Recent Advances in Medical and Aesthetic Dermatology

Several exciting recent advances in medical and aesthetic dermatology include innovations in pioneering botanical blends for hair care, a new device to treat solar lentigines and superficial skin lesions to enhance aesthetics, scientific breakthroughs for oral sun protection, and new frontiers in red light photodynamic therapy (PDT). This article will discuss how these discoveries and new technologies can be integrated into your practice for patient benefit.

Hair Health

Why go beyond biotin for hair loss? Because there are many new advances in hair health nutraceuticals. When I am providing care to men and women who are seeking nonpharmacologic treatment to maintain their full head of hair, approximately 50% of my patients are proactive and taking the preventive approach to hair care, and the other half of patients who present are men and women who have started to experience thinning and loss. 

With patients who present seeking hair care, I discuss a variety of preventive measures and treatment options that include pharmacologic, supplemental, procedural, and natural approaches. 

Oftentimes, the conversation starts with pharmacologic therapeutics, extends to a regimen that includes biotin, then expands to hair cover up and thickening methods, and concludes with procedural options such as platelet-rich plasma (PRP), and hair transplantation. For the increasing number of patients who desire a natural, noninvasive approach, our discussion often includes a detailed regimen that is complex with some inherent challenges and limitations related to medication side effect concerns and/or procedure-related cost and downtime.

For patients who are searching for a comprehensive solution to hair loss and thinning, emerging research is suggesting that blocking a single receptor is not enough, as the pathophysiology of hair thinning and loss is multifactorial. 

Therefore, the approach to a solution must be multipronged. Hair loss is increasingly seen as a multifactorial etiology, with stress, aging, and inflammation playing prominent roles, while not being currently addressed by monotherapeutic options on the market. 

Until recently, especially for women, the only supplemental therapy, in addition to the limited pharmaceutical options, that we had available in our arsenal was biotin. This begs the question: Why do we use biotin in practice and is there any data that it really works for hair loss?

Biotin is a B vitamin that acts as a cofactor of the carboxylase group of enzymes. Historically, it was noted a long time ago that infants born with a genetic biotin deficiency had alopecia. The correction of this deficiency re-grew hair. 

However, it is difficult to develop an acquired deficiency of biotin as an adult, as plenty of biotin is present in our diet and the bacteria in our gastrointestinal tract continuously synthesize even more. In fact, medical literature contains very little information on biotin for hair loss. An older study documented women treated with biotin for hair loss and showed no effect, though they did document improvement in nails. Limited clinical evidence exists that supports use of biotin for hair loss.^1,2

The advent of nutraceuticals and advances in biotechnology are helping fill the patient desire for natural products that aid hair beauty. Simple hair vitamins, minerals, and marine collagen only provide nutritional support in some cases of hair loss related to nutritional deficiencies. However, certain botanicals and their components have clinical efficacy against the primary causes underlying hair loss—dihydrotestosterone (DHT), inflammation, stress, oxidative damage, and aging—providing efficacy against factors that contribute to hair loss not currently addressed by anything on the market. 

Not all botanical products are created equal due to the lack of oversight, standardization, and clinical testing in the nutraceutical supplement space. Therefore, it is hard to say how much of the phytoactives are present in each batch and whether their integrity is preserved post-extraction.

A new nutraceutical supplement (Nutrafol) is taking a leading role in hair health, as it takes these key factors into consideration (Figure 2). By selectively using clinically efficacious dosages of patented, bio-optimized botanical ingredients that have clinical data on absorption and efficacy, ingredients are standardized to contain consistent fractions of bioactive components.

Nutrafol’s Synergen Complex is composed of bio-optimized curcumin (an anti-inflammatory extract of turmeric that has been shown to lower inflammatory biomarkers), a patented ashwagandha (clinically shown to rebalance the stress response and lower cortisol levels in chronically stressed adults), a dual-patented form of saw palmetto that exceeds USP monograph standards—a recognized DHT inhibitor, and a tocotrienol-rich complex that was shown to counter lipid peroxidation and improve hair growth. 

Several case studies have demonstrated efficacy, in addition to substantial ingredient clinical data. Three placebo-controlled trials are in progress. The supplement is gaining traction with numerous dermatologists as we are incorporating it in our clinical practice either as monotherapy or adjunct therapy to PRP and other procedures such as hair transplantation. 

