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Exp Biol Med (Maywood). 2021 Aug; 246(16): 1829–1837.
Published online 2021 Jun 8. doi: 10.1177/15353702211020701
PMCID: PMC8381699
PMID: 34102897
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This review is focused on evaluation of methods of facial rejuvenation that have not yet been established as the “typical,” mainstream surgical and non-surgical approaches. The ever-reaching goal to obtain the “fountain of youth” makes this a rapidly evolving field in the scope of regenerative medicine. However, these types of changes are frequently investigated and ahead of regulatory and credentialing bodies. Practitioners use products “off-label” on a not infrequent basis, and updated reviews such as this can help to inform clinicians about the evolving standards of care and risks prior to regulatory process completion, while helping patients to achieve their goals of obtaining youth and improving quality of life.
With aging, there are recognized molecular and histologic skin changes including fibroblast senescence, flattened dermal-epidermal junctions leading to the appearance of atrophy, and decrease in Langerhans and dermal cells. 1 Additionally, the facial bone structure also changes with age; the orbital aperture increases in width and area, and the mandible becomes thinner. 2 One of the most effective and logical ways to achieve facial rejuvenation is through regenerative aesthetics, which utilizes the tissue’s own natural potential to combat cell senescence and tissue atrophy through repairing of aging cells and the tissue matrix.
Regenerative interventions are defined as those leading towards renewal, restoration, and regrowth of damaged tissue.3–5 Advances in molecular biology, genetics, and medical technology as well as empirical clinical experience provide a basis of interventions utilizing potential direct regenerative properties (e.g. stem cells) or those having indirect potential by modulating mesenchymal cells or tissue milieu (e.g. gene/cellular therapy techniques, nanotechnology). 6 Additionally, with the advent of artificial intelligence (AI), we can utilize methods of imaging, molecular, and genetic studies to objectively evaluate patients prior to facial rejuvenation procedures. 7 Moreover, in the future, data-driven simulations can be utilized to predict tissue “needs” and predict outcomes. 7 This concept can be used in conjunction with the direct and already established use of stem cells.
With the combination of this multi-faceted approach, comes the idea of precision medicine for facial rejuvenation, whereby the goals are tailored to an individual’s genetic make-up and needs. This review aims to provide an updated resource on the dynamic changing of approaches for facial rejuvenation to give patients and practitioners a thorough understanding to both surgical and non-surgical approaches to restoring youth.
Today, indications for fat grafting to the face for facial rejuvenation include sun damage, volume deficiency such as orbital, tear trough, and temporal hollowing, skin laxity, and rhytids. 8 In addition, fat grafting can be combined with other procedures such as facelifts, blepharoplasty, and laser resurfacing treatments to improve outcomes of facial rejuvenation through a multi-modal technique. Furthermore, fat grafts are biocompatible, clinically versatile, safe and provide a natural appearance. 3
A well-described problem with fat grafting is the variable rates of fat grafting survival. This can range from 25 to 70%,13,14 leading to great efforts to improve fat harvesting, processing, and grafting methods.13,14 Coleman was one of the first to describe that the key to enhancing fat grafting survival was to inject in “miniscule amounts,” thereby increasing the contact of the fat to surrounding vascular tissues. 15 Additionally, protocols developed by investigators from our group standardized the most efficacious ways for procurement, isolation, characterization, and evaluation of human mesenchymal cells. 16
There are different theories for adipocyte survival. One theory proposes that dying adipocytes stimulate phagocytosis leading to transformation of these “wandering cells” into embryonic fat cells, mature cells, and connective tissue, 18 while another theory suggests that the final amount of fat survival depends on the number of viable adipocytes that were grafted. 17 Strategies have been attempted to improve fat grafting outcomes and survival through the discovery of regenerative stem cells. Given the complexity of stem cells and their interaction with the host environment, it may be that specific conditions, such as stem cell dose and timing, determine the anti-senescence (or pro-senescence) fate of fat grafts. 16
Since Zuk et al. first identified regenerative stem cells in adipose tissue, the use of cell therapy for tissue regeneration has become a rapidly evolving field such that regenerative cells including fat cells, adipose-derived stem cells, stromal vascular fraction (SVF), nanofat, and platelet-rich plasma (PRP) have been described specifically for the use of facial rejuvenation.4,18–20 Through the use of these different types of regenerative tissues, one’s youth, beauty, and even function can be restored.
