Abstract: BACKGROUND: Transverse tibial bone transfer is an emerging surgical technique that enhances local blood circulation and promotes angiogenesis, thereby accelerating the healing of diabetic foot ulcers. Although this technique has demonstrated positive clinical outcomes, its specific molecular mechanisms remain unclear. Recently, the role of circular RNA in angiogenesis and wound healing has gained increasing recognition. Circular RNA may influence the healing process by regulating the expression of related genes; however, its involvement in the treatment of diabetic foot ulcers through transverse tibial bone transfer has yet to be explored.
OBJECTIVE: To investigate the therapeutic effects of transverse tibial bone transfer on diabetic foot ulcers in a rabbit model and the mechanism of action. 
METHODS: Eighteen 3-month-old male New Zealand rabbits, weighing 2.8–3.6 kg, were included in this study. After being fed a high-sugar, high-fat diet for 1 month, type II diabetic rabbit models were induced by intravenous injection of alloxan monohydrate. After successful modeling, the right femoral artery at the mid-upper segment was ligated, and the full-thickness skin of the ipsilateral dorsum of the foot was excised to simulate the pathological characteristics of diabetic foot ulcers. The successfully modeled rabbits were then randomly divided into four groups (n = 4 rabbits per group): blank group (no additional treatment), dressing group (routine disinfection with povidone-iodine after modeling), sham surgery group (installing a transverse tibial bone transfer scaffold but without bone transfer procedure), surgery group (installing a transverse tibial bone transfer scaffold plus bone transfer procedure). At 7 and 14 days after surgery, the healing of the foot dorsum ulcers was observed in each group. At 7, 14, and 21 days after surgery, serum levels of vascular endothelial growth factor A and CD31 were measured via enzyme-linked immunosorbent assay. At 14 days after surgery, ulcer tissue samples from each group were collected for histopathological analysis (hematoxylin and eosin staining), CD31 immunofluorescence staining, and Western blot assay to assess vascular endothelial growth factor A and CD31 protein expression levels. At 7, 14, and 21 days after surgery, venous blood samples were collected from the surgery group for whole-genome sequencing, and the differential expression of circular RNA was analyzed.
RESULTS AND CONCLUSION: At 14 and 21 days after surgery, the surgery group exhibited significantly better diabetic foot ulcer recovery compared with the other three groups, demonstrating superior epidermal regeneration, collagen deposition, and angiogenesis. At 14 and 21 days after surgery, the surgery group showed markedly higher serum levels of vascular endothelial growth factor A and CD31 than the other groups (P < 0.01). Gene sequencing analysis revealed the most pronounced changes in circular RNA expression on day 21, particularly the progressive downregulation of circular RNA PDS5B over time. This suggests a potential link between circular RNA PDS5B and angiogenesis and tissue repair mechanisms. All findings indicate that transverse tibial bone transfer effectively enhances diabetic foot ulcer healing in rabbits. The differential expression of circular RNAs, especially the significant decrease in circular RNA PDS5B, suggests that transverse tibial bone transfer may accelerate wound repair and angiogenesis by activating relevant molecular pathways.

Key words: transverse tibial bone transfer, diabetic foot ulcer, diabetes mellitus, angiogenesis, circular RNA (circRNA), circPDS5B