Removal of Cosmetic Lesions

As dermatologists, we know that cryotherapy is a valuable approach to treating actinic keratosis and other superficial cutaneous lesions. Liquid nitrogen (LN) is the most commonly used cryogen and is widely considered a very effective and inexpensive method of lesion removal, but one key drawback to LN-based cryotherapy is the cosmetic side effect profile. LN can result in significant and permanent hypopigmentation, blistering, and scarring. 

Cryo-necrosis occurs in human tissue between -4°F and -22° F. LN freezes tissue at -321°F (-196°C) compared with carbon dioxide (CO₂) which freezes skin at -108°F (-78°C). This temperature differential allows for a softer, more comfortable freeze that is ideal for shallow cosmetic lesions, especially on highly visible areas like the face. The milder freeze produces an effective aesthetic improvement of cosmetic lesions and is less likely to damage surrounding tissue, and in my experience typically does not result in blister formation. 

One innovation in cryotherapy is the CryoCorrect Precision (SkinCeuticals), an FDA-cleared CO₂ cryotherapy device that dispenses a precise flow of CO₂ for targeted lesion freezing (Figure 1). 

 A single-center clinical trial was performed to assess the efficacy and tolerability of the CryoCorrect Precision treatment in 75 patients aged 35 to 65, with Fitzpatrick I to III skin types. The study demonstrated efficacy in treatment of solar lentigines, mild actinic keratosis, and skin tags. A single treatment demonstrated a statistically significant decrease in the intensity and size of treated lesions at weeks 2, 4, and 6 compared with baseline; and at week 6, dark spots were improved in greater than 85% in both size and intensity (Figure 3). Furthermore, 66% of all study participants experienced complete removal of their treated lesion.³ 

For skin tags, one treatment demonstrated a statistically significant decrease in the length and width of skin tags at weeks 1, 2, and 4—with 96% of patients demonstrating complete removal of their treated skin tag by week 4. 

Based upon my clinical experience with the device, a single skin tag treated resolved within 1 week with full removal of the skin tag without any blistering. This represents a true advance, as we know that LN cryotherapy often requires blister formation to be effective.

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Oral Sun Protection

Natural product-based sun protection is a hot topic and an exciting market that is sometimes driven by hype marketing coupled with a lack of scientific data. It is refreshing that new scientific data has emerged supporting polypodium leucotomos extract (PLE) UV photoprotection.⁴

 Polypodium leucotomos is a tropical fern grown in Central and South America and mechanistically functions as a photoprotective agent via antioxidant, immunomodulatory, chemoprotective, and anti-inflammatory effects. PLE is a combination of natural products and is comprised of several components that impart these cutaneous benefits. 

A recent study by Kohli and colleagues⁴ highlights the importance of adding orally administered PLE photoprotective agents (Heliocare, Ferndale Healthcare Inc) to the photoprotection regimen of sunscreen, topical antioxidants, and sun-protective clothing. For the study, 22 participants with Fitzpatrick skin phototype I to III were enrolled and on day 1 were irradiated with UV-A1, UV-B (308-nm excimer laser), and visible light to establish baseline responses to differing light sources. On days 3 and 4, irradiation and evaluation processes were repeated post-oral administration of PLE. The researchers found that 17 of 22 patients demonstrated decreased UV-B-induced skin changes on clinical assessments and these findings were confirmed by colorimetry data.

Histology data demonstrated PLE-associated UVB photoprotection in all 22 patients. Key parameters assessed included biomarkers associated with UV damage including DNA damage (cyclobutane pyrimidine dimers) and apoptosis (sunburn cells).⁴ 

The truly exciting aspect of this research is that these findings conclusively indicate that oral PLE supplementation can result in cutaneous photoprotection. These findings run counter to many years of scientific belief that oral supplementation cannot reach the skin in a meaningful manner and provide UV protection.

It is important to recommend to patients oral photoprotective agents that have demonstrated efficacy in peer-reviewed clinical studies, because with naturally-derived products there is limited FDA oversight and significant variability may exist between products that list PLE as the main component. Differences may exist between plant agricultural methodology, the extraction process, part of the plant used, growing conditions, and other factors that impact the clinically useful content of the PLE.

