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Clinical Practice CPD one point @aestheticsgroup Aesthetics Journal aestheticsjournal.com Aesthetics aestheticsjournal.com Common effective skincare ingredients Dr Sandeep Cliff and Dr Carolina Fernandez provide an in-depth exploration into the common cosmetic ingredients used in cosmeceuticals, and discuss notable new developments The cosmetic industry is a constantly evolving and dynamic arena. New products frequently come into the market harnessing both new and established ingredients. This article investigates commonly used cosmetic ingredients, their application, and the notable developing fields within cosmeceuticals. HYDROXY ACIDS Hydroxy acids (HAs) have been used for their skincare properties since as far back as ancient Egypt, when Cleopatra reportedly bathed in sour milk, a rich source of lactic acid. Lactic acid is a form of alpha hydroxy acids (AHAs). Other HAs include polyhydroxy acids (PHAs), beta hydroxy acids (BHAs), aldobionic acids (BAs) and aromatic hydroxyl acids (AMAs). Alpha hydroxy acids AHAs are naturally-sourced non-toxic carboxyl acid.1 Aside from lactic acid, other AHAs include: glycolic acid, which is sourced naturally from sugar cane; citric acid from citric fruits; malic acid from apples and tartaric acid derived from fruits and grape wine.2 AHAs are used in a wide range of cosmetic products. They destroy the desmosomal attachments between corneocytes, and therefore reduce corneocyte cohesion.3 These properties have led to their successful use in xerosis, icthyosis, follicular hyperkeratosis, and in chemical peels as chemical exfoliants. Glycolic acid is a popular AHA used in chemical peels due to its effectiveness and ease of use.4 In addition, one study by Beradesca et al found AHAs reduced irritation by retaining moisture in the skin and thus improving the skin’s natural barrier function.5 The formulations of glycolic acid used in chemical peels can vary from 20-70%, however it is the pH that is key in controlling the depth and efficacy of the glycolic peel. Moy et al found that a pH range between pH 3.5-4 would be safe for home use products.6 Most AHA preparations come in formulations between 4-10% although stronger concentrations of up to 18% are obtainable for home care use. Reactions occur in less than 1% of patients and do not appear to be dose dependent, although care should be taken when using the higher strengths. Alongside the exfoliating properties of AHAs, it has well-established anti-ageing features. Studies by Ditre et al and Bernstein et al demonstrated that AHAs stimulate epidermal cell proliferation, reverse basal cell atypia and redistribute melanin in photo-aged skin.7,8 Bernstein et al found that AHAs improved dermal collagen quality by increasing hyaluronic acid, glycosaminoglycans and improved the properties of elastic fibres.8 In addition to these findings, Okana et al found AHA to increase dermal thickness, a property unique to hydroxy acids and not found in other forms of chemical exfoliants.9 Lactic acid is thought to be gentler on the skin when compared to other AHAs. Wehr et al found lactic acid to be naturally hydrating as it converts to lactate, a component of natural moisturising factor.10 Concentrations of lactic acid are available from 15-50% with the majority of products being formulated with a strength in the range 4-10%. POLYHYDROXY ACIDS AND BETA HYDROXY ACIDS Further development into HAs has led to the discovery of polyhydroxy acids (PHAs). PHAs contain at least two hydroxyl groups and bionic PHAs have an extra carbohydrate unit.2 Despite bionic PHAs being larger molecules Edison et al found through a 12-week clinical study that PHAs were still able to penetrate and have anti-ageing effects whilst being less irritating when compared to AHA preparation.11 This study assessed the clinical grading of photoaging, had objective and subjective measures Before treatment of irritation as well