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Background Although many treatments for ipsilateral proximal and shaft femoral fractures have been developed, controversy exists regarding their optimal management. The purpose of this retrospective study was to discuss the effectiveness of the bridge-link type combined fixation system (BCFS) and evaluate functional outcomes in treating patients with these complex fractures. Patients and methods We retrospectively reviewed 14 cases of ipsilateral proximal and shaft femoral fractures treated from January 2012 to December 2016. All cases were treated by BCFS combined with minimally invasive percutaneous plate osteosynthesis (MIPPO). Clinical and radiographic data were collected during regular post-operative follow-up visits. Functional outcomes were determined according to the Friedman and Wyman scoring system. Results The proximal femoral fractures were emergency diagnoses in 11 cases and delayed diagnoses in 3 cases. The delay time was 5–6 days, with an average of 5.3 days. The mean operation time was 179.6 min (range 135–231 min) with a blood loss volume that ranged from 430 to 535 ml (average 483.6 ml). Follow-up was conducted in 13 cases between 9 and 30 months post-operation, with an average follow-up time of 17.3 months. The proximal femoral fractures were united in 12 cases at the final follow-up. One case had nonunion 13 months after the operation, underwent valgus intertrochanteric osteotomy, and healed 6 months later. The femoral shaft fractures obtained rigid union at the latest follow-up in 12 cases. One case endured nonunion 12 months after the operation. After the revision surgery and iliac bone grafting, the fracture healed 6 months later. Eight of the cases had good functional results, 4 had fair results, and results were poor in 1 case at the final follow-up. Conclusions The treatment of ipsilateral proximal femoral and shaft fractures with BCFS in combination with MIPPO demonstrated a high likelihood of union for both fractures and good functional results.

Background The aim of this cadaveric study was to compare a polyaxial (NCB®, Zimmer) to a fixed-angle monoaxial locking plate (PERILOC®, Smith & Nephew) in comminuted fractures of the distal femur regarding stability of the construct. Up to date there is no published biomechanical data concerning polyaxial plating in cadaveric distal femurs. Methods Fourteen formalin fixed femora were scanned by dual-energy x-ray absorptiometry. As fracture model an unstable supracondylar comminuted fracture was simulated. Fractures were pairwise randomly fixed either with a mono- (group A) or a polyaxial (group B) distal femur plate. The samples were tested in a servohydraulic mechanical testing system starting with an axial loading of 200 N following an increase of 200 N in every step with 500 cycles in every sequence up to a maximum of 2 000 N. The end points were implant failure or relevant loss of reduction. Data records included for each specimen time, number of cycles, axial load and axial displacement. Statistical analysis was performed using the exact Wilcoxon signed rank test. Results The mean donor age at the time of death was 75 years. The bone mass density (BMD) of the femurs in both groups was comparable and showed no statistically significant differences. Five bones failed before reaching the maximum applied force of 2000 N. Distribution curves of all samples in both groups, showing the plastic deformation in relation to the axial force, showed no statistically significant differences. Conclusions Operative stabilization of distal femur fractures can be successfully and equally well achieved using either a monoaxial or a polyaxial locking plate. Polyaxial screw fixation may have advantages if intramedullary implants are present.

