Journal of Cosmetic and Laser Therapy, 2010; 12: 14–20

ISSN 1476-4172 print/ISSN 1476-4180 online © 2010 Informa UK Ltd. DOI: 10.3109/14764170903449786

Correspondence: Elizabeth T. Ho, SkinMedica, Inc., 5909 Sea Lion Place, Ste H, Carlsbad, CA 92010, USA. E-mail: eho@skinmedica.com

(Received 2 July 2009; accepted 19 October 2009)

ORIGINAL ARTICLE

Combination of physiologically balanced growth factors with antioxidants for reversal of facial photodamage

DEBORAH H. ATKIN 1, NATHAN S. TROOKMAN 2, RONALD L. RIZER 3,LINDA E. SCHRECK 4, ELIZABETH T. HO 4, VINCENT GOTZ 4,ROSANNE O. FORD 4 & RAHUL C. MEHTA 4

1Dermatology and Laser of Del Mar, Del Mar, CA, USA, 2Colorado Springs Dermatology Clinic, Colorado Springs, CO, USA, 3Thomas J. Stephens & Associates, Colorado Springs, CO, USA, and 4SkinMedica, Inc., Carlsbad, CA, USA

AbstractA 3-month, open-label, single-center study was conducted to determine whether a uniquely formulated and physiologically balanced topical treatment serum containing multiple growth factors, cytokines, peptides, antioxidants and depigmenting agents could improve the visible signs of facial photodamage. Thirty-seven females, aged 32–55 years, with mild to severe, fi ne and coarse peri-ocular wrinkles were enrolled and completed the study. Subjects applied the treatment serum to the face twice daily for 3 months in conjunction with a basic skincare regimen. Clinical evaluations of photodamage were performed at baseline and months 1, 2 and 3. Cutometer measurements and subject self-assessment questionnaires were also conducted during the study. Clinical evaluations showed statistically signifi cant reductions in fi ne wrinkles and coarse wrinkles and improvements in skin texture, tone and radiance starting at month 1 with continued improvements at months 2 and 3. Cutometer readings showed decreased skin extensibility and increased resiliency. Subject self-assessments con-fi rmed that the benefi cial effects of the treatment serum were readily observed by the users. The treatment serum was well-tolerated with no treatment-related adverse events reported during the 3-month study. Use of this novel treatment serum produced signifi cant improvements in the visible signs of facial photodamage.

Key Words: Anti-aging , cosmeceuticals , facial photodamage , growth factors

Introduction

Aging of the skin is mediated by a combination of the effects of time (intrinsic aging) and environmen-tal factors (extrinsic aging) on skin cells and their extra-cellular support matrix. Intrinsic aging results from an accumulation of metabolic oxidative damage to the skin microstructure while skin exposure to UV radiation and environmental pollutants causes extrin-sic aging. These two skin aging processes have com-mon biochemical and molecular pathways, including nuclear and mitochondrial DNA damage, inactiva-tion of growth factors (GFs), breakdown of matrix proteins and membrane lipid damage. Clinical man-ifestations of photodamage due to intrinsic and envi-ronmentally induced aging processes include a loss of skin elasticity and fi rmness, fi ne lines and wrinkles, and an uneven skin tone (1,2).

Improved understanding of biochemical mecha-nisms of skin aging has resulted in the identifi cation

of key pathways of intervention to accelerate the reversal of skin aging (3,4). GFs, cytokines and other agents that help rebuild the extracellular matrix are critical in the reversal of the signs of skin aging such as fi ne lines and wrinkles. GFs directly initiate activ-ity that promotes skin repair and also modifi es the activities of skin cells and other cytokines that further enhance skin structure and function. One of the most important roles of these agents in skin is to induce the production of extracellular matrix components such as collagen, by increasing the activity of fi bro-blasts. Successful skin repair requires an essential balance between the function of multiple GFs and cytokines such as TGF-b, TNF-a, PDGF, IL-1, IL-6 and IL-10 (5). Results from clinical studies demon-strate that topical application of a physiologically bal-anced GF mixture results in signifi cantly increased production of new collagen, as indicated by increased grenz-zone thickness (6,7). The clinical benefi ts of

Growth factors and antioxidants for photodamage 15

increased collagen formation are a reduction in the appearance of facial fi ne lines, wrinkles and other signs of skin aging (6,8).

To address the numerous biochemical pathways involved in skin aging, a novel treatment serum (TNS Essential Serum™; SkinMedica, Inc.) was formu-lated with a proprietary combination of ingredients with scientifi cally proven anti-aging benefi ts in a dual-chamber airless pump. One chamber of the pump contains high concentrations of a physiologi-cally balanced mixture of over 110 human GFs and cytokines (TNS Recovery Complex®; SkinMedica, Inc.) (8). The other chamber contains a concentrated blend of antioxidants, collagen-building peptides and depigmenting agents.

