John K. Nia, MD

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

Vaginal rejuvenation encompasses a group of procedures that alter the vaginal anatomy to improve cosmesis or achieve more pleasurable sexual intercourse. External vaginal procedures are defined as those performed on the female genitalia outside of the vaginal introitus, with major structures including the labia majora, mons pubis, labia minora, clitoral hood, clitoral glans, and vaginal vestibule. Internal vaginal procedures are defined as those performed within the vagina, extending from the vaginal introitus to the cervix.

The prevalence of elective vaginal rejuvenation procedures has increased in recent years, a trend that may be attributed to greater exposure through the media, including reality television and pornography. In a survey of 482 women undergoing labiaplasty, nearly all had heard about rejuvenation procedures within the last 2.2 years, and 78% had received their information through the media.¹ Additionally, genital self-image can have a considerable effect on a woman’s sexual behavior and relationships. Genital dissatisfaction has been associated with decreased sexual activity, whereas positive genital self-image correlates with increased sexual desire and less sexual distress or depression.^2,3

Currently, the 2 primary applications of noninvasive vaginal rejuvenation are vaginal laxity and genitourinary syndrome of menopause (GSM). Vaginal laxity occurs in premenopausal or postmenopausal women and is caused by aging, childbearing, or hormonal imbalances. These factors can lead to decreased friction within the vagina during intercourse, which in turn can decrease sexual pleasure. Genitourinary syndrome of menopause, previously known as vulvovaginal atrophy, encompasses genital (eg, dryness, burning, irritation), sexual (eg, lack of lubrication, discomfort or pain, impaired function), and urinary (eg, urgency, dysuria, recurrent urinary tract infections) symptoms of menopause.⁴

Noninvasive procedures are designed to apply ablative or nonablative energy to the vaginal mucosa to tighten a lax upper vagina, also known as a wide vagina.⁵ A wide vagina has been defined as a widened vaginal diameter that interferes with sexual function and sensation.⁶ Decreased sexual sensation also may result from fibrosis or scarring of the vaginal mucosa after prior vaginal surgery, episiotomy, or tears during childbirth.⁷ The objective of rejuvenation procedures to treat the vaginal mucosa is to create increased frictional forces that may lead to increased sexual sensation.⁸ Although there are numerous reports of heightened sexual satisfaction after reduction of the vaginal diameter, a formal link between sexual pleasure and vaginal laxity has yet to be established.^8,9 At present, there are no US Food and Drug Administration (FDA)–approved energy-based devices to treat urinary incontinence or sexual function, and the FDA recently issued an alert cautioning patients on the current lack of safety and efficacy regulations.¹⁰

In this article we review the safety and efficacy data behind lasers and radiofrequency (RF) devices used in noninvasive vaginal rejuvenation procedures.

Lasers

CO₂ Laser
The infrared CO₂ laser utilizes 10,600-nm energy to target and vaporize water molecules within the target tissue. This thermal heating extends to the dermal collagen, which stimulates inflammatory pathways and neocollagenesis.¹¹ The depth of penetration ranges from 20 to 125 μm.¹² Zerbinati et al¹³ demonstrated the histologic and ultrastructural effects of a fractional CO₂ laser on atrophic vaginal mucosa. Comparing pretreatment and posttreatment mucosal biopsies in 5 postmenopausal women, the investigators found that fractional CO₂ laser treatment caused increased epithelial thickness, vascularity, and fibroblast activity, which led to augmented synthesis of collagen and ground substance proteins.¹³

New devices seek to translate these histologic improvements to the aesthetic appearance and function of female genitalia. The MonaLisa Touch (Cynosure), a new fractional CO₂ laser specifically designed for treatment of the vaginal mucosa, uses dermal optical thermolysis (DOT) therapy to apply energy in a noncontinuous mode at 200-μm dots. Salvatore et al¹⁴ examined the use of this device in a noncontrolled study of 50 patients with GSM, with each patient undergoing 3 treatment sessions at monthly intervals. Intravaginal treatments were performed at the following settings: DOT (microablative zone) power of 30 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack parameter of 1 to 3. The investigators used the Vaginal Health Index (VHI) to objectively assess vaginal elasticity, secretions, pH, mucosa integrity, and moisture. Total VHI scores significantly improved between baseline and 1 month following the final treatment (mean score [SD], 13.1 [2.5] vs 23.1 [1.9]; P<.0001). There were no significant adverse events, and 84% of patients reported being satisfied with their outcome; however, the study lacked a comparison or control group, raising the possibility of placebo effect.¹⁴

Other noncontrolled series have corroborated the benefits of CO₂ laser in GSM patients.^15,16 In one of the largest studies to date, Filippini et al¹⁷ reviewed the outcomes of 386 menopausal women treated for GSM. Patients underwent 3 intravaginal laser sessions with the MonaLisa Touch. Intravaginal treatments were performed at a DOT power of 40 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack of 2. For the vulva, the DOT power was reduced to 30 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack of 1. Two months after the final treatment session, patients completed a nonvalidated questionnaire about their symptoms, with improved dryness reported in 60% of patients, improved burning in 56%, improved dyspareunia in 49%, improved itch in 56%, improved soreness in 73%, and improved vaginal introitus pain in 49%. Although most patients did not experience discomfort with the procedure, a minority noted a burning sensation (11%), bother with handpiece movement (6%), or vulvar pain (5%).¹⁷

Recently, Cruz et al¹⁸ performed one of the first randomized, double-blind, placebo-controlled trials comparing fractional CO₂ laser therapy, topical estrogen therapy, and the combination of both treatments in patients with GSM. Forty-five women were included in the study, and validated assessments were performed at baseline and weeks 8 and 20. Intravaginal treatments were performed at a DOT power of 30 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack of 2. Importantly, the study incorporated placebo laser treatments (with the power adjusted to 0.0 W) in the topical estrogen group, thereby decreasing result bias. There was a significant increase in VHI scores from baseline to week 8 (P<.05) and week 20 (P<.01) in all study arms. At week 20, the laser group and laser plus estrogen group showed significant improvements in reported dyspareunia, burning, and dryness, whereas the estrogen arm only reported improvements in dryness (all values P<.05).¹⁸

Erbium-Doped YAG Laser
The erbium-doped YAG (Er:YAG) laser is an ablative laser emitting light at 2940 nm. This wavelength provides an absorption coefficient for water 16 times greater than the CO₂ laser, leading to decreased penetration depth of 1 to 3 μm and reduced damage to the surrounding tissues.^19,20 As such, the Er:YAG laser results in milder postoperative discomfort and faster overall healing times.²¹

In a noncontrolled study of vaginal relaxation syndrome, Lee²² used an Er:YAG laser fitted with Petit Lady (Lutronic) 90° and 360° vaginal scanning scopes. Thirty patients were divided into 2 groups and were treated with 4 sessions at weekly intervals. In group A, the first 2 sessions were performed with the 360° scope, and the last 2 sessions with the 90° scope in multiple micropulse mode (3 multishots; pulse width of 250 μs; 1.7 J delivered per shot). Group B was treated with the 90° scope in all 4 sessions in multiple micropulse mode (same parameters as group A), and during the last 2 sessions patients were additionally treated with 2 passes per session with the 360° scope (long-pulsed mode; pulse width of 1000 μs; 3.7 J delivered per shot). Perineometer measurements taken 2 months after the final treatment showed that the combined patient population experienced significant increases in both maximal vaginal pressure (P<.01) and average vaginal pressure (P<.05). Roughly 76% of patients’ partners noted improved vaginal tightening, and 70% of patients reported being satisfied with their treatment outcome. Histologic specimens taken at baseline and 2 months postprocedure showed evidence of thicker and more cellular epithelia along with more compact lamina propria with denser connective tissue. The sessions were well tolerated, with patients reporting a nonpainful heating sensation in the vagina during treatment. Three patients from the combined patient population experienced a mild burning sensation and vaginal ecchymoses, which lasted 24 to 48 hours following treatment and resolved spontaneously. There was no control group and no reports of major or long-term adverse events.²²

Investigations also have shown the benefit of Er:YAG in the treatment of GSM.^23,24 In a study by Gambacciani et al,²⁴ patients treated with the Er:YAG laser FotonaSmooth (Fotona) every 30 days for 3 months reported significant improvements in vaginal dryness and dyspareunia (P<.01), which lasted up to 6 months posttreatment, though there was no placebo group comparator. Similar results were seen by Gaspar et al²³ using 3 treatments at 3-week intervals, with results sustained up to 18 months after the final session.

Radiofrequency Devices

Radiofrequency devices emit focused electromagnetic waves that heat underlying tissues without targeting melanin. The release of thermal energy induces collagen contraction, neocollagenesis, and neovascularization, all of which aid in restoring the elasticity and moisture of the vaginal mucosa.²⁵ Devices also may be equipped with cooling probes and reverse-heating gradients to protect the surface mucosa while deeper tissues are heated.

Millheiser et al²⁶ performed a noncontrolled pilot study in 24 women with vaginal laxity using the Viveve System (Viveve), a cryogen-cooled monopolar RF device. Participants underwent a single 30-minute session (energy ranging from 75–90 J/cm²) during which the mucosal surface of the vaginal introitus (excluding the urethra) was treated with pulses at 0.5-cm overlapping intervals. Follow-up assessments were completed at 1, 3, and 6 months posttreatment. Self-reported vaginal tightness improved in 67% of participants at 1-month posttreatment and in 87% of participants at 6 months posttreatment (P<.001). There were no adverse events reported.²⁶ Sekiguchi et al²⁷ reported similar benefits lasting up to 12 months after a single 26-minute session at 90 J/cm².

A prospective, randomized, placebo-controlled clinical trial using the Viveve system was recently completed by Krychman et al.²⁸ Participants (N=186) were randomized to receive a single session of active treatment (90 J/cm²) or placebo treatment (1 J/cm²). In both groups, the vaginal introitus was treated with pulses at 0.5 cm in overlapping intervals, with the entire area (excluding the urethra) treated 5 times up to a total of 110 pulses. The primary end point was the proportion of randomized participants reporting no vaginal laxity at 6 months postin-tervention, which was assessed using the Vaginal Laxity Questionnaire. A grade of no vaginal laxity was achieved by 43.5% of participants in the active treatment group and 19.6% of participants in the sham group (P=.002). Overall numbers of treatment-emergent adverse events were comparable between the 2 groups, with the most commonly reported being vaginal discharge (2.6% in the active treatment group vs 3.5% in the sham group). There were no serious adverse events reported in the active treatment group.²⁸

ThermiVa (ThermiGen, LLC), a unipolar RF device, was evaluated by Alinsod²⁹ in the treatment of orgasmic dysfunction. The noncontrolled study included 25 women with self-reported difficulty achieving orgasm during intercourse, each of whom underwent 3 treatment sessions at 1-month intervals. Of the 25 enrolled women, 19 (76%) reported an average reduction in time to orgasm of at least 50%. All anorgasmic patients (n=10) at baseline reported renewed ability to achieve orgasms. Two (8%) patients failed to achieve a significant benefit from the treatments. Of note, the study did not include a control group, and specific data on the durability of beneficial effects was lacking.²⁹

The Ultra Femme 360 (BLT Industries Inc), a monopolar RF device, was evaluated by Lalji and Lozanova³⁰ in a noncontrolled study of 27 women with mild to moderate vaginal laxity and urinary incontinence. Participants underwent 3 treatment sessions at weekly intervals. Vaginal laxity was assessed by a subjective vulvovaginal laxity questionnaire, and data were collected before the first treatment and at 1-month follow-up. All 27 participants reported improvements in vaginal laxity, with the average grade (SD) increasing from very loose (2.19 [1.08]) to moderately tight (5.74 [0.76]; P<.05) on the questionnaire’s 7-point scale. The trial did not include a control group.³⁰

Conclusion

With growing patient interest in vaginal rejuvenation, clinicians are increasingly incorporating a variety of procedures into their practice. Although long-term data on the safety and efficacy of these treatments has yet to be established, current evidence indicates that fractional ablative lasers and RF devices can improve vaginal laxity, sexual sensation, and symptoms of GSM.

To date, major complications have not been reported, but the FDA has advocated caution until regulatory approval is achieved.¹⁰ Concerns exist over the limited number of robust clinical trials as well as the prevalence of advertising campaigns that promise wide-ranging improvements without sufficient evidence. Definitive statements on medical or cosmetic indications will undoubtedly require more thorough investigation. At this time, the safety profile of these devices appears to be favorable, and high rates of patient satisfaction have been reported. As such, noninvasive vaginal rejuvenation procedures may represent a valuable addition to the cosmetic landscape.

Vaginal rejuvenation encompasses a group of procedures that alter the vaginal anatomy to improve cosmesis or achieve more pleasurable sexual intercourse. External vaginal procedures are defined as those performed on the female genitalia outside of the vaginal introitus, with major structures including the labia majora, mons pubis, labia minora, clitoral hood, clitoral glans, and vaginal vestibule. Internal vaginal procedures are defined as those performed within the vagina, extending from the vaginal introitus to the cervix.

The prevalence of elective vaginal rejuvenation procedures has increased in recent years, a trend that may be attributed to greater exposure through the media, including reality television and pornography. In a survey of 482 women undergoing labiaplasty, nearly all had heard about rejuvenation procedures within the last 2.2 years, and 78% had received their information through the media.¹ Additionally, genital self-image can have a considerable effect on a woman’s sexual behavior and relationships. Genital dissatisfaction has been associated with decreased sexual activity, whereas positive genital self-image correlates with increased sexual desire and less sexual distress or depression.^2,3

Currently, the 2 primary applications of noninvasive vaginal rejuvenation are vaginal laxity and genitourinary syndrome of menopause (GSM). Vaginal laxity occurs in premenopausal or postmenopausal women and is caused by aging, childbearing, or hormonal imbalances. These factors can lead to decreased friction within the vagina during intercourse, which in turn can decrease sexual pleasure. Genitourinary syndrome of menopause, previously known as vulvovaginal atrophy, encompasses genital (eg, dryness, burning, irritation), sexual (eg, lack of lubrication, discomfort or pain, impaired function), and urinary (eg, urgency, dysuria, recurrent urinary tract infections) symptoms of menopause.⁴

Noninvasive procedures are designed to apply ablative or nonablative energy to the vaginal mucosa to tighten a lax upper vagina, also known as a wide vagina.⁵ A wide vagina has been defined as a widened vaginal diameter that interferes with sexual function and sensation.⁶ Decreased sexual sensation also may result from fibrosis or scarring of the vaginal mucosa after prior vaginal surgery, episiotomy, or tears during childbirth.⁷ The objective of rejuvenation procedures to treat the vaginal mucosa is to create increased frictional forces that may lead to increased sexual sensation.⁸ Although there are numerous reports of heightened sexual satisfaction after reduction of the vaginal diameter, a formal link between sexual pleasure and vaginal laxity has yet to be established.^8,9 At present, there are no US Food and Drug Administration (FDA)–approved energy-based devices to treat urinary incontinence or sexual function, and the FDA recently issued an alert cautioning patients on the current lack of safety and efficacy regulations.¹⁰

In this article we review the safety and efficacy data behind lasers and radiofrequency (RF) devices used in noninvasive vaginal rejuvenation procedures.

Lasers

CO₂ Laser
The infrared CO₂ laser utilizes 10,600-nm energy to target and vaporize water molecules within the target tissue. This thermal heating extends to the dermal collagen, which stimulates inflammatory pathways and neocollagenesis.¹¹ The depth of penetration ranges from 20 to 125 μm.¹² Zerbinati et al¹³ demonstrated the histologic and ultrastructural effects of a fractional CO₂ laser on atrophic vaginal mucosa. Comparing pretreatment and posttreatment mucosal biopsies in 5 postmenopausal women, the investigators found that fractional CO₂ laser treatment caused increased epithelial thickness, vascularity, and fibroblast activity, which led to augmented synthesis of collagen and ground substance proteins.¹³

New devices seek to translate these histologic improvements to the aesthetic appearance and function of female genitalia. The MonaLisa Touch (Cynosure), a new fractional CO₂ laser specifically designed for treatment of the vaginal mucosa, uses dermal optical thermolysis (DOT) therapy to apply energy in a noncontinuous mode at 200-μm dots. Salvatore et al¹⁴ examined the use of this device in a noncontrolled study of 50 patients with GSM, with each patient undergoing 3 treatment sessions at monthly intervals. Intravaginal treatments were performed at the following settings: DOT (microablative zone) power of 30 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack parameter of 1 to 3. The investigators used the Vaginal Health Index (VHI) to objectively assess vaginal elasticity, secretions, pH, mucosa integrity, and moisture. Total VHI scores significantly improved between baseline and 1 month following the final treatment (mean score [SD], 13.1 [2.5] vs 23.1 [1.9]; P<.0001). There were no significant adverse events, and 84% of patients reported being satisfied with their outcome; however, the study lacked a comparison or control group, raising the possibility of placebo effect.¹⁴

Other noncontrolled series have corroborated the benefits of CO₂ laser in GSM patients.^15,16 In one of the largest studies to date, Filippini et al¹⁷ reviewed the outcomes of 386 menopausal women treated for GSM. Patients underwent 3 intravaginal laser sessions with the MonaLisa Touch. Intravaginal treatments were performed at a DOT power of 40 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack of 2. For the vulva, the DOT power was reduced to 30 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack of 1. Two months after the final treatment session, patients completed a nonvalidated questionnaire about their symptoms, with improved dryness reported in 60% of patients, improved burning in 56%, improved dyspareunia in 49%, improved itch in 56%, improved soreness in 73%, and improved vaginal introitus pain in 49%. Although most patients did not experience discomfort with the procedure, a minority noted a burning sensation (11%), bother with handpiece movement (6%), or vulvar pain (5%).¹⁷

Recently, Cruz et al¹⁸ performed one of the first randomized, double-blind, placebo-controlled trials comparing fractional CO₂ laser therapy, topical estrogen therapy, and the combination of both treatments in patients with GSM. Forty-five women were included in the study, and validated assessments were performed at baseline and weeks 8 and 20. Intravaginal treatments were performed at a DOT power of 30 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack of 2. Importantly, the study incorporated placebo laser treatments (with the power adjusted to 0.0 W) in the topical estrogen group, thereby decreasing result bias. There was a significant increase in VHI scores from baseline to week 8 (P<.05) and week 20 (P<.01) in all study arms. At week 20, the laser group and laser plus estrogen group showed significant improvements in reported dyspareunia, burning, and dryness, whereas the estrogen arm only reported improvements in dryness (all values P<.05).¹⁸

Erbium-Doped YAG Laser
The erbium-doped YAG (Er:YAG) laser is an ablative laser emitting light at 2940 nm. This wavelength provides an absorption coefficient for water 16 times greater than the CO₂ laser, leading to decreased penetration depth of 1 to 3 μm and reduced damage to the surrounding tissues.^19,20 As such, the Er:YAG laser results in milder postoperative discomfort and faster overall healing times.²¹

In a noncontrolled study of vaginal relaxation syndrome, Lee²² used an Er:YAG laser fitted with Petit Lady (Lutronic) 90° and 360° vaginal scanning scopes. Thirty patients were divided into 2 groups and were treated with 4 sessions at weekly intervals. In group A, the first 2 sessions were performed with the 360° scope, and the last 2 sessions with the 90° scope in multiple micropulse mode (3 multishots; pulse width of 250 μs; 1.7 J delivered per shot). Group B was treated with the 90° scope in all 4 sessions in multiple micropulse mode (same parameters as group A), and during the last 2 sessions patients were additionally treated with 2 passes per session with the 360° scope (long-pulsed mode; pulse width of 1000 μs; 3.7 J delivered per shot). Perineometer measurements taken 2 months after the final treatment showed that the combined patient population experienced significant increases in both maximal vaginal pressure (P<.01) and average vaginal pressure (P<.05). Roughly 76% of patients’ partners noted improved vaginal tightening, and 70% of patients reported being satisfied with their treatment outcome. Histologic specimens taken at baseline and 2 months postprocedure showed evidence of thicker and more cellular epithelia along with more compact lamina propria with denser connective tissue. The sessions were well tolerated, with patients reporting a nonpainful heating sensation in the vagina during treatment. Three patients from the combined patient population experienced a mild burning sensation and vaginal ecchymoses, which lasted 24 to 48 hours following treatment and resolved spontaneously. There was no control group and no reports of major or long-term adverse events.²²

Investigations also have shown the benefit of Er:YAG in the treatment of GSM.^23,24 In a study by Gambacciani et al,²⁴ patients treated with the Er:YAG laser FotonaSmooth (Fotona) every 30 days for 3 months reported significant improvements in vaginal dryness and dyspareunia (P<.01), which lasted up to 6 months posttreatment, though there was no placebo group comparator. Similar results were seen by Gaspar et al²³ using 3 treatments at 3-week intervals, with results sustained up to 18 months after the final session.

Radiofrequency Devices

Radiofrequency devices emit focused electromagnetic waves that heat underlying tissues without targeting melanin. The release of thermal energy induces collagen contraction, neocollagenesis, and neovascularization, all of which aid in restoring the elasticity and moisture of the vaginal mucosa.²⁵ Devices also may be equipped with cooling probes and reverse-heating gradients to protect the surface mucosa while deeper tissues are heated.

Millheiser et al²⁶ performed a noncontrolled pilot study in 24 women with vaginal laxity using the Viveve System (Viveve), a cryogen-cooled monopolar RF device. Participants underwent a single 30-minute session (energy ranging from 75–90 J/cm²) during which the mucosal surface of the vaginal introitus (excluding the urethra) was treated with pulses at 0.5-cm overlapping intervals. Follow-up assessments were completed at 1, 3, and 6 months posttreatment. Self-reported vaginal tightness improved in 67% of participants at 1-month posttreatment and in 87% of participants at 6 months posttreatment (P<.001). There were no adverse events reported.²⁶ Sekiguchi et al²⁷ reported similar benefits lasting up to 12 months after a single 26-minute session at 90 J/cm².

