New Frontiers in Skin Rejuvenation, Including Stem Cells and Autologous Therapies Aunna Pourang, MDa, Helena Rockwell, BScb, Kian Karimi, MDc,* KEYWORDS Stem cells Rejuvenation Aesthetic Cosmetic Fat transfer Platelet therapy Adipose Thread lift KEY POINTS Minimally invasive cosmetic procedures are increasing in demand and popularity with a recent trend toward a more natural look. Autologous therapies, such as adipose-derived stem cells, stromal vascular fraction, microfat, nanofat, and platelet therapies, have been shown to effectively rejuvenate the skin. Innovations in botulinum toxin, fillers, and thread lifts parallel the increasing trends in autologous therapy use in aesthetic medicine. A combination approach using both autologous and traditional aesthetic therapies can provide optimal aesthetic outcomes. Video content accompanies this article at http://www.facialplastic.theclinics.com. INTRODUCTION platelets and fibrin from the person’s blood, aging can be delayed or “reversed” with relative safety Minimally invasive cosmetic procedures continue and efficacy. Much of the research on autologous to dominate the aesthetic arena. There are a large therapy is in its infancy, but this revolutionary tech- number of younger patients requesting cosmetic nology holds great promise. procedures with a focus on maintaining a youthful, 1 Noninvasive cosmetic procedures, in general, natural look. For this reason, so-called prejuvena- continue to dominate aesthetics. New develop- tion has become a popular aesthetic goal for many. ments in technologies of botulinum toxin, fillers, There is nothing more natural than a person’s and threads provide patients with multiple own tissues. Autologous therapies are increasingly options. A combination approach of all available being implemented for skin rejuvenation purposes interventions can be used in clinical practice in individuals of all ages. Using an individual’s own to provide patients with optimal, tailored skin fat, yielding nanofat, adipose-derived stem cells rejuvenation. (ASCs), and stromal vascular fraction, as well as Disclosure: K. Karimi is the medical director of CosmoFrance, Inc, which manufactures and distributes platelet- rich fibrin centrifuges and tubes as well as polydioxanone (PDO) threads. A. Pourang has served as a faculty member for LearnSkin.com. H. Rockwell has no relevant financial disclosures. a Department of Dermatology, University of California, Davis, 3301 C Street, Suite 1400, Sacramento, CA 95816, USA; b University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA; c Rejuva Medical Aesthetics, 11645 Wilshire Boulevard #605, Los Angeles, CA 90025, USA * Corresponding author. E-mail address: [email protected] Facial Plast Surg Clin N Am 28 (2020) 101–117 https://doi.org/10.1016/j.fsc.2019.09.009 1064-7406/20/Ó 2019 Elsevier Inc. All rights reserved. facialplastic.theclinics.com 102 Pourang et al Regenerative Medicine and plastic surgery practice.2 Because pure ASCs alone require in vitro expansion, which can The therapeutic potential for autologous therapy is be time consuming and labor intensive, SVF is an area of medicine that continues to be explored often used because it already contains ASCs. in many fields, from orthopedics to dermatology and plastic surgery.2 An individual’s tissues and Mechanisms of action and clinical applications cells are processed outside of the body and rein- The regenerative potential of SVF and ASCs is troduced back into the donor, with minimal risk thought to be caused by various mechanisms. of hypersensitivity reactions. Autologous therapies The regenerative ability of the skin is maintained vary and involve different cell types and growth by the stem cells that are present in the hair follicle, factors that help regenerate tissues. interfollicular epidermis, and sebaceous glands, as well as being influenced by mesenchymal- Stem Cells epithelial crosstalk through secreted stimulatory The regenerative potential of stem cells has factors.22–25 Intradermal adipocyte lineage cells expanded beyond the treatment of chronic degen- have been found to be necessary in driving hair fol- erative diseases and into aesthetic medicine. licle stem cell activation and likely play a role in Compared with embryonic stem cells or induced other epithelial stem cell functions.24,26 ASCs are pluripotent stem cells, mesenchymal stem cells also thought to stimulate the recruitment of endog- (MSCs) are preferred for use in clinical practice enous stem cells and promote their differentiation given the high availability, ability to differentiate to cells that are needed, such as at a site of tissue into many cell types, and relative lack of ethical injury.13 In addition, stem cells, in general, have concerns.2 