To explore the clinical benefi ts of this topical treatment serum, a 3-month clinical study was con-ducted evaluating the safety and effi cacy of the treat-ment serum when used by females with mild to severe facial photodamage.

Materials and methods

The criteria for study participation included female subjects aged 30–55 years (having a Fitzpatrick skin phototype of I–IV) with mild to severe, fi ne and coarse wrinkles in the periocular area. In addition to the treatment serum, subjects agreed to the use of a standard skincare regimen including a cleanser, light moisturizer and sunscreen. Subjects also agreed not to begin the usage of any new facial products other than the provided materials for the duration of the study.

Subjects were excluded from the study if they had used topical retinoids within 4 months of the study start, had received injections of dermal fi llers or bot-ulinum toxin or had undergone facial peels or facial resurfacing procedures within 6 months or used other forms of anti-aging products on the face within 1 month of the study start. Subjects with known allergies to the facial product regimen were also excluded.

Institutional Review Board approval was obtained for this open-label, single-center study. The study was conducted according to ethical and regulatory principles from the International Conference on Harmonization and good clinical practices. Prior to treatment, the subjects provided informed consent.

Subjects applied the treatment serum twice daily (morning and evening) to the entire face for 3 months. In addition, subjects used a basic skincare regimen: cleanser and light moisturizer twice daily and a sun-screen in the morning and during the day as needed. Subjects kept daily diaries of all product usage.

Clinical evaluations were conducted at baseline (Visit 1), month 1 (Visit 2), month 2 (Visit 3) and month 3 (Visit 4). Subjects participated in the fol-lowing procedures at each visit.

Clinical grading

Fine wrinkles and coarse wrinkles were assessed on each subject’s right and left periocular area using a 10-point scale (where 0 � none, 0.5–3.5 � mild, 4–6.5 � moderate and 7–9 � severe). Ten-point scales were used to assess skin texture (where 0 � smooth, 9 � rough), skin tone (0 � clear/even, 9 � blotchy/uneven) and skin radiance (0 � dull/fl at matte, 9 � bright/luminous/radiant). All grading assessments were performed by the same investigator at each visit.

Cutometer

At baseline, month 1 and month 3, a single Cutom-eter MPA 580 (Courage + Khazaka) measurement was taken on the right ocular bone, directly in line with the center of the eye, of each subject to measure the visco-elastic properties of the skin.

Safety

Tolerability of the study medication was assessed at all visits by the reporting of adverse events and by objective and subjective assessments. Objective irri-tation (erythema, edema and scaling) and subjective irritation (burning/stinging, itching and tingling) were assessed using a 4-point scale (where 0 � none, 1 � mild, 2 � moderate and 3 � severe).

Digital photography

Digital images were taken using raking light (stan-dard color) including right and left sides of the face and full frontal views of each subject’s face.

Self-Assessment Questionnaires

Subjects completed a Self-Assessment Questionnaire at baseline, month 1 and month 3, where they rated their facial skin condition on a 4-point scale (1 � excel-lent, 2 � good, 3 � fair and 4 � poor). At month 1 and month 3, subjects also assessed the treatment serum’s effi cacy and aesthetic attributes using the following 4-point scale: strongly agree, agree, disagree, strongly disagree. Subjects rated their overall satisfaction with the treatment serum at months 1 and 3 on a 4-point scale, where 1 � excellent, 2 � good, 3 � fair and 4 � poor.

Statistical analysis

Mean clinical grading scores at months 1, 2 and 3 were compared to mean baseline scores using a Stu-dent’s paired t-test. For the subject Self-Assessment Questionnaires, the percent incidence of positive responders were reported for the treatment serum’s

16 D. H. Atkin et al.

effi cacy and aesthetic attributes sections (month 1 and month 3). In addition, the mean scores for skin condition ratings at month 1 and month 3 were com-pared with the mean baseline scores using a Stu-dent’s paired t-test. Changes from baseline were considered signifi cant at the p � 0.05 level.

Results

Thirty-seven female subjects (aged 32–55 years) with mild to severe, fi ne and coarse periocular wrinkles were enrolled and completed the study. The majority of subjects (89%) were of Caucasian or mixed Cau-casian ethnicity. Clinical evaluations showed statisti-cally signifi cant reductions ( p � 0.0001) in mean clinical assessment scores for fi ne and coarse peri-ocular wrinkles, as presented in Figure 1. A 12% reduction from baseline in fi ne wrinkles was seen after 1 month of product use with further improve-ment to 30% reduction from baseline with continued product use for 3 months. The improvement in coarse wrinkles was even greater, with 20% reduction from baseline after 1 month of product use which increased to 42% reduction with continued product use for 3 months.