Hip fracture is the most disastrous osteoporotic fracture, characterized by high mortality, morbidity and institutionalization for the patient and by high economic costs for the health care system. The morphology of the upper part of the femur can influence the risk of hip fracture, e.g., a longer femoral neck is associated with a higher risk of cervical fractures, but not trochanteric ones. In this study, we evaluated the prediction of hip fracture risk by morphological parameters estimated from DXA measurements, and we compared their predictive value for cervical and trochanteric fractures in elderly women by reanalyzing previously published data (Duboeuf et al. J Bone Miner Res 1997 12 1895). This nested case-control study was performed in 232 elderly community-dwelling women from the EPIDOS cohort, including 65 women who sustained a hip fracture. After adjustment for confounding variables, women who sustained a cervical fracture had lower areal bone mineral density (aBMD), lower cortical thickness and a higher average buckling ratio (P<0.005 for all) as well as longer femoral neck (P<0.01) than controls. Women who sustained a trochanteric fracture had lower aBMD, lower cortical thickness and higher buckling ratio than controls (P<0.0001) and than women who sustained a cervical fracture (P<0.05). Their bending resistance (cross-sectional moment of inertia-CSMI, section modulus) was significantly lower in comparison with controls (P<0.05-0.001). A decrease in aBMD, cortical thickness, CSMI and section modulus as well as an increase in buckling ratio were predictive of all hip fractures (OR -1.42-2.46 per 1 SD, P<0.05-0.0001), but the ORs for all structural parameters were markedly higher for trochanteric than for cervical fractures. CSMI and section modulus were predictive of trochanteric, but not cervical fractures. However, aBMD was strongly correlated with the CSA, cortical thickness and buckling ratio (r2>0.74), which suggests that they convey the same information. CSMI and section modulus correlated with aBMD more weakly, but their OR lost statistical significance after adjustment for aBMD. In conclusion, low femoral neck aBMD, CSA and cortical thickness as well as a high buckling ratio are associated with the higher risk of hip fracture, especially trochanteric ones. These indices are highly correlated with aBMD and convey the same message. The calculated CSMI and section modulus predict trochanteric fractures, but not cervical fractures, and their statistical significance is lost after adjustment for aBMD, indicating that they reflect mainly aBMD, not mechanical properties. Thus, the independent contribution of the external diameter of the femoral neck to the risk of hip fracture cannot be reliably estimated by this technique.

Objectives Exosomes, as important players in intercellular communication due to their ability to transfer certain molecules to target cells, are believed to take similar effects in promoting bone regeneration with their derived stem cells. Studies have suggested that umbilical cord mesenchymal stem cells (uMSCs) could promote angiogenesis. This study investigated whether exosomes derived from uMSCs (uMSC‐Exos) could enhance fracture healing as primary factors by promoting angiogenesis. Materials and Methods uMSCs were obtained to isolate uMSC‐Exos by ultrafiltration, with exosomes from human embryonic kidney 293 cells (HEK293) and phosphate‐buffered saline (PBS) being used as control groups. NanoSight, laser light scattering spectrometer, transmission electron microscopy and Western blotting were used to identify exosomes. Next, uMSC‐Exos combined with hydrogel were transplanted into the fracture site in a rat model of femoral fracture. Bone healing processes were monitored and evaluated by radiographic methods on days 7, 14, 21 and 31 after surgery; angiogenesis of the fracture sites was assessed by radiographic and histological strategies on post‐operative day 14. In vitro, the expression levels of osteogenesis‐ or angiogenesis‐related genes after being cultured with uMSC‐Exos were identified by qRT‐PCR. The internalization ability of exosomes was determined using the PKH67 assay. Cell cycle analysis, EdU incorporation and immunofluorescence staining, scratch wound assay and tube formation analysis were also used to determine the altered abilities of human umbilical vein endothelial cells (HUVECs) administered with uMSC‐Exos in proliferation, migration and angiogenesis. Finally, to further explore the underlying molecular mechanisms, specific RNA inhibitors or siRNAs were used, and the subsequent effects were observed. Results uMSC‐Exos had a diameter of approximately 100 nm, were spherical, meanwhile expressing CD9, CD63 and CD81. Transplantation of uMSC‐Exos markedly enhanced angiogenesis and bone healing processes in a rat model of femoral fracture. In vitro, other than enhancing osteogenic differentiation, uMSC‐Exos increased the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor‐1α (HIF‐1α). uMSC‐Exos were taken up by HUVECs and enhanced their proliferation, migration and tube formation. Finally, by using specific RNA inhibitors or siRNAs, it has been confirmed that HIF‐1α played an important role in the uMSC‐Exos‐induced VEGF expression, pro‐angiogenesis and enhanced fracture repair, which may be one of the underlying mechanisms. Conclusions These results revealed a novel role of exosomes in uMSC‐mediated therapy and suggested that implanted uMSC‐Exos may represent a crucial clinical strategy to accelerate fracture healing via the promotion of angiogenesis. HIF‐1α played an important role in this process. Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF‐1α‐mediated promotion of angiogenesis in a rat model.

