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CosmoDerma

Review Article

Regenerative medicine in aesthetics

Hitaishi Mehta1, Anuradha Bishnoi1, Sunil Dogra1
Department of Dermatology Venereology & Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
1

ABSTRACT
Regenerative medicine refers to the restoration of the form and function of damaged and diseased tissues by
upregulation of natural regenerative processes present in the human body. Applications of regenerative medicine in
dermatology are numerous, ranging from the acceleration of wound healing, hair restoration, mesenchymal stem cell
augmented fat transfer, skin rejuvenation, enhancing results, and reducing downtime postprocedure and postlaser,
*Corresponding author: etc. In modern aesthetic practice, the most prominent among current regenerative treatments are platelet-rich plasma
Sunil Dogra, (PRP), stem cells, growth factors, and most recently, exosomes. Most of the modalities available at present lack
Professor, Department of high-quality evidence supporting their use and good quality clinical trials are required for the optimization of cellular
source, dose, and administration intervals before these modalities are deemed acceptable for use at a wider scale.
Dermatology, Venereology
and Leprology, Postgraduate Keywords: Aesthetics, Regenerative, Stem cells, Platelet-rich plasma, Exosomes
Institute of Medical Education
and Research, Sector 12,
Chandigarh 160012, India.
REGENERATIVE MEDICINE IN AESTHETICS
[email protected]
Regenerative medicine can be defined as “an interdisciplinary field of research and clinical
Received : 13 April 2022 applications focused on the repair, replacement or regeneration of cells, tissues or organs to
Accepted : 16 May 2022 restore impaired function resulting from any cause, including congenital defects, disease,
Published : 01 June 2022 trauma, and aging.” The idea behind regenerative medicine is to restore form and function to
damaged and diseased tissues through biological approaches. Modern regenerative treatments
DOI work at the cellular level to upregulate natural regenerative processes present in the human
10.25259/CSDM_46_2022
body. Applications of regenerative medicine in dermatology are numerous, ranging from the
Quick Response Code: acceleration of wound healing with platelet-rich fibrin (PRF), hair restoration, skin rejuvenation,
mesenchymal stem cell augmented fat transfer, enhancing results, and reducing downtime
postprocedure and postlaser, etc.
Regenerative medicine aims at understanding the cell to cell interactions and what drives
them, in order to harness them for therapeutic use without causing injury. Procedures such
as radiofrequency ablation and carboxytherapy employ natural healing mechanisms of the
skin and may be considered a form of regenerative therapy. In modern aesthetic practice, the
most prominent among current regenerative treatments are platelet-rich plasma (PRP), stem
cells, growth factors, and most recently, exosomes. The idea is to develop safe and effective
therapies which produce desired results either alone or in combination with existing therapies.
Regenerative medicine is among the most rapidly growing branches of science, and knowledge
regarding the basic principles of regenerative aesthetics is imperative among dermatologists
and aesthetic practitioners.

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 Mehta, et al.: Regenerative aesthetics