A prospective, randomized, placebo-controlled clinical trial using the Viveve system was recently completed by Krychman et al.²⁸ Participants (N=186) were randomized to receive a single session of active treatment (90 J/cm²) or placebo treatment (1 J/cm²). In both groups, the vaginal introitus was treated with pulses at 0.5 cm in overlapping intervals, with the entire area (excluding the urethra) treated 5 times up to a total of 110 pulses. The primary end point was the proportion of randomized participants reporting no vaginal laxity at 6 months postin-tervention, which was assessed using the Vaginal Laxity Questionnaire. A grade of no vaginal laxity was achieved by 43.5% of participants in the active treatment group and 19.6% of participants in the sham group (P=.002). Overall numbers of treatment-emergent adverse events were comparable between the 2 groups, with the most commonly reported being vaginal discharge (2.6% in the active treatment group vs 3.5% in the sham group). There were no serious adverse events reported in the active treatment group.²⁸

ThermiVa (ThermiGen, LLC), a unipolar RF device, was evaluated by Alinsod²⁹ in the treatment of orgasmic dysfunction. The noncontrolled study included 25 women with self-reported difficulty achieving orgasm during intercourse, each of whom underwent 3 treatment sessions at 1-month intervals. Of the 25 enrolled women, 19 (76%) reported an average reduction in time to orgasm of at least 50%. All anorgasmic patients (n=10) at baseline reported renewed ability to achieve orgasms. Two (8%) patients failed to achieve a significant benefit from the treatments. Of note, the study did not include a control group, and specific data on the durability of beneficial effects was lacking.²⁹

The Ultra Femme 360 (BLT Industries Inc), a monopolar RF device, was evaluated by Lalji and Lozanova³⁰ in a noncontrolled study of 27 women with mild to moderate vaginal laxity and urinary incontinence. Participants underwent 3 treatment sessions at weekly intervals. Vaginal laxity was assessed by a subjective vulvovaginal laxity questionnaire, and data were collected before the first treatment and at 1-month follow-up. All 27 participants reported improvements in vaginal laxity, with the average grade (SD) increasing from very loose (2.19 [1.08]) to moderately tight (5.74 [0.76]; P<.05) on the questionnaire’s 7-point scale. The trial did not include a control group.³⁰

Conclusion

With growing patient interest in vaginal rejuvenation, clinicians are increasingly incorporating a variety of procedures into their practice. Although long-term data on the safety and efficacy of these treatments has yet to be established, current evidence indicates that fractional ablative lasers and RF devices can improve vaginal laxity, sexual sensation, and symptoms of GSM.

To date, major complications have not been reported, but the FDA has advocated caution until regulatory approval is achieved.¹⁰ Concerns exist over the limited number of robust clinical trials as well as the prevalence of advertising campaigns that promise wide-ranging improvements without sufficient evidence. Definitive statements on medical or cosmetic indications will undoubtedly require more thorough investigation. At this time, the safety profile of these devices appears to be favorable, and high rates of patient satisfaction have been reported. As such, noninvasive vaginal rejuvenation procedures may represent a valuable addition to the cosmetic landscape.

Vaginal rejuvenation encompasses a group of procedures that alter the vaginal anatomy to improve cosmesis or achieve more pleasurable sexual intercourse. External vaginal procedures are defined as those performed on the female genitalia outside of the vaginal introitus, with major structures including the labia majora, mons pubis, labia minora, clitoral hood, clitoral glans, and vaginal vestibule. Internal vaginal procedures are defined as those performed within the vagina, extending from the vaginal introitus to the cervix.

The prevalence of elective vaginal rejuvenation procedures has increased in recent years, a trend that may be attributed to greater exposure through the media, including reality television and pornography. In a survey of 482 women undergoing labiaplasty, nearly all had heard about rejuvenation procedures within the last 2.2 years, and 78% had received their information through the media.¹ Additionally, genital self-image can have a considerable effect on a woman’s sexual behavior and relationships. Genital dissatisfaction has been associated with decreased sexual activity, whereas positive genital self-image correlates with increased sexual desire and less sexual distress or depression.^2,3

Currently, the 2 primary applications of noninvasive vaginal rejuvenation are vaginal laxity and genitourinary syndrome of menopause (GSM). Vaginal laxity occurs in premenopausal or postmenopausal women and is caused by aging, childbearing, or hormonal imbalances. These factors can lead to decreased friction within the vagina during intercourse, which in turn can decrease sexual pleasure. Genitourinary syndrome of menopause, previously known as vulvovaginal atrophy, encompasses genital (eg, dryness, burning, irritation), sexual (eg, lack of lubrication, discomfort or pain, impaired function), and urinary (eg, urgency, dysuria, recurrent urinary tract infections) symptoms of menopause.⁴

Noninvasive procedures are designed to apply ablative or nonablative energy to the vaginal mucosa to tighten a lax upper vagina, also known as a wide vagina.⁵ A wide vagina has been defined as a widened vaginal diameter that interferes with sexual function and sensation.⁶ Decreased sexual sensation also may result from fibrosis or scarring of the vaginal mucosa after prior vaginal surgery, episiotomy, or tears during childbirth.⁷ The objective of rejuvenation procedures to treat the vaginal mucosa is to create increased frictional forces that may lead to increased sexual sensation.⁸ Although there are numerous reports of heightened sexual satisfaction after reduction of the vaginal diameter, a formal link between sexual pleasure and vaginal laxity has yet to be established.^8,9 At present, there are no US Food and Drug Administration (FDA)–approved energy-based devices to treat urinary incontinence or sexual function, and the FDA recently issued an alert cautioning patients on the current lack of safety and efficacy regulations.¹⁰

In this article we review the safety and efficacy data behind lasers and radiofrequency (RF) devices used in noninvasive vaginal rejuvenation procedures.

Lasers

CO₂ Laser
The infrared CO₂ laser utilizes 10,600-nm energy to target and vaporize water molecules within the target tissue. This thermal heating extends to the dermal collagen, which stimulates inflammatory pathways and neocollagenesis.¹¹ The depth of penetration ranges from 20 to 125 μm.¹² Zerbinati et al¹³ demonstrated the histologic and ultrastructural effects of a fractional CO₂ laser on atrophic vaginal mucosa. Comparing pretreatment and posttreatment mucosal biopsies in 5 postmenopausal women, the investigators found that fractional CO₂ laser treatment caused increased epithelial thickness, vascularity, and fibroblast activity, which led to augmented synthesis of collagen and ground substance proteins.¹³

New devices seek to translate these histologic improvements to the aesthetic appearance and function of female genitalia. The MonaLisa Touch (Cynosure), a new fractional CO₂ laser specifically designed for treatment of the vaginal mucosa, uses dermal optical thermolysis (DOT) therapy to apply energy in a noncontinuous mode at 200-μm dots. Salvatore et al¹⁴ examined the use of this device in a noncontrolled study of 50 patients with GSM, with each patient undergoing 3 treatment sessions at monthly intervals. Intravaginal treatments were performed at the following settings: DOT (microablative zone) power of 30 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack parameter of 1 to 3. The investigators used the Vaginal Health Index (VHI) to objectively assess vaginal elasticity, secretions, pH, mucosa integrity, and moisture. Total VHI scores significantly improved between baseline and 1 month following the final treatment (mean score [SD], 13.1 [2.5] vs 23.1 [1.9]; P<.0001). There were no significant adverse events, and 84% of patients reported being satisfied with their outcome; however, the study lacked a comparison or control group, raising the possibility of placebo effect.¹⁴

Other noncontrolled series have corroborated the benefits of CO₂ laser in GSM patients.^15,16 In one of the largest studies to date, Filippini et al¹⁷ reviewed the outcomes of 386 menopausal women treated for GSM. Patients underwent 3 intravaginal laser sessions with the MonaLisa Touch. Intravaginal treatments were performed at a DOT power of 40 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack of 2. For the vulva, the DOT power was reduced to 30 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack of 1. Two months after the final treatment session, patients completed a nonvalidated questionnaire about their symptoms, with improved dryness reported in 60% of patients, improved burning in 56%, improved dyspareunia in 49%, improved itch in 56%, improved soreness in 73%, and improved vaginal introitus pain in 49%. Although most patients did not experience discomfort with the procedure, a minority noted a burning sensation (11%), bother with handpiece movement (6%), or vulvar pain (5%).¹⁷

Recently, Cruz et al¹⁸ performed one of the first randomized, double-blind, placebo-controlled trials comparing fractional CO₂ laser therapy, topical estrogen therapy, and the combination of both treatments in patients with GSM. Forty-five women were included in the study, and validated assessments were performed at baseline and weeks 8 and 20. Intravaginal treatments were performed at a DOT power of 30 W, dwell time of 1000 μs, DOT spacing of 1000 μm, and SmartStack of 2. Importantly, the study incorporated placebo laser treatments (with the power adjusted to 0.0 W) in the topical estrogen group, thereby decreasing result bias. There was a significant increase in VHI scores from baseline to week 8 (P<.05) and week 20 (P<.01) in all study arms. At week 20, the laser group and laser plus estrogen group showed significant improvements in reported dyspareunia, burning, and dryness, whereas the estrogen arm only reported improvements in dryness (all values P<.05).¹⁸

Erbium-Doped YAG Laser
The erbium-doped YAG (Er:YAG) laser is an ablative laser emitting light at 2940 nm. This wavelength provides an absorption coefficient for water 16 times greater than the CO₂ laser, leading to decreased penetration depth of 1 to 3 μm and reduced damage to the surrounding tissues.^19,20 As such, the Er:YAG laser results in milder postoperative discomfort and faster overall healing times.²¹

In a noncontrolled study of vaginal relaxation syndrome, Lee²² used an Er:YAG laser fitted with Petit Lady (Lutronic) 90° and 360° vaginal scanning scopes. Thirty patients were divided into 2 groups and were treated with 4 sessions at weekly intervals. In group A, the first 2 sessions were performed with the 360° scope, and the last 2 sessions with the 90° scope in multiple micropulse mode (3 multishots; pulse width of 250 μs; 1.7 J delivered per shot). Group B was treated with the 90° scope in all 4 sessions in multiple micropulse mode (same parameters as group A), and during the last 2 sessions patients were additionally treated with 2 passes per session with the 360° scope (long-pulsed mode; pulse width of 1000 μs; 3.7 J delivered per shot). Perineometer measurements taken 2 months after the final treatment showed that the combined patient population experienced significant increases in both maximal vaginal pressure (P<.01) and average vaginal pressure (P<.05). Roughly 76% of patients’ partners noted improved vaginal tightening, and 70% of patients reported being satisfied with their treatment outcome. Histologic specimens taken at baseline and 2 months postprocedure showed evidence of thicker and more cellular epithelia along with more compact lamina propria with denser connective tissue. The sessions were well tolerated, with patients reporting a nonpainful heating sensation in the vagina during treatment. Three patients from the combined patient population experienced a mild burning sensation and vaginal ecchymoses, which lasted 24 to 48 hours following treatment and resolved spontaneously. There was no control group and no reports of major or long-term adverse events.²²

Investigations also have shown the benefit of Er:YAG in the treatment of GSM.^23,24 In a study by Gambacciani et al,²⁴ patients treated with the Er:YAG laser FotonaSmooth (Fotona) every 30 days for 3 months reported significant improvements in vaginal dryness and dyspareunia (P<.01), which lasted up to 6 months posttreatment, though there was no placebo group comparator. Similar results were seen by Gaspar et al²³ using 3 treatments at 3-week intervals, with results sustained up to 18 months after the final session.

Radiofrequency Devices

Radiofrequency devices emit focused electromagnetic waves that heat underlying tissues without targeting melanin. The release of thermal energy induces collagen contraction, neocollagenesis, and neovascularization, all of which aid in restoring the elasticity and moisture of the vaginal mucosa.²⁵ Devices also may be equipped with cooling probes and reverse-heating gradients to protect the surface mucosa while deeper tissues are heated.

Millheiser et al²⁶ performed a noncontrolled pilot study in 24 women with vaginal laxity using the Viveve System (Viveve), a cryogen-cooled monopolar RF device. Participants underwent a single 30-minute session (energy ranging from 75–90 J/cm²) during which the mucosal surface of the vaginal introitus (excluding the urethra) was treated with pulses at 0.5-cm overlapping intervals. Follow-up assessments were completed at 1, 3, and 6 months posttreatment. Self-reported vaginal tightness improved in 67% of participants at 1-month posttreatment and in 87% of participants at 6 months posttreatment (P<.001). There were no adverse events reported.²⁶ Sekiguchi et al²⁷ reported similar benefits lasting up to 12 months after a single 26-minute session at 90 J/cm².

A prospective, randomized, placebo-controlled clinical trial using the Viveve system was recently completed by Krychman et al.²⁸ Participants (N=186) were randomized to receive a single session of active treatment (90 J/cm²) or placebo treatment (1 J/cm²). In both groups, the vaginal introitus was treated with pulses at 0.5 cm in overlapping intervals, with the entire area (excluding the urethra) treated 5 times up to a total of 110 pulses. The primary end point was the proportion of randomized participants reporting no vaginal laxity at 6 months postin-tervention, which was assessed using the Vaginal Laxity Questionnaire. A grade of no vaginal laxity was achieved by 43.5% of participants in the active treatment group and 19.6% of participants in the sham group (P=.002). Overall numbers of treatment-emergent adverse events were comparable between the 2 groups, with the most commonly reported being vaginal discharge (2.6% in the active treatment group vs 3.5% in the sham group). There were no serious adverse events reported in the active treatment group.²⁸

ThermiVa (ThermiGen, LLC), a unipolar RF device, was evaluated by Alinsod²⁹ in the treatment of orgasmic dysfunction. The noncontrolled study included 25 women with self-reported difficulty achieving orgasm during intercourse, each of whom underwent 3 treatment sessions at 1-month intervals. Of the 25 enrolled women, 19 (76%) reported an average reduction in time to orgasm of at least 50%. All anorgasmic patients (n=10) at baseline reported renewed ability to achieve orgasms. Two (8%) patients failed to achieve a significant benefit from the treatments. Of note, the study did not include a control group, and specific data on the durability of beneficial effects was lacking.²⁹

The Ultra Femme 360 (BLT Industries Inc), a monopolar RF device, was evaluated by Lalji and Lozanova³⁰ in a noncontrolled study of 27 women with mild to moderate vaginal laxity and urinary incontinence. Participants underwent 3 treatment sessions at weekly intervals. Vaginal laxity was assessed by a subjective vulvovaginal laxity questionnaire, and data were collected before the first treatment and at 1-month follow-up. All 27 participants reported improvements in vaginal laxity, with the average grade (SD) increasing from very loose (2.19 [1.08]) to moderately tight (5.74 [0.76]; P<.05) on the questionnaire’s 7-point scale. The trial did not include a control group.³⁰

Conclusion

With growing patient interest in vaginal rejuvenation, clinicians are increasingly incorporating a variety of procedures into their practice. Although long-term data on the safety and efficacy of these treatments has yet to be established, current evidence indicates that fractional ablative lasers and RF devices can improve vaginal laxity, sexual sensation, and symptoms of GSM.

To date, major complications have not been reported, but the FDA has advocated caution until regulatory approval is achieved.¹⁰ Concerns exist over the limited number of robust clinical trials as well as the prevalence of advertising campaigns that promise wide-ranging improvements without sufficient evidence. Definitive statements on medical or cosmetic indications will undoubtedly require more thorough investigation. At this time, the safety profile of these devices appears to be favorable, and high rates of patient satisfaction have been reported. As such, noninvasive vaginal rejuvenation procedures may represent a valuable addition to the cosmetic landscape.

Acne vulgaris is prevalent in the general population, with 40 to 50 million affected individuals in the United States.¹ Severe inflammation and injury can lead to disfiguring scarring, which has a considerable impact on quality of life.² Numerous therapeutic options for acne scarring are available, including microneedling with and without platelet-rich plasma (PRP), lasers, chemical peels, and dermal fillers, with different modalities suited to individual patients and scar characteristics. This article reviews updates in treatment options for acne scarring.

Microneedling

Microneedling, also known as percutaneous collagen induction or collagen induction therapy, has been utilized for more than 2 decades.³ Dermatologic indications for microneedling include skin rejuvenation,^4-6 atrophic acne scarring,^7-9 and androgenic alopecia.^10,11 Microneedling also has been used to enhance skin penetration of topically applied drugs.^12-15 Fernandes¹⁶ described percutaneous collagen induction as the skin’s natural response to injury. Microneedling creates small wounds as fine needles puncture the epidermis and dermis, resulting in a cascade of growth factors that lead to tissue proliferation, regeneration, and a collagen remodeling phase that can last for several months.^8,16

Microneedling has gained popularity in the treatment of acne scarring.⁷ Alam et al⁹ conducted a split-face randomized clinical trial (RCT) to evaluate acne scarring after 3 microneedling sessions performed at 2-week intervals. Twenty participants with acne scarring on both sides of the face were enrolled in the study and one side of the face was randomized for treatment. Participants had at least two 5×5-cm areas of acne scarring graded as 2 (moderately atrophic scars) to 4 (hyperplastic or papular scars) on the quantitative Global Acne Scarring Classification system. A roller device with a 1.0-mm depth was used on participants with fine, less sebaceous skin and a 2.0-mm device for all others. Two blinded investigators assessed acne scars at baseline and at 3 and 6 months after treatment. Scar improvement was measured using the quantitative Goodman and Baron scale, which provides a score according to type and number of scars.¹⁷ Mean scar scores were significantly reduced at 6 months compared to baseline on the treatment side (P=.03) but not the control side. Participants experienced minimal pain associated with microneedling therapy, rated 1.08 of 10, and adverse effects were limited to mild transient erythema and edema.⁹ Several other clinical trials have demonstrated clinical improvements with microneedling.^18-20

The benefits of microneedling also have been observed on a histologic level. One group of investigators explored the effects of microneedling on dermal collagen in the treatment of various atrophic acne scars in 10 participants.⁷ After 6 treatment sessions performed at 2-week intervals, dermal collagen was assessed via punch biopsy. A roller device with a needle depth of 1.5 mm was used for all patients. At 1 month after treatment compared to baseline, mean (SD) levels of type I collagen were significantly increased (67.1% [4.2%] vs 70.4% [5.4%]; P=.01) as well as at 3 months after treatment compared to baseline for type III collagen (61.4% [3.6%] vs 74.3% [7.4%]; P=.01), type VII collagen (15.2% [2.1%] vs 21.3% [1.2%]; P=.03), and newly synthesized collagen (14.5% [5.8%] vs 19.5% [3.2%]; P=.02). Total elastin levels were significantly decreased at 3 months after treatment compared to baseline (51.3% [6.7%] vs 46.9% [4.3%]; P=.04). Adverse effects were limited to transient erythema and edema.⁷

Microneedling With Platelet-Rich Plasma

Microneedling has been combined with platelet-rich plasma (PRP) in the treatment of atrophic acne scars.²¹ In addition to inducing new collagen synthesis, microneedling aids in the absorption of PRP, an autologous concentrate of platelets that is obtained through peripheral venipuncture. The concentrate is centrifuged into 3 layers: (1) platelet-poor plasma, (2) PRP, and (3) erythrocytes.²² Platelet-rich plasma contains growth factors such as platelet-derived growth factor, transforming growth factor (TGF), and vascular endothelial growth factor, as well as cell adhesion molecules.^22,23 The application of PRP is thought to result in upregulated protein synthesis, greater collagen remodeling, and accelerated wound healing.²¹

Several studies have shown that the addition of PRP to microneedling can improve treatment outcome (Table 1).^24-27 Severity of acne scarring can be improved, such as reduced scar depth, by using both modalities synergistically (Figure).²⁴ Asif et al²⁶ compared microneedling with PRP to microneedling with distilled water in the treatment of 50 patients with atrophic acne scars graded 2 to 4 (mild to severe acne scarring) on the Goodman’s Qualitative classification and equal Goodman’s Qualitative and Quantitative scores on both halves of the face.^17,28 The right side of the face was treated with a 1.5-mm microneedling roller with intradermal and topical PRP, while the left side was treated with distilled water (placebo) delivered intradermally. Patients underwent 3 treatment sessions at 1-month intervals. The area treated with microneedling and PRP showed a 62.20% improvement from baseline after 3 treatments, while the placebo-treated area showed a 45.84% improvement on the Goodman and Baron quantitative scale.²⁶

Chawla²⁵ compared microneedling with topical PRP to microneedling with topical vitamin C in a split-face study of 30 participants with atrophic acne scarring graded 2 to 4 on the Goodman and Baron scale. A 1.5-mm roller device was used. Patients underwent 4 treatment sessions at 1-month intervals, and treatment efficacy was evaluated using the qualitative Goodman and Baron scale.²⁸ Participants experienced positive outcomes overall with both treatments. Notably, 18.5% (5/27) on the microneedling with PRP side demonstrated excellent response compared to 7.4% (2/27) on the microneedling with vitamin C side.²⁵

Laser Treatment

Laser skin resurfacing has shown to be efficacious in the treatment of both acne vulgaris and acne scarring. Various lasers have been utilized, including nonfractional CO₂ and erbium-doped:YAG (Er:YAG) lasers, as well as ablative fractional lasers (AFLs) and nonablative fractional lasers (NAFLs).²⁹

One retrospective study of 58 patients compared the use of 2 resurfacing lasers—10,600-nm nonfractional CO₂ and 2940-nm Er:YAG—and 2 fractional lasers—1550-nm NAFL and 10,600-nm AFL—in the treatment of atrophic acne scars.²⁹ A retrospective photographic analysis was performed by 6 blinded dermatologists to evaluate clinical improvement on a scale of 0 (no improvement) to 10 (excellent improvement). The mean improvement scores of the CO₂, Er:YAG, AFL, and NAFL groups were 6.0, 5.8, 2.2, and 5.2, respectively, and the mean number of treatments was 1.6, 1.1, 4.0, and 3.4, respectively. Thus, patients in the fractional laser groups required more treatments; however, those in the resurfacing laser groups had longer recovery times, pain, erythema, and postinflammatory hyperpigmentation. The investigators concluded that 3 consecutive AFL treatments could be as effective as a single resurfacing treatment with lower risk for complications.²⁹

