28, total RNA including miRNA was extracted from the newly generated tissue at the fracture site. Microarray analysis was performed with miRNA samples from each group on post-fracture day 14. For further analysis, we selected highly up-regulated five miRNAs in the standard healing fracture group from the microarray data. Real-time PCR was performed with miRNA samples at each time point above mentioned to compare the expression levels of the selected miRNAs between standard healing fractures and unhealing fractures and investigate their time-course changes. Results Microarray and real-time polymerase chain reaction (PCR) analyses on day 14 revealed that five miRNAs, miR-140-3p, miR-140-5p, miR-181a-5p, miR-181d-5p, and miR-451a, were significantly highly expressed in standard healing fractures compared with unhealing fractures. Real-time PCR analysis further revealed that in standard healing fractures, the expression of all five of these miRNAs peaked on day 14 and declined thereafter. Conclusion Our results suggest that the five miRNAs identified using microarray and real-time PCR analyses may play important roles during fracture healing. These findings provide valuable information to further understand the molecular mechanism of fracture healing and may lead to the development of miRNA-based tissue engineering strategies to promote fracture healing.