STEM CELLS in hair density on trichogram was noted after 3 monthly

injections of this protein extract and noticeable improvements
The cardinal properties of stem cells, that is, self-renewal were seen clinically after 4–5 months.[11]
and plasticity have been utilized in the field of regenerative
medicine. According to their differentiation potential, they Other stem cell sources that have been used for AGA include
may be categorized into totipotent, pluripotent, multipotent, HFSCs and bone marrow-derived mononuclear cells. HFSCs
and unipotent stem cells.[1] Totipotent and pluripotent stem have been obtained by splitting and centrifugation of scalp
cells are only found in the embryo and can differentiate into biopsies, and a significant increase in hair count and density
cell lines of all three germ layers. Derivation of embryonic was observed as compared to placebo in split-scalp studies
stem cells (ESCs) requires disruption of the early embryo and after three injections administered 45 days apart.[12] No
is hence associated with several ethical concerns. Somatic cells significant difference in stem cell count and hair density was
from adults may be reprogrammed by activation of certain noted in a study that compared autologous HFSCs and bone
transcription factors to generate induced pluripotent stem marrow-derived mononuclear cells as stem cell sources.[13]
cells.[2] Adult stem cells include multipotent and unipotent
stem cells which have gained popularity in recent times due Stem cells in skin rejuvenation
to their role in tissue maintenance and injury repair.
ADSCs have been demonstrated to have a whitening effect,
Umbilical cord blood is a source of multipotent stem cells anti-oxidant action, and stimulate fibroblast proliferation
that does not require surgical intervention for retrieval in preclinical studies, suggesting their possible role in the
as it is obtained after clamping of the umbilical cord.[3] treatment of skin aging.[14-17] This has been translated to
Sources of autologous stem cells include adipose-derived clinical improvement in several studies, most of which
stem cells (ADSCs), hair follicle stem cells (HFSCs), dermal combined stem cells with microneedling.[18] Zhou et al.
fibroblast-derived stem cells, and melanocyte stem cells.[4] compared the combination of ADSCs and fractional carbon
ADSCs represent the most popular stem cells utilized dioxide laser with fractional carbon dioxide laser alone in a
in aesthetics due to their abundance, safety, and ease of split-face trial of 13 patients with acne scars and nine patients
harvesting.[5] A stromal vascular fraction (SVF) is obtained with skin rejuvenation needs.[19] A higher improvement in
by centrifugation of aspirate obtained via liposuction.[6] In patient satisfaction, skin elasticity, and hydration was noted
addition to adipocyte stem cells, SVF consists of preadipocytes, in the combination group. Recently, nano fat emulsions have
pericytes, hematopoietic progenitor cells, fibroblasts, been utilized for facial rejuvenation.[20] These are obtained by
myocytes, monocytes, endothelial cells, macrophages, and mechanical emulsification of liposuction aspirate to yield a
lymphocytes. ADSCs may be isolated from SVF or the SVF liquid solution. Other stem cells that have been utilized for
may be used directly for aesthetic procedures. facial rejuvenation include ESCs and amniotic membrane
stem cells.[21,22]
Stem cells in hair restoration
Stem cells in wound healing
Stem cells are present in hair follicle bulge and dermal
papilla and are essential for the normal hair cycle. Exogenous Stem cells possess the ability to induce cellular differentiation,
stem cells are an exciting approach to the management of regeneration, ability to release of growth factors, and
androgenetic alopecia (AGA) due to their potential role in immunomodulation. These properties may be useful in the
hair growth and regeneration. Several studies have utilized management of chronic nonhealing ulcers. Among various
ADSCs as a remedy for AGA. A pilot case series of nine cutaneous stem cell sources, SVF from adipose tissue has
patients utilizing SVF-enhanced autologous fat transfer been used widely, due to its ability to differentiate into
reported a 23% increase in hair density after 24 weeks.[7] different components that may expedite wound healing,
A large study of 71 AGA patients (STYLE trial) compared such as hematopoietic stem cells, fibroblasts, pericytes,
two doses of ADSCs with autologous fat transfer and saline.[8] endothelial cells, and preadipocytes. Garg et al. described
Low dose ADSCs were found to significantly improve hair the successful use of a combination of erbium YAG laser,
density in the subgroup with early hair loss in this study. PRP, and autologous fat transplantation in a patient with a
Topically applied ADSCs have also shown promise as a recurrent trophic ulcer.[23]
therapy for AGA.[9]
Other dermatologic disorders in which stem cell therapy
Other studies have utilized an ADSC-conditioned medium, has been utilized include pemphigus, systemic sclerosis,
which comprises a lyophilized form of protein secreted from systemic lupus erythematosus, psoriasis, vitiligo, and
cultured ADSCs amassed from healthy adults. This medium epidermolysis bullosa.[24] It must be noted that stem cell
is rich in growth factors that enhance the longevity and therapies are still in their nascent stages. Potential adverse
multiplication of dermal papilla cells.[10] A significant increase effects such as rejection, malignant potential, uncontrolled