Statistically signifi cant ( p � 0.0001) improve-ments in mean clinical assessment scores for skin textural roughness are shown in Figure 2. A 67% decrease from baseline in textural roughness score was seen after 1 month of product use. The score further decreased to 89% below baseline levels after 3 months of product use.

Figure 3 shows the clinical assessment scores for unevenness of skin tone and skin radiance. A statisti-cally signifi cant ( p � 0.02) decrease from baseline was observed in unevenness of skin tone starting at month 1 with continued improvements at months 2 and 3. Similarly, a signifi cant increase ( p � 0.02) in skin radiance was seen starting as early as month 1, with improvements through month 3.

Elasticity of skin was assessed quantitatively by measurement of skin extensibility and resiliency using a cutometer. Mean cutometer readings showed a signifi cant ( p � 0.03) decrease in skin extensibility as well as a signifi cant ( p � 0.03) increase in resil-iency at months 1 and 3 (Figure 4).

The percentage of subjects who selected strongly agree or agree in response to the Self-Assessment Questionnaires at month 1 and month 3 are pre-sented in Table I. In all parameters, 81% or higher

-50

-40

-30

-20

-10

0%

Ch

an

ge

fro

m B

as

elin

e

All P�0.0001*

* Month 1, n � 37; Month 2, n � 35; Month 3, n � 36

Month 1 Month 2 Month 3 Month 1 Month 2 Month 3

Coarse Wrinkles Fine Wrinkles

Figure 1. Mean reductions in periocular wrinkles at months 1, 2 and 3 compared with baseline.

-89%

-78%

-67%

-100

-80

-60

-40

-20

0Month 1 Month 2 Month 3

% C

han

ge f

rom

Baselin

e

All P�0.0001*

* Month 1, n � 37; Month

Figure 2. Mean reductions in textural roughness at months 1, 2 and 3 compared with baseline.

Month 1

Month 1

Month 2

Month 2

Month 3

Month 3

-18

-12

-6

0

6

12

% C

ha

ng

e f

rom

Ba

se

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* Month 1, n � 37; Month 2, n � 35; Month 3, n � 36

Unevenness

Radiance

All P� 0.02*

Figure 3. Mean reductions in skin unevenness and mean improvements in skin radiance at months 1, 2 and 3 compared with baseline.

Month 1

Month 1 Month 3

Month 3

-16

-8

0

8

% C

han

ge f

rom

Baselin

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All

*Month 1, n=37; Month 3, n=36

Extensibility

Resiliency

Figure 4. Mean improvements in extensibility and resiliency at months 1 and 3 compared with baseline.

Growth factors and antioxidants for photodamage 17

of subjects agreed that the treatment serum was effective in improving the appearance and texture of their facial skin at the end of treatment. Subject sat-isfaction with treatment serum performance was high: 97% of subjects rated their overall satisfaction as excellent or good at month 3.

To quantify improvement, subjects rated the con-dition of their facial skin pre- and post-treatment. Subjects perceived signifi cant improvements in their facial skin after 1 month of treatment, with increas-ing improvements reported at month 3 (all p � 0.05). Mean scores for self-assessed skin condition param-eters are presented in Table II. (Note a lower value signifi es improvement.)

Representative examples of clinical responses are seen in photographs displayed in Figures 5–8. Improvements in peri-ocular fi ne wrinkles were dem-onstrated in a 49-year-old female subject after 2 months of product use (Figure 5). In addition, visible improvement in hyperpigmentation is displayed in Figure 6, where a 51-year-old female presented with a darkened lesion on her right zygomatic process at baseline. After 3 months of product use, the lesion had faded. A 54-year-old female subject presenting with coarse side forehead wrinkles saw visible

improvement after 1 month of treatment, as shown in Figure 7. Overall improvements in unevenness of skin tone, radiance and textural roughness were also demonstrated in a 50-year-old female subject, as shown in Figure 8.

The treatment serum was well-tolerated and there were no treatment-related adverse events reported during the course of the study. Mean scores for edema, scaling, burning/stinging, itching and tin-gling remained less than mild throughout the study (all scores � 0.07 on the 0–4 scale).