as measuring pinch recoil, tolerance and a silicone replicas of the crow’s feet area. Edison et al demonstrated AHAs to have superior anti-ageing properties however PHAs were tolerated better, with anti-ageing effects.11 Further evidence to support their gentler profile on the skin comes from Rizer et al, who described PHAs to have enhanced water-binding and gel matrix forming properties that moisturise, protect and soothe the skin, making it suitable for sensitive skin types.12 Additionally, their gentler profile has made them useful for sensitive areas such as use around the eyelids.12,13 After treatment Furthermore, lactobionic acid and maltobionic acid, two common bionic hydroxy acids and similar to PHAs, have antioxidant properties. At the same time, they are stronger humectants compared to traditional AHA.13,14,15 Beta hydroxyl acids (BHAs) are expensive and commercially difficult to obtain. They are lipophilic, making them water soluble and able to penetrate hair follicles and sebaceous glands. They exhibit comedolytic properties, making them suitable in patients with acne.16 Salicylic acid has been referred to as an AMA, however, Draelos classified it as a prototypical BHA.2 Like other hydroxy acids it is used to breakdown the junctions between keratinocytes. It is frequently used in the treatment of acne, seborrhoeic dermatitis and in hyperkeratotic conditions such as psoriasis, calluses, Final formulation study showing treatment of crow’s feet, demonstrating efficacy of corns, keratosis pilaris and warts. Salicylic acid’s comedolytic properties makes it a useful ingredient in acne combined ingredients after 12 weeks medication.16 On application to the skin the salicylic acid frosts, signifying adequate application. Salicylic Reproduced from Aesthetics | Volume 1/Issue 5 - April 2014 aestheticsjournal.com @aestheticsgroup Aesthetics Journal Clinical Practice CPD Aesthetics aestheticsjournal.com peels are often combined with other peeling agents and humectants, as they can be quite drying and irritating if used on their own. Yu and Van Scott17 and Bernstein et al 8 demonstrated that unlike the other hydroxy acids which have been shown to increase dermal thickness, salicylic acid results in a reduction of dermal thickness and thus is not suitable for use in anti-ageing products. It is also essential to note that salicylic acid can cause unwanted hyperpigmentation, which is more commonly reported in Fitzpatrick skin types IV, V and VI.18, 19 ANTIOXIDANTS, SUNSCREENS AND SUN BLOCKS The link between ultraviolet (UV) radiation and permanent skin damage, including skin cancer and ageing, has been well-established. Lowe et al20 and Fisher et al21 found damage occurring due to two distinct processes. Firstly: oxidative damage from UV radiation induced reactive oxygen species (ROS) causing oxidative damage to cellular lipids, proteins and DNA. This results in increased inflammation and poorly formed collagen and elastin within the dermal matrix. Secondly: direct damage to cellular DNA that can lead to abnormal function including tumor formation. Antioxidants have a role in anti-ageing products by limiting the damage caused by free radicals from ultraviolet light and environmental toxins. Over time this can manifest clinically as abnormal melanin production, age spots, reduced cell turnover, dryness and rough skin. The free radical damage to the deeper dermis results in poorly formed collagen and elastin, leading to wrinkles. Potent antioxidants include Vitamin C and E, green tea, soya bean derivative genistein, pomegranate extract, reservatrol, magnesium, selenium and carotenoids. Passi et al22 described how topical antioxidant applications increased the level of antioxidants present in the sebum, whilst oral preparations increase the antioxidant activity in the stratum corneum. This suggests that combination treatment may enhance antioxidant activity throughout the skin and thus limit the extent of damage