Background The optimal surgical treatment for patients presenting with (impending and complete) pathological proximal femoral fractures is predicated on prognosis. Guidelines recommend a preoperative biopsy to exclude sarcomas, however no evidence confirms a benefit. Objective This study aimed to describe the diagnostic accuracy, morbidity and sarcoma incidence of biopsy results in these patients. Material and Methods All patients ( n  = 153) presenting with pathological proximal femoral fractures between 2000 and 2019 were retrospectively evaluated. Patients after inadvertent surgery ( n  = 25) were excluded. Descriptive statistics were used to evaluate the accuracy and morbidity of diagnostic biopsies. Results Of 112/128 patients who underwent biopsy, nine (8%) biopsies were unreliable either due to being inconclusive ( n  = 5) or because the diagnosis changed after resection ( n  = 4). Of impending fractures, 32% fractured following needle core biopsy. Median time from diagnosis to surgery was 30 days (interquartile range 21–46). The overall biopsy positive predictive value (PPV) to differentiate between sarcoma and non-sarcoma was 1.00 (95% confidence interval [CI] 0.88–1.00). In patients with a previous malignancy ( n  = 24), biopsy ( n  = 23) identified the diagnosis in 83% (PPV 0.91, 95% CI 0.71–0.99), of whom five (24%) patients had a new diagnosis. In patients without a history of cancer ( n  = 61), final diagnosis included carcinomas ( n  = 24, 39.3%), sarcomas ( n  = 24, 39.3%), or hematological malignancies ( n  = 13, 21.3%). Biopsy ( n  = 58) correctly identified the diagnosis in 66% of patients (PPV 0.80, 95% CI 0.67–0.90). Conclusion This study confirms the importance of a preoperative biopsy in solitary pathological proximal femoral fractures due to the risk of sarcoma in patients with and without a history of cancer. However, biopsy delays the time to definite surgery, results can be inconclusive or false, and it risks completion of impending fractures.

Mesenchymal stem cells (MSCs) have the potential to reduce healing time and treat nonunion in fracture patients. In this study, bone marrow MSCs-derived extracellular vesicles (B-EVs) were firstly extracted and identified. CD9 −/− and normal mice were enrolled for the establishment of fracture models and then injected with B-EVs. Osteoblast differentiation and fracture recovery were estimated. The levels of osteoblast-related genes were detected, and differentially expressed microRNAs (miRs) in B-EVs-treated normal fracture mice were screened and verified. The downstream mechanisms of miR were predicted and assessed. The loss-of functions of miR-335 in B-EV and gain-of-functions of VapB were performed in animal and cell experiments to evaluate their roles in bone fracture. Collectively, B-EVs promoted bone fracture recovery and osteoblast differentiation by releasing miR-335. miR-335 downregulation in B-EVs impaired B-EV functions in fracture recovery and osteoblast differentiation. miR-335 could target VapB, and VapB overexpression reversed the effects of B-EVs on osteoblast differentiation. B-EV treatment activated the Wnt/β-catenin pathway in fracture mice and osteoblasts-like cells. Taken together, the study suggested that B-EVs carry miR-335 to promote bone fracture recovery via VapB and the Wnt/β-catenin pathway. This study may offer insights into bone fracture treatment.