A split-face RCT compared the use of the fractional Er:YAG laser on one side of the face to microneedling with a 2.0-mm needle on the other side for treatment of atrophic acne scars.³⁰ Thirty patients underwent 5 treatments at 1-month intervals. At 3-month follow-up, the areas treated with the Er:YAG laser showed 70% improvement from baseline compared to 30% improvement in the areas treated with microneedling (P<.001). Histologically, the Er:YAG laser showed a higher increase in dermal collagen than microneedling (P<.001). Furthermore, the Er:YAG laser yielded significantly lower pain scores (P<.001); however, patients reported higher rates of erythema, swelling, superficial crusting, and total downtime.³⁰

Lasers With PRP
More recent studies have examined the use of laser therapy in addition to PRP for the treatment of acne scars (Table 2).^31-34 Abdel Aal et al³³ examined the use of the ablative fractional CO₂ laser with and without intradermal PRP in a split-face study of 30 participants with various types of acne scarring (ie, boxcar, ice pick, and rolling scars). Participants underwent 2 treatments at 4-week intervals. Evaluations were performed by 2 blinded dermatologists 6 months after the final laser treatment using the qualitative Goodman and Baron scale.²⁸ Both treatments yielded improvement in scarring, but the PRP-treated side showed shorter durations of postprocedure erythema (P=.0052) as well as higher patient satisfaction scores (P<.001) than laser therapy alone.³³

In another split-face study, Gawdat et al³² examined combination treatment with the ablative fractional CO₂ laser and PRP in 30 participants with atrophic acne scars graded 2 to 4 on the qualitative Goodman and Baron scale.²⁸ Participants were randomized to 2 different treatment groups: In group 1, half of the face was treated with the fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and intradermal saline. In group 2, half of the face was treated with fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and topical PRP. All patients underwent 3 treatment sessions at 1-month intervals with assessment occurring a 6-month follow-up using the qualitative Goodman and Baron Scale.²⁸ In all participants, areas treated with the combined laser and PRP showed significant improvement in scarring (P=.03) and reduced recovery time (P=.02) compared to areas treated with laser therapy only. Patients receiving intradermal or topical PRP showed no statistically significant differences in improvement of scarring or recovery time; however, areas treated with topical PRP had significantly lower pain levels (P=.005).³²

Lee et al³¹ conducted a split-face study of 14 patients with moderate to severe acne scarring treated with an ablative fractional CO₂ laser followed by intradermal PRP or intradermal normal saline injections. Patients underwent 2 treatment sessions at 4-week intervals. Photographs taken at baseline and 4 months posttreatment were evaluated by 2 blinded dermatologists for clinical improvement using a quartile grading system. Erythema was assessed using a skin color measuring device. A blinded dermatologist assessed patients for adverse events. At 4-month follow-up, mean (SD) clinical improvement on the side receiving intradermal PRP was significantly better than the control side (2.7 [0.7] vs 2.3 [0.5]; P=.03). Erythema on posttreatment day 4 was significantly less on the side treated with PRP (P=.01). No adverse events were reported.³¹

Another split-face study compared the use of intradermal PRP to intradermal normal saline following fractional CO₂ laser treatment.³⁴ Twenty-five participants with moderate to severe acne scars completed 2 treatment sessions at 4-week intervals. Additionally, skin biopsies were collected to evaluate collagen production using immunohistochemistry, quantitative polymerase chain reaction, and western blot techniques. Experimental fibroblasts and keratinocytes were isolated and cultured. The cultures were irradiated with a fractional CO₂ laser and treated with PRP or platelet-poor plasma. Cultures were evaluated at 30 minutes, 24 hours, and 48 hours. Participants reported 75% improvement of acne scarring from baseline in the side treated with PRP compared to 50% improvement of acne scarring from baseline in the control group (P<.001). On days 7 and 84, participants reported greater improvement on the side treated with PRP (P=.03 and P=.02, respectively). On day 28, skin biopsy evaluation yielded higher levels of TGF-β1 (P=.02), TGF-β3 (P=.004), c-myc (P=.004), type I collagen (P=.03), and type III collagen (P=.03) on the PRP-treated side compared to the control side. Transforming growth factor β increases collagen and fibroblast production, while c-myc leads to cell cycle progression.^35-37 Similarly, TGF-β1, TGF-β3, types I andIII collagen, and p-Akt were increased in all cultures treated with PRP and platelet-poor plasma in a dose-dependent manner.³⁴ p-Akt is thought to regulate wound healing³⁸; however, PRP-treated keratinocytes yielded increased epidermal growth factor receptor and decreased keratin-16 at 48 hours, which suggests PRP plays a role in increasing epithelization and reducing laser-induced keratinocyte damage.³⁹ Adverse effects (eg, erythema, edema, oozing) were less frequent in the PRP-treated side.³⁴

Chemical Peels

Chemical peels are widely used in the treatment of acne scarring.⁴⁰ Peels improve scarring through destruction of the epidermal and/or dermal layers, leading to skin exfoliation, rejuvenation, and remodeling. Superficial peeling agents, which extend to the dermoepidermal junction, include resorcinol, tretinoin, glycolic acid, lactic acid, salicylic acid, and trichloroacetic acid (TCA) 10% to 35%.⁴¹ Medium-depth peeling agents extend to the upper reticular dermis and include phenol, TCA 35% to 50%, and Jessner solution (resorcinol, lactic acid, and salicylic acid in ethanol) followed by TCA 35%.⁴¹ Finally, the effects of deep peeling agents reach the mid reticular dermis and include the Baker-Gordon or Litton phenol formulas.⁴¹ Deep peels are associated with higher rates of adverse outcomes including infection, dyschromia, and scarring.^41,42

An RCT was performed to evaluate the use of a deep phenol 60% peel compared to microneedling with a 1.5-mm roller device plus a TCA 20% peel in the treatment of atrophic acne scars.⁴³ Twenty-four patients were randomly and evenly assigned to both treatment groups. The phenol group underwent a single treatment session, while the microneedling plus TCA group underwent 4 treatment sessions at 6-week intervals. Both groups were instructed to use daily topical tretinoin and hydroquinone 2% in the 2 weeks prior to treatment. Posttreatment results were evaluated using a quartile grading scale. Scarring improved from baseline by 75.12% (P<.001) in the phenol group and 69.43% (P<.001) in the microneedling plus TCA group, with no significant difference between groups. Adverse effects in the phenol group included erythema and hyperpigmentation, while adverse events in the microneedling plus TCA group included transient pain, edema, erythema, and desquamation.⁴³

Another study compared the use of a TCA 15% peel with microneedling to PRP with microneedling and microneedling alone in the treatment of atrophic acne scars.⁴⁴ Twenty-four patients were randomly assigned to the 3 treatment groups (8 to each group) and underwent 6 treatment sessions with 2-week intervals. A roller device with a 1.5-mm needle was used for microneedling. Microneedling plus TCA and microneedling plus PRP were significantly more effective than microneedling alone (P=.011 and P=.015, respectively); however, the TCA 15% peel with microneedling resulted in the largest increase in epidermal thickening. The investigators concluded that combined use of a TCA 15% peel and microneedling was the most effective in treating atrophic acne scarring.⁴⁴

Dermal Fillers

Dermal or subcutaneous fillers are used to increase volume in depressed scars and stimulate the skin’s natural production.⁴⁵ Tissue augmentation methods commonly are used for larger rolling acne scars. Options for filler materials include autologous fat, bovine, or human collagen derivatives; hyaluronic acid; and polymethyl methacrylate microspheres with collagen.⁴⁵ Newer fillers are formulated with lidocaine to decrease pain associated with the procedure.⁴⁶ Hyaluronic acid fillers provide natural volume correction and have limited potential to elicit an immune response due to their derivation from bacterial fermentation. Fillers using polymethyl methacrylate microspheres with collagen are permanent and effective, which may lead to reduced patient costs; however, they often are not a first choice for treatment.^45,46 Furthermore, if dermal fillers consist of bovine collagen, it is necessary to perform skin testing for allergy prior to use. Autologous fat transfer also has become popular for treatment of acne scarring, especially because there is no risk of allergic reaction, as the patient’s own fat is used for correction.⁴⁶ However, this method requires a high degree of skill, and results are unpredictable, generally lasting from 6 months to several years.

Therapies on the horizon include autologous cell therapy. A multicenter, double-blinded, placebo-controlled RCT examined the use of an autologous fibroblast filler in the treatment of bilateral, depressed, and distensible acne scars that were graded as moderate to severe.⁴⁷ Autologous fat fibroblasts were harvested from full-thickness postauricular punch biopsies. In this split-face study, 99 participants were treated with an intradermal autologous fibroblast filler on one cheek and a protein-free cell-culture medium on the contralateral cheek. Participants received an average of 5.9 mL of both autologous fat fibroblasts and cell-culture medium over 3 treatment sessions at 2-week intervals. The autologous fat fibroblasts were associated with greater improvement compared to cell-culture medium based on participant (43% vs 18%), evaluator (59% vs 42%), and independent photographic viewer’s assessment.⁴⁷

Conclusion

Acne scarring is a burden affecting millions of Americans. It often has a negative impact on quality of life and can lead to low self-esteem in patients. Numerous trials have indicated that microneedling is beneficial in the treatment of acne scarring, and emerging evidence indicates that the addition of PRP provides measurable benefits. Similarly, the addition of PRP to laser therapy may reduce recovery time as well as the commonly associated adverse events of erythema and pain. Chemical peels provide the advantage of being easily and efficiently performed in the office setting. Finally, the wide range of available dermal fillers can be tailored to treat specific types of acne scars. Autologous dermal fillers recently have been used and show promising benefits. It is important to consider desired outcome, cost, and adverse events when discussing therapeutic options for acne scarring with patients. The numerous therapeutic options warrant further research and well-designed RCTs to ensure optimal patient outcomes.

Acne vulgaris is prevalent in the general population, with 40 to 50 million affected individuals in the United States.¹ Severe inflammation and injury can lead to disfiguring scarring, which has a considerable impact on quality of life.² Numerous therapeutic options for acne scarring are available, including microneedling with and without platelet-rich plasma (PRP), lasers, chemical peels, and dermal fillers, with different modalities suited to individual patients and scar characteristics. This article reviews updates in treatment options for acne scarring.

Microneedling

Microneedling, also known as percutaneous collagen induction or collagen induction therapy, has been utilized for more than 2 decades.³ Dermatologic indications for microneedling include skin rejuvenation,^4-6 atrophic acne scarring,^7-9 and androgenic alopecia.^10,11 Microneedling also has been used to enhance skin penetration of topically applied drugs.^12-15 Fernandes¹⁶ described percutaneous collagen induction as the skin’s natural response to injury. Microneedling creates small wounds as fine needles puncture the epidermis and dermis, resulting in a cascade of growth factors that lead to tissue proliferation, regeneration, and a collagen remodeling phase that can last for several months.^8,16

Microneedling has gained popularity in the treatment of acne scarring.⁷ Alam et al⁹ conducted a split-face randomized clinical trial (RCT) to evaluate acne scarring after 3 microneedling sessions performed at 2-week intervals. Twenty participants with acne scarring on both sides of the face were enrolled in the study and one side of the face was randomized for treatment. Participants had at least two 5×5-cm areas of acne scarring graded as 2 (moderately atrophic scars) to 4 (hyperplastic or papular scars) on the quantitative Global Acne Scarring Classification system. A roller device with a 1.0-mm depth was used on participants with fine, less sebaceous skin and a 2.0-mm device for all others. Two blinded investigators assessed acne scars at baseline and at 3 and 6 months after treatment. Scar improvement was measured using the quantitative Goodman and Baron scale, which provides a score according to type and number of scars.¹⁷ Mean scar scores were significantly reduced at 6 months compared to baseline on the treatment side (P=.03) but not the control side. Participants experienced minimal pain associated with microneedling therapy, rated 1.08 of 10, and adverse effects were limited to mild transient erythema and edema.⁹ Several other clinical trials have demonstrated clinical improvements with microneedling.^18-20

The benefits of microneedling also have been observed on a histologic level. One group of investigators explored the effects of microneedling on dermal collagen in the treatment of various atrophic acne scars in 10 participants.⁷ After 6 treatment sessions performed at 2-week intervals, dermal collagen was assessed via punch biopsy. A roller device with a needle depth of 1.5 mm was used for all patients. At 1 month after treatment compared to baseline, mean (SD) levels of type I collagen were significantly increased (67.1% [4.2%] vs 70.4% [5.4%]; P=.01) as well as at 3 months after treatment compared to baseline for type III collagen (61.4% [3.6%] vs 74.3% [7.4%]; P=.01), type VII collagen (15.2% [2.1%] vs 21.3% [1.2%]; P=.03), and newly synthesized collagen (14.5% [5.8%] vs 19.5% [3.2%]; P=.02). Total elastin levels were significantly decreased at 3 months after treatment compared to baseline (51.3% [6.7%] vs 46.9% [4.3%]; P=.04). Adverse effects were limited to transient erythema and edema.⁷

Microneedling With Platelet-Rich Plasma

Microneedling has been combined with platelet-rich plasma (PRP) in the treatment of atrophic acne scars.²¹ In addition to inducing new collagen synthesis, microneedling aids in the absorption of PRP, an autologous concentrate of platelets that is obtained through peripheral venipuncture. The concentrate is centrifuged into 3 layers: (1) platelet-poor plasma, (2) PRP, and (3) erythrocytes.²² Platelet-rich plasma contains growth factors such as platelet-derived growth factor, transforming growth factor (TGF), and vascular endothelial growth factor, as well as cell adhesion molecules.^22,23 The application of PRP is thought to result in upregulated protein synthesis, greater collagen remodeling, and accelerated wound healing.²¹

Several studies have shown that the addition of PRP to microneedling can improve treatment outcome (Table 1).^24-27 Severity of acne scarring can be improved, such as reduced scar depth, by using both modalities synergistically (Figure).²⁴ Asif et al²⁶ compared microneedling with PRP to microneedling with distilled water in the treatment of 50 patients with atrophic acne scars graded 2 to 4 (mild to severe acne scarring) on the Goodman’s Qualitative classification and equal Goodman’s Qualitative and Quantitative scores on both halves of the face.^17,28 The right side of the face was treated with a 1.5-mm microneedling roller with intradermal and topical PRP, while the left side was treated with distilled water (placebo) delivered intradermally. Patients underwent 3 treatment sessions at 1-month intervals. The area treated with microneedling and PRP showed a 62.20% improvement from baseline after 3 treatments, while the placebo-treated area showed a 45.84% improvement on the Goodman and Baron quantitative scale.²⁶

Chawla²⁵ compared microneedling with topical PRP to microneedling with topical vitamin C in a split-face study of 30 participants with atrophic acne scarring graded 2 to 4 on the Goodman and Baron scale. A 1.5-mm roller device was used. Patients underwent 4 treatment sessions at 1-month intervals, and treatment efficacy was evaluated using the qualitative Goodman and Baron scale.²⁸ Participants experienced positive outcomes overall with both treatments. Notably, 18.5% (5/27) on the microneedling with PRP side demonstrated excellent response compared to 7.4% (2/27) on the microneedling with vitamin C side.²⁵

Laser Treatment

Laser skin resurfacing has shown to be efficacious in the treatment of both acne vulgaris and acne scarring. Various lasers have been utilized, including nonfractional CO₂ and erbium-doped:YAG (Er:YAG) lasers, as well as ablative fractional lasers (AFLs) and nonablative fractional lasers (NAFLs).²⁹

One retrospective study of 58 patients compared the use of 2 resurfacing lasers—10,600-nm nonfractional CO₂ and 2940-nm Er:YAG—and 2 fractional lasers—1550-nm NAFL and 10,600-nm AFL—in the treatment of atrophic acne scars.²⁹ A retrospective photographic analysis was performed by 6 blinded dermatologists to evaluate clinical improvement on a scale of 0 (no improvement) to 10 (excellent improvement). The mean improvement scores of the CO₂, Er:YAG, AFL, and NAFL groups were 6.0, 5.8, 2.2, and 5.2, respectively, and the mean number of treatments was 1.6, 1.1, 4.0, and 3.4, respectively. Thus, patients in the fractional laser groups required more treatments; however, those in the resurfacing laser groups had longer recovery times, pain, erythema, and postinflammatory hyperpigmentation. The investigators concluded that 3 consecutive AFL treatments could be as effective as a single resurfacing treatment with lower risk for complications.²⁹

A split-face RCT compared the use of the fractional Er:YAG laser on one side of the face to microneedling with a 2.0-mm needle on the other side for treatment of atrophic acne scars.³⁰ Thirty patients underwent 5 treatments at 1-month intervals. At 3-month follow-up, the areas treated with the Er:YAG laser showed 70% improvement from baseline compared to 30% improvement in the areas treated with microneedling (P<.001). Histologically, the Er:YAG laser showed a higher increase in dermal collagen than microneedling (P<.001). Furthermore, the Er:YAG laser yielded significantly lower pain scores (P<.001); however, patients reported higher rates of erythema, swelling, superficial crusting, and total downtime.³⁰

Lasers With PRP
More recent studies have examined the use of laser therapy in addition to PRP for the treatment of acne scars (Table 2).^31-34 Abdel Aal et al³³ examined the use of the ablative fractional CO₂ laser with and without intradermal PRP in a split-face study of 30 participants with various types of acne scarring (ie, boxcar, ice pick, and rolling scars). Participants underwent 2 treatments at 4-week intervals. Evaluations were performed by 2 blinded dermatologists 6 months after the final laser treatment using the qualitative Goodman and Baron scale.²⁸ Both treatments yielded improvement in scarring, but the PRP-treated side showed shorter durations of postprocedure erythema (P=.0052) as well as higher patient satisfaction scores (P<.001) than laser therapy alone.³³

In another split-face study, Gawdat et al³² examined combination treatment with the ablative fractional CO₂ laser and PRP in 30 participants with atrophic acne scars graded 2 to 4 on the qualitative Goodman and Baron scale.²⁸ Participants were randomized to 2 different treatment groups: In group 1, half of the face was treated with the fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and intradermal saline. In group 2, half of the face was treated with fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and topical PRP. All patients underwent 3 treatment sessions at 1-month intervals with assessment occurring a 6-month follow-up using the qualitative Goodman and Baron Scale.²⁸ In all participants, areas treated with the combined laser and PRP showed significant improvement in scarring (P=.03) and reduced recovery time (P=.02) compared to areas treated with laser therapy only. Patients receiving intradermal or topical PRP showed no statistically significant differences in improvement of scarring or recovery time; however, areas treated with topical PRP had significantly lower pain levels (P=.005).³²

Lee et al³¹ conducted a split-face study of 14 patients with moderate to severe acne scarring treated with an ablative fractional CO₂ laser followed by intradermal PRP or intradermal normal saline injections. Patients underwent 2 treatment sessions at 4-week intervals. Photographs taken at baseline and 4 months posttreatment were evaluated by 2 blinded dermatologists for clinical improvement using a quartile grading system. Erythema was assessed using a skin color measuring device. A blinded dermatologist assessed patients for adverse events. At 4-month follow-up, mean (SD) clinical improvement on the side receiving intradermal PRP was significantly better than the control side (2.7 [0.7] vs 2.3 [0.5]; P=.03). Erythema on posttreatment day 4 was significantly less on the side treated with PRP (P=.01). No adverse events were reported.³¹

Another split-face study compared the use of intradermal PRP to intradermal normal saline following fractional CO₂ laser treatment.³⁴ Twenty-five participants with moderate to severe acne scars completed 2 treatment sessions at 4-week intervals. Additionally, skin biopsies were collected to evaluate collagen production using immunohistochemistry, quantitative polymerase chain reaction, and western blot techniques. Experimental fibroblasts and keratinocytes were isolated and cultured. The cultures were irradiated with a fractional CO₂ laser and treated with PRP or platelet-poor plasma. Cultures were evaluated at 30 minutes, 24 hours, and 48 hours. Participants reported 75% improvement of acne scarring from baseline in the side treated with PRP compared to 50% improvement of acne scarring from baseline in the control group (P<.001). On days 7 and 84, participants reported greater improvement on the side treated with PRP (P=.03 and P=.02, respectively). On day 28, skin biopsy evaluation yielded higher levels of TGF-β1 (P=.02), TGF-β3 (P=.004), c-myc (P=.004), type I collagen (P=.03), and type III collagen (P=.03) on the PRP-treated side compared to the control side. Transforming growth factor β increases collagen and fibroblast production, while c-myc leads to cell cycle progression.^35-37 Similarly, TGF-β1, TGF-β3, types I andIII collagen, and p-Akt were increased in all cultures treated with PRP and platelet-poor plasma in a dose-dependent manner.³⁴ p-Akt is thought to regulate wound healing³⁸; however, PRP-treated keratinocytes yielded increased epidermal growth factor receptor and decreased keratin-16 at 48 hours, which suggests PRP plays a role in increasing epithelization and reducing laser-induced keratinocyte damage.³⁹ Adverse effects (eg, erythema, edema, oozing) were less frequent in the PRP-treated side.³⁴

Chemical Peels

Chemical peels are widely used in the treatment of acne scarring.⁴⁰ Peels improve scarring through destruction of the epidermal and/or dermal layers, leading to skin exfoliation, rejuvenation, and remodeling. Superficial peeling agents, which extend to the dermoepidermal junction, include resorcinol, tretinoin, glycolic acid, lactic acid, salicylic acid, and trichloroacetic acid (TCA) 10% to 35%.⁴¹ Medium-depth peeling agents extend to the upper reticular dermis and include phenol, TCA 35% to 50%, and Jessner solution (resorcinol, lactic acid, and salicylic acid in ethanol) followed by TCA 35%.⁴¹ Finally, the effects of deep peeling agents reach the mid reticular dermis and include the Baker-Gordon or Litton phenol formulas.⁴¹ Deep peels are associated with higher rates of adverse outcomes including infection, dyschromia, and scarring.^41,42

An RCT was performed to evaluate the use of a deep phenol 60% peel compared to microneedling with a 1.5-mm roller device plus a TCA 20% peel in the treatment of atrophic acne scars.⁴³ Twenty-four patients were randomly and evenly assigned to both treatment groups. The phenol group underwent a single treatment session, while the microneedling plus TCA group underwent 4 treatment sessions at 6-week intervals. Both groups were instructed to use daily topical tretinoin and hydroquinone 2% in the 2 weeks prior to treatment. Posttreatment results were evaluated using a quartile grading scale. Scarring improved from baseline by 75.12% (P<.001) in the phenol group and 69.43% (P<.001) in the microneedling plus TCA group, with no significant difference between groups. Adverse effects in the phenol group included erythema and hyperpigmentation, while adverse events in the microneedling plus TCA group included transient pain, edema, erythema, and desquamation.⁴³

Another study compared the use of a TCA 15% peel with microneedling to PRP with microneedling and microneedling alone in the treatment of atrophic acne scars.⁴⁴ Twenty-four patients were randomly assigned to the 3 treatment groups (8 to each group) and underwent 6 treatment sessions with 2-week intervals. A roller device with a 1.5-mm needle was used for microneedling. Microneedling plus TCA and microneedling plus PRP were significantly more effective than microneedling alone (P=.011 and P=.015, respectively); however, the TCA 15% peel with microneedling resulted in the largest increase in epidermal thickening. The investigators concluded that combined use of a TCA 15% peel and microneedling was the most effective in treating atrophic acne scarring.⁴⁴

Dermal Fillers

Dermal or subcutaneous fillers are used to increase volume in depressed scars and stimulate the skin’s natural production.⁴⁵ Tissue augmentation methods commonly are used for larger rolling acne scars. Options for filler materials include autologous fat, bovine, or human collagen derivatives; hyaluronic acid; and polymethyl methacrylate microspheres with collagen.⁴⁵ Newer fillers are formulated with lidocaine to decrease pain associated with the procedure.⁴⁶ Hyaluronic acid fillers provide natural volume correction and have limited potential to elicit an immune response due to their derivation from bacterial fermentation. Fillers using polymethyl methacrylate microspheres with collagen are permanent and effective, which may lead to reduced patient costs; however, they often are not a first choice for treatment.^45,46 Furthermore, if dermal fillers consist of bovine collagen, it is necessary to perform skin testing for allergy prior to use. Autologous fat transfer also has become popular for treatment of acne scarring, especially because there is no risk of allergic reaction, as the patient’s own fat is used for correction.⁴⁶ However, this method requires a high degree of skill, and results are unpredictable, generally lasting from 6 months to several years.

