Tibial cortex transverse transport potentiates diabetic wound healing via activation of SDF-1/CXCR4 signaling

Abstract

Background The current treatments for diabetic foot ulcers have disadvantages of slow action and numerous complications. Tibial cortex transverse transport (TTT) surgery is an extension of the Ilizarov technique used to treat diabetic foot ulcers, and can shorten the repair time of diabetic foot ulcers. This study assessed the TTT technique for its effectiveness in healing diabetic foot ulcer skin lesions and its related molecular mechanisms. Methods Diabetic rat models were established by injecting healthy Sprague-Dawley rats with streptozotocin (STZ). The effects of TTT surgery on the model rats were assessed by recording changes in body weight, analyzing skin wound pictures, and performing H&E staining to assess the recovery of wounded skin. The numbers of endothelial progenitor cells (EPCs) in peripheral blood were analyzed by flow cytometry, and levels of CXCR4 and SDF-1 expression were qualitatively analyzed by immunofluorescence, immunohistochemistry, qRT-PCR, and western blotting. Results Both the histological results and foot wound pictures indicated that TTT promoted diabetic wound healing. Flow cytometry results showed that TTT increased the numbers of EPCs in peripheral blood as determined by CD34 and CD133 expression. In addition, activation of the SDF-1/CXCR4 signaling pathway and an accumulation of EPCs were observed in skin ulcers sites after TTT surgery. Finally, the levels of SDF-1 and CXCR4 mRNA and protein expression in the TTT group were higher than those in a blank or fixator group. Conclusion TTT promoted skin wound healing in diabetic foot ulcers possibly by activating the SDF-1/CXCR4 signaling pathway.

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

“…Using a similar rat model of TTT, another study tried to examine the effect of TTT on DFU and reported positive results. 20 However, the skin defect created was relatively small (4 mm × 5 mm) and hindlimb ischemia was not induced simultaneously. 20 Thus, this model mimicked only mild DFU.…”

“… 20 However, the skin defect created was relatively small (4 mm × 5 mm) and hindlimb ischemia was not induced simultaneously. 20 Thus, this model mimicked only mild DFU. According to the clinical guideline of TTT treatment, this technique should be applied to severe DFU rather than acute traumatic foot wound or mild DFU considering cost-effectiveness of TTT.…”

“…Recently, TTT was established in relatively small animal-rat. 19 , 20 Yang et al established a rat model of TTT and assessed the effect of TTT on foot wound. 19 However, the bone transport protocol used did not fully resemble a clinical TTT protocol and only simple non-diabetic traumatic foot wounds were created.…”

“… 19 Using a similar rat model of TTT, another study intended to evaluate the effect of TTT on DFU. 20 However, only minor DFUs (relative small wound size and without comorbidities such as ischemia) were established. 20 According to clinical studies, TTT is suggested to apply to severe DFU, rather than non-diabetic traumatic foot wounds or mild DFU, considering the cost-effectiveness of the technique.…”

“… 20 However, only minor DFUs (relative small wound size and without comorbidities such as ischemia) were established. 20 According to clinical studies, TTT is suggested to apply to severe DFU, rather than non-diabetic traumatic foot wounds or mild DFU, considering the cost-effectiveness of the technique. 6 , 21 , 22 Thus, an animal model of severe DFU treated using TTT is needed for exploration of the underlying mechanism.…”