Exosomal miR-423-5p Derived from Cerebrospinal Fluid Pulsation Stress-Stimulated Osteoblasts Improves Angiogenesis of Endothelial Cells via DUSP8/ERK1/2 Signaling Pathway.

Exosomes secreted from osteoblasts (OBs) can regulate the angiogenesis of endothelial cells (ECs); however, whether cerebrospinal fluid pulsation (CSFP) stress, a special mechanical stimulation, can influence the cell's communication in the context of angiogenesis remains unknown. In this study, the effect of exosomes derived from CSFP stress-stimulated OBs on facilitating the angiogenesis of ECs was investigated. First, OBs were cultured in a CSFP bioreactor, and exosomes derived from OBs were isolated and identified. Cell Counting Kit 8 assay, transwell migration assay, wound healing migration assay, and tube formation assay were conducted to assess the effects of CSFP stress-stimulated OBs-derived exosomes (CSFP-Exos) on the angiogenesis of ECs. Then high-throughput RNA sequencing was used to determine the miRNA profiles of Non-CSFP stress-stimulated OBs-derived exosomes (NCSFP-Exos) and CSFP-Exos, and the luciferase reporter gene assay was performed to confirm the binging of miR-423-5p to DUSP8. In addition, the Matrigel plug assay was performed to explore whether exosomal miR-423-5p has the same effects in vivo. Our results suggested that CSFP-Exos can promote the angiogenesis of ECs, and miR-423-5p was enriched in CSFP-Exos. Moreover, miR-423-5p could promote the effect of angiogenesis via directly targeting dual-specificity phosphatase 8 (DUSP8), which inhibited the ERK1/2 signaling pathway. In conclusion, exosomal miR-423-5p derived from CSFP stress-stimulated OBs could promote the angiogenesis of ECs by the DUSP8/ERK1/2 signaling pathway.

Anteromedial Cortical Support in Reduction of Trochanteric Hip Fractures: From Definition to Application.

➤ The concept of anteromedial cortical support (AMCS) serves as valuable guidance for the intraoperative reduction of trochanteric hip fractures.➤ Positive medial cortical support (MCS) and positive or neutral anterior cortical support (ACS) are desirable. Some evidence has suggested that positive MCS is potentially superior to neutral MCS.➤ Experimental studies underscore the vital importance of the anteromedial wall and reveal why positive MCS potentially outperforms neutral MCS.➤ Incorporating the AMCS concept, the Chang reduction quality criteria (CRQC) are a reliable alternative approach to evaluate the reduction quality of trochanteric hip fractures.

Relative instability ratios of bone wall defects in trochanteric hip fractures: A finite element analysis.

Background: For decades, medial and lateral wall fragments of trochanteric hip fractures were considered two pivotal factors that could influence the stability of postoperative femur-implant complex. However, most studies seemed to misunderstand the concept of the posteromedial fragment and equated it with the medial wall, which overlooked vital roles of the anteromedial wall. Roles of the posterior coronal bone fragment were also highlighted in some research. However, influences of the bone walls above the trochanteric fracture instability are yet to be investigated and quantified by means of finite element analysis. Methods: Eight trochanteric fracture fixation models with different wall defects were constructed. Outcome indicators were the von Mises stress of the implant models, the maximum/minimum principal strain, the risky tensile/compressive volume and the volume ratios of the bone models, the femoral head vertex displacement, and the fracture surface gap. Based on these indicator values, the relative instability ratios were computed. Results: Outcome indicators, absolute values, and nephograms of all models showed the same upward and concentrating trends with exerted hip contact loads shifting from static walking to dynamic climbing. Similarly, these indicators also exhibited the same trends when the eight models were solved in sequence. Moreover, the relative instability ratio of the medial wall (100%), particularly the anteromedial part (78.7%), was higher than the figure for the lateral wall (36.6%). Conclusion: The anteromedial wall played relatively pivotal stabilizing roles in trochanteric hip fractures compared with the posteromedial wall and the lateral wall, which indicated that orthopedic surgeons should attach more importance to the anteromedial cortex support in an operating theatre.

Positive medial cortical support versus anatomical reduction for trochanteric hip fractures: Finite element analysis and biomechanical testing.

