A Whole-Course-Repair System Based on Neurogenesis-Angiogenesis Crosstalk and Macrophage Reprogramming Promotes Diabetic Wound Healing.

Diabetic wound (DW) therapy is currently a big challenge in medicine and strategies to enhance neurogenesis and angiogenesis have appeared to be a promising direction. However, the current treatments have failed to coordinate neurogenesis and angiogenesis simultaneously, leading to an increased disability rate caused by DWs. Herein, a whole-course-repair system is introduced by a hydrogel to concurrently achieve a mutually supportive cycle of neurogenesis-angiogenesis under a favorable immune-microenvironment. This hydrogel can first be one-step packaged in a syringe for later in situ local injections to cover wounds long-termly for accelerated wound healing via the synergistic effect of magnesium ions (Mg2+ ) and engineered small extracellular vesicles (sEVs). The self-healing and bio-adhesive properties of the hydrogel make it an ideal physical barrier for DWs. At the inflammation stage, the formulation can recruit bone marrow-derived mesenchymal stem cells to the wound sites and stimulate them toward neurogenic differentiation, while providing a favorable immune microenvironment via macrophage reprogramming. At the proliferation stage of wound repair, robust angiogenesis occurs by the synergistic effect of the newly differentiated neural cells and the released Mg2+ , allowing a regenerative neurogenesis-angiogenesis cycle to take place at the wound site. This whole-course-repair system provides a novel platform for combined DW therapy.

The clinical efficacy and safety of double reverse traction repositor and traction table in the reduction of unstable intertrochanteric fractures in elderly patients: a retrospective comparative study.

Background: Currently, we found that double reverse traction repositor (DRTR) is a treatment with operation convenience and fast in our clinical work. However, the clinical efficacy and safety of DRTR in the reduction of unstable intertrochanteric fractures in elderly patients remain unknown. Therefore, the study aimed to compare the clinical efficacy and safety of DRTR and traction table (TT) in the reduction of unstable intertrochanteric fractures in elderly patients. Methods: From October 2018 to December 2020, the elderly patients with unstable intertrochanteric fractures were reviewed. 22 patients treated with TT and 20 patients treated with DRTR met the inclusion criteria of this study, and baseline clinical characteristics were recorded. The reduction time, operation time, incision length and intraoperative blood loss were reviewed. The safety outcome was assessed by postoperative complications, and the efficacy outcomes were evaluated by the fracture healing time based on the radiographs conducted at each follow-up (1, 3, 6, 12 months after surgery) and hip function (hip flexion, Harris Hip Score) at the final follow-up (12 months after surgery). Results: There were no significant differences in terms of demographics and fracture characteristics of cases enrolled. In DRTR group, the average intraoperative reduction time [(34.8±7.6) min] and the average operation time [(87.1±12.2) min] were superior to those [(56.6±9.3); (123.1±15.0) min] in TT group (P<0.0001). However, there were no statistical significance in terms of the average incision lengths [(6.4±0.9) vs. (6.8±1.1) cm; P=0.1619], , the average intraoperative blood loss [(152.6±22.9) vs. (146.8±20.7) mL; P=0.3941], the average fracture healing times [(13.8±1.5) vs. (14.4±1.8) weeks; P=0.2350] and the average Harris hip score a year after operation [(84.4±6.6) vs. (82.7±7.2); P=0.4496] between the two groups. One patient in TT group experienced lower extremity intermuscular venous thrombosis postoperatively. No other operation-related complications were observed postoperatively nor during follow-up. Conclusions: Minimally invasive reduction with DRTR in unstable intertrochanteric fractures could effectively shorten the intraoperative reduction time and operation time in this study. Therefore, minimally invasive reduction with DRTR might be a good choice for intertrochanteric reduction of unstable intertrochanteric fractures.

Traction-bed-assisted reduction and double-plate fixation for treatment of comminuted femoral intertrochanteric fractures with coronal split.