Therapies on the horizon include autologous cell therapy. A multicenter, double-blinded, placebo-controlled RCT examined the use of an autologous fibroblast filler in the treatment of bilateral, depressed, and distensible acne scars that were graded as moderate to severe.⁴⁷ Autologous fat fibroblasts were harvested from full-thickness postauricular punch biopsies. In this split-face study, 99 participants were treated with an intradermal autologous fibroblast filler on one cheek and a protein-free cell-culture medium on the contralateral cheek. Participants received an average of 5.9 mL of both autologous fat fibroblasts and cell-culture medium over 3 treatment sessions at 2-week intervals. The autologous fat fibroblasts were associated with greater improvement compared to cell-culture medium based on participant (43% vs 18%), evaluator (59% vs 42%), and independent photographic viewer’s assessment.⁴⁷

Conclusion

Acne scarring is a burden affecting millions of Americans. It often has a negative impact on quality of life and can lead to low self-esteem in patients. Numerous trials have indicated that microneedling is beneficial in the treatment of acne scarring, and emerging evidence indicates that the addition of PRP provides measurable benefits. Similarly, the addition of PRP to laser therapy may reduce recovery time as well as the commonly associated adverse events of erythema and pain. Chemical peels provide the advantage of being easily and efficiently performed in the office setting. Finally, the wide range of available dermal fillers can be tailored to treat specific types of acne scars. Autologous dermal fillers recently have been used and show promising benefits. It is important to consider desired outcome, cost, and adverse events when discussing therapeutic options for acne scarring with patients. The numerous therapeutic options warrant further research and well-designed RCTs to ensure optimal patient outcomes.

Acne vulgaris is prevalent in the general population, with 40 to 50 million affected individuals in the United States.¹ Severe inflammation and injury can lead to disfiguring scarring, which has a considerable impact on quality of life.² Numerous therapeutic options for acne scarring are available, including microneedling with and without platelet-rich plasma (PRP), lasers, chemical peels, and dermal fillers, with different modalities suited to individual patients and scar characteristics. This article reviews updates in treatment options for acne scarring.

Microneedling

Microneedling, also known as percutaneous collagen induction or collagen induction therapy, has been utilized for more than 2 decades.³ Dermatologic indications for microneedling include skin rejuvenation,^4-6 atrophic acne scarring,^7-9 and androgenic alopecia.^10,11 Microneedling also has been used to enhance skin penetration of topically applied drugs.^12-15 Fernandes¹⁶ described percutaneous collagen induction as the skin’s natural response to injury. Microneedling creates small wounds as fine needles puncture the epidermis and dermis, resulting in a cascade of growth factors that lead to tissue proliferation, regeneration, and a collagen remodeling phase that can last for several months.^8,16

Microneedling has gained popularity in the treatment of acne scarring.⁷ Alam et al⁹ conducted a split-face randomized clinical trial (RCT) to evaluate acne scarring after 3 microneedling sessions performed at 2-week intervals. Twenty participants with acne scarring on both sides of the face were enrolled in the study and one side of the face was randomized for treatment. Participants had at least two 5×5-cm areas of acne scarring graded as 2 (moderately atrophic scars) to 4 (hyperplastic or papular scars) on the quantitative Global Acne Scarring Classification system. A roller device with a 1.0-mm depth was used on participants with fine, less sebaceous skin and a 2.0-mm device for all others. Two blinded investigators assessed acne scars at baseline and at 3 and 6 months after treatment. Scar improvement was measured using the quantitative Goodman and Baron scale, which provides a score according to type and number of scars.¹⁷ Mean scar scores were significantly reduced at 6 months compared to baseline on the treatment side (P=.03) but not the control side. Participants experienced minimal pain associated with microneedling therapy, rated 1.08 of 10, and adverse effects were limited to mild transient erythema and edema.⁹ Several other clinical trials have demonstrated clinical improvements with microneedling.^18-20

The benefits of microneedling also have been observed on a histologic level. One group of investigators explored the effects of microneedling on dermal collagen in the treatment of various atrophic acne scars in 10 participants.⁷ After 6 treatment sessions performed at 2-week intervals, dermal collagen was assessed via punch biopsy. A roller device with a needle depth of 1.5 mm was used for all patients. At 1 month after treatment compared to baseline, mean (SD) levels of type I collagen were significantly increased (67.1% [4.2%] vs 70.4% [5.4%]; P=.01) as well as at 3 months after treatment compared to baseline for type III collagen (61.4% [3.6%] vs 74.3% [7.4%]; P=.01), type VII collagen (15.2% [2.1%] vs 21.3% [1.2%]; P=.03), and newly synthesized collagen (14.5% [5.8%] vs 19.5% [3.2%]; P=.02). Total elastin levels were significantly decreased at 3 months after treatment compared to baseline (51.3% [6.7%] vs 46.9% [4.3%]; P=.04). Adverse effects were limited to transient erythema and edema.⁷

Microneedling With Platelet-Rich Plasma

Microneedling has been combined with platelet-rich plasma (PRP) in the treatment of atrophic acne scars.²¹ In addition to inducing new collagen synthesis, microneedling aids in the absorption of PRP, an autologous concentrate of platelets that is obtained through peripheral venipuncture. The concentrate is centrifuged into 3 layers: (1) platelet-poor plasma, (2) PRP, and (3) erythrocytes.²² Platelet-rich plasma contains growth factors such as platelet-derived growth factor, transforming growth factor (TGF), and vascular endothelial growth factor, as well as cell adhesion molecules.^22,23 The application of PRP is thought to result in upregulated protein synthesis, greater collagen remodeling, and accelerated wound healing.²¹

Several studies have shown that the addition of PRP to microneedling can improve treatment outcome (Table 1).^24-27 Severity of acne scarring can be improved, such as reduced scar depth, by using both modalities synergistically (Figure).²⁴ Asif et al²⁶ compared microneedling with PRP to microneedling with distilled water in the treatment of 50 patients with atrophic acne scars graded 2 to 4 (mild to severe acne scarring) on the Goodman’s Qualitative classification and equal Goodman’s Qualitative and Quantitative scores on both halves of the face.^17,28 The right side of the face was treated with a 1.5-mm microneedling roller with intradermal and topical PRP, while the left side was treated with distilled water (placebo) delivered intradermally. Patients underwent 3 treatment sessions at 1-month intervals. The area treated with microneedling and PRP showed a 62.20% improvement from baseline after 3 treatments, while the placebo-treated area showed a 45.84% improvement on the Goodman and Baron quantitative scale.²⁶

Chawla²⁵ compared microneedling with topical PRP to microneedling with topical vitamin C in a split-face study of 30 participants with atrophic acne scarring graded 2 to 4 on the Goodman and Baron scale. A 1.5-mm roller device was used. Patients underwent 4 treatment sessions at 1-month intervals, and treatment efficacy was evaluated using the qualitative Goodman and Baron scale.²⁸ Participants experienced positive outcomes overall with both treatments. Notably, 18.5% (5/27) on the microneedling with PRP side demonstrated excellent response compared to 7.4% (2/27) on the microneedling with vitamin C side.²⁵

Laser Treatment

Laser skin resurfacing has shown to be efficacious in the treatment of both acne vulgaris and acne scarring. Various lasers have been utilized, including nonfractional CO₂ and erbium-doped:YAG (Er:YAG) lasers, as well as ablative fractional lasers (AFLs) and nonablative fractional lasers (NAFLs).²⁹

One retrospective study of 58 patients compared the use of 2 resurfacing lasers—10,600-nm nonfractional CO₂ and 2940-nm Er:YAG—and 2 fractional lasers—1550-nm NAFL and 10,600-nm AFL—in the treatment of atrophic acne scars.²⁹ A retrospective photographic analysis was performed by 6 blinded dermatologists to evaluate clinical improvement on a scale of 0 (no improvement) to 10 (excellent improvement). The mean improvement scores of the CO₂, Er:YAG, AFL, and NAFL groups were 6.0, 5.8, 2.2, and 5.2, respectively, and the mean number of treatments was 1.6, 1.1, 4.0, and 3.4, respectively. Thus, patients in the fractional laser groups required more treatments; however, those in the resurfacing laser groups had longer recovery times, pain, erythema, and postinflammatory hyperpigmentation. The investigators concluded that 3 consecutive AFL treatments could be as effective as a single resurfacing treatment with lower risk for complications.²⁹

A split-face RCT compared the use of the fractional Er:YAG laser on one side of the face to microneedling with a 2.0-mm needle on the other side for treatment of atrophic acne scars.³⁰ Thirty patients underwent 5 treatments at 1-month intervals. At 3-month follow-up, the areas treated with the Er:YAG laser showed 70% improvement from baseline compared to 30% improvement in the areas treated with microneedling (P<.001). Histologically, the Er:YAG laser showed a higher increase in dermal collagen than microneedling (P<.001). Furthermore, the Er:YAG laser yielded significantly lower pain scores (P<.001); however, patients reported higher rates of erythema, swelling, superficial crusting, and total downtime.³⁰

Lasers With PRP
More recent studies have examined the use of laser therapy in addition to PRP for the treatment of acne scars (Table 2).^31-34 Abdel Aal et al³³ examined the use of the ablative fractional CO₂ laser with and without intradermal PRP in a split-face study of 30 participants with various types of acne scarring (ie, boxcar, ice pick, and rolling scars). Participants underwent 2 treatments at 4-week intervals. Evaluations were performed by 2 blinded dermatologists 6 months after the final laser treatment using the qualitative Goodman and Baron scale.²⁸ Both treatments yielded improvement in scarring, but the PRP-treated side showed shorter durations of postprocedure erythema (P=.0052) as well as higher patient satisfaction scores (P<.001) than laser therapy alone.³³

In another split-face study, Gawdat et al³² examined combination treatment with the ablative fractional CO₂ laser and PRP in 30 participants with atrophic acne scars graded 2 to 4 on the qualitative Goodman and Baron scale.²⁸ Participants were randomized to 2 different treatment groups: In group 1, half of the face was treated with the fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and intradermal saline. In group 2, half of the face was treated with fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and topical PRP. All patients underwent 3 treatment sessions at 1-month intervals with assessment occurring a 6-month follow-up using the qualitative Goodman and Baron Scale.²⁸ In all participants, areas treated with the combined laser and PRP showed significant improvement in scarring (P=.03) and reduced recovery time (P=.02) compared to areas treated with laser therapy only. Patients receiving intradermal or topical PRP showed no statistically significant differences in improvement of scarring or recovery time; however, areas treated with topical PRP had significantly lower pain levels (P=.005).³²

Lee et al³¹ conducted a split-face study of 14 patients with moderate to severe acne scarring treated with an ablative fractional CO₂ laser followed by intradermal PRP or intradermal normal saline injections. Patients underwent 2 treatment sessions at 4-week intervals. Photographs taken at baseline and 4 months posttreatment were evaluated by 2 blinded dermatologists for clinical improvement using a quartile grading system. Erythema was assessed using a skin color measuring device. A blinded dermatologist assessed patients for adverse events. At 4-month follow-up, mean (SD) clinical improvement on the side receiving intradermal PRP was significantly better than the control side (2.7 [0.7] vs 2.3 [0.5]; P=.03). Erythema on posttreatment day 4 was significantly less on the side treated with PRP (P=.01). No adverse events were reported.³¹

Another split-face study compared the use of intradermal PRP to intradermal normal saline following fractional CO₂ laser treatment.³⁴ Twenty-five participants with moderate to severe acne scars completed 2 treatment sessions at 4-week intervals. Additionally, skin biopsies were collected to evaluate collagen production using immunohistochemistry, quantitative polymerase chain reaction, and western blot techniques. Experimental fibroblasts and keratinocytes were isolated and cultured. The cultures were irradiated with a fractional CO₂ laser and treated with PRP or platelet-poor plasma. Cultures were evaluated at 30 minutes, 24 hours, and 48 hours. Participants reported 75% improvement of acne scarring from baseline in the side treated with PRP compared to 50% improvement of acne scarring from baseline in the control group (P<.001). On days 7 and 84, participants reported greater improvement on the side treated with PRP (P=.03 and P=.02, respectively). On day 28, skin biopsy evaluation yielded higher levels of TGF-β1 (P=.02), TGF-β3 (P=.004), c-myc (P=.004), type I collagen (P=.03), and type III collagen (P=.03) on the PRP-treated side compared to the control side. Transforming growth factor β increases collagen and fibroblast production, while c-myc leads to cell cycle progression.^35-37 Similarly, TGF-β1, TGF-β3, types I andIII collagen, and p-Akt were increased in all cultures treated with PRP and platelet-poor plasma in a dose-dependent manner.³⁴ p-Akt is thought to regulate wound healing³⁸; however, PRP-treated keratinocytes yielded increased epidermal growth factor receptor and decreased keratin-16 at 48 hours, which suggests PRP plays a role in increasing epithelization and reducing laser-induced keratinocyte damage.³⁹ Adverse effects (eg, erythema, edema, oozing) were less frequent in the PRP-treated side.³⁴

Chemical Peels

Chemical peels are widely used in the treatment of acne scarring.⁴⁰ Peels improve scarring through destruction of the epidermal and/or dermal layers, leading to skin exfoliation, rejuvenation, and remodeling. Superficial peeling agents, which extend to the dermoepidermal junction, include resorcinol, tretinoin, glycolic acid, lactic acid, salicylic acid, and trichloroacetic acid (TCA) 10% to 35%.⁴¹ Medium-depth peeling agents extend to the upper reticular dermis and include phenol, TCA 35% to 50%, and Jessner solution (resorcinol, lactic acid, and salicylic acid in ethanol) followed by TCA 35%.⁴¹ Finally, the effects of deep peeling agents reach the mid reticular dermis and include the Baker-Gordon or Litton phenol formulas.⁴¹ Deep peels are associated with higher rates of adverse outcomes including infection, dyschromia, and scarring.^41,42

An RCT was performed to evaluate the use of a deep phenol 60% peel compared to microneedling with a 1.5-mm roller device plus a TCA 20% peel in the treatment of atrophic acne scars.⁴³ Twenty-four patients were randomly and evenly assigned to both treatment groups. The phenol group underwent a single treatment session, while the microneedling plus TCA group underwent 4 treatment sessions at 6-week intervals. Both groups were instructed to use daily topical tretinoin and hydroquinone 2% in the 2 weeks prior to treatment. Posttreatment results were evaluated using a quartile grading scale. Scarring improved from baseline by 75.12% (P<.001) in the phenol group and 69.43% (P<.001) in the microneedling plus TCA group, with no significant difference between groups. Adverse effects in the phenol group included erythema and hyperpigmentation, while adverse events in the microneedling plus TCA group included transient pain, edema, erythema, and desquamation.⁴³

Another study compared the use of a TCA 15% peel with microneedling to PRP with microneedling and microneedling alone in the treatment of atrophic acne scars.⁴⁴ Twenty-four patients were randomly assigned to the 3 treatment groups (8 to each group) and underwent 6 treatment sessions with 2-week intervals. A roller device with a 1.5-mm needle was used for microneedling. Microneedling plus TCA and microneedling plus PRP were significantly more effective than microneedling alone (P=.011 and P=.015, respectively); however, the TCA 15% peel with microneedling resulted in the largest increase in epidermal thickening. The investigators concluded that combined use of a TCA 15% peel and microneedling was the most effective in treating atrophic acne scarring.⁴⁴

Dermal Fillers

Dermal or subcutaneous fillers are used to increase volume in depressed scars and stimulate the skin’s natural production.⁴⁵ Tissue augmentation methods commonly are used for larger rolling acne scars. Options for filler materials include autologous fat, bovine, or human collagen derivatives; hyaluronic acid; and polymethyl methacrylate microspheres with collagen.⁴⁵ Newer fillers are formulated with lidocaine to decrease pain associated with the procedure.⁴⁶ Hyaluronic acid fillers provide natural volume correction and have limited potential to elicit an immune response due to their derivation from bacterial fermentation. Fillers using polymethyl methacrylate microspheres with collagen are permanent and effective, which may lead to reduced patient costs; however, they often are not a first choice for treatment.^45,46 Furthermore, if dermal fillers consist of bovine collagen, it is necessary to perform skin testing for allergy prior to use. Autologous fat transfer also has become popular for treatment of acne scarring, especially because there is no risk of allergic reaction, as the patient’s own fat is used for correction.⁴⁶ However, this method requires a high degree of skill, and results are unpredictable, generally lasting from 6 months to several years.

Therapies on the horizon include autologous cell therapy. A multicenter, double-blinded, placebo-controlled RCT examined the use of an autologous fibroblast filler in the treatment of bilateral, depressed, and distensible acne scars that were graded as moderate to severe.⁴⁷ Autologous fat fibroblasts were harvested from full-thickness postauricular punch biopsies. In this split-face study, 99 participants were treated with an intradermal autologous fibroblast filler on one cheek and a protein-free cell-culture medium on the contralateral cheek. Participants received an average of 5.9 mL of both autologous fat fibroblasts and cell-culture medium over 3 treatment sessions at 2-week intervals. The autologous fat fibroblasts were associated with greater improvement compared to cell-culture medium based on participant (43% vs 18%), evaluator (59% vs 42%), and independent photographic viewer’s assessment.⁴⁷

Conclusion

Acne scarring is a burden affecting millions of Americans. It often has a negative impact on quality of life and can lead to low self-esteem in patients. Numerous trials have indicated that microneedling is beneficial in the treatment of acne scarring, and emerging evidence indicates that the addition of PRP provides measurable benefits. Similarly, the addition of PRP to laser therapy may reduce recovery time as well as the commonly associated adverse events of erythema and pain. Chemical peels provide the advantage of being easily and efficiently performed in the office setting. Finally, the wide range of available dermal fillers can be tailored to treat specific types of acne scars. Autologous dermal fillers recently have been used and show promising benefits. It is important to consider desired outcome, cost, and adverse events when discussing therapeutic options for acne scarring with patients. The numerous therapeutic options warrant further research and well-designed RCTs to ensure optimal patient outcomes.

Regenerative medicine encompasses innovative therapies that allow the body to repair or regenerate aging cells, tissues, and organs. The skin is a particularly attractive organ for the application of novel regenerative therapies due to its easy accessibility. Among these therapies, stem cells and platelet-rich plasma (PRP) have garnered interest based on their therapeutic potential in scar reduction, antiaging effects, and treatment of alopecia.

Stem cells possess the cardinal features of self-renewal and plasticity. Self-renewal refers to symmetric cell division generating daughter cells identical to the parent cell.¹ Plasticity is the ability to generate cell types other than the germ line or tissue lineage from which stem cells derive.² Stem cells can be categorized according to their differentiation potential. Totipotent stem cells may develop into any primary germ cell layer (ectoderm, mesoderm, endoderm) of the embryo, as well as extraembryonic tissue such as the trophoblast, which gives rise to the placenta. Pluripotent stem cells such as embryonic stem cells have the capacity to differentiate into any derivative of the 3 germ cell layers but have lost their ability to differentiate into the trophoblast.³ Adults lack totipotent or pluripotent cells; they have multipotent or unipotent cells. Multipotent stem cells are able to differentiate into multiple cell types from similar lineages; mesenchymal stem cells (MSCs), for example, can differentiate into adipogenic, osteogenic, chondrogenic, and myogenic cells.⁴ Unipotent stem cells have the lowest differentiation potential and can only self-regenerate. Herein, we review stem cell sources and their therapeutic potential in aesthetic dermatology.

Multipotent Stem Cells

Multipotent stem cells derived from the bone marrow, umbilical cord, adipose tissue, dermis, or hair follicle bulge have various clinical applications in dermatology. Stem cells from these sources are primarily utilized in an autologous manner in which they are processed outside the body and reintroduced into the donor. Autologous multipotent hematopoietic bone marrow cells were first successfully used for the treatment of chronic wounds and show promise for the treatment of atrophic scars.^5,6 However, due to the invasive nature of extracting bone marrow stem cells and their declining number with age, other sources of multipotent stem cells have fallen into favor.