BACKGROUND AND OBJECTIVES: The anatomical reduction (AR) is usually considered the best option for fractures. Nevertheless, in unstable trochanteric hip fractures (UTHF), previous clinical reports found that the positive medial cortical support (PMCS, an over-reduction technique) attained higher mechanical stability, but this challenging clinical finding still needs experimental validation. METHODS: This study constructed in-silico and biomechanical PMCS and AR models, with the use of the most clinically-representative geometry design of fracture models, the multi-directional design in FE analysis, and the subject-specific (osteoporotic) bone material properties, to make the models better mimic the actual condition in clinical settings. Then multiple performance variables (von-Mises stress, strain, integral axial stiffness, displacement, structural changes, etc.) were assessed to uncover details of integral and regional stability. RESULTS: Among in-silico comparison, PMCS models showed significantly lower maximum displacement than AR models, and the maximum von Mises stress of implants (MVMS-I) was significantly lower in PMCS models than in AR models (highest MVMS-I in -30°-A3-AR of 1055.80 ± 93.37 MPa). Besides, PMCS models had significantly lower maximum von Mises stress along fracture surfaces (MVMS-F) (highest MVMS-F in 30°-A2-AR of 416.40 ± 38.01 MPa). Among biomechanical testing comparison, PMCS models showed significantly lower axial displacement. Significantly lower change of neck-shaft angle (CNSA) was observed in A2-PMCS models. A fair amount of AR models converted into the obvious negative medial cortical support (NMCS) condition, whereas all PMCS models kept the PMCS condition. The results were also validated through comparison to previous clinical data. CONCLUSIONS: The PMCS is superior to the AR in the UTHF surgery. The current study opens up the second thought of the role of over-reduction technique in bone surgery.

Computational evaluation of the axis-blade angle for measurements of implant positions in trochanteric hip fractures: A finite element analysis.

BACKGROUND: Recently, a novel approach axis-blade angle (ABA) was developed to measure implant positions during trochanteric hip fracture surgery. It was defined as the sum of two angles α and ß measured between the femoral neck axis and helical blade axis in anteroposterior and lateral X-ray films, respectively. Although its clinical practicability has been confirmed, the mechanism is yet to be investigated by means of finite element (FE) analysis. METHODS: Computed tomography images of four femurs and dimensions of one implant at three angles were obtained to construct FE models. For each femur, 15 FE models in an arrangement (intramedullary nails at three angles multiplying five blade positions) were established. Under the simulation of normal walking loads, the ABA, von Mises stress (VMS), maximum/minimum principal strain and displacement were analyzed. RESULTS: When the ABA increased, all outcome indicators initially decreased till reaching inferior-middle site and then increased while the blade positions within the femoral head shifted from the superior-anterior quadrant toward the inferior-posterior quadrant, where the ABA were higher. Only the peak VMS of implant models in the inferior-posterior quadrant (particularly the inferior-middle site within) with blades in did not reach the yielding (risky) cut-off. CONCLUSIONS: From the perspective of angles, ABA, this study demonstrated the inferior-posterior quadrant as the relatively stable and safe regions, especially the inferior-middle site within. This was similar but more elaborate compared with previous studies and clinical practice. Therefore, ABA could be employed as a promising approach to anchor the implants into the optimal region.

The Impact of Banana-Shaped Fragments on Trochanteric Hip Fractures Treated by PFNA.

Background: Regarding trochanteric hip fractures, one type of posterior coronal fragments was described as the "banana-shaped fragment", while the impact of the banana-shaped fragment on mechanical stability has not been further studied. The current study investigated the association between the banana-shaped fragment and mechanical complications after surgery. Methods: This retrospective cohort study included 273 patients treated by proximal femoral nail antirotation (PFNA) in the full analysis. The age, the sex, the fracture side, the follow-up time, the American Society of Anesthesiologists classification, the operators, the fracture classification, the tip-apex distance, the blade positions, the reduction quality and the bone mineral density were analyzed in relation to mechanical complications, through univariate and multivariate approaches. Results: Mechanical complications happened in 33 patients. The banana-shaped fragment (adjusted odds ratio 5.240, 95% CI 2.172 to 12.641; p < 0.001), the tip-apex distance and the reduction quality showed significant association with mechanical complications in both univariate and multivariate analysis. Moreover, for 118 patients with the banana-shaped fragment, we found that the use of wire cerclage couldn't significantly lower the rates of mechanical complications (p = 0.648). Conclusions: The banana-shaped fragment had a negative impact on mechanical stability of trochanteric hip fractures treated by PFNA. In the perioperative period, the BSF should be carefully evaluated, and its specific handling deserves further study.

Exosomal let-7f-5p derived from mineralized osteoblasts promotes the angiogenesis of endothelial cells via the DUSP1/Erk1/2 signaling pathway.

