Chronic Diabetic Wounds and Their Treatment with Skin Substitutes

Abstract

With the global prevalence of type 2 diabetes mellitus steeply rising, instances of chronic, hard-healing, or non-healing diabetic wounds and ulcers are predicted to increase. The growing understanding of healing and regenerative mechanisms has elucidated critical regulators of this process, including key cellular and humoral components. Despite this, the management and successful treatment of diabetic wounds represents a significant therapeutic challenge. To this end, the development of novel therapies and biological dressings has gained increased interest. Here we review key differences between normal and chronic non-healing diabetic wounds, and elaborate on recent advances in wound healing treatments with a particular focus on biological dressings and their effect on key wound healing pathways.

Keywords: chronic wounds; diabetes; matrices; skin dressings; skin substitutes; wound healing.

Figure 1

Overview of Normal vs. Impaired Wound Healing. (A): The first phase of wound healing is hemostasis. Platelets form a clot at the site of injury, and chemoattractants are released, recruiting key inflammatory cells. Next, inflammation takes charge, with infiltrating neutrophils and mast cells releasing pro-inflammatory cytokines and inducing strong sanitizing effects. This is accompanied by neutrophil extracellular trap (NETosis) induction, which assists in capturing and destroying invading pathogens. Tissue-resident macrophages react to pathogen- and damage-associated molecular patterns (PAMPs & DAMPs), activating. Later a provisional matrix comprised of fibronectin and other provisional extracellular matrix (ECM) components forms from the clot. (B): Impaired wounds see an upregulated influx of neutrophils and mast cells, leading to an overactive inflammatory response, causing collateral damage and extending the inflammatory phase to the detriment of subsequent phases. (C): Following resolution of strong inflammation, the proliferative phase begins. Crucially, endothelial progenitor cells are stimulated by growth factors to induce angiogenesis. This angiogenesis allows for wound-resident cells to be supplied with oxygen and nutrients, facilitating their function. Infiltrating monocytes differentiate into M1 and M2 macrophage subsets. M1 macrophages maintain a strong inflammatory profile, but are counterbalanced by pro-regenerative M2 macrophages which release anti-inflammatory cytokines, growth factors, and proteases which replace the provisional ECM with collagens, assisted by properly functioning fibroblasts. This process results in thick granular tissue and full keratinocyte coverage. (D): Impaired wounds result in poor angiogenesis and, in the case of T2DM, glycated proteins. This hypoxic environment induces oxidative stress, driving inflammatory M1 macrophage polarization and impairment of fibroblasts, resulting in poor ECM reorganization and a persistent inflammatory environment. (E): Remodeling is carried out by macrophages, fibroblasts, and myofibroblasts re-organizing the provisional ECM into a coherent scar structure primarily by means of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), resulting in tissue with strong tensile strength and functionality. (F): Impaired wound-resident cells remain ineffective and pro-inflammatory. Collagen reorganization resolves poorly, resulting in weak, non-functional skin that is apt to re-injure and potentially ulcerate, perpetually inflamed.