Red Light Photodynamic Therapy

The 5-aminolaevulinic acid (ALA)-based product, Ameluz (aminolevulinic acid hydrochloride) gel, 10%, has been generating buzz regarding the re-introduction of red light PDT to US-based dermatologists. The gel is FDA approved in the United States for the treatment of lesion-directed and is the first PDT field-directed treatment of actinic keratosis of mild to moderate severity on the face and scalp (Figures 4 and 5).⁵

Other exciting novel aspects include the innovation associated with ALA being delivered by nanoemulsion technology, which allows for ALA to be delivered in a gel formulation. Research has shown increased ALA depth of penetration compared with other current, commercially available ALA delivery approaches.^6,7 

Additionally, a key strength of red light PDT is the increased depth of penetration of red light (up to 8 mm deep) compared with blue light which has a maximum penetration depth of 2 mm. Furthermore, red light generates less free radicals than blue light, therefore, red light PDT is more of a targeted therapy. The clinical data indicates that Ameluz PDT results in the highest actinic keratosis complete clearance, which is the current FDA outcome measure guideline requirement for PDT studies.

Phase 3 clinical study results on the use of Ameluz to treat basal cell carcinoma (BCC) and its approval in the European Union for the treatment of superficial and nodular BCC has been garnering attention in the field. This data brings new hope for patients that new minimally invasive treatments for BCCs may be imminent in the United States. 

A new potential treatment for BCCs represents a significant advance for patients who have superficial and nodular BCCs but lack access to Mohs surgery or prefer a minimally invasive approach for the treatment of their BCC skin cancer. A key takeaway from the phase 3 study results is that treatment of BCCs with Ameluz plus LED red light resulted in an excellent cosmetic outcome.^8,9

Dermatologists can easily integrate red light PDT into their practice. The RhodoLED (Biofrontera) light therapy lamp (a narrowband, red light illumination source) is on the market and offers shorter duration of irradiation treatment compared with an available blue light PDT from DUSA (10 minutes vs 16 minutes and 40 seconds, respectively). 

Other light systems were studied with Ameluz, including the Omnilux LED Professional system. The Omnilux system was studied in 2 phase 3 Ameluz-red LED PDT clinical trials and demonstrated equivalent results and represents an alternate light source that has several practical benefits for dermatologists and our patients, including size, modularity, and flexible array.¹⁰

Overall, these innovations are just some of the new technologies advancing the field of medical and aesthetic dermatology. 

Dr Jagdeo is an associate professor of dermatology at University of California, Davis in Davis, CA.

Disclosure: Honorarium (Nutrafol, L’Oreal/SkinCeutifcals, Global Med Technologis), Speaker (L’Oreal/SkinCeuticals), Scientific Advisory Board (Heliocare, Global Med Technologies).

References

1. Soleymani T, Lo Sicco K, Shapiro J. The infatuation with biotin supplementation: Is there truth behind its rising popularity? A comparative analysis of clinical efficacy versus social popularity. J Drugs Dermatol. 2017;16(5):496-500.

2. Trüeb RM. Serum biotin levels in women complaining of hair loss. Int J Trichology. 2016;8(2):73-77. 

3. Du A, Yatskayer M, Lynch S, Manco M. Evaluation of the efficacy and tolerability of a cryotherapy device with and without a serum in treating localized benign skin lesions. Presented at: 2017 American Academy of Dermatology Annual Meeting; March 3-7, 2017; Orlando, Florida.

4. Kohli I, Shafi R, Isedeh P, et al. The impact of oral Polypodium leucotomos extract on ultraviolet B response: A human clinical study. J Am Acad Dermatol. 2017;77(1):33-41.e1. 

5. Dirschka T, Radny P, Dominicus R, et al; AK-CT002 Study Group. Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. Br J Dermatol. 2012;166(1):137-146. 

6. Maisch T, Santarelli F, Schreml S, Babilas P, Szeimies RM. Fluorescence induction of protoporphyrin IX by a new 5-aminolevulinic acid nanoemulsion used for photodynamic therapy in a full-thickness ex vivo skin model. Exp Dermatol. 2010;19(8):e302-305.

7. Schmitz L, Novak B, Hoeh AK, Luebbert H, Dirschka T. Epidermal penetration and protoporphyrin IX formation of two different 5-aminolevulinic acid formulations in ex vivo human skin. Photodiagnosis Photodyn Ther. 2016;14:40-46.

8. Biofrontera announces 12-month follow-up results of phase III trial evaluating Ameluz® for basal cell carcinoma [press release]. Leverkusen, Germany: Biofrontera AG; October 20, 2016. https://adhoc.pressetext.com/news/20161020019. Accessed October 2, 2017.

9. European Commission extends Ameluz approval to basal cell carcinoma. Reuters. January 30, 2017. https://www.reuters.com/article/idUSFWN1FK0O7. Accessed October 2, 2017.

10. Dirschka T, Radny P, Dominicus R, et al. Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. Br J Dermatol. 2012;166(1):137-46. 