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 Mehta, et al.: Regenerative aesthetics

proliferation, cross-contamination with other cell lineages, sessions per month and hair regrowth (r = 0.5, P = 0.03),
and hyperimmune response cannot be ignored. No standard while mean age was negatively correlated with the percentage
protocols are available for obtaining autologous stem cells, change in hair density (r = -0.56, P = 0.016).[30] Most studies
and as a result standardization and quality remain an issue. that recruited both men and women indicate that PRP
Large-scale studies and randomized controlled trials are treatment may be more effective in male AGA. Several
necessary, along with strict regulatory oversight. Stem cells randomized controlled trials have demonstrated synergistic
are currently not approved for commercial use in India and effects of the combination of PRP with oral finasteride and
their use outside the purview of clinical trials is prohibited. topical minoxidil.[31-34] Overall, the evidence suggests that
Among dermatological disorders, the use of Hematopoetic PRP is a safe and effective treatment for hair loss due to AGA.
Stem Cell Transplantation (HSCT) is permitted for children
(but not adults) with systemic sclerosis.[24] Growth factors in skin rejuvenation

Tissue regeneration properties of PRP have been utilized

GROWTH FACTORS
for facial rejuvenation, both topically and as intradermal
Growth factors are chemical messengers that act by modifying injections. Most of the clinical benefits have been reported by
the cellular microenvironment to enhance cell growth, uncontrolled studies such as case reports and case series, many
differentiation, and tissue repair. PRP is a platelet concentrate of which have failed to describe the method of PRP preparation
derived from whole blood. It is rich in growth factors that and activation and lacked clearly defined endpoints. Efficacy in
modulate biological activities, including stimulation of controlled studies with a high level of evidence has been less
stem cell proliferation and differentiation, angiogenesis, and promising. A recent split-face study of 19 women compared
collagen production. The growth factors secreted from PRP the efficacy of lyophilized PRP with saline injection.[35]
include (but are not limited to) transforming growth factor-β, A higher increase in dermal thickness was observed with
platelet-derived growth factor, insulin-like growth factor-1 saline solution, with no difference in collagen synthesis among
(IGF-1), hepatocyte growth factor (HGF), keratinocyte the two arms. The synergistic effect of PRP with hyaluronic
growth factor (KGF), epidermal growth factor and vascular acid was reported by another large trial, and significant
endothelial growth factor. The biological characteristics of PRP improvement in skin elasticity and facial appearance was noted
depend upon the concentration of platelets and the method of with the combination as compared to either therapy alone.[36]
preparation. Platelet concentration up to five times is generally Increased concentration of growth factors has been observed
considered adequate for its biological action, with higher to improve efficacy, although not in direct proportion to the
concentration not necessarily producing better results.[25] No concentration.[37] Microneedling with PRP and PRP injection
standard guidelines have been formulated for the preparation can be combined, as the former improves skin texture while
of PRP. On the basis of composition, PRP has been classified the latter improves volume by stimulating collagen production.
into pure PRP, leukocyte and PRP, pure PRF, and leukocyte
and PRF.[26] PRP is currently being used in aesthetics for Growth factors in acne scars
skin rejuvenation, hair restoration, and scar repair, usually Several studies have utilized PRP as an adjunctive treatment
combined with other procedures such as microneedling. to microneedling and fractional carbon dioxide laser in acne
scarring. A systematic review analyzing the utility of PRP in
Growth factors in hair restoration acne scarring concluded that two to three consecutive monthly
AGA is characterized by premature termination of the sessions of PRP in combination with fractional carbon
anagen phase of the hair cycle due to dysregulation of dioxide laser may improve the results and reduce postlaser
the β-catenin/WNT pathway. Growth factors in PRP are downtime.[38] The evidence in support of microneedling and
individually known to play important roles in the regulation PRP combination is however scarce. Although some studies
of the hair cycle.[27–29] They act either by regulating of have reported improved results with a combination,[39–41]
β-catenin/WNT pathway or by providing a permissive others have shown no added benefits.[42,43] It is notable that
microenvironment for hair growth. The therapeutic efficacy patients subjectively report higher satisfaction rates with
of PRP in patients with AGA has been demonstrated in a combination of PRP and microneedling owing to the
several clinical trials. A quantitative meta-analysis included reduction in post-procedure erythema and edema. Objective
17 trials of PRP therapy in AGA, including both male and evidence regarding improvement of acne scarring with the
female AGA, monotherapy, and combination therapy. A combination is lacking.
significant increase in hair density was noted, from 141.9 ± Considered one of the safest aesthetic procedures and cures
108.2 hairs/cm2 at baseline to 177.5 ± 129.7 hairs/cm2 at the end for all, the future of PRP is quite promising. The major
of the treatment period (P = 0.0004).[30] A significant positive limitation in the evaluation of therapeutic efficacy of PRP is
correlation was observed between the number of treatment the lack of standardized protocol for PRP preparation and

