Ischemic skin wound healing models in rats

Ischemia is a major factor contributing to delayed healing (or nonhealing) of wounds. Two models of ischemic skin wound healing have been developed in the rat using single-pedicle or bipedicle dorsal skin flaps. These models simulate many of the molecular abnormalities that characterize the environment of ischemic human chronic wounds, including delayed healing, increased levels of inflammatory cytokines, and elevated proteases. The bipedicle skin flap model produces moderate transient ischemia that causes delayed healing of full-thickness skin excision wounds. The single-pedicle skin flap model produces more severe tissue ischemia that eventually leads to necrosis of the distal segment of the flap. Both models can be used to elucidate mechanisms of wound healing and to evaluate potential wound therapies. For example, healing of full-thickness excisional wounds created in the bipedicle skin flap model is delayed approximately 30 percent compared to wounds created in nonischemic rat skin. Analysis of biopsies from ischemic wounds showed increased levels of pro-inflammatory cytokine proteins and mRNAs at day 13 after surgery compared to biopsies of wounds created in nonischemic skin or uninjured normal skin. Levels of matrix metalloproteinases and serine proteases also were elevated in ischemic wounds 13 days after injury compared to nonischemic wounds or normal unwounded skin. Topical treatment of ischemic wounds in the bipedicle skin flap with platelet-derived growth factor (PDGF) accelerated healing. Investigations using the single-pedicle skin flap model also have shown that treatment with a growth factor (transforming growth factor beta-1, TGF-beta1) improved flap survival and increased tensile strength of incisions in both irradiated and nonirradiated skin flaps. Gene transfection experiments showed that simple lipid:DNA plasmid complexes could transfect skin cells as late as eight days after flap elevation in a 4-mm diameter area around the site of injection. The single-pedicle and bipedicle dorsal rat skin flap models can be used to investigate various aspects of ischemic skin wound healing and treatment.