An innovative ischemic diabetic flap model for chronic wound research

Preclinical animal models that are simple, reproducible, and capable of partially mimicking the pathophysiological features of clinical diabetic foot ulcers (DFUs) are essential for advancing research on refractory wound healing. Compared to mice, Sprague-Dawley (SD) rats offer advantages such as reduced stress and greater ease of modeling. Additionally, type 2 diabetes induced in rats via a high-fat diet combined with intraperitoneal streptozotocin (STZ) injection is more cost-effective than genotyped rats. To simulate ulcers caused by diabetic vasculopathy, we established two bipedicle ischemic flaps of different widths (2 cm and 2.5 cm, both 11 cm long) on the backs of diabetic rats. Two full-thickness skin defects (6 mm in diameter) were created bilaterally at the flap midpoint to prevent fascial contraction that is a common issue in conventional models. As controls, we created bipedicle ischemic flaps (11 cm long, 2 cm wide) and corresponding wounds on the backs of normal SD rats. Additionally, classic full-thickness wounds (6 mm in diameter) were established at the same location on diabetic rats without flaps. We evaluated wound healing rates, epithelialization, neocollagenesis, angiogenesis, macrophage polarization, and the expression levels of pro-inflammatory factors and MMPs. The wounds within the 2.0 cm-wide ischemic flaps exhibited delayed epithelialization, reduced neocollagenesis, and an increased number of CD31-positive endothelial cells, with elevated VEGF-A expression but fewer mature blood vessels. Higher levels of IL-1β, TNF-α, IL-6 MMP2 and MMP9, and M1 macrophages were also observed. In conclusion, a bipedicle ischemic flap (11 cm long, 2 cm wide) combined with full-thickness skin defects on the backs of type 2 diabetic rats induced by a high-fat diet with STZ injection provides an effective model for studying DFU-associated vasculopathy and chronic inflammation.