Umbilical cord blood is a source of multipotent hematopoietic stem cells for which surgical intervention is not necessary because they are retrieved after umbilical cord clamping.⁷ Advantages of sourcing stem cells from umbilical cord blood includes high regenerative power compared to a newborn’s skin and low immunogenicity given that the newborn is immunologically immature.⁸

Another popular source for autologous stem cells is adipose tissue due to its ease of accessibility and relative abundance. Given that adipose tissue–derived stem cells (ASCs) are capable of differentiating into adipocytes that help maintain volume over time, they are being used for midface contouring, lip augmentation, facial rejuvenation, facial scarring, lipodystrophy, penile girth enhancement, and vaginal augmentation. Adipose tissue–derived stem cells also are capable of differentiating into other types of tissue, including cartilage and bone. Thus, they have been successfully harnessed in the treatment of patients affected by systemic sclerosis and Parry-Romberg syndrome as well in the functional and aesthetic reconstruction of various military combat–related deformities.^9,10

Adipose tissue–derived stem cells are commonly harvested from lipoaspirate of the abdomen and are combined with supportive mechanical scaffolds such as hydrogels. Lipoaspirate itself can serve as a scaffold for ASCs. Accordingly, ASCs also are being utilized as a scaffold for autologous fat transfer procedures in an effort to increase the viability of transplanted donor tissue, a process known as cell-assisted lipotransfer (CAL). In CAL, a fraction of the aspirated fat is processed for isolation of ASCs, which are then recombined with the remainder of the aspirated fat prior to grafting.¹¹ However, there is conflicting evidence as to whether CAL leads to improved graft success relative to conventional autologous fat transfer.^12,13

The skin also serves as an easily accessible and abundant autologous source of stem cells. A subtype of dermal fibroblasts has been proven to have multipotent potential.^14,15 These dermal fibroblasts are harvested from one area of the skin using punch biopsy and are processed and reinjected into another desired area of the skin.¹⁶ Autologous human fibroblasts have proven to be effective for the treatment of wrinkles, rhytides, and acne scars.¹⁷ In June 2011, the US Food and Drug Administration approved azficel-T, an autologous cellular product created by harvesting fibroblasts from a patient’s own postauricular skin, culture-expanding them in vitro for 3 months, and reinjecting the cells into the desired area of dermis in a series of treatments. This product was the first personalized cell therapy approved by the US Food and Drug Administration for aesthetic uses, specifically for the improvement of nasolabial fold wrinkles.¹⁸

In adults, hair follicles contain an area known as the bulge, which is a site rich in epithelial and melanocytic stem cells. Bulge stem cells have the ability to reproduce the interfollicular epidermis, hair follicle structures, and sebaceous glands, and they have been used to construct entirely new hair follicles in an artificial in vivo system.¹⁹ Sugiyama-Nakagiri et al²⁰ demonstrated that an entire hair follicle epithelium and interfollicular epidermis can be regenerated using cultured bulge stem cells. The cultured bulge stem cells were mixed with dermal papilla cells from neonatal rat vibrissae and engrafted into a silicone chamber implanted on the backs of severe combined immune deficient (SCID) mice. The grafts exhibited tufts of hair as well as a complete interfollicular epidermis at 4 weeks after transplantation.²⁰ Thus, these bulge stem cells have the potential to treat male androgenic alopecia and female pattern hair loss. Bulge stem cells also have been shown to accelerate wound healing.²¹ Additionally, autologous melanocytic stem cells located at the hair follicle bulge are effective for treating vitiligo and are being investigated for the treatment of hair graying.²²

Induced Pluripotent Stem Cells

Given the ethical concerns that surround the procurement and use of embryonic stem cells, efforts have been made to retrieve pluripotent stem cells from adults. A major breakthrough occurred in 2006 when researchers altered the genes of specialized adult mouse cells to cause dedifferentiation and the return to an embryoniclike stem cell state.²³ Mouse somatic cells were reprogrammed through the activation of a combination of transcription factors. The resulting cells were termed induced pluripotent stem cells (iPSCs) and have since been recreated in human cell lines. The discovery of iPSCs precipitated a translational science revolution. Physician-scientists sought ways to apply the reprogrammed cells to the pathophysiology of obscure diseases, examination of drug targets, and regeneration of human tissue.²⁴ Tissue regeneration via induced naïve somatic cells has shown promise as a future method to treat neurologic, cardiovascular, and ophthalmologic diseases.²⁵

As the technology of cultivating and identifying optimal sources of iPSCs continues to advance, stem cell–based treatments have evolved as leading prospects in the field of biogerontology.^26-29 Although much of the research in antiaging medicine has utilized iPSCs to reprogram cell senescence, the altering of iPSCs at a cellular level also allows for the stimulation of collagen synthesis. This potential for collagen generation may have direct applicability in dermatologic practice, particularly for aesthetic treatments.

Much of the research into iPSC-derived collagen has focused on genodermatoses. Itoh et al³⁰ examined the creation of collagen through iPSCs to identify possible treatments for recessive dystrophic epidermolysis bullosa (DEB). Recessive DEB is characterized by mutations in the COL7A1 gene, which encodes type VII collagen, a basement membrane protein and component of the anchoring fibrils essential for skin integrity.³¹ Itoh et al³⁰ began with source cells obtained from a skin biopsy. The cells were dedifferentiated to iPSCs and then induced into dermal fibroblasts according to the methods established in prior studies of embryonic stem cells, namely with the use of ascorbic acid and transforming growth factor b. The newly formed fibroblasts were determined to be functional based on their ability to synthesize mature type VII collagen.³⁰ Once the viability of the iPSC-derived fibroblasts was confirmed in vitro, the cells were further tested through combination with human keratinocytes on SCID mice. The human keratinocytes grew together with the iPSC-derived fibroblasts, producing type VII collagen in the basement membrane zone and creating an epidermis with the normal markers.³⁰ Similarly, Robbins et al³² utilized SCID mice to successfully demonstrate that the transfection of keratinocytes from patients with junctional epidermolysis bullosa into SCID mice produced phenotypically normal skin.

Sebastiano et al³³ combined the concepts of iPSCs and genome editing in another study of recessive DEB. The investigators first cultured iPSCs from biopsies of affected patients. After deriving iPSCs and correcting their mutation via adenovirus-associated viral gene editing, the COL7A1 mutation-free cells were differentiated into keratinocytes. These iPSC-derived keratinocytes were subsequently grafted onto mice, which led to the production of wild-type collagen VII and a stratified epidermis. Despite this successful outcome, the grafts of iPSC-derived epidermis did not survive longer than 1 month.³³

One of the many obstacles facing the practical use of stem cells is their successful incorporation into human tissue. A possible solution was uncovered by Zhang et al³⁴ who examined iPSC-derived MSCs. Mesenchymal stem cells communicate via paracrine mechanisms, whereby exosomes containing RNA and proteins are released to potentiate a regenerative effect.³⁵ Zhang et al³⁴ found that injecting exosomes from human iPSC-derived MSCs into the wound sites of rats stimulated the production of type I collagen, type III collagen, and elastin. The wound sites demonstrated accelerated closure, narrower scar widths, and increased collagen maturity.

Understanding the role that local environment plays in stem cell differentiation, Xu et al³⁶ aimed to create an extracellular scaffold to induce fibroblast behavior from iPSCs. The authors engineered a framework similar to the normal extracellular membrane using proteoglycans, glycosaminoglycans, fibrinogen, and connective tissue growth factor. The iPSCs were then applied to the scaffolding, which led to successful fibroblast differentiation and type I collagen synthesis.³⁶ This use of local biosignaling cues holds important ramifications for controlling the fate of stem cells that have been introduced into a new environment.

Although the application of iPSCs in clinical dermatology has yet to be achieved, progress in the field is moving at a rapid pace. Several logistical elements require further mastery before therapeutics can be delivered. These areas include the optimal environment for iPSC differentiation, methods for maximization of graft survival, and different modes of transplanting iPSC-derived cells into patients. In cosmetic practice, success will depend on intradermal injections of collagen-producing iPSC-derived cells that possess long-term proliferative potential. Current research in mice models has demonstrated viability up to 16 weeks after intradermal injection of such cells.³⁷

Plant Stem Cells

In discussing the dermatologic applications of stem cell technology, clinicians should be aware of the plant stem cell products that have become a popular cosmeceutical trend. Companies advertise plant cells as a natural source of regenerative cells that can induce rejuvenation in human skin; however, there are no significant data to indicate that plant stem cells encourage or activate cellular growth in humans. Indeed, for stem cells to differentiate and produce viable components, the cells must first be incorporated as living components in the host tissue. Because plant stem cells do not survive in human tissue and plant cell cytokines fail to interact with the receptors on human cells, their current value in cosmeceuticals may be overstated.

Platelet-Rich Plasma

Platelet-rich plasma also is commonly associated with stem cell therapy, as PRP is known to potentiate stem cell proliferation, migration, and differentiation. However, PRP does not contain stem cells and is instead autologous plasma concentrated with platelets. In fact, platelets cannot even be classified as cells given that they lack a nucleus; platelets are considered cell fragments. The regenerative potential of PRP can be attributed to the growth factors released from platelets, which play an important role in tissue regeneration and repair. Platelet-rich plasma currently is being used in dermatology for skin rejuvenation (reduction of wrinkles and furrows) and treatment of acne scars.³⁸ There also is evidence supporting the effectiveness of PRP for alopecia and wound therapy, as growth factors play a vital role in hair growth and wound healing.³⁸ Apart from the use of PRP on its own, it can be used as a supplement to enhance the effects of antiaging procedures such as microneedling.³⁹

Future Directions

Multipotent stem cells and iPSCs discussed herein provide much promise in the field of regenerative dermatology. They are increasingly accessible and circumvent the use of ethically questionable embryonic stem cells. Although there is a general consensus on the great potential of stem cells for treating aesthetic skin conditions, high-quality randomized controlled trials remain scarce within the literature. Recognizing and optimizing these opportunities remains the next step in the future delivery of evidence-based care in regenerative dermatology.

Regenerative medicine encompasses innovative therapies that allow the body to repair or regenerate aging cells, tissues, and organs. The skin is a particularly attractive organ for the application of novel regenerative therapies due to its easy accessibility. Among these therapies, stem cells and platelet-rich plasma (PRP) have garnered interest based on their therapeutic potential in scar reduction, antiaging effects, and treatment of alopecia.

Stem cells possess the cardinal features of self-renewal and plasticity. Self-renewal refers to symmetric cell division generating daughter cells identical to the parent cell.¹ Plasticity is the ability to generate cell types other than the germ line or tissue lineage from which stem cells derive.² Stem cells can be categorized according to their differentiation potential. Totipotent stem cells may develop into any primary germ cell layer (ectoderm, mesoderm, endoderm) of the embryo, as well as extraembryonic tissue such as the trophoblast, which gives rise to the placenta. Pluripotent stem cells such as embryonic stem cells have the capacity to differentiate into any derivative of the 3 germ cell layers but have lost their ability to differentiate into the trophoblast.³ Adults lack totipotent or pluripotent cells; they have multipotent or unipotent cells. Multipotent stem cells are able to differentiate into multiple cell types from similar lineages; mesenchymal stem cells (MSCs), for example, can differentiate into adipogenic, osteogenic, chondrogenic, and myogenic cells.⁴ Unipotent stem cells have the lowest differentiation potential and can only self-regenerate. Herein, we review stem cell sources and their therapeutic potential in aesthetic dermatology.

Multipotent Stem Cells

Multipotent stem cells derived from the bone marrow, umbilical cord, adipose tissue, dermis, or hair follicle bulge have various clinical applications in dermatology. Stem cells from these sources are primarily utilized in an autologous manner in which they are processed outside the body and reintroduced into the donor. Autologous multipotent hematopoietic bone marrow cells were first successfully used for the treatment of chronic wounds and show promise for the treatment of atrophic scars.^5,6 However, due to the invasive nature of extracting bone marrow stem cells and their declining number with age, other sources of multipotent stem cells have fallen into favor.

Umbilical cord blood is a source of multipotent hematopoietic stem cells for which surgical intervention is not necessary because they are retrieved after umbilical cord clamping.⁷ Advantages of sourcing stem cells from umbilical cord blood includes high regenerative power compared to a newborn’s skin and low immunogenicity given that the newborn is immunologically immature.⁸

Another popular source for autologous stem cells is adipose tissue due to its ease of accessibility and relative abundance. Given that adipose tissue–derived stem cells (ASCs) are capable of differentiating into adipocytes that help maintain volume over time, they are being used for midface contouring, lip augmentation, facial rejuvenation, facial scarring, lipodystrophy, penile girth enhancement, and vaginal augmentation. Adipose tissue–derived stem cells also are capable of differentiating into other types of tissue, including cartilage and bone. Thus, they have been successfully harnessed in the treatment of patients affected by systemic sclerosis and Parry-Romberg syndrome as well in the functional and aesthetic reconstruction of various military combat–related deformities.^9,10

Adipose tissue–derived stem cells are commonly harvested from lipoaspirate of the abdomen and are combined with supportive mechanical scaffolds such as hydrogels. Lipoaspirate itself can serve as a scaffold for ASCs. Accordingly, ASCs also are being utilized as a scaffold for autologous fat transfer procedures in an effort to increase the viability of transplanted donor tissue, a process known as cell-assisted lipotransfer (CAL). In CAL, a fraction of the aspirated fat is processed for isolation of ASCs, which are then recombined with the remainder of the aspirated fat prior to grafting.¹¹ However, there is conflicting evidence as to whether CAL leads to improved graft success relative to conventional autologous fat transfer.^12,13

The skin also serves as an easily accessible and abundant autologous source of stem cells. A subtype of dermal fibroblasts has been proven to have multipotent potential.^14,15 These dermal fibroblasts are harvested from one area of the skin using punch biopsy and are processed and reinjected into another desired area of the skin.¹⁶ Autologous human fibroblasts have proven to be effective for the treatment of wrinkles, rhytides, and acne scars.¹⁷ In June 2011, the US Food and Drug Administration approved azficel-T, an autologous cellular product created by harvesting fibroblasts from a patient’s own postauricular skin, culture-expanding them in vitro for 3 months, and reinjecting the cells into the desired area of dermis in a series of treatments. This product was the first personalized cell therapy approved by the US Food and Drug Administration for aesthetic uses, specifically for the improvement of nasolabial fold wrinkles.¹⁸

In adults, hair follicles contain an area known as the bulge, which is a site rich in epithelial and melanocytic stem cells. Bulge stem cells have the ability to reproduce the interfollicular epidermis, hair follicle structures, and sebaceous glands, and they have been used to construct entirely new hair follicles in an artificial in vivo system.¹⁹ Sugiyama-Nakagiri et al²⁰ demonstrated that an entire hair follicle epithelium and interfollicular epidermis can be regenerated using cultured bulge stem cells. The cultured bulge stem cells were mixed with dermal papilla cells from neonatal rat vibrissae and engrafted into a silicone chamber implanted on the backs of severe combined immune deficient (SCID) mice. The grafts exhibited tufts of hair as well as a complete interfollicular epidermis at 4 weeks after transplantation.²⁰ Thus, these bulge stem cells have the potential to treat male androgenic alopecia and female pattern hair loss. Bulge stem cells also have been shown to accelerate wound healing.²¹ Additionally, autologous melanocytic stem cells located at the hair follicle bulge are effective for treating vitiligo and are being investigated for the treatment of hair graying.²²

Induced Pluripotent Stem Cells

Given the ethical concerns that surround the procurement and use of embryonic stem cells, efforts have been made to retrieve pluripotent stem cells from adults. A major breakthrough occurred in 2006 when researchers altered the genes of specialized adult mouse cells to cause dedifferentiation and the return to an embryoniclike stem cell state.²³ Mouse somatic cells were reprogrammed through the activation of a combination of transcription factors. The resulting cells were termed induced pluripotent stem cells (iPSCs) and have since been recreated in human cell lines. The discovery of iPSCs precipitated a translational science revolution. Physician-scientists sought ways to apply the reprogrammed cells to the pathophysiology of obscure diseases, examination of drug targets, and regeneration of human tissue.²⁴ Tissue regeneration via induced naïve somatic cells has shown promise as a future method to treat neurologic, cardiovascular, and ophthalmologic diseases.²⁵

As the technology of cultivating and identifying optimal sources of iPSCs continues to advance, stem cell–based treatments have evolved as leading prospects in the field of biogerontology.^26-29 Although much of the research in antiaging medicine has utilized iPSCs to reprogram cell senescence, the altering of iPSCs at a cellular level also allows for the stimulation of collagen synthesis. This potential for collagen generation may have direct applicability in dermatologic practice, particularly for aesthetic treatments.

Much of the research into iPSC-derived collagen has focused on genodermatoses. Itoh et al³⁰ examined the creation of collagen through iPSCs to identify possible treatments for recessive dystrophic epidermolysis bullosa (DEB). Recessive DEB is characterized by mutations in the COL7A1 gene, which encodes type VII collagen, a basement membrane protein and component of the anchoring fibrils essential for skin integrity.³¹ Itoh et al³⁰ began with source cells obtained from a skin biopsy. The cells were dedifferentiated to iPSCs and then induced into dermal fibroblasts according to the methods established in prior studies of embryonic stem cells, namely with the use of ascorbic acid and transforming growth factor b. The newly formed fibroblasts were determined to be functional based on their ability to synthesize mature type VII collagen.³⁰ Once the viability of the iPSC-derived fibroblasts was confirmed in vitro, the cells were further tested through combination with human keratinocytes on SCID mice. The human keratinocytes grew together with the iPSC-derived fibroblasts, producing type VII collagen in the basement membrane zone and creating an epidermis with the normal markers.³⁰ Similarly, Robbins et al³² utilized SCID mice to successfully demonstrate that the transfection of keratinocytes from patients with junctional epidermolysis bullosa into SCID mice produced phenotypically normal skin.

Sebastiano et al³³ combined the concepts of iPSCs and genome editing in another study of recessive DEB. The investigators first cultured iPSCs from biopsies of affected patients. After deriving iPSCs and correcting their mutation via adenovirus-associated viral gene editing, the COL7A1 mutation-free cells were differentiated into keratinocytes. These iPSC-derived keratinocytes were subsequently grafted onto mice, which led to the production of wild-type collagen VII and a stratified epidermis. Despite this successful outcome, the grafts of iPSC-derived epidermis did not survive longer than 1 month.³³

One of the many obstacles facing the practical use of stem cells is their successful incorporation into human tissue. A possible solution was uncovered by Zhang et al³⁴ who examined iPSC-derived MSCs. Mesenchymal stem cells communicate via paracrine mechanisms, whereby exosomes containing RNA and proteins are released to potentiate a regenerative effect.³⁵ Zhang et al³⁴ found that injecting exosomes from human iPSC-derived MSCs into the wound sites of rats stimulated the production of type I collagen, type III collagen, and elastin. The wound sites demonstrated accelerated closure, narrower scar widths, and increased collagen maturity.

Understanding the role that local environment plays in stem cell differentiation, Xu et al³⁶ aimed to create an extracellular scaffold to induce fibroblast behavior from iPSCs. The authors engineered a framework similar to the normal extracellular membrane using proteoglycans, glycosaminoglycans, fibrinogen, and connective tissue growth factor. The iPSCs were then applied to the scaffolding, which led to successful fibroblast differentiation and type I collagen synthesis.³⁶ This use of local biosignaling cues holds important ramifications for controlling the fate of stem cells that have been introduced into a new environment.

Although the application of iPSCs in clinical dermatology has yet to be achieved, progress in the field is moving at a rapid pace. Several logistical elements require further mastery before therapeutics can be delivered. These areas include the optimal environment for iPSC differentiation, methods for maximization of graft survival, and different modes of transplanting iPSC-derived cells into patients. In cosmetic practice, success will depend on intradermal injections of collagen-producing iPSC-derived cells that possess long-term proliferative potential. Current research in mice models has demonstrated viability up to 16 weeks after intradermal injection of such cells.³⁷

Plant Stem Cells

In discussing the dermatologic applications of stem cell technology, clinicians should be aware of the plant stem cell products that have become a popular cosmeceutical trend. Companies advertise plant cells as a natural source of regenerative cells that can induce rejuvenation in human skin; however, there are no significant data to indicate that plant stem cells encourage or activate cellular growth in humans. Indeed, for stem cells to differentiate and produce viable components, the cells must first be incorporated as living components in the host tissue. Because plant stem cells do not survive in human tissue and plant cell cytokines fail to interact with the receptors on human cells, their current value in cosmeceuticals may be overstated.

Platelet-Rich Plasma

Platelet-rich plasma also is commonly associated with stem cell therapy, as PRP is known to potentiate stem cell proliferation, migration, and differentiation. However, PRP does not contain stem cells and is instead autologous plasma concentrated with platelets. In fact, platelets cannot even be classified as cells given that they lack a nucleus; platelets are considered cell fragments. The regenerative potential of PRP can be attributed to the growth factors released from platelets, which play an important role in tissue regeneration and repair. Platelet-rich plasma currently is being used in dermatology for skin rejuvenation (reduction of wrinkles and furrows) and treatment of acne scars.³⁸ There also is evidence supporting the effectiveness of PRP for alopecia and wound therapy, as growth factors play a vital role in hair growth and wound healing.³⁸ Apart from the use of PRP on its own, it can be used as a supplement to enhance the effects of antiaging procedures such as microneedling.³⁹

Future Directions

Multipotent stem cells and iPSCs discussed herein provide much promise in the field of regenerative dermatology. They are increasingly accessible and circumvent the use of ethically questionable embryonic stem cells. Although there is a general consensus on the great potential of stem cells for treating aesthetic skin conditions, high-quality randomized controlled trials remain scarce within the literature. Recognizing and optimizing these opportunities remains the next step in the future delivery of evidence-based care in regenerative dermatology.

Regenerative medicine encompasses innovative therapies that allow the body to repair or regenerate aging cells, tissues, and organs. The skin is a particularly attractive organ for the application of novel regenerative therapies due to its easy accessibility. Among these therapies, stem cells and platelet-rich plasma (PRP) have garnered interest based on their therapeutic potential in scar reduction, antiaging effects, and treatment of alopecia.

