Huang Xiajie, Liu Jie, Wu Xiaomei, Mo Yangzhou, Luo Xiping, Yang Yongge, Yang Chaoquan, Liang Xinyun, Liang Rongyuan, Chen Yeping, Fan Zezhen, Lu William, Chen Yan, Hua Qikai
Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China.
Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, People's Republic of China.
J Inflamm Res. 2025 Feb 5;18:1755-1772. doi: 10.2147/JIR.S493505. eCollection 2025.
Microinjury can trigger in situ tissue repair. Bone transport consists of continuous microinjuries/microfracture and induces bone formation and angiogenesis. Tibial cortex transverse transport (TTT) was found to promote angiogenesis at the foot and the healing of diabetic foot ulcers (DFUs). However, the underlying mechanism remains largely unknown.
We divided 72 Sprague-Dawley rats with DFUs into the control, sham, and TTT groups. Wound measurement and histology were performed to evaluate the wound healing processes. Enzyme-linked immunosorbent assay, flow cytometry, immunohistochemistry, and Western Blot were used to assess angiogenesis and the activity of endothelial progenitor cells (EPCs) and the Ras/Raf/MEK/ERK signaling pathway.
We found accelerated wound healing, improved epidermal continuity, and increased dermal thickness in the TTT group than the control and the sham groups. Higher levels of serum TGF-β1, PDGF-BB, and VEGF were detected in the TTT group. These changes were in parallel with the expression of TGF-β1, PDGF-BB, and VEGF in the foot wounds and the frequency of EPCs in both bone marrow and peripheral circulation, which implied that the secreted TGF-β1, PDGF-BB, and VEGF promote proliferation and migration of EPCs to the foot wounds. The expression of CD31 cells, SMA-α cells, and the Ras/Raf/MEK/ERK pathway was higher in the TTT group than in the control and sham groups.
The findings showed that TTT enhanced the production of growth factors that in turn activated EPC proliferation and migration through the Ras/Raf/MEK/ERK pathway, ultimately contributing to angiogenesis and DFU healing. Based on these findings, we proposed a theory that remote continuous microinjuries can trigger the repair of target tissues (ie, microinjury-induced remote repair, MIRR). Future studies are needed to validate this theory.
微损伤可触发原位组织修复。骨搬运由持续的微损伤/微骨折组成，并诱导骨形成和血管生成。胫骨皮质横向搬运（TTT）被发现可促进足部血管生成及糖尿病足溃疡（DFU）的愈合。然而，其潜在机制仍 largely 未知。
我们将 72 只患有 DFU 的斯普拉格 - 道利大鼠分为对照组、假手术组和 TTT 组。进行伤口测量和组织学检查以评估伤口愈合过程。采用酶联免疫吸附测定、流式细胞术、免疫组织化学和蛋白质印迹法来评估血管生成以及内皮祖细胞（EPC）的活性和 Ras/Raf/MEK/ERK 信号通路。
我们发现与对照组和假手术组相比，TTT 组伤口愈合加速、表皮连续性改善且真皮厚度增加。TTT 组检测到更高水平的血清转化生长因子 -β1（TGF -β1）、血小板衍生生长因子 -BB（PDGF -BB）和血管内皮生长因子（VEGF）。这些变化与足部伤口中 TGF -β1、PDGF -BB 和 VEGF 的表达以及骨髓和外周循环中 EPC 的频率平行，这表明分泌的 TGF -β1、PDGF -BB 和 VEGF 促进 EPC 向足部伤口的增殖和迁移。TTT 组中 CD31 细胞、平滑肌肌动蛋白 -α（SMA -α）细胞的表达以及 Ras/Raf/MEK/ERK 通路比对照组和假手术组更高。
研究结果表明，TTT 增强了生长因子的产生，这些生长因子进而通过 Ras/Raf/MEK/ERK 通路激活 EPC 的增殖和迁移，最终促进血管生成和 DFU 愈合。基于这些发现，我们提出了一种理论，即远程持续微损伤可触发靶组织的修复（即微损伤诱导的远程修复，MIRR）。未来需要进一步研究来验证这一理论。