caused by free radical and ROS. The Council Directive 76/768/ EEC of 27th July 1976 initially listed sunscreens as cosmetic products, and more recently in July 2013 the EU Cosmetic Directive (EC 1223/2009) has set European regulations.23 Sunscreens provide chemical protection, whilst sunblocks provide physical protection against ultra-violet radiation. Zinc oxide, titanium dioxide and iron oxide are some of the commonly used physical sunblocks. They scatter and block UV light penetrating the skin. The main cosmetic problem with sunblock is that when applied appropriately it leaves a noticeable tint on the skin. New micronised formulations are better at blending in to the skin, however they are not as effective on darker pigmented skin. Chemical sunscreens include phenylbenzimidazole sulfonic acid, avobenzone, octyl methoxycinnamate, salicylates, benzophenones, dibenzoylmethanes, ecamsule and octocrylene. They work solely by absorbing UV light. Additionally, it should be noted that chemical sunscreen use has been linked to the development of both dermatitis and photocontact allergy.24 The Food and Drug Administration (FDA) have monitored closely the sunscreen field. In June 2012 they provided guidance on sun protection. According to these recommendations all sunscreens should provide both UVA and UVB protection of at least sun protection factor (SPF) 15, in order to be labeled as sun protection. Products with SPF between 2 and 14 help only against sunburn and are required to carry a warning for skin cancer and ageing. Sunscreens are not waterproof. The FDA describes sunscreens as, “Very water resistant” if they provide 80 minutes of protection in water, and, “Water resistant” if protection last for at least 40 minutes in water. The National Institute for Health and Care Excellence (NICE) in 2011 stated that SPF 15 is sufficient in strength to protect against sun damage25, however it must be applied at a recommended 2mg/cm². This is technically challenging as a standard adult would require approximately 35ml of sunscreen for adequate coverage, which would need to be repeated every 2-3 hours. Before treatment CHEMICAL PEELING AGENTS Chemical peeling agents are another area of vast interest and development within the cosmetics industry. As mentioned earlier hydroxy acids have a long history of use as chemical exfoliants. Other chemical exfoliants include resorcinol, phenol and trichloroacetic acid. Phenol After treatment Phenol peels by themselves or in combination provide a deep peel and are more complex to use. They require appropriate sedation and monitoring with post-treatment care and adequate post-procedure pain relief.26 The mask is removed after a period of between 24-48 hours after which an occlusive biosynthetic material is applied alongside topical antiseptic, antibacterial and steroidal agents. It may take up to three months for the skin to fully heal and like other deep peels should only be performed under specialist supervision e.g. with a dermatologist or plastic surgeon. Resorcinol Before and after treatment with 8% lactobionic acid showing increased viable epidermal thickness Resorcinol, a derivative of phenol, is a commonly used agent in combination peels, e.g. in Jessner’s peels. Arthur Rook in the Textbook of Dermatology described resorcinol disrupting hydrogen bonds in keratin and also showed it to have a useful role in pigmentation disorders.27 Despite this, resorcinol was linked to adverse reactions including methemoglobinemia and tachycardia.28 Epidemiological studies showed an association between phenol-derived compounds and the development of thyroid dysfunction.29 Recent reviews however, demonstrate no significant evidence to support resorcinol’s relation to thyroid abnormalities.26 Jessner’s solution Both Jessner’s solution and modified Jessner’s solution are popular chemical peels. They are used in combination with other ingredients and this then allows for a reduced concentration