Stem cells possess the cardinal features of self-renewal and plasticity. Self-renewal refers to symmetric cell division generating daughter cells identical to the parent cell.¹ Plasticity is the ability to generate cell types other than the germ line or tissue lineage from which stem cells derive.² Stem cells can be categorized according to their differentiation potential. Totipotent stem cells may develop into any primary germ cell layer (ectoderm, mesoderm, endoderm) of the embryo, as well as extraembryonic tissue such as the trophoblast, which gives rise to the placenta. Pluripotent stem cells such as embryonic stem cells have the capacity to differentiate into any derivative of the 3 germ cell layers but have lost their ability to differentiate into the trophoblast.³ Adults lack totipotent or pluripotent cells; they have multipotent or unipotent cells. Multipotent stem cells are able to differentiate into multiple cell types from similar lineages; mesenchymal stem cells (MSCs), for example, can differentiate into adipogenic, osteogenic, chondrogenic, and myogenic cells.⁴ Unipotent stem cells have the lowest differentiation potential and can only self-regenerate. Herein, we review stem cell sources and their therapeutic potential in aesthetic dermatology.

Multipotent Stem Cells

Multipotent stem cells derived from the bone marrow, umbilical cord, adipose tissue, dermis, or hair follicle bulge have various clinical applications in dermatology. Stem cells from these sources are primarily utilized in an autologous manner in which they are processed outside the body and reintroduced into the donor. Autologous multipotent hematopoietic bone marrow cells were first successfully used for the treatment of chronic wounds and show promise for the treatment of atrophic scars.^5,6 However, due to the invasive nature of extracting bone marrow stem cells and their declining number with age, other sources of multipotent stem cells have fallen into favor.

Umbilical cord blood is a source of multipotent hematopoietic stem cells for which surgical intervention is not necessary because they are retrieved after umbilical cord clamping.⁷ Advantages of sourcing stem cells from umbilical cord blood includes high regenerative power compared to a newborn’s skin and low immunogenicity given that the newborn is immunologically immature.⁸

Another popular source for autologous stem cells is adipose tissue due to its ease of accessibility and relative abundance. Given that adipose tissue–derived stem cells (ASCs) are capable of differentiating into adipocytes that help maintain volume over time, they are being used for midface contouring, lip augmentation, facial rejuvenation, facial scarring, lipodystrophy, penile girth enhancement, and vaginal augmentation. Adipose tissue–derived stem cells also are capable of differentiating into other types of tissue, including cartilage and bone. Thus, they have been successfully harnessed in the treatment of patients affected by systemic sclerosis and Parry-Romberg syndrome as well in the functional and aesthetic reconstruction of various military combat–related deformities.^9,10

Adipose tissue–derived stem cells are commonly harvested from lipoaspirate of the abdomen and are combined with supportive mechanical scaffolds such as hydrogels. Lipoaspirate itself can serve as a scaffold for ASCs. Accordingly, ASCs also are being utilized as a scaffold for autologous fat transfer procedures in an effort to increase the viability of transplanted donor tissue, a process known as cell-assisted lipotransfer (CAL). In CAL, a fraction of the aspirated fat is processed for isolation of ASCs, which are then recombined with the remainder of the aspirated fat prior to grafting.¹¹ However, there is conflicting evidence as to whether CAL leads to improved graft success relative to conventional autologous fat transfer.^12,13

The skin also serves as an easily accessible and abundant autologous source of stem cells. A subtype of dermal fibroblasts has been proven to have multipotent potential.^14,15 These dermal fibroblasts are harvested from one area of the skin using punch biopsy and are processed and reinjected into another desired area of the skin.¹⁶ Autologous human fibroblasts have proven to be effective for the treatment of wrinkles, rhytides, and acne scars.¹⁷ In June 2011, the US Food and Drug Administration approved azficel-T, an autologous cellular product created by harvesting fibroblasts from a patient’s own postauricular skin, culture-expanding them in vitro for 3 months, and reinjecting the cells into the desired area of dermis in a series of treatments. This product was the first personalized cell therapy approved by the US Food and Drug Administration for aesthetic uses, specifically for the improvement of nasolabial fold wrinkles.¹⁸

In adults, hair follicles contain an area known as the bulge, which is a site rich in epithelial and melanocytic stem cells. Bulge stem cells have the ability to reproduce the interfollicular epidermis, hair follicle structures, and sebaceous glands, and they have been used to construct entirely new hair follicles in an artificial in vivo system.¹⁹ Sugiyama-Nakagiri et al²⁰ demonstrated that an entire hair follicle epithelium and interfollicular epidermis can be regenerated using cultured bulge stem cells. The cultured bulge stem cells were mixed with dermal papilla cells from neonatal rat vibrissae and engrafted into a silicone chamber implanted on the backs of severe combined immune deficient (SCID) mice. The grafts exhibited tufts of hair as well as a complete interfollicular epidermis at 4 weeks after transplantation.²⁰ Thus, these bulge stem cells have the potential to treat male androgenic alopecia and female pattern hair loss. Bulge stem cells also have been shown to accelerate wound healing.²¹ Additionally, autologous melanocytic stem cells located at the hair follicle bulge are effective for treating vitiligo and are being investigated for the treatment of hair graying.²²

Induced Pluripotent Stem Cells

Given the ethical concerns that surround the procurement and use of embryonic stem cells, efforts have been made to retrieve pluripotent stem cells from adults. A major breakthrough occurred in 2006 when researchers altered the genes of specialized adult mouse cells to cause dedifferentiation and the return to an embryoniclike stem cell state.²³ Mouse somatic cells were reprogrammed through the activation of a combination of transcription factors. The resulting cells were termed induced pluripotent stem cells (iPSCs) and have since been recreated in human cell lines. The discovery of iPSCs precipitated a translational science revolution. Physician-scientists sought ways to apply the reprogrammed cells to the pathophysiology of obscure diseases, examination of drug targets, and regeneration of human tissue.²⁴ Tissue regeneration via induced naïve somatic cells has shown promise as a future method to treat neurologic, cardiovascular, and ophthalmologic diseases.²⁵

As the technology of cultivating and identifying optimal sources of iPSCs continues to advance, stem cell–based treatments have evolved as leading prospects in the field of biogerontology.^26-29 Although much of the research in antiaging medicine has utilized iPSCs to reprogram cell senescence, the altering of iPSCs at a cellular level also allows for the stimulation of collagen synthesis. This potential for collagen generation may have direct applicability in dermatologic practice, particularly for aesthetic treatments.

Much of the research into iPSC-derived collagen has focused on genodermatoses. Itoh et al³⁰ examined the creation of collagen through iPSCs to identify possible treatments for recessive dystrophic epidermolysis bullosa (DEB). Recessive DEB is characterized by mutations in the COL7A1 gene, which encodes type VII collagen, a basement membrane protein and component of the anchoring fibrils essential for skin integrity.³¹ Itoh et al³⁰ began with source cells obtained from a skin biopsy. The cells were dedifferentiated to iPSCs and then induced into dermal fibroblasts according to the methods established in prior studies of embryonic stem cells, namely with the use of ascorbic acid and transforming growth factor b. The newly formed fibroblasts were determined to be functional based on their ability to synthesize mature type VII collagen.³⁰ Once the viability of the iPSC-derived fibroblasts was confirmed in vitro, the cells were further tested through combination with human keratinocytes on SCID mice. The human keratinocytes grew together with the iPSC-derived fibroblasts, producing type VII collagen in the basement membrane zone and creating an epidermis with the normal markers.³⁰ Similarly, Robbins et al³² utilized SCID mice to successfully demonstrate that the transfection of keratinocytes from patients with junctional epidermolysis bullosa into SCID mice produced phenotypically normal skin.

Sebastiano et al³³ combined the concepts of iPSCs and genome editing in another study of recessive DEB. The investigators first cultured iPSCs from biopsies of affected patients. After deriving iPSCs and correcting their mutation via adenovirus-associated viral gene editing, the COL7A1 mutation-free cells were differentiated into keratinocytes. These iPSC-derived keratinocytes were subsequently grafted onto mice, which led to the production of wild-type collagen VII and a stratified epidermis. Despite this successful outcome, the grafts of iPSC-derived epidermis did not survive longer than 1 month.³³

One of the many obstacles facing the practical use of stem cells is their successful incorporation into human tissue. A possible solution was uncovered by Zhang et al³⁴ who examined iPSC-derived MSCs. Mesenchymal stem cells communicate via paracrine mechanisms, whereby exosomes containing RNA and proteins are released to potentiate a regenerative effect.³⁵ Zhang et al³⁴ found that injecting exosomes from human iPSC-derived MSCs into the wound sites of rats stimulated the production of type I collagen, type III collagen, and elastin. The wound sites demonstrated accelerated closure, narrower scar widths, and increased collagen maturity.

Understanding the role that local environment plays in stem cell differentiation, Xu et al³⁶ aimed to create an extracellular scaffold to induce fibroblast behavior from iPSCs. The authors engineered a framework similar to the normal extracellular membrane using proteoglycans, glycosaminoglycans, fibrinogen, and connective tissue growth factor. The iPSCs were then applied to the scaffolding, which led to successful fibroblast differentiation and type I collagen synthesis.³⁶ This use of local biosignaling cues holds important ramifications for controlling the fate of stem cells that have been introduced into a new environment.

Although the application of iPSCs in clinical dermatology has yet to be achieved, progress in the field is moving at a rapid pace. Several logistical elements require further mastery before therapeutics can be delivered. These areas include the optimal environment for iPSC differentiation, methods for maximization of graft survival, and different modes of transplanting iPSC-derived cells into patients. In cosmetic practice, success will depend on intradermal injections of collagen-producing iPSC-derived cells that possess long-term proliferative potential. Current research in mice models has demonstrated viability up to 16 weeks after intradermal injection of such cells.³⁷

Plant Stem Cells

In discussing the dermatologic applications of stem cell technology, clinicians should be aware of the plant stem cell products that have become a popular cosmeceutical trend. Companies advertise plant cells as a natural source of regenerative cells that can induce rejuvenation in human skin; however, there are no significant data to indicate that plant stem cells encourage or activate cellular growth in humans. Indeed, for stem cells to differentiate and produce viable components, the cells must first be incorporated as living components in the host tissue. Because plant stem cells do not survive in human tissue and plant cell cytokines fail to interact with the receptors on human cells, their current value in cosmeceuticals may be overstated.

Platelet-Rich Plasma

Platelet-rich plasma also is commonly associated with stem cell therapy, as PRP is known to potentiate stem cell proliferation, migration, and differentiation. However, PRP does not contain stem cells and is instead autologous plasma concentrated with platelets. In fact, platelets cannot even be classified as cells given that they lack a nucleus; platelets are considered cell fragments. The regenerative potential of PRP can be attributed to the growth factors released from platelets, which play an important role in tissue regeneration and repair. Platelet-rich plasma currently is being used in dermatology for skin rejuvenation (reduction of wrinkles and furrows) and treatment of acne scars.³⁸ There also is evidence supporting the effectiveness of PRP for alopecia and wound therapy, as growth factors play a vital role in hair growth and wound healing.³⁸ Apart from the use of PRP on its own, it can be used as a supplement to enhance the effects of antiaging procedures such as microneedling.³⁹

Future Directions

Multipotent stem cells and iPSCs discussed herein provide much promise in the field of regenerative dermatology. They are increasingly accessible and circumvent the use of ethically questionable embryonic stem cells. Although there is a general consensus on the great potential of stem cells for treating aesthetic skin conditions, high-quality randomized controlled trials remain scarce within the literature. Recognizing and optimizing these opportunities remains the next step in the future delivery of evidence-based care in regenerative dermatology.

Several concepts of ideal aesthetic measurements can be traced back to ancient Greek and European Renaissance art. In examining canons of beauty, these classical ideals often are compared to modern-day standards, allowing clinicians to delineate the parameters of an attractive facial appearance and facilitate the planning of cosmetic procedures.

Given the growing number of available cosmetic interventions, dermatologists have a powerful ability to modify facial proportions; however, changes to individual structures should be made with a mindful approach to improving overall facial harmony. This article reviews the established parameters of facial beauty to assist the clinician in enhancing cosmetic outcomes.

Canons of Facial Aesthetics

Horizontal Thirds
In his writings on human anatomy, Leonardo da Vinci described dividing the face into equal thirds (Figure 1). The upper third measures from the trichion (the midline point of the normal hairline) to the glabella (the smooth prominence between the eyebrows). The middle third measures from the glabella to the subnasale (the midline point where the nasal septum meets the upper lip). The lower third measures from the subnasale to the menton (the most inferior point of the chin).¹

Although the validity of the canon is intended to apply across race and gender, these proportions may vary by ethnicity (Table). In white individuals, the middle third of the face tends to be shorter than the upper and lower thirds.² This same relationship has been observed in black males.³ In Chinese females, the upper third commonly is shorter than the middle and lower thirds, correlating with a less prominent forehead. In contrast, black females tend to have a relatively longer upper third.⁴

The relationship between modern perceptions of attractiveness and the neoclassical norm of equal thirds remains a topic of interest. Milutinovic et al¹ examined facial thirds in white female celebrities from beauty and fashion magazines and compared them to a group of anonymous white females from the general population. The group of anonymous females showed statistically significant (P<.05) differences between the sizes of the 3 facial segments, whereas the group of celebrity faces demonstrated uniformity between the facial thirds.¹

The lower face can itself be divided into thirds, with the upper third measured from the subnasale to the stomion (the midline point of the oral fissure when the lips are closed), and the lower two-thirds measured from the stomion to the menton (Figure 1). Mommaerts and Moerenhout⁵ examined photographs of 105 attractive celebrity faces and compared their proportions to those of classical sculptures of gods and goddesses (antique faces). The authors identified an upper one-third to lower two-thirds ratio of 69.8% in celebrity females and 69.1% in celebrity males; these ratios were not significantly different from the 72.4% seen in antique females and 73.1% in antique males. The authors concluded that a 30% upper lip to 70% lower lip-chin proportion may be the most appropriate to describe contemporary standards.⁵

Vertical Fifths
In the vertical dimension, the neoclassical canon of facial proportions divides the face into equal fifths (Figure 2).⁶ The 2 most lateral fifths are measured from the lateral helix of each ear to the exocanthus of each eye. The eye fissure lengths (measured between the endocanthion and exocanthion of each eye) represent one-fifth. The middle fifth is measured between the medial canthi of both eyes (endocanthion to endocanthion). This distance is equal to the width of the nose, as measured between both alae. Finally, the width of the mouth represents 1.5-times the width of the nose. These ratios of the vertical fifths apply to both males and females.⁶

Anthropometric studies have examined deviations from the neoclassical canon according to ethnicity. Wang et al⁷ compared the measurements of North American white and Han Chinese patients to these standards. White patients demonstrated a greater ratio of mouth width to nose width relative to the canon. In contrast, Han Chinese patients demonstrated a relatively wider nose and narrower mouth.⁷

In black individuals, it has been observed that the dimensions of most facial segments correspond to the neoclassical standards; however, nose width is relatively wider in black individuals relative to the canon as well as relative to white individuals.⁸

Milutinovic et al¹ also compared vertical fifths between white celebrities and anonymous females. In the anonymous female group, statistically significant (P<.05) variations were found between the sizes of the different facial components. In contrast, the celebrity female group showed balance between the widths of vertical fifths.¹

Lips
In the lower facial third, the lips represent a key element of attractiveness. Recently, lip augmentation, aimed at creating fuller and plumper lips, has dominated the popular culture and social media landscape.⁹ Although the aesthetic ideal of lips continues to evolve over time, recent studies have aimed at quantifying modern notions of attractive lip appearance.

Popenko et al¹⁰ examined lip measurements using computer-generated images of white women with different variations of lip sizes and lower face proportions. Computer-generated faces were graded on attractiveness by more than 400 individuals from focus groups. An upper lip to lower lip ratio of 1:2 was judged to be the most attractive, while a ratio of 2:1 was judged to be the least attractive. Results also showed that the surface area of the most attractive lips comprised roughly 10% of the lower third of the face.¹⁰

Penna et al¹¹ analyzed various parameters of the lips and lower facial third using photographs of 176 white males and females that were judged on attractiveness by 250 volunteer evaluators. Faces were graded on a scale from 1 (absolutely attractive) to 7 (absolutely unattractive). Attractive males and females (grades 1 and 2) both demonstrated an average ratio of upper vermilion height to nose-mouth distance (measured from the subnasalae to the lower edge of the upper vermilion border) of 0.28, which was significantly greater than the average ratio observed in less attractive individuals (grades 6 or 7)(P<.05). In addition, attractive males and females demonstrated a ratio of upper vermilion height to nose-chin distance (measured from the subnasalae to the menton) of 0.09, which again was larger than the average ratio seen in less attractive individuals. Figure 3 demonstrates an aesthetic ideal of the lips derived from these 2 studies, though consideration should be given to the fact that these studies were based in white populations.

Golden Ratio
The golden ratio, also known as Phi, can be observed in nature, art, and architecture. Approximately equal to 1.618, the golden ratio also has been identified as a possible marker of beauty in the human face and has garnered attention in the lay press. The ratio has been applied to several proportions and structures in the face, such as the ratio of mouth width to nose width or the ratio of tooth height to tooth width, with investigation providing varying levels of validation about whether these ratios truly correlate with perceptions of beauty.¹² Swift and Remington¹³ advocated for application of the golden ratio toward a comprehensive set of facial proportions. Marquardt¹⁴ used the golden ratio to create a 3-dimensional representation of an idealized face, known as the golden decagon mask. Although the golden ratio and the golden decagon mask have been proposed as analytic tools, their utility in clinical practice may be limited. Firstly, due to its popularity in the lay press, the golden ratio has been inconsistently applied to a wide range of facial ratios, which may undermine confidence in its representation as truth rather than coincidence. Secondly, although some authors have found validity of the golden decagon mask in representing unified ratios of attractiveness, others have asserted that it characterizes a masculinized white female and fails to account for ethnic differences.^15-19

Age-Related Changes

In addition to the facial proportions guided by genetics, several changes occur with increased age. Over the course of a lifetime, predictable patterns emerge in the dimensions of the skin, soft tissue, and bone. These alterations in structural proportions may ultimately lead to an unevenness in facial aesthetics.

In skeletal structure, gradual bone resorption and expansion causes a reduction in facial height as well as an increase in facial width and depth.²⁰ Fat atrophy and hypertrophy affect soft tissue proportions, visualized as hollowing at the temples, cheeks, and around the eyes, along with fullness in the submental region and jowls.²¹ Finally, decreases in skin elasticity and collagen exacerbate the appearance of rhytides and sagging. In older patients who desire a more youthful appearance, various applications of dermal fillers, fat grafting, liposuction, and skin tightening techniques can help to mitigate these changes.

Conclusion

Improving facial aesthetics relies on an understanding of the norms of facial proportions. Although cosmetic interventions commonly are advertised or described based on a single anatomical unit, it is important to appreciate the relationships between facial structures. Most notably, clinicians should be mindful of facial ratios when considering the introduction of filler materials or implants. Augmentation procedures at the temples, zygomatic arch, jaw, chin, and lips all have the possibility to alter facial ratios. Changes should therefore be considered in the context of improving overall facial harmony, with the clinician remaining cognizant of the ideal vertical and horizontal divisions of the face. Understanding such concepts and communicating them to patients can help in appropriately addressing all target areas, thereby leading to greater patient satisfaction.

Several concepts of ideal aesthetic measurements can be traced back to ancient Greek and European Renaissance art. In examining canons of beauty, these classical ideals often are compared to modern-day standards, allowing clinicians to delineate the parameters of an attractive facial appearance and facilitate the planning of cosmetic procedures.

Given the growing number of available cosmetic interventions, dermatologists have a powerful ability to modify facial proportions; however, changes to individual structures should be made with a mindful approach to improving overall facial harmony. This article reviews the established parameters of facial beauty to assist the clinician in enhancing cosmetic outcomes.

Canons of Facial Aesthetics

Horizontal Thirds
In his writings on human anatomy, Leonardo da Vinci described dividing the face into equal thirds (Figure 1). The upper third measures from the trichion (the midline point of the normal hairline) to the glabella (the smooth prominence between the eyebrows). The middle third measures from the glabella to the subnasale (the midline point where the nasal septum meets the upper lip). The lower third measures from the subnasale to the menton (the most inferior point of the chin).¹

Although the validity of the canon is intended to apply across race and gender, these proportions may vary by ethnicity (Table). In white individuals, the middle third of the face tends to be shorter than the upper and lower thirds.² This same relationship has been observed in black males.³ In Chinese females, the upper third commonly is shorter than the middle and lower thirds, correlating with a less prominent forehead. In contrast, black females tend to have a relatively longer upper third.⁴

The relationship between modern perceptions of attractiveness and the neoclassical norm of equal thirds remains a topic of interest. Milutinovic et al¹ examined facial thirds in white female celebrities from beauty and fashion magazines and compared them to a group of anonymous white females from the general population. The group of anonymous females showed statistically significant (P<.05) differences between the sizes of the 3 facial segments, whereas the group of celebrity faces demonstrated uniformity between the facial thirds.¹

The lower face can itself be divided into thirds, with the upper third measured from the subnasale to the stomion (the midline point of the oral fissure when the lips are closed), and the lower two-thirds measured from the stomion to the menton (Figure 1). Mommaerts and Moerenhout⁵ examined photographs of 105 attractive celebrity faces and compared their proportions to those of classical sculptures of gods and goddesses (antique faces). The authors identified an upper one-third to lower two-thirds ratio of 69.8% in celebrity females and 69.1% in celebrity males; these ratios were not significantly different from the 72.4% seen in antique females and 73.1% in antique males. The authors concluded that a 30% upper lip to 70% lower lip-chin proportion may be the most appropriate to describe contemporary standards.⁵

Vertical Fifths
In the vertical dimension, the neoclassical canon of facial proportions divides the face into equal fifths (Figure 2).⁶ The 2 most lateral fifths are measured from the lateral helix of each ear to the exocanthus of each eye. The eye fissure lengths (measured between the endocanthion and exocanthion of each eye) represent one-fifth. The middle fifth is measured between the medial canthi of both eyes (endocanthion to endocanthion). This distance is equal to the width of the nose, as measured between both alae. Finally, the width of the mouth represents 1.5-times the width of the nose. These ratios of the vertical fifths apply to both males and females.⁶

Anthropometric studies have examined deviations from the neoclassical canon according to ethnicity. Wang et al⁷ compared the measurements of North American white and Han Chinese patients to these standards. White patients demonstrated a greater ratio of mouth width to nose width relative to the canon. In contrast, Han Chinese patients demonstrated a relatively wider nose and narrower mouth.⁷

In black individuals, it has been observed that the dimensions of most facial segments correspond to the neoclassical standards; however, nose width is relatively wider in black individuals relative to the canon as well as relative to white individuals.⁸

Milutinovic et al¹ also compared vertical fifths between white celebrities and anonymous females. In the anonymous female group, statistically significant (P<.05) variations were found between the sizes of the different facial components. In contrast, the celebrity female group showed balance between the widths of vertical fifths.¹

Lips
In the lower facial third, the lips represent a key element of attractiveness. Recently, lip augmentation, aimed at creating fuller and plumper lips, has dominated the popular culture and social media landscape.⁹ Although the aesthetic ideal of lips continues to evolve over time, recent studies have aimed at quantifying modern notions of attractive lip appearance.

