Systematic Reviews
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Jul 26, 2020; 12(7): 659-675
Published online Jul 26, 2020. doi: 10.4252/wjsc.v12.i7.659
Role of stem cell therapies in treating chronic wounds: A systematic review
Anjali C Raghuram, Roy P Yu, Andrea Y Lo, Cynthia J Sung, Melissa Bircan, Holly J Thompson, Alex K Wong
Anjali C Raghuram, Roy P Yu, Andrea Y Lo, Cynthia J Sung, Melissa Bircan, Alex K Wong, Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, CA 90033, United States
Holly J Thompson, Wilson Dental Library, Herman Ostrow School of Dentistry of USC, Los Angeles, CA 90089, United States
Author contributions: Raghuram AC and Wong AK contributed to the study conception and design; Raghuram AC, Yu RP, Lo AY, Sung CJ, Bircan M and Thompson HJ contributed to literature review and analysis; Raghuram AC, Yu RP, Lo AY and Wong AK drafted, critically revised and edited the manuscript; Raghuram AC, Yu RP, Lo AY and Wong AK approved the final version.
Conflict-of-interest statement: While there is no conflict of interest relevant to this review article, we wish to disclose that Alex K. Wong’s laboratory receives research funding for pre-clinical wound healing studies from ACell, Inc.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
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:
Corresponding author: Alex K Wong, MD, Associate Professor, Surgeon, Division of Plastic and Reconstructive Surgery, Keck School of Medicine of the University of Southern California, 1510 San Pablo Street, Los Angeles, CA 90033, United States.
Received: February 26, 2020
Peer-review started: February 26, 2020
First decision: April 22, 2020
Revised: May 3, 2020
Accepted: May 27, 2020
Article in press: May 27, 2020
Published online: July 26, 2020
Research background

Chronic wounds are defined as those that do not heal within a period of 3 mo, resulting in significant patient morbidity and healthcare burden. Due to local tissue hypoxia, bacterial colonization, ischemia-reperfusion injury, and diminished stem cell populations, these wounds do not progress through the normal wound healing phases. Further, non-healing wounds are attributable to a host of etiologies, including arterial disease, diabetes, vasculitis, venous valve insufficiency, irradiation, and malignancy. Their complex pathophysiology poses a formidable treatment challenge, and presently, there are ineffective techniques to facilitate wound closure and improved patient symptomatology. Stem cell therapies have therefore emerged as a unique therapeutic approach to modulate the chronic wound environment in favor of healing. In this systematic review, we evaluate literature over the past two decades to ascertain clinical findings associated with stem cell therapies for treating chronic wounds.

Research motivation

While adipose-derived stem cells (ADSCs) and bone marrow-derived stem cells (BMMSCs) have been tested the most frequently in clinical settings, it is unclear how other emerging stem cell therapy types function in healing chronic wounds. It is critical that we comprehensively consider a variety of stem cell therapies for the treatment of a diverse scope of non-healing wounds in order to provide maximal clinical benefit to wound care specialists and providers.

Research objectives

To investigate the scope of a variety of stem cell therapies, including adipose-derived stem cells (ADSCs), bone marrow-derived stem cells (BMMSCs), bone marrow-derived mononuclear cells (BMMNCs), epidermally-derived mesenchymal stem cells (EMSCs), fibroblast stem cells (FSCs), keratinocyte stem cells (KSCs), placental mesenchymal stem cells (PMSCs), umbilical cord mesenchymal stem cells (UMSCs), and embryonic stem cells (ESCs), for the treatment of chronic, non-healing wounds.

Research methods

We performed a systematic review of the literature according to the 2009 PRISMA guidelines. Five authors conducted a search in five databases (PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus) to identify relevant publications, articles, and abstracts reporting clinical stem cell therapy use for chronic wounds from the years 2000 to 2019.

Research results

A total of 43 studies were included in this review. The studies reported that ADSCs and BMMSCs have been tested in the widest scope of clinical applications, including the treatment of severe radiation-associated wounds, venous leg ulcers, chronic fistulae, chronic diabetic ulcers, and advanced pressure ulcers from spinal cord injury. Enhanced testing of other stem cell therapy types has provided informative guidelines for therapy optimization, including seeding stem cells into artificial dermal, wound matrix, and hydrogel scaffolds for improved cell survival and proliferation in the wound beds. FSCs and KSCs can be delivered with additives, including fibrin, to strengthen cell properties of adherence, migration, and epithelial monolayer formation. Improved wound healing with each of the stem cell therapy types was determined on the basis of histological and functional parameters. No studies reported significant complications with clinical use of any of the investigated therapies.

Research conclusions

Stem cells promote healing of chronic wounds by restoring impaired signaling pathways for growth factors, ensuring delivery of important cytokines and chemokines, inducing vascularization and innervation, and modulating inflammatory processes. Selecting optimal therapy for various wounds is contingent on patient variables, including age, sex, and stem cell donor site, as well as processing variables, such as culturing after cell harvest and potential for malignant transformation. Additional clinical studies are required to replicate the strength of the literature findings for ADSCs and BMMSCs and substantiate use of a wider scope of stem cell therapies for treating non-healing wounds.

Research perspectives

There is limited clinical evidence examining the use of EMSCs, FSCs, KSCs, PMSCs, UMSCs, and ESCs for the treatment of chronic wounds, though these stem cells have demonstrated potential in preclinical in vitro and in vivo work. Further studies exploring the use of these therapies for clinically diverse patient wounds would be highly informative. In addition to aforementioned artificial dermal, wound matrix, and hydrogel scaffolds, there is ongoing development with newer cell delivery constructs, such as electrospun fiber scaffolds to facilitate creation of layered skin substitute dressings. As the etiology of chronic wounds varies from patient to patient, it is necessary to personalize therapeutic approaches. The goal of future investigations will be to further realize improved patient wound closure and histologic markers of wound healing, as well as decreased pain, disfigurement, and healthcare system burden.