Several exciting recent advances in medical and aesthetic dermatology include innovations in pioneering botanical blends for hair care, a new device to treat solar lentigines and superficial skin lesions to enhance aesthetics, scientific breakthroughs for oral sun protection, and new frontiers in red light photodynamic therapy (PDT). This article will discuss how these discoveries and new technologies can be integrated into your practice for patient benefit.

Hair Health

Why go beyond biotin for hair loss? Because there are many new advances in hair health nutraceuticals. When I am providing care to men and women who are seeking nonpharmacologic treatment to maintain their full head of hair, approximately 50% of my patients are proactive and taking the preventive approach to hair care, and the other half of patients who present are men and women who have started to experience thinning and loss. 

With patients who present seeking hair care, I discuss a variety of preventive measures and treatment options that include pharmacologic, supplemental, procedural, and natural approaches. 

Oftentimes, the conversation starts with pharmacologic therapeutics, extends to a regimen that includes biotin, then expands to hair cover up and thickening methods, and concludes with procedural options such as platelet-rich plasma (PRP), and hair transplantation. For the increasing number of patients who desire a natural, noninvasive approach, our discussion often includes a detailed regimen that is complex with some inherent challenges and limitations related to medication side effect concerns and/or procedure-related cost and downtime.

For patients who are searching for a comprehensive solution to hair loss and thinning, emerging research is suggesting that blocking a single receptor is not enough, as the pathophysiology of hair thinning and loss is multifactorial. 

Therefore, the approach to a solution must be multipronged. Hair loss is increasingly seen as a multifactorial etiology, with stress, aging, and inflammation playing prominent roles, while not being currently addressed by monotherapeutic options on the market. 

Until recently, especially for women, the only supplemental therapy, in addition to the limited pharmaceutical options, that we had available in our arsenal was biotin. This begs the question: Why do we use biotin in practice and is there any data that it really works for hair loss?

Biotin is a B vitamin that acts as a cofactor of the carboxylase group of enzymes. Historically, it was noted a long time ago that infants born with a genetic biotin deficiency had alopecia. The correction of this deficiency re-grew hair. 

However, it is difficult to develop an acquired deficiency of biotin as an adult, as plenty of biotin is present in our diet and the bacteria in our gastrointestinal tract continuously synthesize even more. In fact, medical literature contains very little information on biotin for hair loss. An older study documented women treated with biotin for hair loss and showed no effect, though they did document improvement in nails. Limited clinical evidence exists that supports use of biotin for hair loss.^1,2

The advent of nutraceuticals and advances in biotechnology are helping fill the patient desire for natural products that aid hair beauty. Simple hair vitamins, minerals, and marine collagen only provide nutritional support in some cases of hair loss related to nutritional deficiencies. However, certain botanicals and their components have clinical efficacy against the primary causes underlying hair loss—dihydrotestosterone (DHT), inflammation, stress, oxidative damage, and aging—providing efficacy against factors that contribute to hair loss not currently addressed by anything on the market. 

Not all botanical products are created equal due to the lack of oversight, standardization, and clinical testing in the nutraceutical supplement space. Therefore, it is hard to say how much of the phytoactives are present in each batch and whether their integrity is preserved post-extraction.

A new nutraceutical supplement (Nutrafol) is taking a leading role in hair health, as it takes these key factors into consideration (Figure 2). By selectively using clinically efficacious dosages of patented, bio-optimized botanical ingredients that have clinical data on absorption and efficacy, ingredients are standardized to contain consistent fractions of bioactive components.

Nutrafol’s Synergen Complex is composed of bio-optimized curcumin (an anti-inflammatory extract of turmeric that has been shown to lower inflammatory biomarkers), a patented ashwagandha (clinically shown to rebalance the stress response and lower cortisol levels in chronically stressed adults), a dual-patented form of saw palmetto that exceeds USP monograph standards—a recognized DHT inhibitor, and a tocotrienol-rich complex that was shown to counter lipid peroxidation and improve hair growth. 

Several case studies have demonstrated efficacy, in addition to substantial ingredient clinical data. Three placebo-controlled trials are in progress. The supplement is gaining traction with numerous dermatologists as we are incorporating it in our clinical practice either as monotherapy or adjunct therapy to PRP and other procedures such as hair transplantation. 