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 Mehta, et al.: Regenerative aesthetics

activation. Little is known about the biological action and elongation was noted in another study, with increased
tissue interactions of PRP. The need for repeated injections expression of growth factors such as HGF, IGF-1, and KGF in
and lack of long-term safety and efficacy data are other DPCs.[54] DPC-derived exosomes may be a promising agent
limitations to PRP therapy. for the prevention and treatment of hair loss. Suspension
mediums such as cryogel wound dressings[55] and hyaluronic
EXOSOMES acid patches [56] have been utilized to increase the efficiency
and prolong the action of exosome injections in promoting
Exosomes are cell-originated vesicular structures with hair regrowth.
a lipid bilayer membrane containing proteins, nucleic
acids, and lipids secreted by various cells. They have been Exosomes in skin rejuvenation
demonstrated to play an important role in cell-to-cell
communication and modulation of cellular replication, Regulation of the properties of human dermal fibroblasts
differentiation, and apoptosis. Endogenic exosomes in the (HDF) via exosomes may potentially have a role as an anti-
skin have been implicated in various chronic inflammatory aging therapy. Exosomes derived from HDF spheroids led
skin diseases.[44] Exosomes derived from stem cells may have to increased production of procollagen type I and decreased
a potential therapeutic role in hair restoration by regulation expression of matrix metalloproteinase-1 in a nude mice
of hair cycle, in skin pigmentation by modulation of melanin photoaging model, via upregulation of TGF-β and down-
synthesis, in skin rejuvenation and scar repair by alteration regulation of tumor necrosis factor-α.[57] Human-induced
of collagen synthesis. pleuripotent cell-derived exosomes amended changes of
photoaging in HDFs by increasing collagen I production,
Exosomes in scar repair reduction of expression of MMP-1/3, and downregulation
of senescence-associated β-galactosidase production.[58]
Exosome-mediated intercellular communication among Embryonic stem cell-derived exosomes have exhibited
macrophages, fibrocytes, and fibroblasts/myofibroblasts amelioration of senescence via modulation of the TGF-β
are essential for scar formation.[45,46] Blockade of exosome receptor 2 pathway in HDFs.[59]
generation by M2 macrophages has been successfully
used to suppress hypertrophic scar formation.[45] Hu et al.
Exosomes in skin pigmentation
demonstrated the wound healing potential of adipose
mesenchymal stem cells (ASC) derived exosomes in a mouse Exosomes derived from keratinocytes have an important
model.[47] ASCs-derived exosomes were internalized by role in pigment production by melanocytes.[60] Keratinocyte
fibroblasts and optimized their migration and replicative derived exosomes had a high concentration of miR-330–
capabilities along with collagen and elastin production. 5p which led to an increased expression of miR-330–5p
Further exploration of the role of ASCs-derived exosomes in melanocytes, with the end result of decreased melanin
revealed their role in extracellular matrix remodeling and production and tyrosinase gene expression.[60] Phototype-
scarless wound repair, by regulation of collagen type III dependence and UV-B mediated modulation of miRNA
to type I ratio, transforming growth factor (TGF)—β3 profile of keratinocyte-derived exosomes was reported by
to TGF-β1 ratio, and matrix metalloproteinase-3 to tissue Cicero et al.[61] Kim et al. reported stimulation of melanin
inhibitor of metalloproteinase-1 ratio, and by modulation production by inhibition of MITF expression by miR-675
of fibroblast differentiation.[48] Exosomes derived from other from keratinocyte-derived exosomes.[62] Further studies on
types of mesenchymal stem cells (MSCs), such as induced exosome-mediated interaction between keratinocytes and
pleuripotent stem cells,[49] human menstrual blood-MSCs,[50] melanocytes present an exciting prospect for the regulation
human umbilical cord MSCs,[51] human umbilical cord of pigment production in healthy and diseased states.
plasma cells[52] have also been demonstrated to modulate scar
The promising field of exosomes is however not devoid of
repair in mouse models.
limitations. Lack of standardization in isolation, production,
yield, and identification compromises the qualitative analysis
Exosomes in hair restoration
of exosomes. Complete isolation of exosomes from the source
Hair follicle stem cells and dermal papilla cells (DPCs) are is difficult, improvement in isolation techniques is desirable to
essential for hair growth and maintenance of the normal hair improve yield and purity. The existing literature only pertains
cycle. Exosomes derived from DPCs have been observed to to preclinical studies and hence may not be predictive of
accelerate the onset of the anagen phase and delay catagen human skin. The mechanism of exosomes and the biological
in mouse model.[53] Stimulation of β-catenin and the sonic information transmitted by them is quite complex and not
hedgehog was observed, with enhanced stimulation and entirely understood at present. As demonstrated by the
migration of outer root sheath cells. Increased hair shaft pre-clinical data, exosomes derived from different sources may