Blood vessel formation is the prerequisite for the survival and growth of tissue-engineered bone. Mineralized osteoblasts (MOBs) have been shown to regulate angiogenesis through the secretion of exosomes containing various pro-angiogenic factors. However, whether the mineralized osteoblast-derived exosomes (MOB-Exos) containing let-7f-5p can regulate the angiogenesis of endothelial cells (ECs) is still unknown. In this study, the angiogenic capabilities of ECs respectively treated with MOB-Exos, let-7f-5p mimicked MOB-Exos (miR mimic group), and let-7f-5p inhibited MOB-Exos (miR inhibitor group) were compared through in vitro and in vivo studies. Moreover, the potential mechanism of MOB-Exo let-7f-5p regulating angiogenesis was explored by verifying the role of the Erk1/2 signaling pathway and target gene DUSP1. The results showed that MOB-Exos could significantly promote the angiogenesis of ECs, which could be enhanced by mimicked exosomal let-7f-5p and attenuated by inhibited exosomal let-7f-5p. Let-7f-5p could suppress the luciferase activity of wide-type DUSP1, and the mutation of DUSP1 could abrogate the repressive ability of let-7f-5p. Furthermore, the expression of DUSP1 exhibited a reversed trend to that of pErk1/2. The expression of pErk1/2 was significantly higher in the miR mimic group and lower in the miR inhibitor group than that in the MOB-Exos group, while inhibition of pErk1/2 could partly impair the angiogenic capabilities of ECs. In conclusion, we concluded that exosomal let-7f-5p derived from MOBs could promote the angiogenesis of ECs via activating the DUSP1/Erk1/2 signaling pathway, which might be a promising target for promoting the angiogenesis of tissue-engineered bone.

When to Reduce and Fix Displaced Lesser Trochanter in Treatment of Trochanteric Fracture: A Systematic Review.

Purpose: To systematically evaluate the benefits of reducing and fixing displaced lesser trochanter (LT) of trochanteric fractures and when this procedure is worth the effect. Methods: From database establishment through March 2021, four online databases (PubMed, Cochrane, Embase, and Web of Science) were searched for relevant literature that investigated reduction and fixation for displaced LT of trochanteric fractures. The papers were then screened by two reviewers independently and in duplicate according to prior inclusion and exclusion criteria. Demographic data as well as data on fracture types, surgical protocols, and surgical outcomes were recorded, analyzed, and interpreted. Results: Total 10 clinical studies with 928 patients were included, in which 48 cases had intact LT and 880 cases involved the displaced LT, of which 196 (22.27%) cases underwent reduction and fixation for LT while the rest of 684 (77.73%) cases not. In these studies, complications were evaluated as a more applicable predictive parameter for operation than postoperative hip function. Conclusion: It was beneficial to reduce and fix the displaced LT when one of the conditions below occurred: displacement distance of LT ≥2 cm, quantity of comminuted LT fragments ≥2, and range of LT fragments in medial wall ≥75%; the fracture line of LT fragments reaching or exceeding the midline of the posterior wall.

Wnt/ß-Catenin Pathway Balances Scaffold Degradation and Bone Formation in Tissue-Engineered Laminae.

Tissue engineering provides a promising way for the regeneration of artificial vertebral laminae. Previous studies have confirmed the feasibility of reconstructing vertebral laminae via hydroxyapatite-collagen I scaffolds and mesenchymal stromal cells. However, there were no studies exploring the degradation of hydroxyapatite-collagen I scaffolds and the function of Wnt/ß-catenin pathway in the process. In this study, tissue-engineered laminae (TEL) were constructed by nanohydroxyapatite/collagen I scaffolds and umbilical cord Wharton's Jelly mesenchymal stromal cells (WJ-MSCs). Cell attachment was observed by scanning electron microscopy, and cell viability was confirmed by Live/Dead staining. The rat models were randomly divided into control and ß-catenin inhibition groups. Vertebral lamina defect rat models were made on the fifth lumbar vertebrate, and TEL was implanted into the defect site. After 14 weeks, the newborn laminae were harvested for microcomputed tomography, histology, or transcriptional profile analysis. We found that, for the control group, the newborn lamina formation matched with the scaffold degradation and complete newborn laminae formed at the 14th week; for the ß-catenin inhibition group, the scaffold degradation rate overrated the lamina formation and no complete artificial laminae were formed at the 14th week. In addition, the osteoclastic genes, such as Cathepsin K or RANKL, in the control groups were significantly lower than the ß-catenin inhibition group, and the antiosteoclastic gene, OPG, in the control group was significantly higher than the ß-catenin inhibition group. In conclusion, inhibition of Wnt/ß-catenin pathway led to speedy scaffold degradation and deferred artificial lamina formation. Wnt/ß-catenin pathway played a critical role in maintaining the balance between scaffold degradation and bone formation in the process of vertebral lamina reconstruction.