Aspirated adipose tissue is made up of adipocytes and progenitor cells, and it is now known that these preadipocyte progenitor and adipocyte-derived stem cells are attributed to the long-term survival of fat grafting. 13 Adipose-derived stem cells (ADSCs) are an alternate source (as opposed to mesenchymal cells derived from bone) of adult multipotent stem cells found within the perivascular adipose stroma. 4 These cells have the ability of self-renewal, differentiation into other mesoderm derivatives, and have paracrine properties, with ability of secreting growth factors and promoting angiogenesis and anti-apoptosis. 21 Due to ease of harvest and ability to harvest in large quantities, ADSCs have become a frequently used adult stem cell population for regenerative medicine and supplementation of fat grafts for facial contouring. 22
Not only do these cells have the ability to differentiate, but studies have also shown the trophic abilities of these stem cells. It appears that fat processing and enrichment with autologous stem cells improves fat cell viability and clinical volume retention (Figure 1). Intravenous injection of ADSCs with fat grafting has helped to improve retention of the grafted fat as well as significantly higher adipogenesis gene expression and vasularity.23,24 Additionally, SVF, which is the substance created after collagenase digestion of perivascularr adipose tissue and stroma, contains numerous types of progenitor stem cells including ADSCs, pericytes, endothelial progenitor cells, hematopoietic cells, and fibroblasts. 25 These cells within the SVF secrete growth factors and cytokines contributing to its regenerative properties through stimulating tissue growth and angiogenesis. 24 Cell-assisted lipotransfer is the use of SVF-enriched fat grafts, and studies using this technique have shown that there is improved fat retention of the grafted fat versus just fat grafting alone.22,26–28 A unique form of SVF was studied in the form of a gel product that has been processed to have high concentrations of ADSCs and other SVF cells without the pro-inflammatory lipids, therefore, producing long-term higher volume retention and rejuvenation effects. 28
[IMG alt="An external file that holds a picture, illustration, etc.Object name is 10.1177_15353702211020701-fig1.jpg"]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381699/bin/10.1177_15353702211020701-fig1.jpg[/IMG]
Figure 1.
Partitioning and processing of procured fat allows enrichment of the injectate with autologous stem cells. The Celution System equipment allows separation of stem cells within an hour and administration of the stem cell bolus back into the prepared fat for administration during the same operative procedure, in a sterile closed system.
Published online 2021 Jun 8. doi: 10.1177/15353702211020701
PMCID: PMC8381699
PMID: 34102897
Regenerative and stem cell-based techniques for facial rejuvenation
J Sarah Crowley,[IMG alt="corresponding author"]https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/corrauth.gif[/IMG] Amy Liu,[IMG alt="corresponding author"]https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/corrauth.gif[/IMG] and Marek Dobke[IMG alt="corresponding author"]https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/corrauth.gif[/IMG]Author information Copyright and License information PMC Disclaimer
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Abstract
This review discusses the most novel ideas and modalities being incorporated into facial rejuvenation. Recent innovative techniques include the use of regenerative stem cell techniques and regeneration supportive modalities such as nano-technology or gene therapies. This review aims to investigate approaches that are less well known and lacking established evidence in order to proactively study these techniques prior to them becoming popularized. These applications and relevant research were reviewed in the context of both surgical and non-surgical modalities in clinical practice. Future directions include the concept of “precision cosmetic medicine” utilizing gene editing and cellular therapies to tailor rejuvenation techniques based on each individual’s genetic make-up and therefore needs.This review is focused on evaluation of methods of facial rejuvenation that have not yet been established as the “typical,” mainstream surgical and non-surgical approaches. The ever-reaching goal to obtain the “fountain of youth” makes this a rapidly evolving field in the scope of regenerative medicine. However, these types of changes are frequently investigated and ahead of regulatory and credentialing bodies. Practitioners use products “off-label” on a not infrequent basis, and updated reviews such as this can help to inform clinicians about the evolving standards of care and risks prior to regulatory process completion, while helping patients to achieve their goals of obtaining youth and improving quality of life.
Introduction
Facial rejuvenation is a rapidly growing field as patients seek to obtain “the fountain of youth.” Moreover, there has been a significant amount of dedicated research with attempts to delay or reverse aging on both a cellular and macroscale level. A thorough approach to facial rejuvenation necessitates a multi-modal approach that addresses all of the changes that occur with aging including damage to the skin, volume loss of all the tissues of the face including fat and bone, and tissue laxity. With careful evaluation of all of these facets, it is clear that a surgical facelift alone would not address the volume loss and skin damage.With aging, there are recognized molecular and histologic skin changes including fibroblast senescence, flattened dermal-epidermal junctions leading to the appearance of atrophy, and decrease in Langerhans and dermal cells. 1 Additionally, the facial bone structure also changes with age; the orbital aperture increases in width and area, and the mandible becomes thinner. 2 One of the most effective and logical ways to achieve facial rejuvenation is through regenerative aesthetics, which utilizes the tissue’s own natural potential to combat cell senescence and tissue atrophy through repairing of aging cells and the tissue matrix.
Regenerative interventions are defined as those leading towards renewal, restoration, and regrowth of damaged tissue.3–5 Advances in molecular biology, genetics, and medical technology as well as empirical clinical experience provide a basis of interventions utilizing potential direct regenerative properties (e.g. stem cells) or those having indirect potential by modulating mesenchymal cells or tissue milieu (e.g. gene/cellular therapy techniques, nanotechnology). 6 Additionally, with the advent of artificial intelligence (AI), we can utilize methods of imaging, molecular, and genetic studies to objectively evaluate patients prior to facial rejuvenation procedures. 7 Moreover, in the future, data-driven simulations can be utilized to predict tissue “needs” and predict outcomes. 7 This concept can be used in conjunction with the direct and already established use of stem cells.
