Tibial Cortex Transverse Transport Facilitates Severe Diabetic Foot Wound Healing via HIF-1α-Induced Angiogenesis.

Purpose: Management of severe diabetic foot ulcers (DFUs) remains challenging. Tibial cortex transverse transport (TTT) facilitates healing and limb salvage in patients with recalcitrant DFUs. However, the underlying mechanism is largely unknown, necessitating the establishment of an animal model and mechanism exploration. Methods: Severe DFUs were induced in rats, then assigned to TTT, sham, or control groups (n=16/group). The TTT group underwent a tibial corticotomy, with 6 days each of medial and lateral transport; the sham group had a corticotomy without transport. Ulcer healing was assessed through Laser Doppler, CT angiography, histology, and immunohistochemistry. Serum HIF-1α, PDGF-BB, SDF-1, and VEGF levels were measured by ELISA. Results: The TTT group showed lower percentages of wound area, higher dermis thickness (all p < 0.001 expect for p = 0.001 for TTT vs Sham at day 6) and percentage of collagen content (all p < 0.001) than the other two groups. The TTT group had higher perfusion and vessel volume in the hindlimb (all p < 0.001). The number of CD31+ cells (all p < 0.001) and VEGFR2+ cells (at day 6, TTT vs Control, p = 0.001, TTT vs Sham, p = 0.006; at day 12, TTT vs Control, p = 0.003, TTT vs Sham, p = 0.01) were higher in the TTT group. The activity of HIF-1α, PDGF-BB, and SDF-1 was increased in the TTT group (all p < 0.001 except for SDF-1 at day 12, TTT vs Sham, p = 0.005). The TTT group had higher levels of HIF-1α, PDGF-BB, SDF-1, and VEGF in serum than the other groups (all p < 0.001). Conclusion: TTT enhanced neovascularization and perfusion at the hindlimb and accelerated healing of the severe DFUs. The underlying mechanism is related to HIF-1α-induced angiogenesis.

Tibial cortex transverse transport promotes ischemic diabetic foot ulcer healing via enhanced angiogenesis and inflammation modulation in a novel rat model.

BACKGROUND: Tibial Cortex Transverse Transport (TTT) represents an innovative surgical method for treating lower extremity diabetic foot ulcers (DFUs), yet its underlying mechanisms remain elusive. Establishing an animal model that closely mirrors clinical scenarios is both critical and novel for elucidating the mechanisms of TTT. METHODS: We established a diabetic rat model with induced hindlimb ischemia to mimic the clinical manifestation of DFUs. TTT was applied using an external fixator for regulated bone movement. Treatment efficacy was evaluated through wound healing assessments, histological analyses, and immunohistochemical techniques to elucidate biological processes. RESULTS: The TTT group demonstrated expedited wound healing, improved skin tissue regeneration, and diminished inflammation relative to controls. Marked neovascularization and upregulation of angiogenic factors were observed, with the HIF-1α/SDF-1/CXCR4 pathway and an increase in EPCs being pivotal in these processes. A transition toward anti-inflammatory M2 macrophages indicated TTT's immunomodulatory capacity. CONCLUSION: Our innovative rat model effectively demonstrates the therapeutic potential of TTT in treating DFUs. We identified TTT's roles in promoting angiogenesis and modulating the immune system. This paves the way for further in-depth research and potential clinical applications to improve DFU management strategies.

Efficacy and safety of unilateral tibial cortex transverse transport on bilateral diabetic foot ulcers: A propensity score matching study.

Background: Tibial Cortex Transverse Transport (TTT) has been demonstrated to be an effective treatment for unilateral diabetic foot ulcers (UDFUs). However, this retrospective study was designed to compare the efficacy and safety of unilateral TTT on bilateral diabetic foot ulcers (BDFUs). Methods: This retrospective study included a review of patients with TTT treated from January 2017 to August 2019, Propensity Score Matching (PSM) was performed to compare patients with BDFUs to those with UDFUs. Ulcer healing, recurrence, and major amputation rates were evaluated at 1-year follow-up. Changes in foot vessels were assessed in the BDFUs group using computed tomography angiography (CTA). Results: A total of 140 patients with DFUs (106 UDFUs and 34 BDFUs) were included in the study. UDFUs and BDFUs were matched in a 1:1 ratio (34 in each group) using PSM. No significant difference was observed at 1-year-follow-up [91.2% (31/34) vs. 76.5% (26/34), OR 0.315 (95% CI 0.08 to 1.31), P â€‹= â€‹0.10] and 6-month-follow-up [70.6% (24/34) vs. 50.0% (17/34), OR 0.85 (95% CI 0.15 to 1.13), P â€‹= â€‹0.08] in two groups. Significant differences in rates of major amputation and recurrence between the groups (P â€‹> â€‹0.05) were not observed. The BDFUs group appeared more angiogenesis of the foot by CTA after 8 weeks of operation. Conclusion: Results of this study suggest that severe BDFUs can be effectively treated by unilateral TTT. TTT is easy to operate and effective, which may be a good alternative for treating severe BDFUs. The translational potential of this article: In previous retrospective clinical studies, TTT has demonstrated promising clinical outcomes in the management of diabetic foot ulcers. In this current study, we aim to investigate the potential use of TTT in treating distant tissue defects by evaluating the limited availability and safety of TTT for the management of bilateral diabetic foot. While additional basic and clinical research is necessary to fully elucidate the underlying mechanisms, our study offers insight into the potential therapeutic use of TTT for this condition.

