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World J Diabetes. Jan 15, 2023; 14(1): 35-47
Published online Jan 15, 2023. doi: 10.4239/wjd.v14.i1.35
Future applications of exosomes delivering resolvins and cytokines in facilitating diabetic foot ulcer healing
Joshua P B Littig, Rebecca Moellmer, Devendra K Agrawal, Vikrant Rai
Joshua P B Littig, Devendra K Agrawal, Vikrant Rai, Translational Research, Western University of Health Sciences, Pomona, CA 91766, United States
Rebecca Moellmer, College of Podiatry, Western University of Health Sciences, Pomona, CA 91766, United States
Author contributions: Littig JPB and Rai V conceptualized and wrote the initial draft; Moellmer R and Agrawal DK critically reviewed and edited the manuscript; Littig JPB, Moellmer R, Agrawal DK and Rai V finalized the manuscript.
Supported by the Intramural Grant IMR Rai 12397B from the Western University of Health Sciences, Pomona, California; and the Grants from the National Institutes of Health, United States, R01 HL144125 and R01 HL147662.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Vikrant Rai, MBBS, PhD, Assistant Professor, Translational Research, Western University of Health Sciences, 309 E Second Street, Pomona, CA 91766, United States. vrai@westernu.edu
Received: October 3, 2022
Peer-review started: October 3, 2022
First decision: November 18, 2022
Revised: November 22, 2022
Accepted: December 21, 2022
Article in press: December 21, 2022
Published online: January 15, 2023
Processing time: 92 Days and 4.3 Hours
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: Diabetic foot ulcer; Chronic inflammation; Amputation; Exosomes; Cytokines; Resolvins

Core Tip: Nonhealing diabetic foot ulcers (DFUs) are a debilitating condition with the risk of amputation despite the advanced treatment strategies. Chronic inflammation, decreased granulation tissue formation, and decreased angiogenesis underlies the pathogenesis of nonhealing. Targeted delivery of therapeutics targeting immune cell infiltration and chronic inflammation with loaded exosomes may increase the efficacy of treatment. We herein discuss the potential of exosomes loaded with resolvins and drugs targeting inflammatory cytokines to promote DFUs healing.