Removal of Cosmetic Lesions

As dermatologists, we know that cryotherapy is a valuable approach to treating actinic keratosis and other superficial cutaneous lesions. Liquid nitrogen (LN) is the most commonly used cryogen and is widely considered a very effective and inexpensive method of lesion removal, but one key drawback to LN-based cryotherapy is the cosmetic side effect profile. LN can result in significant and permanent hypopigmentation, blistering, and scarring. 

Cryo-necrosis occurs in human tissue between -4°F and -22° F. LN freezes tissue at -321°F (-196°C) compared with carbon dioxide (CO₂) which freezes skin at -108°F (-78°C). This temperature differential allows for a softer, more comfortable freeze that is ideal for shallow cosmetic lesions, especially on highly visible areas like the face. The milder freeze produces an effective aesthetic improvement of cosmetic lesions and is less likely to damage surrounding tissue, and in my experience typically does not result in blister formation. 

One innovation in cryotherapy is the CryoCorrect Precision (SkinCeuticals), an FDA-cleared CO₂ cryotherapy device that dispenses a precise flow of CO₂ for targeted lesion freezing (Figure 1). 

 A single-center clinical trial was performed to assess the efficacy and tolerability of the CryoCorrect Precision treatment in 75 patients aged 35 to 65, with Fitzpatrick I to III skin types. The study demonstrated efficacy in treatment of solar lentigines, mild actinic keratosis, and skin tags. A single treatment demonstrated a statistically significant decrease in the intensity and size of treated lesions at weeks 2, 4, and 6 compared with baseline; and at week 6, dark spots were improved in greater than 85% in both size and intensity (Figure 3). Furthermore, 66% of all study participants experienced complete removal of their treated lesion.³ 

For skin tags, one treatment demonstrated a statistically significant decrease in the length and width of skin tags at weeks 1, 2, and 4—with 96% of patients demonstrating complete removal of their treated skin tag by week 4. 

Based upon my clinical experience with the device, a single skin tag treated resolved within 1 week with full removal of the skin tag without any blistering. This represents a true advance, as we know that LN cryotherapy often requires blister formation to be effective.

{{pagebreak}}

Oral Sun Protection

Natural product-based sun protection is a hot topic and an exciting market that is sometimes driven by hype marketing coupled with a lack of scientific data. It is refreshing that new scientific data has emerged supporting polypodium leucotomos extract (PLE) UV photoprotection.⁴

 Polypodium leucotomos is a tropical fern grown in Central and South America and mechanistically functions as a photoprotective agent via antioxidant, immunomodulatory, chemoprotective, and anti-inflammatory effects. PLE is a combination of natural products and is comprised of several components that impart these cutaneous benefits. 

A recent study by Kohli and colleagues⁴ highlights the importance of adding orally administered PLE photoprotective agents (Heliocare, Ferndale Healthcare Inc) to the photoprotection regimen of sunscreen, topical antioxidants, and sun-protective clothing. For the study, 22 participants with Fitzpatrick skin phototype I to III were enrolled and on day 1 were irradiated with UV-A1, UV-B (308-nm excimer laser), and visible light to establish baseline responses to differing light sources. On days 3 and 4, irradiation and evaluation processes were repeated post-oral administration of PLE. The researchers found that 17 of 22 patients demonstrated decreased UV-B-induced skin changes on clinical assessments and these findings were confirmed by colorimetry data.

Histology data demonstrated PLE-associated UVB photoprotection in all 22 patients. Key parameters assessed included biomarkers associated with UV damage including DNA damage (cyclobutane pyrimidine dimers) and apoptosis (sunburn cells).⁴ 

The truly exciting aspect of this research is that these findings conclusively indicate that oral PLE supplementation can result in cutaneous photoprotection. These findings run counter to many years of scientific belief that oral supplementation cannot reach the skin in a meaningful manner and provide UV protection.

It is important to recommend to patients oral photoprotective agents that have demonstrated efficacy in peer-reviewed clinical studies, because with naturally-derived products there is limited FDA oversight and significant variability may exist between products that list PLE as the main component. Differences may exist between plant agricultural methodology, the extraction process, part of the plant used, growing conditions, and other factors that impact the clinically useful content of the PLE.