Background: A coronal comminuted femoral intertrochanteric fracture is a special type of fracture that easily leads to internal fixation failure, and the current internal fixation techniques remain controversial. This study aims to evaluate the effect of traction-bed-assisted reduction and double-plate internal fixation in the treatment of comminuted and coronally split intertrochanteric femoral fracture. Method: Retrospective analyses of the clinical data of 83 patients diagnosed with, and treated for, comminuted and coronally split intertrochanteric femoral fracture from December 2017 to November 2019 were conducted. Among the total number of 83 patients, 40 patients received traction-bed-assisted reduction and PFNA fixation (the control group), whereas 43 patients received traction-bed-assisted reduction and double-plate internal fixation (the experimental group). The major indicators for the research analysis such as the general information of patients, perioperative data, and follow-up data of both groups were collected, sorted out, and meticulously analyzed. Results: The time taken for traction-bed-assisted reduction and double-plate intern fixation in the experimental group was significantly shorter than that in the control group (P < .05). The post-operative Harris Hip Score (HHS) at 3 months and at the final follow-up after the surgery was significantly better in the experimental group compared with that in the control group, both of which were statistically significant (P < .05). However, there were statistically no significant differences between the two groups in terms of preoperative hemoglobin (Hb) level, amount of intraoperative total blood loss, immediate post-operative Hb level, incidence of wound infection within 14 days post-operatively, time taken to step up on the ground after surgery, HHS 2 weeks after surgery, time taken for fracture healing, and the incidence of complications (P > .05). Conclusion: The use of a traction bed to achieve adequate reduction, followed by internal fixation using double plates, comparatively takes less time for both reduction and operation in the treatment of comminuted and coronally split intertrochanteric femoral fractures, which also restores proper hip joint movements relatively early and hence provides better hip joint functions in the long run.

MiR-1224-5p modulates osteogenesis by coordinating osteoblast/osteoclast differentiation via the Rap1 signaling target ADCY2.

MicroRNAs (miRNAs) broadly regulate normal biological functions of bone and the progression of fracture healing and osteoporosis. Recently, it has been reported that miR-1224-5p in fracture plasma is a potential therapy for osteogenesis. To investigate the roles of miR-1224-5p and the Rap1 signaling pathway in fracture healing and osteoporosis development and progression, we used BMMs, BMSCs, and skull osteoblast precursor cells for in vitro osteogenesis and osteoclastogenesis studies. Osteoblastogenesis and osteoclastogenesis were detected by ALP, ARS, and TRAP staining and bone slice resorption pit assays. The miR-1224-5p target gene was assessed by siRNA-mediated target gene knockdown and luciferase reporter assays. To explore the Rap1 pathway, we performed high-throughput sequencing, western blotting, RT-PCR, chromatin immunoprecipitation assays and immunohistochemical staining. In vivo, bone healing was judged by the cortical femoral defect, cranial bone defect and femoral fracture models. Progression of osteoporosis was evaluated by an ovariectomy model and an aged osteoporosis model. We discovered that the expression of miR-1224-5p was positively correlated with fracture healing progression. Moreover, in vitro, overexpression of miR-1224-5p slowed Rankl-induced osteoclast differentiation and promoted osteoblast differentiation via the Rap1-signaling pathway by targeting ADCY2. In addition, in vivo overexpression of miR-1224-5p significantly promoted fracture healing and ameliorated the progression of osteoporosis caused by estrogen deficiency or aging. Furthermore, knockdown of miRNA-1224-5p inhibited bone regeneration in mice and accelerated the progression of osteoporosis in elderly mice. Taken together, these results identify miR-1224-5p as a key bone osteogenic regulator, which may be a potential therapeutic target for osteoporosis and fracture nonunion.

Clinical Application Study of Minimally Invasive Double-Reverse Traction in Complex Tibial Plateau Fractures.

The aim of this study was to evaluate the clinical application of double-reverse traction for minimally invasive reduction of complex tibial plateau fractures. A retrospective analysis was performed to identify all patients admitted to the Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from March 2017 to December 2019 with Schatzker type VI tibial plateau fractures. 12 patients were identified (7 men and 5 women) with an average age of 46.15 ± 13 (39-58) years old. All patients were treated with double-reverse traction and closed reduction. After the fracture was reduced, the bone plate was fixed by percutaneous minimally invasive implantation. Outcomes assessed in this study include operation time and intraoperative blood loss. Imaging was performed during the postoperative follow-up, and functional recovery was evaluated at the final follow-up according to the Hospital for Special Surgery (HSS) score and the International Knee Joint Literature Committee (IKDC) functional score. Patients were followed up for 12.54 ± 1.5 (8-15) months. The average operation time was 63.63 ± 21 (35-120) minutes, and the average intraoperative blood loss was 105.45 ± 21 (60-200) mL. The Rasmussen imaging score was either excellent or good in all cases. The knee joint HSS score was 86.15 ± 6 (79-90) points, and the IKDC score was 80.01 ± 11 (75-90) points. No complications, such as wound infection, incision disunion, loosening of internal fixation, and internal fixation failure, occurred. In the treatment of Schatzker VI type complex tibial plateau fracture, the dual-reverse traction minimally invasive technique has the advantages of safety and effectiveness, less soft tissue injury, and allowing early joint movement, which is worthy of clinical promotion.

