Exosomes and Their Bioengineering Strategies in the Cutaneous Wound Healing and Related Complications: Current Knowledge and Future Perspectives

Abstract

Exosomes, as therapeutically relevant cell-secreted extracellular vesicles, have attracted enormous interest because they participate in intercellular communication and facilitate wound healing. Stem cell-derived exosomes exhibit similar biological effects to source cells with the exception of low immunogenicity and no tumorigenicity, as well as superior efficacy in promoting wound healing. Exosomes accelerate wound healing by promoting angiogenesis and cell proliferation, as well as balancing inflammatory responses. Particularly, when exosomes are genetically modified or used in combination with materials, they can exhibit better comprehensive therapeutic properties, such as enriching active ingredients, targeted delivery, and physiological barrier to penetration, which are not available in traditional single products. Besides, exosomes have also been considered for diagnostic and therapeutic uses related to wounds, such as repairing complex wounds, enhancing graft success, treating related complications, and serving as diagnostic biomarkers. However, their clinical applications still face challenges, as reliable commercial products are not yet available. This review will focus on recent research advances that describe the characteristics and isolation of exosomes, introduce the sources of exosomes suitable for wound repair and related complications, illustrate the value of engineered exosomes and their development directions in the future, and provide evidence for the potential therapeutic application of exosomes in wound healing, as well as discuss potential risks, challenges, and solutions for future applications.

Keywords: biomarkers.; biomaterials; complex wounds; complications; engineered exosomes; exosomes; stem cells; wound healing.

Figure 1

Illustration of the major populations of extracellular vesicles. Exosomes are endosome-derived EVs formed by inward budding from the cell membrane. Microvesicles arise from fission and outward budding of the plasma membrane. Oncosomes are membrane-derived extracellular vesicles secreted by cancer cells. Plasma membrane blebbing is the apoptotic or pyroptotic body produced by programmed cell death. Migrasomes originate from migrating cells. M = mitochondria, RER = rough endoplasmic reticulum, Mic = micronuclei, RF = retraction fibrils.

Figure 2

Schematic process for producing self-derived exosomes as a new biological theranostic agent. Generally, any somatic cell can be induced to produce iPSCs for exosome production by in vitro reprogramming. For example, peripheral blood mononuclear cells can be induced into iPSCs, and then plasmids containing specific genes can be introduced into the cells. Exosomes can be harvested from cell culture and modified to increase their substrates and functions. Particularly, quality-controlled exosomes can well meet the requirements of clinical application.

Figure 3

Extracellular vesicle (EV) biogenesis, subpopulations, and conventional and novel methods of exosome isolation.

Figure 4

Role of exosomes in different stages of wound healing.

Figure 5

Schematic diagram of an exosome-combined multifunctional dressing for diabetic wound repair. This study synthesized a composite material containing F127-PEI, APu, Multifunctional FEP Scaffold Dressing, and exosomes. The dressing has multifunctional properties such as efficient antibacterial/resistant bacteria, rapid hemostasis, self-healing, tissue adhesion, and good UV shielding properties. This provides a typical research idea for the application of engineered exosomes in complex wound repair. This picture is reprinted with permission from . Copyright 2022 American Chemical Society.

Figure 6

The potential application of exosomes in wounds.