With the combination of this multi-faceted approach, comes the idea of precision medicine for facial rejuvenation, whereby the goals are tailored to an individual’s genetic make-up and needs. This review aims to provide an updated resource on the dynamic changing of approaches for facial rejuvenation to give patients and practitioners a thorough understanding to both surgical and non-surgical approaches to restoring youth.
Autologous fat and regenerative cell types
At the core of facial rejuvenation is the use of the regenerative properties of stem cells derived from autologous fat. The use of autologous fat for regenerative or reparative techniques was first described by Neuber in 1893 when he described harvesting a patient’s arm fat in order to correct facial scarring contour deformities. 8 Since that time there have been numerous methods, and described applications for the use of fat grafting to the body, but one of the most popularized purposes today is for facial rejuvenation and contouring.8–12Today, indications for fat grafting to the face for facial rejuvenation include sun damage, volume deficiency such as orbital, tear trough, and temporal hollowing, skin laxity, and rhytids. 8 In addition, fat grafting can be combined with other procedures such as facelifts, blepharoplasty, and laser resurfacing treatments to improve outcomes of facial rejuvenation through a multi-modal technique. Furthermore, fat grafts are biocompatible, clinically versatile, safe and provide a natural appearance. 3
A well-described problem with fat grafting is the variable rates of fat grafting survival. This can range from 25 to 70%,13,14 leading to great efforts to improve fat harvesting, processing, and grafting methods.13,14 Coleman was one of the first to describe that the key to enhancing fat grafting survival was to inject in “miniscule amounts,” thereby increasing the contact of the fat to surrounding vascular tissues. 15 Additionally, protocols developed by investigators from our group standardized the most efficacious ways for procurement, isolation, characterization, and evaluation of human mesenchymal cells. 16
There are different theories for adipocyte survival. One theory proposes that dying adipocytes stimulate phagocytosis leading to transformation of these “wandering cells” into embryonic fat cells, mature cells, and connective tissue, 18 while another theory suggests that the final amount of fat survival depends on the number of viable adipocytes that were grafted. 17 Strategies have been attempted to improve fat grafting outcomes and survival through the discovery of regenerative stem cells. Given the complexity of stem cells and their interaction with the host environment, it may be that specific conditions, such as stem cell dose and timing, determine the anti-senescence (or pro-senescence) fate of fat grafts. 16
Since Zuk et al. first identified regenerative stem cells in adipose tissue, the use of cell therapy for tissue regeneration has become a rapidly evolving field such that regenerative cells including fat cells, adipose-derived stem cells, stromal vascular fraction (SVF), nanofat, and platelet-rich plasma (PRP) have been described specifically for the use of facial rejuvenation.4,18–20 Through the use of these different types of regenerative tissues, one’s youth, beauty, and even function can be restored.
Aspirated adipose tissue is made up of adipocytes and progenitor cells, and it is now known that these preadipocyte progenitor and adipocyte-derived stem cells are attributed to the long-term survival of fat grafting. 13 Adipose-derived stem cells (ADSCs) are an alternate source (as opposed to mesenchymal cells derived from bone) of adult multipotent stem cells found within the perivascular adipose stroma. 4 These cells have the ability of self-renewal, differentiation into other mesoderm derivatives, and have paracrine properties, with ability of secreting growth factors and promoting angiogenesis and anti-apoptosis. 21 Due to ease of harvest and ability to harvest in large quantities, ADSCs have become a frequently used adult stem cell population for regenerative medicine and supplementation of fat grafts for facial contouring. 22
Not only do these cells have the ability to differentiate, but studies have also shown the trophic abilities of these stem cells. It appears that fat processing and enrichment with autologous stem cells improves fat cell viability and clinical volume retention (Figure 1). Intravenous injection of ADSCs with fat grafting has helped to improve retention of the grafted fat as well as significantly higher adipogenesis gene expression and vasularity.23,24 Additionally, SVF, which is the substance created after collagenase digestion of perivascularr adipose tissue and stroma, contains numerous types of progenitor stem cells including ADSCs, pericytes, endothelial progenitor cells, hematopoietic cells, and fibroblasts. 25 These cells within the SVF secrete growth factors and cytokines contributing to its regenerative properties through stimulating tissue growth and angiogenesis. 24 Cell-assisted lipotransfer is the use of SVF-enriched fat grafts, and studies using this technique have shown that there is improved fat retention of the grafted fat versus just fat grafting alone.22,26–28 A unique form of SVF was studied in the form of a gel product that has been processed to have high concentrations of ADSCs and other SVF cells without the pro-inflammatory lipids, therefore, producing long-term higher volume retention and rejuvenation effects. 28
[IMG alt="An external file that holds a picture, illustration, etc.Object name is 10.1177_15353702211020701-fig1.jpg"]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381699/bin/10.1177_15353702211020701-fig1.jpg[/IMG]
Figure 1.
Partitioning and processing of procured fat allows enrichment of the injectate with autologous stem cells. The Celution System equipment allows separation of stem cells within an hour and administration of the stem cell bolus back into the prepared fat for administration during the same operative procedure, in a sterile closed system.