Dual-Targeted Nanoplatform Regulating the Bone Immune Microenvironment Enhances Fracture Healing.

The immune system and skeletal system are closely linked. Macrophages are one of the most important immune cells for bone remodeling, playing a prohealing role mainly through M2 phenotype polarization. Baicalein (5,6,7-trihydroxyflavone, BCL) has been well documented to have a noticeable promotion effect on M2 macrophage polarization. However, due to the limitations in targeted delivery to macrophages and the toxic effect on other organs, BCL has rarely been used in the treatment of bone fractures. In this study, we developed mesoporous silica and Fe3O4 composite-targeted nanoparticles loaded with BCL (BCL@MMSNPs-SS-CD-NW), which could be magnetically delivered to the fracture site. This induced macrophage recruitment in a targeted manner, polarizing them toward the M2 phenotype, which was demonstrated to induce mesenchymal stem cells (MSCs) toward osteoblastic differentiation. The mesoporous silicon nanoparticles (MSNs) were prepared with surface sulfhydrylation and amination modification, and the mesoporous channels were blocked with ß-cyclodextrin. The outer layer of the mesoporous silicon was added with an amantane-modified NW-targeting peptide to obtain the targeted nanosystem. After entering macrophages, BCL could be released from nanoparticles since the disulfide linker could be cleaved by intracellular glutathione (GSH), resulting in the removal of cyclodextrin (CD) gatekeeper, which is a key element in the pro-bone-remodeling functions such as anti-inflammation and induction of M2 macrophage polarization to facilitate osteogenic differentiation. This nanosystem passively accumulated in the fracture site, promoting osteogenic differentiation activities, highlighting a potent therapeutic benefit with high biosafety.

M2 Macrophagy-derived exosomal miRNA-5106 induces bone mesenchymal stem cells towards osteoblastic fate by targeting salt-inducible kinase 2 and 3.

BACKGROUND: Osteoblast differentiation is a vital process for fracture healing, and exosomes are nanosized membrane vesicles that can deliver therapeutic drugs easily and safely. Macrophages participate in the regulation of various biological processes in vivo, and macrophage-derived exosomes (MD-Exos) have recently been a topic of increasing research interest. However, few study has explored the link between MD-Exos and osteoblast differentiation. Herein, we sought to identify miRNAs differentially expressed between M1 and M2 macrophage-derived exosomes, and to evaluate their roles in the context of osteoblast differentiation. RESULTS: We found that microRNA-5106 (miR-5106) was significantly overexpressed in M2 macrophage-derived exosomes (M2D-Exos), while its expression was decreased in M1 macrophage-derived exosomes (M1D-Exos), and we found that this exosomal miRNA can induce bone mesenchymal stem cell (BMSC) osteogenic differentiation via directly targeting the Salt-inducible kinase 2 and 3 (SIK2 and SIK3) genes. In addition, the local injection of both a miR-5106 agonist or M2D-Exos to fracture sites was sufficient to accelerate healing in vivo. CONCLUSIONS: Our study demonstrates that miR-5106 is highly enriched in M2D-Exos, and that it can be transferred to BMSCs wherein it targets SIK2 and SIK3 genes to promote osteoblast differentiation.

Methyltransferase-like 3-mediated N6-methyladenosine modification of miR-7212-5p drives osteoblast differentiation and fracture healing.

