Abstract
Chronic non-healing wounds, frequently caused by diabetes, lead to lower quality of life, infection, and amputation. These wounds have limited treatment options. We have previously engineered growth factors to bind to exposed extracellular matrix (ECM) in the wound environment using the heparin-binding domain of placental growth factor-2 (PlGF-2123–144), which binds promiscuously to ECM proteins. Here, in the type 1 diabetic (T1D) NOD mouse model, engineered growth factors (eGFs) improved both re-epithelialization and granulation tissue formation. eGFs were even more potent in combination, and the “triple therapy” of vascular endothelial growth factor-A (VEGF-PlGF-2123–144), platelet-derived growth factor-BB (PDGF-BB-PlGF-2123–144), and heparin-binding epidermal growth factor (HB-EGF-PlGF-2123–144) both improved wound healing and remained at the site of administration for significantly longer than wild-type growth factors. In addition, we also found that changes in the cellular milieu of a wound, including changing amounts of M1 macrophages, M2 macrophages and effector T cells, are most predictive of wound-healing success in the NOD mouse model. These results suggest that the triple therapy of VEGF-PlGF-2123–144, PDGF-BB-PlGF-2123–144, and HB-EGF-PlGF-2123–144 may be an effective therapy for chronic non-healing wounds in that occur as a complication of diabetes.
Highlights
Diabetes is a major health scourge that affects more than 415 million people worldwide
The addition of Heparin-binding epidermal growth factor (HB-EGF) resulted in an increase in granulation tissue as compared to wounds treated with fibrin alone after 1 week (Fig. 1c)
Treatment with the triple therapy (VEGF-A-PlGF-2123–144, Platelet-derived growth factor-BB (PDGF-BB)-PlGF-2123–144, and HB-EGF-PlGF2123–144) increased both wound closure and granulation tissue compared to the non-obese diabetic (NOD) control mouse, and compared to the non-diabetic NOD variant NOR mouse (Fig. 1c, d)
Summary
Diabetes is a major health scourge that affects more than 415 million people worldwide. One in eleven adults has diabetes, and 12% of all global health expenditures are related to diabetes[1], including chronic non-healing diabetic wounds. The risk for diabetic patients to develop lower extremity non-healing wounds ranges from 15% to 25% during their lifetime[2,3], and about 33% of the direct costs of diabetes are linked with the treatment of diabetic foot ulcers[4]. Type 1 diabetes (T1D) affects 1.25 million Americans, 5% of diabetics overall, and primarily manifests in children[5]. T1D has only 5–10% of the prevalence of type 2 diabetes (T2D), the health complications for T1D are more severe[6,7], with persons with T1D heal both acute and chronic wounds poorly, independent of their glycemic control[8]
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