Future applications of exosomes delivering resolvins and cytokines in facilitating diabetic foot ulcer healing

Abstract

Type 2 diabetes mellitus (T2DM) increases the risk of many lethal and debilitating conditions. Among them, foot ulceration due to neuropathy, vascular disease, or trauma affects the quality of life of millions in the United States and around the world. Physiological wound healing is stalled in the inflammatory phase by the chronicity of inflammation without proceeding to the resolution phase. Despite advanced treatment, diabetic foot ulcers (DFUs) are associated with a risk of amputation. Thus, there is a need for novel therapies to address chronic inflammation, decreased angiogenesis, and impaired granulation tissue formation contributing to the non-healing of DFUs. Studies have shown promising results with resolvins (Rv) and anti-inflammatory therapies that resolve inflammation and enhance tissue healing. But many of these studies have encountered difficulty in the delivery of Rv in terms of efficiency, tissue targetability, and immunogenicity. This review summarized the perspective of optimizing the therapeutic application of Rv and cytokines by pairing them with exosomes as a novel strategy for targeted tissue delivery to treat non-healing chronic DFUs. The articles discussing the T2DM disease state, current research on Rv for treating inflammation, the role of Rv in enhancing wound healing, and exosomes as a delivery vehicle were critically reviewed to find support for the proposition of using Rv and exosomes in combination for DFUs therapy. The literature reviewed suggests the beneficial role of Rv and exosomes and exosomes loaded with anti-inflammatory agents as promising therapeutic agents in ulcer healing.

Keywords: Amputation; Chronic inflammation; Cytokines; Diabetic foot ulcer; Exosomes; Resolvins.

Figure 1

Inflammation-mediated pathogenesis of diabetic foot ulcer, the role of resolvins, and phases of wound healing. Resolvins [specialized pro-resolving mediators (SPMs)] facilitate the resolution of inflammation and progression of the wound to the resolution phase followed by remodeling and healing (SPMs shown in green). However, persistent infiltration of immune cells and increased secretion of cytokines mediate chronic inflammation and hold the wound in the inflammation phase without progressing to resolution or proliferative phase (red arrow). This leads to the chronicity of inflammation and nonhealing of diabetic foot ulcers. ILV: Intraluminal vesicle.

Figure 2

Exosome formation through the endosomal pathway. Endocytosis produces endocytic vesicles which will fuse to form early endosomes. Endosomes mature into multivesicular bodies (MVBs) and parts of their membranes endocytose to form intraluminal vesicles (ILVs) within themselves. With 2 stages of endocytosis, the orientation of the bilaminar membrane of the ILVs will possess the same orientation as the cell’s membrane. The MVBs fuse to the cellular membrane to release the ILVs now referred to as exosomes. IL: Interleukin; TNF: Tumor necrosis factor.