N6-methyladenosine (m6A) modification has been reported in various diseases and implicated in increasing numbers of biological processes. However, previous studies have not focused on the role of m6A modification in fracture healing. Here, we demonstrated that m6A modifications are decreased during fracture healing and that methyltransferase-like 3 (METTL3) is the main factor involved in the abnormal changes in m6A modifications. Down-regulation of METTL3 promotes osteogenic processes both in vitro and in vivo, and this effect is recapitulated by the suppression of miR-7212-5p maturation. Further studies have shown that miR-7212-5p inhibits osteoblast differentiation in MC3T3-E1 cells by targeting FGFR3. The present study demonstrated an important role of the METTL3/miR-7212-5p/FGFR3 axis and provided new insights on m6A modification in fracture healing.

Comparative study of sacroiliac screw placement guided by 3D-printed template technology and X-ray fluoroscopy.

OBJECTIVE: To compare the clinical effect of 3D-printed template technology with X-ray fluoroscopy in assisting surgery for sacroiliac screws placement. DESIGN: Institutional review board-approved retrospective analysis. PATIENTS: The clinical data of 31 cases of sacroiliac complex injury between January 2015 and December 2016 were analyzed. There were 16 patients, males 11 and females 5, who underwent surgery assisted by 3D-printed template in template group, and that of contemporaneous 15 patients, males 11 and females 4, who underwent traditional surgery were gathered as fluoroscopy group. All those patients were followed up for more than 6 months. MAIN OUTCOME MEASURES: The operation time and X-ray fluoroscopy times for each screw placement, and the Matta and Majeed score were analyzed and the difference between the two group was tested. RESULTS: All cases were followed up for 6-20 months, average 11.4 ± 0.6 months. In template group, 19 screws were implanted. Each screw spent 25-38 min, average 27.2 ± 5.3 min, and need 2-5 times fluoroscopy, average 2.7 ± 0.5. The fracture reduction quality was evaluated by Matta score scale: excellent 10, well 4, fair 2, good rate 87.5%; and pelvic function were evaluated by Majeed score scale: excellent 11, well 3, fair 2, and good rate 87.5%. In fluoroscopy group, 17 screws were implanted. Each screw spent 45-70 min, average 60.3 ± 5.8 min, and needs 11-23 times fluoroscopy, average 15.4 ± 3.5. The fracture reduction quality was evaluated by Matta score scale: excellent 7, well 6, fair 2, and good rate 86.7%; and pelvic function was evaluated by Majeed score scale: excellent 6, well 6, fair 3, and good rate 80.0%. The difference in operation time, X-ray fluoroscopy times between template group and fluoroscopy group had statistical significance. But the Matta and Majeed score had no difference between two groups. CONCLUSION: Compared with traditional surgery, 3D-printed template technology-assisted surgery for sacroiliac screws placement in sacroiliac complex injury patients possesses advantage such as shortened operation time and reduced X-ray exposure times. This technology improves the safety profile of this operation and should be further studied in future clinical applications.

Long Noncoding RNA FAM83H-AS1 Modulates SpA-Inhibited Osteogenic Differentiation in Human Bone Mesenchymal Stem Cells.

Osteomyelitis, an infection of the bone and bone marrow, imposes a heavy burden on public health care systems owing to its progressive bone destruction and sequestration. Human bone mesenchymal stem cells (hBMSCs) play a key role in the process of bone formation, and mounting evidence has confirmed that long noncoding RNAs (lncRNAs) are involved in hBMSC osteogenic differentiation. Nevertheless, the exact function and molecular mechanism of lncRNAs in osteogenic differentiation during osteomyelitis development remain to be explored. In this study, hBMSCs were treated with staphylococcal protein A (SpA) during osteogenic differentiation induction to mimic osteomyelitis in vitro The results of lncRNA microarray analysis revealed that FAM83H-AS1 presented the lowest expression among the significantly downregulated lncRNAs. Functionally, ectopic expression of FAM83H-AS1 contributed to osteogenic differentiation of SpA-induced hBMSCs. Additionally, our findings revealed that FAM83H-AS1 negatively regulated microRNA 541-3p (miR-541-3p), and WNT3A was validated as a target gene of miR-541-3p. Mechanically, FAM83H-AS1 elevated WNT3A expression by competitively binding with miR-541-3p. Lastly, it was demonstrated that FAM83H-AS1/miR-541-3p/WNT3A ameliorated SpA-mediated inhibition of the osteogenic differentiation of hBMSCs, which provided a novel therapeutic strategy for patients with osteomyelitis.