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 Mehta, et al.: Regenerative aesthetics

have similar actions, which type of exosome produces higher 8. Kuka G, Epstein J, Aronowitz J, Glasgold MJ, Rogal JG,
clinical efficacy with fewer side effects remains to be explored. Brown W, et al. Cell enriched autologous fat grafts to follicular
niche improves hair regrowth in early androgenetic alopecia.
Aesthet Surg J 2020;40:Np328-np39.
CONCLUSION 9. Tak YJ, Lee SY, Cho AR, Kim YS. A randomized, double-blind,
The rapidly expanding realm of regenerative medicine is vehicle-controlled clinical study of hair regeneration using
adipose-derived stem cell constituent extract in androgenetic
undoubtedly going to play an important role in the field of
alopecia. Stem Cells Transl Med 2020;9:839–49.
aesthetics. There is an increasing demand from patients as
10. Won CH, Yoo HG, Kwon OS, Sung MY, Kang YJ,
well as physicians for effective aesthetic procedures that are Chung JH, et al. Hair growth promoting effects of adipose
safe and harness the natural regenerative mechanisms of the tissue-derived stem cells. J Dermatol Sci 2010;57:134–7.
human body. Most of the modalities available at present lack 11. Fukuoka H, Narita K, Suga H. Hair regeneration therapy:
high-quality evidence supporting their use and good quality Application of adipose-derived stem cells. Curr Stem Cell Res
clinical trials are required for the optimization of cellular Ther 2017;12:531–4.
source, dose, and administration intervals before these 12. Gentile P, Scioli MG, Cervelli V, Orlandi A, Garcovich S.
modalities are deemed acceptable for use at a wider scale. Autologous micrografts from scalp tissue: Trichoscopic and
We offer key insights into this exciting branch of science that long-term clinical evaluation in male and female androgenetic
may be the future of aesthetics in the coming decades. alopecia. BioMed Research International 2020;2020:7397162.
13. Elmaadawi IH, Mohamed BM, Ibrahim ZAS, Abdou SM,
El Attar YA, Youssef A, et al. Stem cell therapy as a novel
Declaration of patient consent
therapeutic intervention for resistant cases of alopecia areata
Patient consent not required as there are no patients in this and androgenetic alopecia. J Dermatolog Treat 2018;29:431–40.
study. 14. Kim WS, Park SH, Ahn SJ, Kim HK, Park JS, Lee GY, et al.
Whitening effect of adipose-derived stem cells: A critical role of
TGF-beta 1. Biol Pharm Bull 2008;31:606–10.
Financial support and sponsorship
15. Kim WS, Park BS, Kim HK, Park JS, Kim KJ, Choi JS, et al.
Nil. Evidence supporting antioxidant action of adipose-derived
stem cells: Protection of human dermal fibroblasts from
Conflict of interest oxidative stress. J Dermatol Sci 2008;49:133–42.
16. Song SY, Jung JE, Jeon YR, Tark KC, Lew DH. Determination of
Author Sunil Dogra is the Deputy Editor of the journal. adipose-derived stem cell application on photo-aged fibroblasts,
based on paracrine function. Cytotherapy 2011;13:378–84.
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