Efficacy and safety of small extracellular vesicle interventions in wound healing and skin regeneration: A systematic review and meta-analysis of animal studies

Abstract

Small extracellular vesicles (sEVs) have been proposed as a possible solution to the current lack of therapeutic interventions for endogenous skin regeneration. We conducted a systematic review of the available evidence to assess sEV therapeutic efficacy and safety in wound healing and skin regeneration in animal models. 68 studies were identified in Web of Science, Scopus, and PubMed that satisfied a set of prespecified inclusion criteria. We critically analyzed the quality of studies that satisfied our inclusion criteria, with an emphasis on methodology, reporting, and adherence to relevant guidelines (including MISEV2018 and ISCT criteria). Overall, our systematic review and meta-analysis indicated that sEV interventions promoted skin regeneration in diabetic and non-diabetic animal models and influenced various facets of the healing process regardless of cell source, production protocol and disease model. The EV source, isolation methods, dosing regimen, and wound size varied among the studies. Modification of sEVs was achieved mainly by manipulating source cells via preconditioning, nanoparticle loading, genetic manipulation, and biomaterial incorporation to enhance sEV therapeutic potential. Evaluation of potential adverse effects received only minimal attention, although none of the studies reported harmful events. Risk of bias as assessed by the SYRCLE's ROB tool was uncertain for most studies due to insufficient reporting, and adherence to guidelines was limited. In summary, sEV therapy has enormous potential for wound healing and skin regeneration. However, reproducibility and comprehensive evaluation of evidence are challenged by a general lack of transparency in reporting and adherence to guidelines. Methodological rigor, standardization, and risk analysis at all stages of research are needed to promote translation to clinical practice.

Natural Killer Cell-Derived Extracellular Vesicles as a Promising Immunotherapeutic Strategy for Cancer: A Systematic Review

“…Size is commonly used to classify EVs [ 113 ]. The largest EVs are the apoptotic bodies (1000–5000 nm), followed by microvesicles (50–1000 nm), with exosomes (30–150 nm) being the smallest [ 114 ]. The term “exosome” is often incorrectly used interchangeably with “extracellular vesicle” to describe the small EV preparation [ 42 ].…”

Extracellular vesicles and their cells of origin: Open issues in autoimmune diseases

“…Immune biocompatibility of EVs is the other criterion to be investigated in autoimmune diseases. It was shown in a previous study that although both autologous and allogeneic small EVs may have efficient therapeutic effects, autologous EVs are more viable and impactful in damaged tissues ( 216 , 217 ).…”

“…Moreover, the clinical practice of EVs is challenged by their heterogeneity to some extent. Optimization of current digital assays has been proposed to do single-vesicle-resolution studies, especially during the clinical analysis of liquid biopsies (215). Immune biocompatibility of EVs is the other criterion to be investigated in autoimmune diseases.…”

“…EVs were reported to demonstrate cell and tissue-specific autonomous targeting capabilities (139,215). The interactions between EVs and the neighboring or distant acceptor cells occur through diverse mechanisms.…”

Knowledge mapping of extracellular vesicles in wound healing: A bibliometric analysis (2002‐2022)

“…12,13 In recent years, many scholars began to try to use foreign bodies to promote wound healing and made great breakthroughs. [14][15][16] Biliometric is a literature analysis method that analyzes the output and status of publications in a particular research field from a quantitative and qualitative perspective. 17,18 During the analysis, we can obtain detailed information about authors, keywords, journals, countries, institutions, references, and so forth in the relevant research field.…”