Discussion

Increasing evidence suggests the central role of reactive oxygen species (ROS) in the mechanisms of both intrinsic and extrinsic aging (9,10). At the molecular level, ROS causes a cascade of biochemi-cal events in the skin, resulting in the production of matrix metalloproteinases (MMPs) and proinfl am-matory cytokines, which lead to increased collagen degradation, suppression of collagen synthesis and breakdown of the dermal matrix (11–13). Incorpo-rating knowledge of biochemical pathways involved in skin aging along with an increased understanding of cosmetic ingredients and their associated target activity is a rational approach to the development of next generation anti-aging products. Since there are multiple processes involved in skin repair, a combi-nation product is likely to produce enhanced results in reversing the signs of skin aging.

The benefi cial clinical effects of a physiologically balanced mixture of GFs and cytokines in reducing facial lines and wrinkles have been previously established (6–8). Likewise, the benefi ts of antioxi-dants on skin photoaging have been demonstrated in clinical trials (14,15). The next logical step in the

Table I. Subject Self-Assessment Questionnaire.

Month 1 ( n � 37) Month 3 ( n � 37)

‘Immediately after applying the treatment serum … ’ Agree strongly, agree Agree strongly, agree my skin feels softer and smoother 81% 97% my skin feels fi rmer and tightened 92% 97%

‘With continued use, the treatment serum …’ Agree strongly, Agree Agree strongly, Agree improves the smoothness of my skin 84% 95% makes my skin feel fi rmer and tightened 95% 95% improves the evenness of my skin tone 70% 86% increases the elasticity of my skin 81% 97% makes my skin look healthier and more youthful 70% 92% decreases the appearance of uneven skin tone and discolorations 59% 81% improves the texture of my skin 76% 92% increases the radiance and clarity of my skin 70% 89% improves the appearance of fi ne lines/wrinkles 76% 89% is convenient to use as part of my daily skincare regimen 89% 95% improves the softness of my skin 86% 95% improves the overall appearance of my skin 78% 95%

Excellent or good Excellent or goodOverall satisfaction with treatment serum 76% 97%

Table II. Subject Self-Assessment of skin condition

BaselineMonth 1 (n � 37)

Month 3 (n � 37)

Smoothness of my skin 2.6 1.9 1.7Firmness of my skin 2.7 1.9 1.7Evenness of my skin tone 3.0 2.2 2.1Glow or radiance of my skin 3.0 2.2 1.9Youthful look of my skin 3.0 2.2 1.9Health of my skin 2.5 2.1 1.8

Scale: 1, excellent; 2, good; 3, fair; 4, poor.

18 D. H. Atkin et al.

evolution of products to accelerate the reversal of the signs and symptoms of skin aging is to complement the effects of products containing a mixture of multiple GFs and cytokines with a combination of antioxidants, matrix building agents and skin conditioners.

The extracellular matrix building effects of the GFs may be potentiated by various bioactive pep-tides. The treatment serum contains palmitoyl trip-eptide, which is a synthetic peptide that mimics the sequence of the protein thrombospondin-1 (TSP-1). TSP-1 has been shown to activate latent tissue growth factor beta (TGF-β), a GF involved in the stimulation of collagen matrix production (16). Hydroxyproline is an important amino acid in the structure of collagen. It provides stability to the collagen helical structure and plays a critical role in susceptibility to proteolytic degradation (17). The peptide dipalmi-toyl hydroxyproline was incorporated in the treat-ment serum for its effects on collagen structure and function.

The treatment serum also contains broad-spectrum protection against free radicals using a combination of established and scientifi cally proven antioxidants such as vitamins C and E, ergothionine, blackberry leaf extract, coenzyme Q-10, green tea extract, sericin and saccharomyces ferment fi ltrate. Vitamin E is considered the most important free radical scavenger in the lipid component of cells (18). Tetrahexyldecyl ascorbate, a lipid-soluble form of vitamin C, in combination with vitamin E has been clinically shown to increase production of grenz-zone collagen (14,15). Ergothionine is a natu-ral water-soluble antioxidant found in food plants

and animal tissues that has also been shown to pos-sess anti-infl ammatory activity and provide protec-tion against DNA damage (19). Matrix degrading enzymes from the matrix metalloproteinase family can be suppressed by ergothionine and antioxidant botanical extracts such as blackberry leaf extract (20). Coenzyme Q-10 is a potent lipid-soluble antioxidant that provides protection to cell membranes and other lipid structures (21). Sericin peptide has been shown to provide protection against oxidative stress (22). In addition, sericin also provides moisturization as it resembles the natural moisturizing factor (NMF) (23). A combination of these antioxidants with green tea extract and saccharomyces ferment fi ltrate help provide broad spectrum protection against both intrinsic and extrinsic free radicals. The treatment serum also contains alpha-arbutin, which has been shown to reduce skin pigmentation by multiple mechanisms (24) and hyaluronic fi lling spheres to provide a rapid smoothing effect on wrinkles.