Popenko et al¹⁰ examined lip measurements using computer-generated images of white women with different variations of lip sizes and lower face proportions. Computer-generated faces were graded on attractiveness by more than 400 individuals from focus groups. An upper lip to lower lip ratio of 1:2 was judged to be the most attractive, while a ratio of 2:1 was judged to be the least attractive. Results also showed that the surface area of the most attractive lips comprised roughly 10% of the lower third of the face.¹⁰

Penna et al¹¹ analyzed various parameters of the lips and lower facial third using photographs of 176 white males and females that were judged on attractiveness by 250 volunteer evaluators. Faces were graded on a scale from 1 (absolutely attractive) to 7 (absolutely unattractive). Attractive males and females (grades 1 and 2) both demonstrated an average ratio of upper vermilion height to nose-mouth distance (measured from the subnasalae to the lower edge of the upper vermilion border) of 0.28, which was significantly greater than the average ratio observed in less attractive individuals (grades 6 or 7)(P<.05). In addition, attractive males and females demonstrated a ratio of upper vermilion height to nose-chin distance (measured from the subnasalae to the menton) of 0.09, which again was larger than the average ratio seen in less attractive individuals. Figure 3 demonstrates an aesthetic ideal of the lips derived from these 2 studies, though consideration should be given to the fact that these studies were based in white populations.

Golden Ratio
The golden ratio, also known as Phi, can be observed in nature, art, and architecture. Approximately equal to 1.618, the golden ratio also has been identified as a possible marker of beauty in the human face and has garnered attention in the lay press. The ratio has been applied to several proportions and structures in the face, such as the ratio of mouth width to nose width or the ratio of tooth height to tooth width, with investigation providing varying levels of validation about whether these ratios truly correlate with perceptions of beauty.¹² Swift and Remington¹³ advocated for application of the golden ratio toward a comprehensive set of facial proportions. Marquardt¹⁴ used the golden ratio to create a 3-dimensional representation of an idealized face, known as the golden decagon mask. Although the golden ratio and the golden decagon mask have been proposed as analytic tools, their utility in clinical practice may be limited. Firstly, due to its popularity in the lay press, the golden ratio has been inconsistently applied to a wide range of facial ratios, which may undermine confidence in its representation as truth rather than coincidence. Secondly, although some authors have found validity of the golden decagon mask in representing unified ratios of attractiveness, others have asserted that it characterizes a masculinized white female and fails to account for ethnic differences.^15-19

Age-Related Changes

In addition to the facial proportions guided by genetics, several changes occur with increased age. Over the course of a lifetime, predictable patterns emerge in the dimensions of the skin, soft tissue, and bone. These alterations in structural proportions may ultimately lead to an unevenness in facial aesthetics.

In skeletal structure, gradual bone resorption and expansion causes a reduction in facial height as well as an increase in facial width and depth.²⁰ Fat atrophy and hypertrophy affect soft tissue proportions, visualized as hollowing at the temples, cheeks, and around the eyes, along with fullness in the submental region and jowls.²¹ Finally, decreases in skin elasticity and collagen exacerbate the appearance of rhytides and sagging. In older patients who desire a more youthful appearance, various applications of dermal fillers, fat grafting, liposuction, and skin tightening techniques can help to mitigate these changes.

Conclusion

Improving facial aesthetics relies on an understanding of the norms of facial proportions. Although cosmetic interventions commonly are advertised or described based on a single anatomical unit, it is important to appreciate the relationships between facial structures. Most notably, clinicians should be mindful of facial ratios when considering the introduction of filler materials or implants. Augmentation procedures at the temples, zygomatic arch, jaw, chin, and lips all have the possibility to alter facial ratios. Changes should therefore be considered in the context of improving overall facial harmony, with the clinician remaining cognizant of the ideal vertical and horizontal divisions of the face. Understanding such concepts and communicating them to patients can help in appropriately addressing all target areas, thereby leading to greater patient satisfaction.

Several concepts of ideal aesthetic measurements can be traced back to ancient Greek and European Renaissance art. In examining canons of beauty, these classical ideals often are compared to modern-day standards, allowing clinicians to delineate the parameters of an attractive facial appearance and facilitate the planning of cosmetic procedures.

Given the growing number of available cosmetic interventions, dermatologists have a powerful ability to modify facial proportions; however, changes to individual structures should be made with a mindful approach to improving overall facial harmony. This article reviews the established parameters of facial beauty to assist the clinician in enhancing cosmetic outcomes.

Canons of Facial Aesthetics

Horizontal Thirds
In his writings on human anatomy, Leonardo da Vinci described dividing the face into equal thirds (Figure 1). The upper third measures from the trichion (the midline point of the normal hairline) to the glabella (the smooth prominence between the eyebrows). The middle third measures from the glabella to the subnasale (the midline point where the nasal septum meets the upper lip). The lower third measures from the subnasale to the menton (the most inferior point of the chin).¹

Although the validity of the canon is intended to apply across race and gender, these proportions may vary by ethnicity (Table). In white individuals, the middle third of the face tends to be shorter than the upper and lower thirds.² This same relationship has been observed in black males.³ In Chinese females, the upper third commonly is shorter than the middle and lower thirds, correlating with a less prominent forehead. In contrast, black females tend to have a relatively longer upper third.⁴

The relationship between modern perceptions of attractiveness and the neoclassical norm of equal thirds remains a topic of interest. Milutinovic et al¹ examined facial thirds in white female celebrities from beauty and fashion magazines and compared them to a group of anonymous white females from the general population. The group of anonymous females showed statistically significant (P<.05) differences between the sizes of the 3 facial segments, whereas the group of celebrity faces demonstrated uniformity between the facial thirds.¹

The lower face can itself be divided into thirds, with the upper third measured from the subnasale to the stomion (the midline point of the oral fissure when the lips are closed), and the lower two-thirds measured from the stomion to the menton (Figure 1). Mommaerts and Moerenhout⁵ examined photographs of 105 attractive celebrity faces and compared their proportions to those of classical sculptures of gods and goddesses (antique faces). The authors identified an upper one-third to lower two-thirds ratio of 69.8% in celebrity females and 69.1% in celebrity males; these ratios were not significantly different from the 72.4% seen in antique females and 73.1% in antique males. The authors concluded that a 30% upper lip to 70% lower lip-chin proportion may be the most appropriate to describe contemporary standards.⁵

Vertical Fifths
In the vertical dimension, the neoclassical canon of facial proportions divides the face into equal fifths (Figure 2).⁶ The 2 most lateral fifths are measured from the lateral helix of each ear to the exocanthus of each eye. The eye fissure lengths (measured between the endocanthion and exocanthion of each eye) represent one-fifth. The middle fifth is measured between the medial canthi of both eyes (endocanthion to endocanthion). This distance is equal to the width of the nose, as measured between both alae. Finally, the width of the mouth represents 1.5-times the width of the nose. These ratios of the vertical fifths apply to both males and females.⁶

Anthropometric studies have examined deviations from the neoclassical canon according to ethnicity. Wang et al⁷ compared the measurements of North American white and Han Chinese patients to these standards. White patients demonstrated a greater ratio of mouth width to nose width relative to the canon. In contrast, Han Chinese patients demonstrated a relatively wider nose and narrower mouth.⁷

In black individuals, it has been observed that the dimensions of most facial segments correspond to the neoclassical standards; however, nose width is relatively wider in black individuals relative to the canon as well as relative to white individuals.⁸

Milutinovic et al¹ also compared vertical fifths between white celebrities and anonymous females. In the anonymous female group, statistically significant (P<.05) variations were found between the sizes of the different facial components. In contrast, the celebrity female group showed balance between the widths of vertical fifths.¹

Lips
In the lower facial third, the lips represent a key element of attractiveness. Recently, lip augmentation, aimed at creating fuller and plumper lips, has dominated the popular culture and social media landscape.⁹ Although the aesthetic ideal of lips continues to evolve over time, recent studies have aimed at quantifying modern notions of attractive lip appearance.

Popenko et al¹⁰ examined lip measurements using computer-generated images of white women with different variations of lip sizes and lower face proportions. Computer-generated faces were graded on attractiveness by more than 400 individuals from focus groups. An upper lip to lower lip ratio of 1:2 was judged to be the most attractive, while a ratio of 2:1 was judged to be the least attractive. Results also showed that the surface area of the most attractive lips comprised roughly 10% of the lower third of the face.¹⁰

Penna et al¹¹ analyzed various parameters of the lips and lower facial third using photographs of 176 white males and females that were judged on attractiveness by 250 volunteer evaluators. Faces were graded on a scale from 1 (absolutely attractive) to 7 (absolutely unattractive). Attractive males and females (grades 1 and 2) both demonstrated an average ratio of upper vermilion height to nose-mouth distance (measured from the subnasalae to the lower edge of the upper vermilion border) of 0.28, which was significantly greater than the average ratio observed in less attractive individuals (grades 6 or 7)(P<.05). In addition, attractive males and females demonstrated a ratio of upper vermilion height to nose-chin distance (measured from the subnasalae to the menton) of 0.09, which again was larger than the average ratio seen in less attractive individuals. Figure 3 demonstrates an aesthetic ideal of the lips derived from these 2 studies, though consideration should be given to the fact that these studies were based in white populations.

Golden Ratio
The golden ratio, also known as Phi, can be observed in nature, art, and architecture. Approximately equal to 1.618, the golden ratio also has been identified as a possible marker of beauty in the human face and has garnered attention in the lay press. The ratio has been applied to several proportions and structures in the face, such as the ratio of mouth width to nose width or the ratio of tooth height to tooth width, with investigation providing varying levels of validation about whether these ratios truly correlate with perceptions of beauty.¹² Swift and Remington¹³ advocated for application of the golden ratio toward a comprehensive set of facial proportions. Marquardt¹⁴ used the golden ratio to create a 3-dimensional representation of an idealized face, known as the golden decagon mask. Although the golden ratio and the golden decagon mask have been proposed as analytic tools, their utility in clinical practice may be limited. Firstly, due to its popularity in the lay press, the golden ratio has been inconsistently applied to a wide range of facial ratios, which may undermine confidence in its representation as truth rather than coincidence. Secondly, although some authors have found validity of the golden decagon mask in representing unified ratios of attractiveness, others have asserted that it characterizes a masculinized white female and fails to account for ethnic differences.^15-19

Age-Related Changes

In addition to the facial proportions guided by genetics, several changes occur with increased age. Over the course of a lifetime, predictable patterns emerge in the dimensions of the skin, soft tissue, and bone. These alterations in structural proportions may ultimately lead to an unevenness in facial aesthetics.

In skeletal structure, gradual bone resorption and expansion causes a reduction in facial height as well as an increase in facial width and depth.²⁰ Fat atrophy and hypertrophy affect soft tissue proportions, visualized as hollowing at the temples, cheeks, and around the eyes, along with fullness in the submental region and jowls.²¹ Finally, decreases in skin elasticity and collagen exacerbate the appearance of rhytides and sagging. In older patients who desire a more youthful appearance, various applications of dermal fillers, fat grafting, liposuction, and skin tightening techniques can help to mitigate these changes.

Conclusion

Improving facial aesthetics relies on an understanding of the norms of facial proportions. Although cosmetic interventions commonly are advertised or described based on a single anatomical unit, it is important to appreciate the relationships between facial structures. Most notably, clinicians should be mindful of facial ratios when considering the introduction of filler materials or implants. Augmentation procedures at the temples, zygomatic arch, jaw, chin, and lips all have the possibility to alter facial ratios. Changes should therefore be considered in the context of improving overall facial harmony, with the clinician remaining cognizant of the ideal vertical and horizontal divisions of the face. Understanding such concepts and communicating them to patients can help in appropriately addressing all target areas, thereby leading to greater patient satisfaction.

Local anesthesia is a central component of successful interventions in cosmetic dermatology. The number of anesthetic medications and administration techniques has grown in recent years as outpatient cosmetic procedures continue to expand. Pain is a common barrier to cosmetic procedures, and alleviating the fear of painful interventions is critical to patient satisfaction and future visits. To accommodate a multitude of cosmetic interventions, it is important for clinicians to be well versed in applications of topical and regional anesthesia. In this article, we review pain management strategies for use in cosmetic practice.

Local Anesthetics

The sensation of pain is carried to the central nervous system by unmyelinated C nerve fibers. Local anesthetics (LAs) act by blocking fast voltage-gated sodium channels in the cell membrane of the nerve, thereby inhibiting downstream propagation of an action potential and the transmission of painful stimuli.¹ The chemical structure of LAs is fundamental to their mechanism of action and metabolism. Local anesthetics contain a lipophilic aromatic group, an intermediate chain, and a hydrophilic amine group. Broadly, agents are classified as amides or esters depending on the chemical group attached to the intermediate chain.² Amides (eg, lidocaine, bupivacaine, articaine, mepivacaine, prilocaine, levobupivacaine) are metabolized by the hepatic system; esters (eg, procaine, proparacaine, benzocaine, chlorprocaine, tetracaine, cocaine) are metabolized by plasma cholinesterase, which produces para-aminobenzoic acid, a potentially dangerous metabolite that has been implicated in allergic reactions.³

Lidocaine is the most prevalent LA used in dermatology practices. Importantly, lidocaine is a class IB antiarrhythmic agent used in cardiology to treat ventricular arrhythmias.⁴ As an anesthetic, a maximum dose of 4.5 mg/kg can be administered, increasing to 7.0 mg/kg when mixed with epinephrine; with higher doses, there is a risk for central nervous system and cardiovascular toxicity.⁵ Initial symptoms of lidocaine toxicity include dizziness, tinnitus, circumoral paresthesia, blurred vision, and a metallic taste in the mouth.⁶ Systemic absorption of topical anesthetics is heightened across mucosal membranes, and care should be taken when applying over large surface areas.

Allergic reactions to LAs may be local or less frequently systemic. It is important to note that LAs tend to show cross-reactivity within their class rather than across different classes.⁷ Reactions can be classified as type I or type IV. Type I (IgE-mediated) reactions evolve in minutes to hours, affecting the skin and possibly leading to respiratory and circulatory collapse. Delayed reactions to LAs have increased in recent years, with type IV contact allergy most frequently found in connection with benzocaine and lidocaine.⁸

Topical Anesthesia

Topical anesthetics are effective and easy to use and are particularly valuable in patients with needle phobia. In certain cases, these medications may be applied by the patient prior to arrival, thereby reducing visit time. Topical agents act on nerve fibers running through the dermis; therefore, efficacy is dependent on successful penetration through the stratum corneum and viable epidermis. To enhance absorption, agents may be applied under an occlusive dressing.

Topical anesthetics are most commonly used for injectable fillers, ablative and nonablative laser resurfacing, laser hair removal, and tattoo removal. The eutectic mixture of 2.5% lidocaine and 2.5% prilocaine as well as topical 4% or 5% lidocaine are the most commonly used US Food and Drug Administration–approved products for topical anesthesia. In addition, several compounded pharmacy products are available.

After 60 minutes of application of the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine, a 3-mm depth of analgesia is reached, and after 120 minutes, a 4.5-mm depth is reached.⁹ It elicits a biphasic vascular response of vasoconstriction and blanching followed by vasodilation and erythema.¹⁰ Most adverse events are mild and transient, but allergic contact dermatitis and contact urticaria have been reported.^11-13 In older children and adults, the maximum application area is 200 cm², with a maximum dose of 20 g used for no longer than 4 hours.

The 4% or 5% lidocaine cream uses a liposomal delivery system, which is designed to improve cutaneous penetration and has been shown to provide longer durations of anesthesia than nonliposomal lidocaine preparations.¹⁴ Application should be performed 30 to 60 minutes prior to a procedure. In a study comparing the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine versus lidocaine cream 5% for pain control during laser hair removal with a 1064-nm Nd:YAG laser, no significant differences were found.¹⁵ The maximum application area is 100 cm² in children weighing less than 20 kg. A study of healthy adults demonstrated safety with the use of 30 to 60 g of occluded liposomal lidocaine cream 4%.¹⁶

In addition to US Food and Drug Administration–approved products, several compounded pharmacy products are available for topical anesthesia. These formulations include benzocaine-lidocaine-tetracaine gel, tetracaine-adrenaline-cocaine solution, and lidocaine-epinephrine-tetracaine solution. A triple-anesthetic gel, benzocaine-lidocaine-tetracaine is widely used in cosmetic practice. The product has been shown to provide adequate anesthesia for laser resurfacing after 20 minutes without occlusion.¹⁷ Of note, compounded anesthetics lack standardization, and different pharmacies may follow their own individual protocols.

Regional Anesthesia

Regional nerve blockade is a useful option for more widespread or complex interventions. Using regional nerve blockade, effective analgesia can be delivered to a target area while avoiding the toxicity and pain associated with numerous anesthetic infiltrations. In addition, there is no distortion of the tissue architecture, allowing for improved visual evaluation during the procedure. Recently, hyaluronic acid fillers have been compounded with lidocaine as a means of reducing procedural pain.

Blocks for Dermal Fillers

Forehead
For dermal filler injections of the glabellar and frontalis lines, anesthesia of the forehead may be desired. The supraorbital and supratrochlear nerves supply this area. The supraorbital nerve can be injected at the supraorbital notch, which is measured roughly 2.7 cm from the glabella. The orbital rim should be palpated with the nondominant hand, and 1 to 2 mL of anesthetic should be injected just below the rim (Figure 1). The supratrochlear nerve is located roughly 1.7 cm from the midline and can be similarly injected under the orbital rim with 1 to 2 mL of anesthetic (Figure 1).

Lateral Temple Region
Anesthesia of the zygomaticotemporal nerve can be used to reduce pain from dermal filler injections of the lateral canthal and temporal areas. The nerve is identified by first palpating the zygomaticofrontal suture. A long needle is then inserted posteriorly, immediately behind the concave surface of the lateral orbital rim, and 1 to 2 mL of anesthetic is injected (Figure 1).

Malar Region
Blockade of the zygomaticofacial nerve is commonly performed in conjunction with the zygomaticotemporal nerve and provides anesthesia to the malar region for cheek augmentation procedures. To identify the target area, the junction of the lateral and inferior orbital rim should be palpated. With the needle placed just lateral to this point, 1 to 2 mL of anesthetic is injected (Figure 1).

Blocks for Perioral Fillers

Upper Lips/Nasolabial Folds
Bilateral blockade of the infraorbital nerves provides anesthesia to the upper lip and nasolabial folds prior to filler injections. The infraorbital nerve can be targeted via an intraoral route where it exits the maxilla at the infraorbital foramen. The nerve is anesthetized by palpating the infraorbital ridge and injecting 3 to 5 mL of anesthetic roughly 1 cm below this point on the vertical axis of the midpupillary line (Figure 1). The external nasal nerve, thought to be a branch of cranial nerve V, also may be targeted if there is inadequate anesthesia from the infraorbital block. This nerve is reached by injecting at the osseocartilaginous junction of the nasal bones (Figure 1).

Lower Lips
Blockade of the mental nerve provides anesthesia to the lower lips for augmentation procedures. The mental nerve can be targeted on each side at the mental foramen, which is located below the root of the lower second premolar. Aiming roughly 1 cm below the gumline, 3 to 5 mL of anesthetic is injected intraorally (Figure 1). A transcutaneous approach toward the same target also is possible, though this technique risks visible bruising. Alternatively, the upper or lower lips can be anesthetized using 4 to 5 submucosal injections at evenly spaced intervals between the canine teeth.¹⁸

Blocks for Palmoplantar Hyperhidrosis

The treatment of palmoplantar hyperhidrosis benefits from regional blocks. Botulinum toxin has been well established as an effective therapy for the condition.^19-21 Given the sensitivity of palmoplantar sites, it is valuable to achieve effective analgesia of the region prior to dermal injections of botulinum toxin.

Wrists
Sensory innervation of the palm is provided by the median, ulnar, and radial nerves (Figure 2A). At the wrist, the median nerve lies between the tendons of the flexor carpi radialis muscle and the palmaris longus muscle. To facilitate identification of the palmaris longus muscle, instruct the patient to oppose the thumb and little finger while flexing the wrist. The needle should be inserted between the 2 tendons, just proximal to the wrist creases (Figure 2B). Once the fascia is pierced, 3 to 5 mL of anesthetic is injected.

The ulnar nerve is anesthetized between the ulnar artery and the flexor carpi ulnaris muscle. The artery is identified by palpation, and special care should be taken to avoid intra-arterial injection. The needle is directed toward the radial styloid, and 3 to 5 mL of anesthetic is injected roughly 1 cm proximal to the wrist crease (Figure 2B).

Anesthesia of the radial nerve can be considered a field block given the numerous small branches that supply the hand. These branches are reached by injecting anesthetic roughly 2 to 3 cm proximal to the radial styloid with the needle aimed medially and extending the injection dorsally (Figure 2B). A total of 4 to 6 mL of anesthetic is used.

Ankles
An ankle block provides anesthesia to the dorsal and plantar surfaces of the foot.²² The region is supplied by the superficial peroneal nerve, deep peroneal nerve, sural nerve, saphenous nerve, and branches of the posterior tibial nerve (Figure 3A).

To anesthetize the deep peroneal nerve, the extensor hallucis longus tendon is first identified on the anterior surface of the ankle through dorsiflexion of the toes; the dorsalis pedis artery runs in close proximity. The injection should be placed lateral to the tendon and artery (Figure 3B). The needle should be inserted until bone is reached, withdrawn slightly, and then 3 to 5 mL of anesthetic should be injected. To block the saphenous nerve, the needle can then be directed superficially toward the medial malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C). To block the superficial peroneal nerve, the needle should then be directed toward the lateral malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C).

