Extracellular vesicles (EVs) are lipid-enveloped nanoparticles formed naturally by cells that act in the intercellular transfer of biological material, such as proteins, ribonucleic acids, and metabolites.

Pre-clinical data suggest the use of EVs in regenerative processes such as:¹

Advantages of EVs over stem cell therapies

EVs tend to show the following benefits over stem cell therapies:¹

Applications of EVs in regenerative dermatology

Multiple features of EVs have made them promising candidates for various therapeutic approaches, including recent applications in regenerative dermatology. Some of the positive outcomes of mesenchymal (MSC) EVs are attributed to their effects on fibroblasts and their capacity to modulate the local inflammatory environment.¹

The therapeutic efficacy of MSC-EVs seems to be inversely related to the donor’s developmental maturity from which they are obtained. On increasing passage, a reduction was observed in the pro-vascularising activity of MSC-EVs. While developing EVs therapeutically, basic parameters must be carefully considered. These parameters are related to the cell source, the method of culture (e.g., 2-dimensional vs. 3-dimensional), frequency and timing of EV collection, the method of EV isolation applied (e.g., ultracentrifugation, size-exclusion chromatography, and tangential flow filtration), and the addition of exogenous priming agents to cell cultures (e.g., hypoxia or stimulation with inflammatory cytokines). However, if these theories are autologously developed, the consequence of donor maturity on MSC-EV potency could prove to be a limiting factor.¹

Figure 1: Production criteria overview and their impact on the final preparation.

Adapted from: Davies OG, et al. J Control Release. 2023.
2D: 2-dimensional; 3D: 3-dimensional; EV: Extracellular vesicle; RNA: Ribonucleic acid.

Post-production parameters required for standardisation
Transparency and standardisation must be considered w.r.t reporting of bioavailability, dosage, and purity for EV preparations as shown in Figure 2.¹

Moreover, as the use of EVs is limited to topical administration in future, one should consider their application using full-thickness human skin models. Combining EVs with conventional skin-puncturing treatments (FDA unapproved for subdermal injection adminstration), such as micro-needling (FDA approval of topical with adjunct administration is unclear), could be a chance for the enhanced delivery of EVs.¹
Data suggest that compared to micro-needling alone, the addition of EVs could augment collagen density and organisation.¹

However, currently, injectable EV therapy has not been approved by the Food and Drug Administration, with the application of EVs in general dermatological practice confined solely to topical administration.
To date, no specific regulatory guidelines have been published concerning EV therapies, and EVs are expected to be regulated as drugs and biological products under section 351 of the Public Health Service Act and the Federal Food Drug & Cosmetics Act because more evidence is required for establishing the safety, efficacy, purity, and potency properties.¹

Conclusion:

• Although EV formulations demonstrated positive effects on the epidermal barrier by decreasing the rates of inflammatory cytokines and inducing de novo production of ceramides after injection in an AD model, these formulations reduced dupilumab facial redness, and were toxicologically safe when tested in rats. But the effects of lyophilisation on the long-term integrity and potency of EV formulations are currently in the nascent stages only, with storage buffer and pH having a significant impact.¹
• An observation in animal models implies that EVs derived from a younger organism can lead to the rejuvenation of older cells. Though the availability of EV formulations is getting frequent in private aesthetics clinics, at present, no EV therapy has been approved for public usage by the Food and Drug Administration or European Medicines Agencies (EMA). Hence, private aesthetic practitioners must exercise caution while combining EV therapies with adjunct treatments in their clinics.¹
• However, chances are that EVs will be regulated as drugs and biological products under section 351 of the Public Health Service (PHS) Act and the Federal Food Drug & Cosmetics & (FD&C) Act. This implies that more studies are required to demonstrate the safety, efficacy, purity, and potency of a product for a given application.¹

Key takeaways

• EVs are extremely complex and heterogenous biological products that are considered beneficial; however, more studies are required to establish its clinical and long-term safety data.¹
• This article showcased the therapeutic and commercial landscape of EVs in regenerative dermatology and cosmetic science.¹