As described above, the treatment serum was spe-cifi cally formulated with unique ingredients to target skin repair pathways and address the clinical mani-festations of photoaging and photodamage. This clinical study demonstrates that the treatment serum resulted in rapid and statistically signifi cant improve-ments in the signs and symptoms of skin aging, uti-lizing both subjective and objective evaluation techniques. Treatment improved the appearance of both fi ne and coarse wrinkles, skin texture and tone, and the resilience and recoil of the skin. These changes were noted at the fi rst evaluation visit (after 1 month of treatment) and were maintained or improved over the next 2 months of the study.

Figure 5. Periocular location of a 49-year-old female subject at (A) baseline and (B) month 2.

Figure 6. Zygomatic process location of a 51-year-old female subject at (A) baseline and (B) month 3.

Growth factors and antioxidants for photodamage 19

Importantly, not only were the investigators able to detect clinically relevant improvements in facial pho-todamage, but the subjects were also able to observe the visual differences in their skin during the 3-month study. At the completion of the study, 97% of the subjects rated their overall satisfaction with the treat-ment serum as excellent or good.

This treatment serum provides physicians and patients with a unique and effective topical combina-tion product to improve the signs of skin aging. Future work should be directed at identifying new targets in the multiple pathways involved in the pro-cess of skin aging and repair and to evaluate various combinations of ingredients to optimize effi cacy. Figure6. Zygomatic process location of a 51-year-old female subject at

(A) baseline and (B) month 3.

Acknowledgements

Financial support of this study was provided by Skin-Medica, Inc.

Declaration of interest: Dr Atkin, Dr Trookman and Dr Rizer are investigators for SkinMedica, Inc. Mr Gotz is a consultant for SkinMedica, Inc. Ms Schreck, Ms Ho, Ms Ford and Dr Mehta are all employees of SkinMedica, Inc. The authors alone are responsible for the content and writing of this paper.

References

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Mehta RC, Fitzpatrick RE. Endogenous growth factors as 3. cosmeceuticals. Dermatol Ther. 2007;20:350–9. Fisher GJ, Wang ZQ, Datta SC, Varani J, Kang S, 4. Voorhees JJ. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med. 1997;337:1419–28. Eming SA, Krieg T, Davidson JM. Infl ammation in 5. wound repair: Molecular and cellular mechanisms. J Invest Dermatol. 2007;127:514–25. Fitzpatrick RE, Rostan EF. Reversal of photodamage with 6. topical growth factors: A pilot study. J Cosmet Laser Ther. 2003;5:25–34. Sundaram H, Mehta RC, Norine JA, Kircik L, Cook-Bolden 7. FE, Atkin DH. Topically applied physiologically balanced growth factors: A new paradigm of skin rejuvenation. J Drugs Dermatol. 2009;8(suppl):4–13. Mehta RC, Smith SR, Grove GL, Ford RO, Canfi eld W, 8. Donofrio LM. Reduction in facial photodamage by a topical growth factor product. J Drugs Dermatol. 2008;7:864–71. Oikarinen A. The aging of skin: Chronoaging versus photoag-9. ing. Photodermatol Photoimmunol Photomed. 1990;7:3–4. Baumann L. Skin ageing and its treatment. J Pathol. 2007;10. 211:241–51. Fisher GJ, Wang ZQ, Datta SC, Varani J, Kang S, Voorhees JJ. 11. Pathophysiology of premature skin aging induced by ultravio-let light. N Engl J Med. 1997;337:1419–28. Varani J, Fisher GJ, Kang S, Voorhees JJ. Molecular mecha-12. nisms of intrinsic skin aging and retinoid-induced repair and reversal. J Invest Dermatol Symp Proc. 1998;3:57–60. Brenneisen P, Wenk J, Klotz LO, Wlaschek M, Briviba K, 13. Krieg T, Sies H. Central role of ferrous/ferric iron in the ultra-violet B irradiation mediated signaling pathway leading to increased interstitial collagenase (matrix-degrading metallo-protease (MMP)-1) and stomelysin-1 (MMP-3) mRNA lev-els in cultured human dermal fi broblasts. J Biol Chem. 1998;273:5279–87. Fitzpatrick RE, Rostan EF. Double-blind, half-face study 14. comparing topical vitamin C and vehicle for rejuvenation of photodamage. Dermatol Surg. 2002;28:231–6.

Figure 7. Right forehead location of a 54-year-old female subject at (A) baseline and (B) month 1.

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