and thus reduced toxicity.30 Modified Jessner’s solution omits resorcinol and consists of 17% salicylic acid, 17% lactic acid and 8% citric acid. In contrast the standard Jessner’s solution is composed of 14% resorcinol, 14% salicylic acid and 14% lactic acid.26 Reproduced from Aesthetics | Volume 1/Issue 5 - April 2014 Clinical Practice CPD @aestheticsgroup Aesthetics Journal aestheticsjournal.com Aesthetics aestheticsjournal.com Trichloroacetic acid Before treatment Trichloroacetic acid (TCA) has been used since the 1880s as a moderate peeling agent.31 It can be used alone or in combination with other peeling agents. TCA can be supplied by a pharmacist using a weight in volume dilution, where 30% TCA is produced by adding water to 30g of TCA to make a 100ml solution.26 Low strength TCA (<20%) has been said to reduce fine lines and superficial wrinkles with no response on scars or deeper wrinkles. Care must be taken with TCA at higher strengths, which results in a stronger peel and papillary dermal necrosis. Recognised side effects of TCA chemical peels are post-inflammatory hyperpigmentation, and scarring, with additional care needed in Fitzpatrick type IV to VI skin.4 TCA denatures proteins and when applied creates a white frost from the resulting keratocogaulation.26 In addition, the authors of Colour Atlas of Chemical Peels describe TCA usefulness in treating hypertrophic actinic keratosis and sebhorreic keratosis.26 After treatment Retinoic Acid There are three main types of vitamin A formulations, retinol, retinal aldehyde and retinoic acid (tretinoin). They have been used to treat photo-damaged skin, hyperpigmentation and acne. Their formulations can vary from mild in cosmetics to higher doses available on prescription for the treatment of acne.32 Vitamin A peels vary in strength from mild retinol peels to higher strength retinoic acid peels. Forehead before and after 16-week treatment with combined ingredients One study showed a 1% tretinoin peel applied for six to eight hours in a sample of 15 women aged 23– final formulation study 40 to be as effective at 2.5 weeks as topical tretinoin used for 4-6 months.33 Patients on retinoids should stop these several days prior to undergoing a chemical peel as they can enhance the penetration of the peel. The retinoids should only be restarted once the skin has fully healed. 26 NEWER INGREDIENTS PEPTIDES Peptides are chains of amino acids. They have recently become a focus of research in the cosmeceutical field. Peptides have shown anti-ageing, pigment modulating, anti-inflammatory and anti-microbial effects in vitro. They target specific receptors and have select actions, which makes them unique ingredients. Research and development continues into their use, particularly in formulating a product that will penetrate the skin and be clinically effective. Signal peptides are composed of a chain of hydrophobic amino acids. Their role is to signal where peptide actions are required. Matrixyl 3000 is a signalling peptide which is made up of palmitoyl pentapeptide and palmitoyl oligopeptide. Fields et al34 demonstrated that Matrixyl 3000 application, when compared to controls, stimulated pro collagen I and III, fibronectin and fibroblasts. Neurotransmitter-inhibiting peptides Neurotransmitter-inhibiting peptides are molecules made of amino acids which bind to its receptor and results in inhibitory effects on the release of neurotransmitter. An interesting example of a neurotransmitter peptide is the hexapeptide sequence that is derived from soluble NSF attachment protein 25 (SNAP-25). SNAP 25 is a crucial component of soluble NSF attachment protein receptor (SNARE) complex which is responsible for the release of vesicles containing acetylcholine from the presynaptic nerve terminal. The hexapeptide acts as a competitive inhibitor by mimicking the N-terminal end of SNAP-25 and thus binding SNARE to create a destabilised complex. Subsequently, acetylcholine release is