Improving revascularization is one of the major measures in fracture treatment. Moderate local inflammation triggers angiogenesis, whereas systemic inflammation hampers angiogenesis. Previous studies showed that Akkermansia muciniphila, a gut probiotic, ameliorates systemic inflammation by tightening the intestinal barrier. In this study, fractured mice intragastrically administrated with A. muciniphila were found to display better fracture healing than mice treated with vehicle. Notably, more preosteclasts positive for platelet-derived growth factor-BB (PDGF-BB) were induced by A. muciniphila at 2 weeks post fracture, coinciding with increased formation of type H vessels, a specific vessel subtype that couples angiogenesis and osteogenesis, and can be stimulated by PDGF-BB. Moreover, A. muciniphila treatment significantly reduced gut permeability and inflammation at the early stage. Dextran sulfate sodium (DSS) was used to disrupt the gut barrier to determine its role in fracture healing and whether A. muciniphila still can stimulate bone fracture healing. As expected, A. muciniphila evidently improved gut barrier, reduced inflammation and restored the impaired bone healing and angiogenesis in DSS-treated mice. Our results suggest that A. muciniphila reduces intestinal permeability and alleviates inflammation, which probably induces more PDGF-BB+ preosteoclasts and type H vessel formation in callus, thereby promoting fracture healing. This study provides the evidence for the involvement of type H vessels in fracture healing and suggests the potential of A. muciniphila as a promising strategy for bone healing. This article has an associated First Person interview with the first author of the paper.

A comprehensive understanding of the key microenvironmental signals regulating bone regeneration is pivotal for the effective design of bioinspired orthopedic materials. Here, we identified citrate as an osteopromotive factor and revealed its metabonegenic role in mediating citrate metabolism and its downstream effects on the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Our studies show that extracellular citrate uptake through solute carrier family 13, member 5 (SLC13a5) supports osteogenic differentiation via regulation of energy-producing metabolic pathways, leading to elevated cell energy status that fuels the high metabolic demands of hMSC osteodifferentiation. We next identified citrate and phosphoserine (PSer) as a synergistic pair in polymeric design, exhibiting concerted action not only in metabonegenic potential for orthopedic regeneration but also in facile reactivity in a fluorescent system for materials tracking and imaging. We designed a citrate/phosphoserine-based photoluminescent biodegradable polymer (BPLP-PSer), which was fabricated into BPLP-PSer/hydroxyapatite composite microparticulate scaffolds that demonstrated significant improvements in bone regeneration and tissue response in rat femoral-condyle and cranial-defect models. We believe that the present study may inspire the development of new generations of biomimetic biomaterials that better recapitulate the metabolic microenvironments of stem cells to meet the dynamic needs of cellular growth, differentiation, and maturation for use in tissue engineering.

The major Food and Drug Association–approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL.

IntroductionDistal femur fractures are challenging injuries historically associated with high rates of nonunion and varus collapse with operative management. As a result, clinical and research interest in dual plating (DP) of distal femur fractures has seen a dramatic increase in recent years. The purpose of this study was to systematically review the literature regarding vascular anatomy and biomechanics of distal femur fractures treated with DP constructs.Materials and methodsA systematic literature review of two medical databases (PubMed & Scopus) was performed to identify peer-reviewed studies on the anatomy and biomechanics regarding DP of distal femur fractures. A total of 1,001 papers were evaluated and 14 papers met inclusion criteria (6 anatomy and 8 biomechanics). Methodological quality scores were used to assess quality and potential bias in the included studies.ResultsIn the biomechanical studies, DP constructs demonstrated greater axial and rotational stiffness, as well as less displacement and fewer incidences of failure compared to all other constructs. Vascular studies showed that the femoral artery crosses the mid-shaft femur approximately 16.0–18.8 cm proximal to the adductor tubercle and it is located on average 16.6–31.1 mm from the femoral shaft at this location, suggesting that medial plate application can be achieved safely in the distal femur. The methodological quality of the included studies was good for biomechanical studies (Traa score 79.1; range 53–92.5) and excellent for anatomical studies (QUACs score 81.9; range 69.0–88.5).ConclusionsExisting biomechanics literature suggests that DP constructs are mechanically stronger than other constructs commonly used in the treatment of distal femur fractures. Furthermore, medial distal femoral anatomy allows for safe application of DP constructs, even in a minimally invasive fashion. Dual plating should be considered for patients with distal femur fractures that have risk factors for instability, varus collapse, or nonunion.