antioxidant capabilities that likely mitigate inflam- ASCs are the multipotent MSC population found mation and wound healing.27 Some investigators in the stromal vascular fraction (SVF) of fat tissue, suggest that the preadipocytes and macrophages with the ability to differentiate into mesoderm, in SVF confer regenerative properties through ectoderm, and endoderm lineages.3–5 ASCs also enhanced immune response or removal of dying show regenerative and wound healing proper- cells, leading to tissue remodeling.28,29 Both ties.6,7 They can be obtained from adipose tissue SVF and ASCs are thought to have properties in large quantities using a standard wet liposuction that increase vascularization, the secretion of procedure under local anesthesia, with minimal growth factors, vascular endothelial growth factor discomfort and morbidity of the patient, and (VEGF), hepatocyte growth factor, and insulinlike without the need for expansion in culture, in growth factor.30–34 Such properties are also likely contrast with bone marrow MSCs (BM-MSCs).8,9 responsible for enhancing fat graft survival. Other sources of stem cells include amniotic fluid Cultured ASCs have been shown to improve stem cells, umbilical cord blood stem cells, and scar outcomes of full-thickness skin defects.35 Wharton jelly, which have greater proliferative Cultured ASCs have also been found to reduce and differentiation potential compared with ASCs wrinkles through collagen and elastic fiber produc- and BM-MSCs, but are limited in cell availability tion and other antiaging effects in the skin through after in vitro expansion.10–12 glycation suppression, antioxidation, and trophic Different methods of ASC isolation have been effects.36,37 SVF, which contains ASCs, has also described in the literature.2,13–15 Lipoaspirate is been used to treat necrosis resulting from facial harvested by using tumescent abdominal liposuc- filler injections.38,39 tion techniques or surgical resection.16 ASCs are usually isolated by collagenase digestion of iso- Scientific evidence and regulatory issues lated white adipose tissue, followed by centrifuga- It is important to keep in mind that stem cell tion to separate the SVF-containing ASCs in the technology is still in its infancy, with US Food pellet fraction from floating adipocytes and and Drug Administration (FDA)–approved trials in blood.8,17–19 SVF is the heterogeneous mixture early phases.2,24,40 Potential side effects of stem of cells obtained by enzymatic separation of adi- cells such as rejection, hyperimmune response, pocytes, and contains fibroblasts, endothelial neoplasm, cross contamination with other stem cells, monocytes, macrophages, granulocytes, cell lines, and uncontrolled differentiation have and lymphocytes.20,21 been proposed.41–44 Human ASCs that have ASCs can ultimately be isolated from SVF after been cultured in vitro for long periods of time separation from adipocytes and can be cultured have been found to produce tumors in immunode- to form fibroblast-like colonies.20 ASCs used alone ficient mice.45 There is also a question as to after expansion in vitro or with SVF are the most whether or not the donor’s age affects the regen- common MSCs used in aesthetic dermatology erative potential of ASCs.46 The lack of safety New Frontiers in Skin Rejuvenation 103 and potential side effects data are limited and superficially with syringe needles. This treatment further randomized clinical trials are necessary.2 has been shown to result in lump-free skin reju- Furthermore, there is no single standard protocol venation and volume enhancement.58 Micro- for obtaining ASCs, which can lead to regulatory SEFFI (M-SEFFI) is a refined version of the SEFFI and quality issues.6,47 procedure, obtaining smoother fat, harvested Some clinicians are even calling on the FDA to with a multiperforated cannula with extremely expedite the oversight of companies and clinics small ports (0.3 mm).21 offering stem cell–based treatments.48 Proced- Nanofat is generated by further processing of ures are being offered in some spalike settings fat via mechanical emulsification. Tonnard and and are at risk for contamination and infection. colleagues20 describe their procedure for nano- Professional groups are requesting that stem cell fat production in which standard high-negative- products be regulated like drugs, that the scope pressure liposuction is used to harvest fat using of practice for such procedures be regulated, a multiport 3-mm cannula with sharp side holes and that these procedures be performed in of 1 mm in diameter. After saline rinsing and state or national facilities accredited by surgical filtering, adipose tissue is then emulsified by associations. shifting the fat 30 times between two 10-mL