The posterior tibial nerve is located posterior to the medial malleolus. The dorsalis pedis artery can be palpated near this location. The needle should be inserted posterior to the artery, extending until bone is reached (Figure 3C). The needle is then withdrawn slightly, and 3 to 5 mL of anesthetic is injected. Finally, the sural nerve is anesthetized between the Achilles tendon and the lateral malleolus, using 5 mL of anesthetic to raise a subcutaneous wheal (Figure 3C).

Conclusion

Proper pain management is integral to ensuring a positive experience for cosmetic patients. Enhanced knowledge of local anesthetic techniques allows the clinician to provide for a variety of procedural indications and patient preferences. As anesthetic strategies are continually evolving, it is important for practitioners to remain informed of these developments.

Local anesthesia is a central component of successful interventions in cosmetic dermatology. The number of anesthetic medications and administration techniques has grown in recent years as outpatient cosmetic procedures continue to expand. Pain is a common barrier to cosmetic procedures, and alleviating the fear of painful interventions is critical to patient satisfaction and future visits. To accommodate a multitude of cosmetic interventions, it is important for clinicians to be well versed in applications of topical and regional anesthesia. In this article, we review pain management strategies for use in cosmetic practice.

Local Anesthetics

The sensation of pain is carried to the central nervous system by unmyelinated C nerve fibers. Local anesthetics (LAs) act by blocking fast voltage-gated sodium channels in the cell membrane of the nerve, thereby inhibiting downstream propagation of an action potential and the transmission of painful stimuli.¹ The chemical structure of LAs is fundamental to their mechanism of action and metabolism. Local anesthetics contain a lipophilic aromatic group, an intermediate chain, and a hydrophilic amine group. Broadly, agents are classified as amides or esters depending on the chemical group attached to the intermediate chain.² Amides (eg, lidocaine, bupivacaine, articaine, mepivacaine, prilocaine, levobupivacaine) are metabolized by the hepatic system; esters (eg, procaine, proparacaine, benzocaine, chlorprocaine, tetracaine, cocaine) are metabolized by plasma cholinesterase, which produces para-aminobenzoic acid, a potentially dangerous metabolite that has been implicated in allergic reactions.³

Lidocaine is the most prevalent LA used in dermatology practices. Importantly, lidocaine is a class IB antiarrhythmic agent used in cardiology to treat ventricular arrhythmias.⁴ As an anesthetic, a maximum dose of 4.5 mg/kg can be administered, increasing to 7.0 mg/kg when mixed with epinephrine; with higher doses, there is a risk for central nervous system and cardiovascular toxicity.⁵ Initial symptoms of lidocaine toxicity include dizziness, tinnitus, circumoral paresthesia, blurred vision, and a metallic taste in the mouth.⁶ Systemic absorption of topical anesthetics is heightened across mucosal membranes, and care should be taken when applying over large surface areas.

Allergic reactions to LAs may be local or less frequently systemic. It is important to note that LAs tend to show cross-reactivity within their class rather than across different classes.⁷ Reactions can be classified as type I or type IV. Type I (IgE-mediated) reactions evolve in minutes to hours, affecting the skin and possibly leading to respiratory and circulatory collapse. Delayed reactions to LAs have increased in recent years, with type IV contact allergy most frequently found in connection with benzocaine and lidocaine.⁸

Topical Anesthesia

Topical anesthetics are effective and easy to use and are particularly valuable in patients with needle phobia. In certain cases, these medications may be applied by the patient prior to arrival, thereby reducing visit time. Topical agents act on nerve fibers running through the dermis; therefore, efficacy is dependent on successful penetration through the stratum corneum and viable epidermis. To enhance absorption, agents may be applied under an occlusive dressing.

Topical anesthetics are most commonly used for injectable fillers, ablative and nonablative laser resurfacing, laser hair removal, and tattoo removal. The eutectic mixture of 2.5% lidocaine and 2.5% prilocaine as well as topical 4% or 5% lidocaine are the most commonly used US Food and Drug Administration–approved products for topical anesthesia. In addition, several compounded pharmacy products are available.

After 60 minutes of application of the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine, a 3-mm depth of analgesia is reached, and after 120 minutes, a 4.5-mm depth is reached.⁹ It elicits a biphasic vascular response of vasoconstriction and blanching followed by vasodilation and erythema.¹⁰ Most adverse events are mild and transient, but allergic contact dermatitis and contact urticaria have been reported.^11-13 In older children and adults, the maximum application area is 200 cm², with a maximum dose of 20 g used for no longer than 4 hours.

The 4% or 5% lidocaine cream uses a liposomal delivery system, which is designed to improve cutaneous penetration and has been shown to provide longer durations of anesthesia than nonliposomal lidocaine preparations.¹⁴ Application should be performed 30 to 60 minutes prior to a procedure. In a study comparing the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine versus lidocaine cream 5% for pain control during laser hair removal with a 1064-nm Nd:YAG laser, no significant differences were found.¹⁵ The maximum application area is 100 cm² in children weighing less than 20 kg. A study of healthy adults demonstrated safety with the use of 30 to 60 g of occluded liposomal lidocaine cream 4%.¹⁶

In addition to US Food and Drug Administration–approved products, several compounded pharmacy products are available for topical anesthesia. These formulations include benzocaine-lidocaine-tetracaine gel, tetracaine-adrenaline-cocaine solution, and lidocaine-epinephrine-tetracaine solution. A triple-anesthetic gel, benzocaine-lidocaine-tetracaine is widely used in cosmetic practice. The product has been shown to provide adequate anesthesia for laser resurfacing after 20 minutes without occlusion.¹⁷ Of note, compounded anesthetics lack standardization, and different pharmacies may follow their own individual protocols.

Regional Anesthesia

Regional nerve blockade is a useful option for more widespread or complex interventions. Using regional nerve blockade, effective analgesia can be delivered to a target area while avoiding the toxicity and pain associated with numerous anesthetic infiltrations. In addition, there is no distortion of the tissue architecture, allowing for improved visual evaluation during the procedure. Recently, hyaluronic acid fillers have been compounded with lidocaine as a means of reducing procedural pain.

Blocks for Dermal Fillers

Forehead
For dermal filler injections of the glabellar and frontalis lines, anesthesia of the forehead may be desired. The supraorbital and supratrochlear nerves supply this area. The supraorbital nerve can be injected at the supraorbital notch, which is measured roughly 2.7 cm from the glabella. The orbital rim should be palpated with the nondominant hand, and 1 to 2 mL of anesthetic should be injected just below the rim (Figure 1). The supratrochlear nerve is located roughly 1.7 cm from the midline and can be similarly injected under the orbital rim with 1 to 2 mL of anesthetic (Figure 1).

Lateral Temple Region
Anesthesia of the zygomaticotemporal nerve can be used to reduce pain from dermal filler injections of the lateral canthal and temporal areas. The nerve is identified by first palpating the zygomaticofrontal suture. A long needle is then inserted posteriorly, immediately behind the concave surface of the lateral orbital rim, and 1 to 2 mL of anesthetic is injected (Figure 1).

Malar Region
Blockade of the zygomaticofacial nerve is commonly performed in conjunction with the zygomaticotemporal nerve and provides anesthesia to the malar region for cheek augmentation procedures. To identify the target area, the junction of the lateral and inferior orbital rim should be palpated. With the needle placed just lateral to this point, 1 to 2 mL of anesthetic is injected (Figure 1).

Blocks for Perioral Fillers

Upper Lips/Nasolabial Folds
Bilateral blockade of the infraorbital nerves provides anesthesia to the upper lip and nasolabial folds prior to filler injections. The infraorbital nerve can be targeted via an intraoral route where it exits the maxilla at the infraorbital foramen. The nerve is anesthetized by palpating the infraorbital ridge and injecting 3 to 5 mL of anesthetic roughly 1 cm below this point on the vertical axis of the midpupillary line (Figure 1). The external nasal nerve, thought to be a branch of cranial nerve V, also may be targeted if there is inadequate anesthesia from the infraorbital block. This nerve is reached by injecting at the osseocartilaginous junction of the nasal bones (Figure 1).

Lower Lips
Blockade of the mental nerve provides anesthesia to the lower lips for augmentation procedures. The mental nerve can be targeted on each side at the mental foramen, which is located below the root of the lower second premolar. Aiming roughly 1 cm below the gumline, 3 to 5 mL of anesthetic is injected intraorally (Figure 1). A transcutaneous approach toward the same target also is possible, though this technique risks visible bruising. Alternatively, the upper or lower lips can be anesthetized using 4 to 5 submucosal injections at evenly spaced intervals between the canine teeth.¹⁸

Blocks for Palmoplantar Hyperhidrosis

The treatment of palmoplantar hyperhidrosis benefits from regional blocks. Botulinum toxin has been well established as an effective therapy for the condition.^19-21 Given the sensitivity of palmoplantar sites, it is valuable to achieve effective analgesia of the region prior to dermal injections of botulinum toxin.

Wrists
Sensory innervation of the palm is provided by the median, ulnar, and radial nerves (Figure 2A). At the wrist, the median nerve lies between the tendons of the flexor carpi radialis muscle and the palmaris longus muscle. To facilitate identification of the palmaris longus muscle, instruct the patient to oppose the thumb and little finger while flexing the wrist. The needle should be inserted between the 2 tendons, just proximal to the wrist creases (Figure 2B). Once the fascia is pierced, 3 to 5 mL of anesthetic is injected.

The ulnar nerve is anesthetized between the ulnar artery and the flexor carpi ulnaris muscle. The artery is identified by palpation, and special care should be taken to avoid intra-arterial injection. The needle is directed toward the radial styloid, and 3 to 5 mL of anesthetic is injected roughly 1 cm proximal to the wrist crease (Figure 2B).

Anesthesia of the radial nerve can be considered a field block given the numerous small branches that supply the hand. These branches are reached by injecting anesthetic roughly 2 to 3 cm proximal to the radial styloid with the needle aimed medially and extending the injection dorsally (Figure 2B). A total of 4 to 6 mL of anesthetic is used.

Ankles
An ankle block provides anesthesia to the dorsal and plantar surfaces of the foot.²² The region is supplied by the superficial peroneal nerve, deep peroneal nerve, sural nerve, saphenous nerve, and branches of the posterior tibial nerve (Figure 3A).

To anesthetize the deep peroneal nerve, the extensor hallucis longus tendon is first identified on the anterior surface of the ankle through dorsiflexion of the toes; the dorsalis pedis artery runs in close proximity. The injection should be placed lateral to the tendon and artery (Figure 3B). The needle should be inserted until bone is reached, withdrawn slightly, and then 3 to 5 mL of anesthetic should be injected. To block the saphenous nerve, the needle can then be directed superficially toward the medial malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C). To block the superficial peroneal nerve, the needle should then be directed toward the lateral malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C).

The posterior tibial nerve is located posterior to the medial malleolus. The dorsalis pedis artery can be palpated near this location. The needle should be inserted posterior to the artery, extending until bone is reached (Figure 3C). The needle is then withdrawn slightly, and 3 to 5 mL of anesthetic is injected. Finally, the sural nerve is anesthetized between the Achilles tendon and the lateral malleolus, using 5 mL of anesthetic to raise a subcutaneous wheal (Figure 3C).

Conclusion

Proper pain management is integral to ensuring a positive experience for cosmetic patients. Enhanced knowledge of local anesthetic techniques allows the clinician to provide for a variety of procedural indications and patient preferences. As anesthetic strategies are continually evolving, it is important for practitioners to remain informed of these developments.

Local anesthesia is a central component of successful interventions in cosmetic dermatology. The number of anesthetic medications and administration techniques has grown in recent years as outpatient cosmetic procedures continue to expand. Pain is a common barrier to cosmetic procedures, and alleviating the fear of painful interventions is critical to patient satisfaction and future visits. To accommodate a multitude of cosmetic interventions, it is important for clinicians to be well versed in applications of topical and regional anesthesia. In this article, we review pain management strategies for use in cosmetic practice.

Local Anesthetics

The sensation of pain is carried to the central nervous system by unmyelinated C nerve fibers. Local anesthetics (LAs) act by blocking fast voltage-gated sodium channels in the cell membrane of the nerve, thereby inhibiting downstream propagation of an action potential and the transmission of painful stimuli.¹ The chemical structure of LAs is fundamental to their mechanism of action and metabolism. Local anesthetics contain a lipophilic aromatic group, an intermediate chain, and a hydrophilic amine group. Broadly, agents are classified as amides or esters depending on the chemical group attached to the intermediate chain.² Amides (eg, lidocaine, bupivacaine, articaine, mepivacaine, prilocaine, levobupivacaine) are metabolized by the hepatic system; esters (eg, procaine, proparacaine, benzocaine, chlorprocaine, tetracaine, cocaine) are metabolized by plasma cholinesterase, which produces para-aminobenzoic acid, a potentially dangerous metabolite that has been implicated in allergic reactions.³

Lidocaine is the most prevalent LA used in dermatology practices. Importantly, lidocaine is a class IB antiarrhythmic agent used in cardiology to treat ventricular arrhythmias.⁴ As an anesthetic, a maximum dose of 4.5 mg/kg can be administered, increasing to 7.0 mg/kg when mixed with epinephrine; with higher doses, there is a risk for central nervous system and cardiovascular toxicity.⁵ Initial symptoms of lidocaine toxicity include dizziness, tinnitus, circumoral paresthesia, blurred vision, and a metallic taste in the mouth.⁶ Systemic absorption of topical anesthetics is heightened across mucosal membranes, and care should be taken when applying over large surface areas.

Allergic reactions to LAs may be local or less frequently systemic. It is important to note that LAs tend to show cross-reactivity within their class rather than across different classes.⁷ Reactions can be classified as type I or type IV. Type I (IgE-mediated) reactions evolve in minutes to hours, affecting the skin and possibly leading to respiratory and circulatory collapse. Delayed reactions to LAs have increased in recent years, with type IV contact allergy most frequently found in connection with benzocaine and lidocaine.⁸

Topical Anesthesia

Topical anesthetics are effective and easy to use and are particularly valuable in patients with needle phobia. In certain cases, these medications may be applied by the patient prior to arrival, thereby reducing visit time. Topical agents act on nerve fibers running through the dermis; therefore, efficacy is dependent on successful penetration through the stratum corneum and viable epidermis. To enhance absorption, agents may be applied under an occlusive dressing.

Topical anesthetics are most commonly used for injectable fillers, ablative and nonablative laser resurfacing, laser hair removal, and tattoo removal. The eutectic mixture of 2.5% lidocaine and 2.5% prilocaine as well as topical 4% or 5% lidocaine are the most commonly used US Food and Drug Administration–approved products for topical anesthesia. In addition, several compounded pharmacy products are available.

After 60 minutes of application of the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine, a 3-mm depth of analgesia is reached, and after 120 minutes, a 4.5-mm depth is reached.⁹ It elicits a biphasic vascular response of vasoconstriction and blanching followed by vasodilation and erythema.¹⁰ Most adverse events are mild and transient, but allergic contact dermatitis and contact urticaria have been reported.^11-13 In older children and adults, the maximum application area is 200 cm², with a maximum dose of 20 g used for no longer than 4 hours.

The 4% or 5% lidocaine cream uses a liposomal delivery system, which is designed to improve cutaneous penetration and has been shown to provide longer durations of anesthesia than nonliposomal lidocaine preparations.¹⁴ Application should be performed 30 to 60 minutes prior to a procedure. In a study comparing the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine versus lidocaine cream 5% for pain control during laser hair removal with a 1064-nm Nd:YAG laser, no significant differences were found.¹⁵ The maximum application area is 100 cm² in children weighing less than 20 kg. A study of healthy adults demonstrated safety with the use of 30 to 60 g of occluded liposomal lidocaine cream 4%.¹⁶

In addition to US Food and Drug Administration–approved products, several compounded pharmacy products are available for topical anesthesia. These formulations include benzocaine-lidocaine-tetracaine gel, tetracaine-adrenaline-cocaine solution, and lidocaine-epinephrine-tetracaine solution. A triple-anesthetic gel, benzocaine-lidocaine-tetracaine is widely used in cosmetic practice. The product has been shown to provide adequate anesthesia for laser resurfacing after 20 minutes without occlusion.¹⁷ Of note, compounded anesthetics lack standardization, and different pharmacies may follow their own individual protocols.

Regional Anesthesia

Regional nerve blockade is a useful option for more widespread or complex interventions. Using regional nerve blockade, effective analgesia can be delivered to a target area while avoiding the toxicity and pain associated with numerous anesthetic infiltrations. In addition, there is no distortion of the tissue architecture, allowing for improved visual evaluation during the procedure. Recently, hyaluronic acid fillers have been compounded with lidocaine as a means of reducing procedural pain.

Blocks for Dermal Fillers

Forehead
For dermal filler injections of the glabellar and frontalis lines, anesthesia of the forehead may be desired. The supraorbital and supratrochlear nerves supply this area. The supraorbital nerve can be injected at the supraorbital notch, which is measured roughly 2.7 cm from the glabella. The orbital rim should be palpated with the nondominant hand, and 1 to 2 mL of anesthetic should be injected just below the rim (Figure 1). The supratrochlear nerve is located roughly 1.7 cm from the midline and can be similarly injected under the orbital rim with 1 to 2 mL of anesthetic (Figure 1).

Lateral Temple Region
Anesthesia of the zygomaticotemporal nerve can be used to reduce pain from dermal filler injections of the lateral canthal and temporal areas. The nerve is identified by first palpating the zygomaticofrontal suture. A long needle is then inserted posteriorly, immediately behind the concave surface of the lateral orbital rim, and 1 to 2 mL of anesthetic is injected (Figure 1).

Malar Region
Blockade of the zygomaticofacial nerve is commonly performed in conjunction with the zygomaticotemporal nerve and provides anesthesia to the malar region for cheek augmentation procedures. To identify the target area, the junction of the lateral and inferior orbital rim should be palpated. With the needle placed just lateral to this point, 1 to 2 mL of anesthetic is injected (Figure 1).

Blocks for Perioral Fillers

Upper Lips/Nasolabial Folds
Bilateral blockade of the infraorbital nerves provides anesthesia to the upper lip and nasolabial folds prior to filler injections. The infraorbital nerve can be targeted via an intraoral route where it exits the maxilla at the infraorbital foramen. The nerve is anesthetized by palpating the infraorbital ridge and injecting 3 to 5 mL of anesthetic roughly 1 cm below this point on the vertical axis of the midpupillary line (Figure 1). The external nasal nerve, thought to be a branch of cranial nerve V, also may be targeted if there is inadequate anesthesia from the infraorbital block. This nerve is reached by injecting at the osseocartilaginous junction of the nasal bones (Figure 1).

Lower Lips
Blockade of the mental nerve provides anesthesia to the lower lips for augmentation procedures. The mental nerve can be targeted on each side at the mental foramen, which is located below the root of the lower second premolar. Aiming roughly 1 cm below the gumline, 3 to 5 mL of anesthetic is injected intraorally (Figure 1). A transcutaneous approach toward the same target also is possible, though this technique risks visible bruising. Alternatively, the upper or lower lips can be anesthetized using 4 to 5 submucosal injections at evenly spaced intervals between the canine teeth.¹⁸

Blocks for Palmoplantar Hyperhidrosis

The treatment of palmoplantar hyperhidrosis benefits from regional blocks. Botulinum toxin has been well established as an effective therapy for the condition.^19-21 Given the sensitivity of palmoplantar sites, it is valuable to achieve effective analgesia of the region prior to dermal injections of botulinum toxin.

Wrists
Sensory innervation of the palm is provided by the median, ulnar, and radial nerves (Figure 2A). At the wrist, the median nerve lies between the tendons of the flexor carpi radialis muscle and the palmaris longus muscle. To facilitate identification of the palmaris longus muscle, instruct the patient to oppose the thumb and little finger while flexing the wrist. The needle should be inserted between the 2 tendons, just proximal to the wrist creases (Figure 2B). Once the fascia is pierced, 3 to 5 mL of anesthetic is injected.

The ulnar nerve is anesthetized between the ulnar artery and the flexor carpi ulnaris muscle. The artery is identified by palpation, and special care should be taken to avoid intra-arterial injection. The needle is directed toward the radial styloid, and 3 to 5 mL of anesthetic is injected roughly 1 cm proximal to the wrist crease (Figure 2B).

Anesthesia of the radial nerve can be considered a field block given the numerous small branches that supply the hand. These branches are reached by injecting anesthetic roughly 2 to 3 cm proximal to the radial styloid with the needle aimed medially and extending the injection dorsally (Figure 2B). A total of 4 to 6 mL of anesthetic is used.

Ankles
An ankle block provides anesthesia to the dorsal and plantar surfaces of the foot.²² The region is supplied by the superficial peroneal nerve, deep peroneal nerve, sural nerve, saphenous nerve, and branches of the posterior tibial nerve (Figure 3A).

To anesthetize the deep peroneal nerve, the extensor hallucis longus tendon is first identified on the anterior surface of the ankle through dorsiflexion of the toes; the dorsalis pedis artery runs in close proximity. The injection should be placed lateral to the tendon and artery (Figure 3B). The needle should be inserted until bone is reached, withdrawn slightly, and then 3 to 5 mL of anesthetic should be injected. To block the saphenous nerve, the needle can then be directed superficially toward the medial malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C). To block the superficial peroneal nerve, the needle should then be directed toward the lateral malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C).

The posterior tibial nerve is located posterior to the medial malleolus. The dorsalis pedis artery can be palpated near this location. The needle should be inserted posterior to the artery, extending until bone is reached (Figure 3C). The needle is then withdrawn slightly, and 3 to 5 mL of anesthetic is injected. Finally, the sural nerve is anesthetized between the Achilles tendon and the lateral malleolus, using 5 mL of anesthetic to raise a subcutaneous wheal (Figure 3C).

Conclusion

Proper pain management is integral to ensuring a positive experience for cosmetic patients. Enhanced knowledge of local anesthetic techniques allows the clinician to provide for a variety of procedural indications and patient preferences. As anesthetic strategies are continually evolving, it is important for practitioners to remain informed of these developments.