Regenerative Medicine in Aesthetics

Regenerative medicine is a broad science using synergistic combinations of cells, biomaterials, and biomolecules to repair, replace, and rejuvenate damaged tissues.1 The goals of anti-aging medicine and regenerative medicine overlap, and recent developments recognize the potential role of adult stem cells, growth factors, and nucleic acid therapies as modulators of antiaging pathways.2

Most of regenerative medicine in aesthetics can be categorized as either stem cells, biochemical cues, or scaffolds—although even energy-based devices are a form of regenerative modality.

Adipose-derived stem cells (ADSCs) are used in aesthetic medicine today, and are typically harvested from fat during liposuction. The relevant portion is referred to as stromal vascular fraction (SVF), and can be used for skin and soft tissue rejuvenation. Exosomes or other factors are also commonly derived from hematopoietic stem cells (HSCs) or mesenchymal stem cells (placental or amnion origin, but also fat, platelets, and bone marrow).

Biochemical cues are growth factors and exosomes, which are highly concentrated in platelet-rich plasma (PRP) and platelet-rich fibrin. Regenerative factors (miRNA, DNA, proteins, cytokines, etc) are often packaged within exosomes as paracrine signals. Nucleotides and individual growth factors are emerging as well within this category.

Scaffolds, meanwhile, can be used to deliver signals and factors, and then are resorbed. They can provide structural support to encourage regeneration (fillers) or promote biosynthesis of collagen and elastin. Scaffolds include CaHA, PLLA, PMMA, hyaluronic acid, and decellularized allograft adipose matrices.

STEM CELLS

Adult stem cells progressively lose the ability to differentiate into a wider range of cell types. The most commonly used stem cells that we have available in aesthetics are ADSCs, usually harvested from a stromal vascular fraction from fat tissue post-liposuction and enzymatic degradation. ADSCs are pluripotent/multipotent; high-quality; and abundant and dense within tissues.

Despite these advantages, stem cells are not very scalable and they cost more.

EXOSOMES

As mechanistic and manufacturing capabilities have improved, exosomes have become a low-cost, easily accessible, reproducible, scalable option. Exosomes are a form of biochemical cue, like platelets, stem cells, polynucleotides, and even synthetic sources such as recombinant growth factors or signaling molecules.

Exosomes can be derived from a range of cell and tissue types, and it is important to evaluate these products carefully. The complement of signals within an exosome are a function of tissue (and even species) of origin. In platelets and stem cells, meanwhile, the biochemical signaling molecules present are determined by cellular origin; younger and healthier sources often give rise to better results, and the activity of signals from senescent cells can have a reduced clinical impact.

Exosomes, briefly, provide an ability for cells to communicate with each other. Many companies are coming to the market with what they claim are exosomes, but what is important is what is actually within the vesicle. They have a number of capabilities—anti-inflammation, wound healing, cell proliferation, etc—but, ultimately, what is in those exosome vesicles? How highly enriched and purified are the vesicles? Are they conditioned media with a small number of exosomes, or are they all highly enriched, isolated exosomes that are purified? That makes a difference.

PRP, for example, is a form of exosome and should be distilled to make it as concentrated as possible. The more highly enriched and highly purified those exosomes are, the more robust of a response they will generate.

Some companies are coming to market with platelet-derived growth factor and insulin-derived growth factor. Often, these exogenous growth factors can be found recombinantly, but they can also be found within the vesicle of certain exosomes, so some companies are promoting the profiling of their exosomes.

SCAFFOLDS

A scaffold involves biomaterial encapsulation and the slow release of biomolecules. It may encourage molecular assembly or induce local processes of remodeling that can lead to tissue regeneration. Scaffolds can be purely structural, or modified to permit controlled delivery of a drug or to sequester and present growth factors. The material itself may stimulate regeneration.

Biomaterial scaffolds used in aesthetics include meshes, sutures, and threads (eg, PLLA, PGLA, PDO); acellular matrices; self-assembling gels (eg, self-assembling peptide or collagen gels); adipose matrices; and fillers.^3,4

One way to differentiate biostimulatory fillers is based on the mechanism of action. For CaHA, the type of response is mechanotransduction;^5-7 for PLLA, it is a subclinical foreign body inflammatory response;⁸ and for PMMA, it is a normal wound healing response.⁹

Multiple modalities within this category can be utilized in the same session. This is useful because it leverages two different mechanisms of action. In traditional layered combination approaches, regenerative technologies are combined with technologies such as energy-based devices for synergistic effects; examples include microfocused ultrasound with visualization (MFU-V) and CaHA, or radiofrequency microneedling and PRP. More novel approaches to combined treatment include hyaluronidase with CaHA and PRP, or combining CaHA, PLLA, hyaluronic acid, and PRP. The addition of anti-aging supplements or adjuncts, such as mTOR inhibitors, NAD+, and resveratrol, also can be useful and create further synergistic effects.

CONCLUSION

The field of regenerative medicine in aesthetics has evolved significantly, encompassing a wide range of innovative therapies and techniques that synergize to promote tissue repair and rejuvenation. Stem cells, particularly ADSCs, offer promising potential due to their high-quality and abundance within tissues, though their scalability and cost remain challenges. Exosomes have emerged as a scalable, cost-effective alternative, facilitating cellular communication and offering therapeutic benefits through enriched biochemical cues. Scaffolds, meanwhile, provide crucial structural support and enable controlled delivery of biomolecules, enhancing tissue regeneration and remodeling.

As our understanding of these modalities deepens, the integration of various regenerative technologies can yield synergistic effects, paving the way for more effective and comprehensive aesthetic treatments. The future of regenerative medicine in aesthetics lies in the continued refinement of these therapies and the development of new combinations that leverage their distinct mechanisms of action, ultimately improving patient outcomes and advancing the field of anti-aging and regenerative medicine.

Disclosures: Dr. Khalifian is a Clinical Investigator and Consultant for Allergan/AbbVie, Galderma, Merz, and BENEV; and an Advisory Board member for Allergan/AbbVie, Galderma, and Merz.

1. Armstrong JPK, Keane TJ, Roques AC, et al. Sci Transl Med. 2020;12(572):eaaz2253.

2. Hare JM, Beerman I. J Gerontol A Biol Sci Med Sci. 2019;74(9):1339-1340.

3. Zarbafian M, Fabi SG, Dayan S, Goldie K. Dermatolog Surg. 2022;48[1]:101-108.

4. Few J. Aesthet Surg J Open Forum. 2022;4:ojac037.

5. Marmur ES, et al. J Cosmet Laser Ther. 2004;6:223-226.

6. Zerbinati N, et al. Arch Dermatol Res. 2017;309(5):389-396.

7. Zerbinati N, Caligaro A. Clin Cosm Invest Dermatol. 2018;11:29-35.

8. Fitzgerald R, et al. Aesthet Surg J. 2018;38(suppl_1):S13-S17.

9. Stein P, et al. J Dermatol Sci. 2015;78:26-33.