inhibited, resulting in muscle relaxation. Fields et al described a 30% reduction in wrinkles and depth when a topical 10% argireline preparation was applied for 30 days. The substantial cost and lack of evidence to confirm its actions at the neuromuscular junction is currently limiting its use. This is an interesting area for continued research and development. Carrier peptides Carrier peptides are transporter molecules which carry trace element around the body. Glycyl L histidyl-L-lysyl (GHK) transports trace metals such as copper. Copper is required by multiple enzymes including superoxide dismutase and tyrosine kinase to function properly. It has been postulated that increased copper levels may result in increased keratinocyte proliferation. HUMAN DERIVED GROWTH FACTORS Other areas of interest include human derived growth factors, which have been investigated to see if their endogenous healing properties can be used for anti-ageing purposes. Growth factors such as platelet derived growth factor, fibroblast growth factor and granulocyte macrophage colony-stimulating growth factors are all naturally present in wounds. These promote healing and tissue regeneration. As they have a role in collagen, elastin and glycosaminoglycan synthesis they have been investigated as a potential ingredient for anti-ageing products. The growth factor proteins are unfortunately too large to penetrate intact skin, however further research is being conducted to see if topical application combined with non-surgical procedures e.g. peels and microdermabrasion, will lead to better penetration.36 In addition plant hormones have been investigated for their possible anti-ageing effects. Phytohormone is the term used to describe plant hormones; these include isoflavonoids, ligands and terpenoids. Another phytohormone, Kinetin (N6-fururyladenine), has also been described as a powerful antioxidant. Suresh Rattan described an in vitro study where the addition of kinetin to a culture medium of human fibroblasts delayed the onset of the ageing process.37 Further investigation into the clinical effectiveness of phytohormones is still required to confirm their clinical effectiveness. Stem Cell technology Plant stem cells are being investigated as a potential new cosmeceutical. In contrast to human stem cells, plant stem cells have the ability to differentiate into any type of cell (totipotent). This would theoretically make it possible to completely rejuvenate any structure within Reproduced from Aesthetics | Volume 1/Issue 5 - April 2014 Clinical Practice CPD @aestheticsgroup Aesthetics Journal the body. Currently there is interest in the apple stem cells (PhytoCellTec Malus Domestica) from the Uttwiler Spatlauber apple. This is an endangered Swiss apple which lost its popularity in the food market due to its bitter taste but investigated further due to its surprising long shelf life. The apple stem cells are thought to be rich in epigenetic factors and metabolites, which protect stem cells and delay senescence of hair follicles.38 A study conducted by Mibelle AG Biochemistry in 2009 showed the application of PhytoCellTec Malus Domestica to cultures of epidermal stem cells prolonged the stem cells colony-forming efficacy. The role of stem cells is currently an exciting avenue for research. CONCLUSION It is clear that there is a wide range of cosmetic ingredients on the market for use in a diverse number of conditions. Some ingredients like the hydroxyl acids have been around for several years and have a broad spectrum of applications, from anti-ageing to acne treatment. Chemical exfoliants vary in their strength resulting in different cosmetic effects and varied pre-procedural and post-procedural care. The number of new agents that are currently being investigated is testimony to the amount of interest and research taking place to develop new products. Currently, exciting areas for development include the use of peptides and PhytoCellTec