Knowledge Domains and Emerging Trends of Osteoblasts-Osteoclasts in Bone Disease From 2002 to 2021: A Bibliometrics Analysis and Visualization Study.

Background: Osteoblasts-Osteoclasts has been a major area in bone disease research for a long time. However, there are few systematic studies in this field using bibliometric analysis. We aimed to perform a bibliometric analysis and visualization study to determine hotspots and trends of osteoblasts-osteoclasts in bone diseases, identify collaboration and influence among authors, countries, institutions, and journals, and assess the knowledge base to develop basic and clinical research in the future. Methods: We collected articles and reviews for osteoblasts-osteoclasts in bone diseases from the Web of Science Core Collection. In addition, we utilized scientometrics software (CiteSpace5.8 and VOSviewer1.6.18) for visual analysis of countries/regions, institutions, authors, references, and keywords in the field. Results: In total, 16,832 authors from 579 institutions in 73 countries/regions have published 3,490 papers in 928 academic journals. The literature in this field is rapidly increasing, with Bone publishing the most articles, whereas Journal of Bone and Mineral Research had the most co-cited journals. These two journals mainly focused on molecular biology and the clinical medicine domain. The countries with the highest number of publications were the US and China, and the University of Arkansas for Medical Sciences was the most active institution. Regarding authors, Stavros C. Manolagas published the most articles, and Hiroshi Takayanagi had the most co-cited papers. Research in this field mainly includes molecular expression and regulatory mechanisms, differentiation, osteoprotection, inflammation, and tumors. The latest research hotspots are oxidative stress, mutation, osteocyte formation and absorption, bone metabolism, tumor therapy, and in-depth mechanisms. Conclusion: We identified the research hotspots and development process of osteoblasts-osteoclasts in bone disease using bibliometric and visual methods. Osteoblasts-osteoclasts have attracted increasing attention in bone disease. This study will provide a valuable reference for researchers concerned with osteoblasts-osteoclasts in bone diseases.

Tibial cortex transverse transport facilitating healing in patients with recalcitrant non-diabetic leg ulcers.

OBJECTIVE: The treatment of recalcitrant not-diabetic leg ulcers remains challenging. Distraction osteogenesis is accompanying by angiogenesis and neovascularization in the surrounding tissues. We previously applied tibial cortex transverse transport (TTT) to patients with recalcitrant diabetic foot ulcers and found neovascularization and increased perfusion in the foot and consequently enhanced healing and limb salvage and reduced recurrence. However, the effects of TTT on recalcitrant non-diabetic leg ulcer remains largely unknown. METHODS: Consecutive patients (n â€‹= â€‹85) with recalcitrant non-diabetic leg ulcers (University of Texas Grade 2-B to 3-D, ie, wound penetrating to the tendon, capsule, bone, or joint with infection and/or ischemia) were recruited and divided into TTT (n â€‹= â€‹42) and control (n â€‹= â€‹43) groups based on the treatment they received. There were 36 (85.7%) arterial ulcers, 4 (9.5%) venous ulcers and 2 (4.8%) mixed ulcers in the TTT group and 32 (74.4%) arterial ulcers, 7 (16.7%) venous ulcers and 4 (9.3%) mixed ulcers in the control group (p â€‹> â€‹0.05). The two groups were matched on demographic and clinical characteristics. Patients in the TTT group underwent tibial corticotomy followed by 4 weeks of distraction medially then laterally, while those in the control group received conventional surgeries (debridements, revascularization, reconstruction with flaps, or skin grafts or equivalents). Ulcer healing and healing time, limb salvage, recurrence, and patient death were evaluated at a 1-year follow-up. Changes in leg small vessels were assessed in the TTT group using computed tomography angiography (CTA). RESULTS: TTT group had higher healing rates at 1-year follow-up than the control group (78.6% [33/42] vs. 58.1% [25/43], OR 2.64 [95% CI 1.10 to 6.85], p â€‹= â€‹0.04). The healing time of the TTT group was shorter than the control group (4.5 vs. 6.1 months, mean difference -1.60 [95% CI -2.93 to -0.26], p â€‹= â€‹0.02). There were no significant differences in rates of major amputation, reulceration, or mortality between the groups (p â€‹> â€‹0.05). TTT group displayed more small vessels 4 weeks postoperatively at the wound area, the foot, and the calf of the ipsilateral side in CTA. All patients in the TTT group achieved good union at the osteotomy site and had no skin or soft tissue necrosis or infection around the incision area. CONCLUSION: The findings showed that TTT facilitated the healing of recalcitrant non-diabetic leg ulcers and reduced the healing time compared with conventional surgeries. They suggest that TTT is an effective procedure to treat recalcitrant non-diabetic foot ulcers compared with standard surgical therapy. The procedure of TTT is relatively simple. Randomized controlled trials are required to confirm these findings. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: TTT can be used as an effective treatment for recalcitrant non-diabetic leg ulcers in patients. The mechanism may be associated with the neovascularization in the ulcerated foot induced by TTT and consequently increased perfusion. Together with previous findings from recalcitrant diabetic leg ulcers, the findings suggest TTT as an effective procedure to treat recalcitrant chronic leg ulcers.