Bone marrow stromal cell-derived exosomal circular RNA improves diabetic foot ulcer wound healing by activating the nuclear factor erythroid 2-related factor 2 pathway and inhibiting ferroptosis.

BACKGROUND: Diabetic foot ulcer (DFU) remains a serious chronic diabetic complication that can lead to disability. CircRNA-itchy E3 ubiquitin protein ligase (circ-ITCH) was observed to be down-regulated in diabetic retinopathy and diabetic nephropathy, and overexpression of circ-ITCH could inhibit the processes of these diseases. However, the detailed physiological and pathological functions of circ-ITCH in wound healing of DFU remain undetermined. METHODS: Exosomes derived from bone marrow stromal cells (BMSCs) were isolated and identified. Cell viability and angiogenesis of human umbilical vein endothelial cells (HUVECs) were evaluated by cell counting kit-8 (CCK-8) and tube formation assays, respectively. The interplays of circ-ITCH, TATA-Box-binding protein associated factor 15 (TAF15) and nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA were analysed by RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH) combined immunofluorescent staining and RNA pull-down assays. qRT-PCR, western blot or immunohistochemistry (IHC) were used to measure the expression of circ-ITCH, TAF15, Nrf2, vascular endothelial growth factor (VEGFR) and ferroptosis-related makers. The mice DFU model was established to verify the in vitro results. RESULTS: Circ-ITCH was down-regulated in in vitro and in vivo models of DFU. Deferoxamine (DFO), an iron chelating agent, improved the viability and angiogenic ability of high glucose (HG)-treated HUVECs. Overexpression of circ-ITCH or co-cultured with exosomal circ-ITCH from BMSCs could alleviate HG-induced ferroptosis and improve the angiogenesis ability of HUVECs. Circ-ITCH in HUVECs recruited TAF15 protein to stabilize Nrf2 mRNA, thus activating the Nrf2 signalling pathway and suppressing ferroptosis. Exosomal circ-ITCH from BMSCs also accelerated the wound healing process by inhibiting ferroptosis in the DFU mice in a time-dependent manner. CONCLUSION: Exosomal circ-ITCH from BMSCs inhibited ferroptosis and improved the angiogenesis of HUVECs through activation of the Nrf2 signalling pathway by recruiting TAF15 protein, ultimately accelerating the wound healing process in DFU.

Comparison of Clinical and Radiological Outcomes between Calibratable Patient-Specific Instrumentation and Conventional Operation for Medial Open-Wedge High Tibial Osteotomy: A Randomized Controlled Trial.

Background: High tibial osteotomy (HTO) is an effective surgery in treating medial compartment knee osteoarthritis (KOA) combined with varus deformity. An accurate orthopaedy is the key and challenge to the success of HTO. Therefore, we designed a calibratable patient-specific instrumentation (PSI) to assist surgery and evaluated its accuracy and clinical outcomes by comparing with conventional operation (CO). Materials and Methods: 37 patients (39 knees) with medial compartment KOA were randomly divided into the PSI and CO groups and underwent medial open-wedge high tibial osteotomy (MOWHTO) from September 2020 to May 2021. The postoperative radiological outcomes were compared with the preoperative measurements or target values to evaluate the accuracy of correction in the two groups. The American Knee Society Score (AKSS), complication rate, number of intraoperative radiation exposures, blood loss volume, and operative duration were analysed to evaluate the clinical outcomes in the two groups. Results: The designed target values were better achieved in the PSI group than in the CO group. The mean absolute difference between the postoperative measurements and preoperative targets was significantly lower in the PSI group than in the CO group (weight-bearing line (WBL) ratio, 1.97 ± 1.83% vs.5.42 ± 4.41%, P = 0.002; hip-knee-ankle (HKA) angle, 1.12 ± 0.86° vs. 2.27 ± 1.97°, P = 0.018). The operative duration was significantly shorter (P = 0.014), and the number of radiation exposures (P < 0.001) and volume of intraoperative blood loss (P = 0.003) were significantly lower in the PSI group than in the CO group. The clinical AKSS score at 3 and 6 months postoperatively and the functional AKSS score at 3 months postoperatively were significantly higher in the PSI group than in the CO group (P = 0.042, 0.040, and 0.034, respectively). Conclusion: For patients with medial compartment KOA, calibratable PSI can assist the surgeon in MOWHTO with superior accuracy and clinical efficacy. This study was conducted under Randomized Controlled Trial Details (RCT) with Registry Number ChiCTR2000038619.