Malus Domestica in anti-ageing preparations. Importantly, it is worth noting that all these products need to be tailored specifically to the individual patient and used in accordance to their skin type and condition, with special care to avoid unwanted side effects. REFERENCES 1. Van Scott, EJ. Yu, RJ. ‘Hyperkeratinization, corneocyte cohesion and alpha hydroxy acids’, J Am Acad Dermatol,11(5 Pt 1) (1984), 2. Draelos, ZD. Cosmetic Dermatology: Products and Procedures. Wiley-Blackwell, Chichester (2011) 3. Van Scott, EJ. Yu, RJ. ‘Actions of alpha hydroxy acids on skin compartments’, J Geriat Dermatol 3 (suppl A) (1995), pp. 19–24 4. Bauman, L. Saghari, S. Chemical peels. Cosmetic Dermatology: Principles and Practice. 2nd ed. McGraw Hill. New York (2009) 5. Berardesca, E. Distante, F. Vignoli, GP. Oresajo, C. Green, B. ‘Alpha hydroxyacids modulate stratum corneum barrier function’. Br J Dermatol 137(6) (1997), 6. Moy, RL. Luftman, D. Kakita, LS. Glycolic Acid Peels. Marcel Dekker, New York: NY (2002) 7. Ditre, CM1. Griffin, TD. Murphy, GF. Sueki, H. Telegan, B. Johnson, WC. Yu, RJ. Van Scott, EJ. ‘Effects of alpha hydroxyacids on photoaged skin: a pilot clinical, histologic and ultrastructural study’, J Am Acad Dermatol 34(2 Pt 1) (1996), pp. 187–95 8. Bernstein, EF1. Underhill, CB. Lakkakorpi, J. Ditre, CM. Uitto, J. Yu, RJ. Scott, EV. ‘Citric acid increases viable epidermal thickness & glycosaminoglycan content of sun-damaged skin’, Dermatol Surg 23(8) (1997), pp. 689–94 9. Okano, Y1. Abe, Y. Masaki, H. Santhanam, U. Ichihashi, M. Funasaka, Y. ‘Biological effects of glycolic acid on dermal matrix metabolism mediated by dermal fibroblasts and epidermal keratinocytes’. Exp Dermatol 12(suppl 2) (2003), pp.57–63 10. Wehr, R. Krochmal, L. Bagatell, F. Ragsdale, W. ‘Controlled two centre study of lactate 12% lotion and a petrolatum based cream in patients with xerosis’, Cutis 37(3) (1986), pp. 205–9 11. Edison, BL. Green, BA. Wildnauer, RH. Sigler, ML. ‘A polyhydroxy acid skin care regimen provides antiaging effects comparable to an alpha-hydroxyacid regimen’. Cutis 73(2 suppl) (2004), pp. 14–7 12. Rizer, R. Turcott, A. Edison, B. Outwater, S. Trookman, N. Ciociola, A. Kohut, B. ‘An evaluation of the tolerance profile of a complete line of gluconolactone-containing skincare formulations in atopic individuals’. Skin Aging 9(suppl) (2001), pp.18–25 13. Green, BA. Briden, ME. ‘PHAs and bionic acids: next generation hydroxy acids’, in: Draelos Z, Dover J, Alam M, Procedures in Cosmetic Dermatology: Cosmeceuticals, 2nd ed. saunders Elsevier, Philadelphia: PA (2009) 14. Green, BA. Edison, BL. Wildnauer, RH. ‘Maltobionic acid, a plant- derived bionic acid for topical anti-aging’, Am Acad of Dermatol 54(3) (2006), p.37 15. Bernstein, EF. Lee, J. Brown, DB. Yu, RJ. Van Scott, EJ, (2001) ‘Glycolic acid treatment increases type I collagen mrNA and hylauronic acid content of human skin’, Dermatol Surg 27(5) (2001), pp. 1–5 16. Davies, M, Marks, R. ‘Studies on the effect of salicylic acid on normal skin’, Br J Dermatol 95(2) (1976), pp. 187–92 17. Yu, RJ, Van Scott, EJ. ‘A-hydroxyacids, polyhydroxy acids, aldobionic acids and their topical actions’, Baran, R. Maibach, HI. eds. Textbook of Cosmetic Dermatology, 3rd edn. Taylor & Francis group, New York: NY (2005) 18. Roberts, WE. ‘Chemical peeling in ethnic/dark skin’, Dermatologic Therapy 17(2) (2004) pp.196–205 19. Grimes, PE. (1999) ‘The safety and efficacy of salicylic acid chemical peels in darker racial ethnic groups’, Dermatol Surg 25(1) (1999), pp. 18–22 20. Lowe NJ, Meyers DP, Wieder JM, Luftman D, Borget T, Lehman MD, Johnson AW, Scott IR. ‘Low doses of repetitive ultraviolet A induce morphologic changes in human skin’. J Invest Dermatol 105 (1995) pp. 739–43 21. Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, Voorhees JJ. ‘Mechanisms aestheticsjournal.com Aesthetics aestheticsjournal.com Dr Sandeep Cliff is a consultant dermatologist and dermatological surgeon based in London and Surrey. He has lectured extensively both nationally and internationally on facial rejuvenation. Dr Carolina Fernandez is a clinical teaching fellow in dermatology based at St. Helier Hospital. Prior to this she completed part of her dermatology registrar training at St Helier Hospital. of photoaging and chronological skin aging’. Arch Dermatol 138 (2002), pp. 1462–70 22. Passi, S, De Pita, O, Grandinetti, M, Simotti, C, Littarru, GP. ‘The combined use of oral and topical lipophilic antioxidants increases their levels both in sebum and stratum corneum’. Biofactors 18 (2003), pp. 289–2897 23. European Commission (2010), Council Directive of 27 July 1976 on the approximation of the laws of the Member States relating to cosmetic products. [Online] Available from http://tinyurl.com/66zzs8j (Accessed 25 May 2012) In Bowes, Lorna, ‘Understanding the dermal effect of heightened exposure to the sun’, Journal of Aesthetic Nursing 1(1), (2012) p. 30 24. Dean, SW. Lane, M. Dunmore, RH. Ruddock, SP. Martin, CN. Kirkland, DJ. Loprieno, N. ‘Development of assays for the detection of photomutagenicity of chemicals during exposure to UV light--I. Assay development’, Mutagenesis 6(5) (1991), pp. 335-341 25. National Institute for Health and Clinical Excellence (2011), Skin Cancer Prevention: Information, Resources and Environmental Changes, http://tiny.cc/fp09cw (Accessed 24 April 2012) 26. Tosti, A. Grimes, P. De Padova, M. ‘Trichlorocetic acid’, Colour Atlas of Chemical Peels. 2nd ed. Springer-Verlag, Berlin (2012) 27. Rook, A. Wilkinson, DS. Ebling, FJG. Textbook of Dermatology. Blackwell Scientific, Oxford (1972) 28. National Institute for Occupational Safety and Health (2011) Resorcinol. [Online] Available from: http://tinyurl.com/nnj4qv2 [Accessed 28 May 2013] 29. Divi, RL. Deorge, DR. ‘Mechanism-based inactivation of lactoperoxidase and thyroid peroxidase by resorcinol derivatives’. Biochemistry. 16;33(32) (1994), pp. 9668-74 30. Brody, HJ. (1992) As quoted in Bowes, Lorna, ‘An introduction to superficial, medium, deep and combination peels’, Journal of Aesthetic Nursing, 2(5) (2013), pp. 224-230 31. Brody, HJ. Monheit, GD. Resnik, SS. Alt, TH. ‘A history of chemical peeling’. Dermatol Surg 26(5) (2000), pp. 405–9 32. Fromage, G. ‘Topical retinoids: exploring the mechanisms of action and medical aesthetic applications’. Journal of Aesthetic Nursing 2(2) (2013), pp.68–75 33. Cucé, LC. Bertino, MC. Scattone, L. Birkenhauer, MC. ‘Tretinoin peeling’, Dermatol Surg 27(1) (2001), pp. 12-4 34. Fields, K. Falla, TJ. Rodan, K. Bush, L. ‘Bioactive peptides: signaling the future’, J Cosmet Dermatol 8 (2009), pp. 8–13 35. Kang YA1, Choi HR, Na JI, Huh CH, Kim MJ, Youn SW, Kim KH, Park KC. ‘Copper-GHK increases integrin expression and p63 positivity by keratinocytes’, Arch Dermatol Res. 301(4) (2009), p. 301–6 36. Fitzpatrick, RE. Rostan, EF. ‘Reversal of photodamage with topical growth factors: a lipot study’. J Cosmet Laser Ther. 5. (2003), p. 25–34 37. Rattan SI, ‘N6-Furfuryladenine (Kinetin) as a potential anti-aging molecule’, J Anti Ag Med 5(1) (2002), p. 113–6 38. Schmid, D. Schurch, C. Blum, P. Belser, E. Zulli, F. ‘Plant stem cell extract for longevity of skin and hair’. International journal of Applied Science, Accessed from SOFW- journal 134 vol 5 (2008) p30-35 <https://www.mibellebiochemistry.com/pdfs/Plant_Stem_Cell_ Extract_for_Longevity_of_Skin_and_Hair_SFW_05_08.pdf> [Accessed March 14 2014] FURTHER READING Bowes, Lorna, ‘An introduction to superficial, medium, deep and combination peels’, Journal of Aesthetic Nursing, 2(5) (2013), pp. 224-230 Bowes, Lorna, ‘Exploring the science of cosmeceuticals used to achieve optiomal skin health’, Journal of Aesthetic Nursing, 1(5) (2012), pp. 232-241 Bowes, Lorna, ‘The science of hydroxy acids: mechanisms of action, types and cosmetic applications’, Journal of Aesthetic Nursing, 2(1) (2013), p. 77 Reproduced from Aesthetics | Volume 1/Issue 5 - April 2014