CircRNA AFF4 promotes osteoblast cells proliferation and inhibits apoptosis via the Mir-7223-5p/PIK3R1 axis.

Fracture healing is a complex process involving various cell types, cytokines, and mRNAs. Here, we report the roles of the circRNA AFF4/miR-7223-5p/PIK3R1 axis during fracture healing. We found that increased expression of PIK3R1 during fracture healing is directly associated with augmented proliferation and decreased apoptosis of MC3T3-E1 cells. Furthermore, miR-7223-5p targeted PI3KR1 and inhibited MC3T3-E1 proliferation while promoting apoptosis. CircRNA AFF4 acted as a sponge of miR-7223-5p, thereby promoting MC3T3-E1 cell proliferation and inhibiting apoptosis. Local injection of circRNA AFF4 into femoral fracture sites promoted fracture healing in vivo while the injection of miR-7223-5p delayed healing. These findings suggest that CircRNA AFF4 promotes fracture healing by targeting the miR-7223-5p/PIK3R1 axis, and suggests miR-7223-5p, CircRNA AFF4, and the miR-7223-5p/PIK3R1 axis are potential therapeutic targets for improving fracture healing.

Z-plasty for severe gluteal muscle contracture in children.

PURPOSE: To review the records of 363 patients with severe gluteal muscle contracture to determine its mechanism, underlying pathology, and treatment outcome. METHODS: Records of 136 males and 227 females aged 5 to 18 (mean, 12.2) years who underwent Z-plasty for bilateral (n=347) or unilateral (n=16) severe gluteal muscle contracture were reviewed. Severe gluteal muscle contracture was classified as typical (n=52) or special (n=311). The typical type is associated with symptoms of positive out-toe gait, Ober sign, back-extending test, cross-leg test, squatting with knee side-by-side test, and hip dysfunction. It is further subdivided into mild (n=0), moderate (n=40), or severe (n=12). The special type is associated with additional symptoms of pelvic tilt and leg length discrepancy (<2 cm in 181 hips, 2-4 cm in 82 hips, and >4 cm in 48 hips). 311 hips had pelvic tilt and 47 hips had lumbar compensatory scoliosis. Treatment outcome was assessed at 6 months. Hip functional score was assessed at the final follow-up. RESULTS: The mean hospitalisation period was 11 days. After a mean follow-up of 1.5 years, the mean hip functional score improved from 8.03 to 11.69; improvement was higher in children (age 5-13 years) than in adolescents (age 14-18 years) [3.7 vs. 2.9, p<0.001]. At 6 months, outcome was excellent in 280 hips, good in 80, fair in 3 hips, and poor in 0. The 3 hips with fair outcome had persistent slight pelvic tilt and swaying gait. Two of them had preoperative leg length discrepancy >4 cm, and intra-operatively the contracture band severely affected the joint capsule. The third patient did not comply with postoperative exercises. CONCLUSION: Surgical treatment for severe gluteal muscle contracture achieved good outcome.

Factors influencing the treatment of severe gluteal muscle contracture in children.

Usually the treatment of severe gluteal muscle contracture in children does not achieve a satisfactory clinical result and the disease is prone to recurrence after surgery. The aim of this study was to analyze the factors influencing the recovery of children with severe gluteal muscle contracture. Between 1997 and 2008, 428 children (mean age: 8 years) were subjected to surgical operations combined with functional exercises and physical therapy and were followed for 12-24 months with satisfactory clinical outcomes. In this series, the outcomes were found to be excellent in 400 cases, good in 22 cases, and fair in six cases with no patient having a poor result. No serious complications, such as sciatic nerve injury, dislocation, or osteonecrosis of the femoral head were found in the patients. Unsteadiness in walking and positive Trendelenburg sign were found in postoperative functional exercises in 16 patients, which may be the result of excessive resection of the gluteus medius and the gluteus minimus. However, the symptoms in all the cases disappeared within 3 months by rigorous functional exercise. We evaluated the factors that potentially influence the clinical outcome retrospectively and it was concluded that the surgery was highly beneficial for the treatment of the patients. Postoperative functional exercise and physical therapy could reduce the complications and maintain the favorable effects of surgery. In addition, the identification of the disease, the age of patients, and the rehabilitation procedures after hospital discharge were found to be very important for the successful treatment of this condition.