Red Light Photodynamic Therapy

The 5-aminolaevulinic acid (ALA)-based product, Ameluz (aminolevulinic acid hydrochloride) gel, 10%, has been generating buzz regarding the re-introduction of red light PDT to US-based dermatologists. The gel is FDA approved in the United States for the treatment of lesion-directed and is the first PDT field-directed treatment of actinic keratosis of mild to moderate severity on the face and scalp (Figures 4 and 5).⁵

Other exciting novel aspects include the innovation associated with ALA being delivered by nanoemulsion technology, which allows for ALA to be delivered in a gel formulation. Research has shown increased ALA depth of penetration compared with other current, commercially available ALA delivery approaches.^6,7 

Additionally, a key strength of red light PDT is the increased depth of penetration of red light (up to 8 mm deep) compared with blue light which has a maximum penetration depth of 2 mm. Furthermore, red light generates less free radicals than blue light, therefore, red light PDT is more of a targeted therapy. The clinical data indicates that Ameluz PDT results in the highest actinic keratosis complete clearance, which is the current FDA outcome measure guideline requirement for PDT studies.

Phase 3 clinical study results on the use of Ameluz to treat basal cell carcinoma (BCC) and its approval in the European Union for the treatment of superficial and nodular BCC has been garnering attention in the field. This data brings new hope for patients that new minimally invasive treatments for BCCs may be imminent in the United States. 

A new potential treatment for BCCs represents a significant advance for patients who have superficial and nodular BCCs but lack access to Mohs surgery or prefer a minimally invasive approach for the treatment of their BCC skin cancer. A key takeaway from the phase 3 study results is that treatment of BCCs with Ameluz plus LED red light resulted in an excellent cosmetic outcome.^8,9

Dermatologists can easily integrate red light PDT into their practice. The RhodoLED (Biofrontera) light therapy lamp (a narrowband, red light illumination source) is on the market and offers shorter duration of irradiation treatment compared with an available blue light PDT from DUSA (10 minutes vs 16 minutes and 40 seconds, respectively). 

Other light systems were studied with Ameluz, including the Omnilux LED Professional system. The Omnilux system was studied in 2 phase 3 Ameluz-red LED PDT clinical trials and demonstrated equivalent results and represents an alternate light source that has several practical benefits for dermatologists and our patients, including size, modularity, and flexible array.¹⁰

Overall, these innovations are just some of the new technologies advancing the field of medical and aesthetic dermatology. 

Dr Jagdeo is an associate professor of dermatology at University of California, Davis in Davis, CA.

Disclosure: Honorarium (Nutrafol, L’Oreal/SkinCeutifcals, Global Med Technologis), Speaker (L’Oreal/SkinCeuticals), Scientific Advisory Board (Heliocare, Global Med Technologies).

References

1. Soleymani T, Lo Sicco K, Shapiro J. The infatuation with biotin supplementation: Is there truth behind its rising popularity? A comparative analysis of clinical efficacy versus social popularity. J Drugs Dermatol. 2017;16(5):496-500.

2. Trüeb RM. Serum biotin levels in women complaining of hair loss. Int J Trichology. 2016;8(2):73-77. 

3. Du A, Yatskayer M, Lynch S, Manco M. Evaluation of the efficacy and tolerability of a cryotherapy device with and without a serum in treating localized benign skin lesions. Presented at: 2017 American Academy of Dermatology Annual Meeting; March 3-7, 2017; Orlando, Florida.

4. Kohli I, Shafi R, Isedeh P, et al. The impact of oral Polypodium leucotomos extract on ultraviolet B response: A human clinical study. J Am Acad Dermatol. 2017;77(1):33-41.e1. 

5. Dirschka T, Radny P, Dominicus R, et al; AK-CT002 Study Group. Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. Br J Dermatol. 2012;166(1):137-146. 

6. Maisch T, Santarelli F, Schreml S, Babilas P, Szeimies RM. Fluorescence induction of protoporphyrin IX by a new 5-aminolevulinic acid nanoemulsion used for photodynamic therapy in a full-thickness ex vivo skin model. Exp Dermatol. 2010;19(8):e302-305.

7. Schmitz L, Novak B, Hoeh AK, Luebbert H, Dirschka T. Epidermal penetration and protoporphyrin IX formation of two different 5-aminolevulinic acid formulations in ex vivo human skin. Photodiagnosis Photodyn Ther. 2016;14:40-46.

8. Biofrontera announces 12-month follow-up results of phase III trial evaluating Ameluz® for basal cell carcinoma [press release]. Leverkusen, Germany: Biofrontera AG; October 20, 2016. https://adhoc.pressetext.com/news/20161020019. Accessed October 2, 2017.

9. European Commission extends Ameluz approval to basal cell carcinoma. Reuters. January 30, 2017. https://www.reuters.com/article/idUSFWN1FK0O7. Accessed October 2, 2017.

10. Dirschka T, Radny P, Dominicus R, et al. Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. Br J Dermatol. 2012;166(1):137-46.