The Tricky Tear Trough: A Review of Topical Cosmeceuticals for Periorbital Skin Rejuvenation

| September 1, 2015

aStacey J. Pilkington, DO; bSarah Belden, DO; aRichard A. Miller, DO aAzeal Dermatology Institute, Boulder, Colorado.; bUniversity Hospitals Regional Hospitals, Traditional Rotating Intern, Richmond Heights, Ohio

Disclosure: The authors report no relevant conflicts of interest.


 

Abstract

There is a growing demand for noninvasive anti-aging products for which the periorbital region serves as a critical aspect of facial rejuvenation. This article reviews a multitude of cosmeceutical ingredients that have good scientific data, specifically for the periorbital region. Topical treatment options have exponentially grown from extensively studied retinoids, to recently developed technology, such as growth factors and peptides. With a focus on the periorbital anatomy, the authors review the mechanisms of action of topical cosmeceutical ingredients, effectiveness of ingredient penetration through the stratum corneum, and validity of clinical trials. (J Clin Aesthet Dermatol. 2015;8(9):39–47.)


 

Due to the Baby Boomer’s continual pursuit to maintain a youthful appearance, there is a new paradigm in treating the signs of aging. The periorbital region serves as a window to a person’s chronological age. Aging photodamaged skin demonstrates epidermal atrophy, pigmentary changes, and the formation of dynamic and resting rhytides. Patients are commonly concerned about the appearance of dark circles, crow’s feet, eyelid bags, dry skin, thin skin, and just “looking tired.” They often seek advice about which treatments are most effective for periorbital rejuvenation. Although aging is inevitable, there are certain features of the periorbital skin that can be addressed to minimize the aged appearance.

There are many effective treatment options including surgical measures and nonsurgical modalities, such as fillers, neuromodulators, lasers, and light technology, but these are costly and have the potential for greater side effects. Therefore, a minimally invasive treatment, such as a topical cosmeceutical, is often the desired first line of defense.

A search for “crow’s feet” on Amazon.com revealed 2,471 products. The upper limit of the price range was more than $1,000 for a 15mL eye serum claiming to “eliminate wrinkles, reduce dark circles, and hydrate the skin around the eyes.” This helps elucidate the demand for products to address these common concerns in the periorbital region. What follows is a review of the common ingredients in topical cosmeceuticals utilized for periorbital rejuvenation.

Anatomy

Aging is a natural process that becomes evident through the evolution of our facial appearance. The physiological changes associated with aging include xerosis, loss of barrier function, loss of elasticity, modification of rhytides, slower turnover of epidermal cells, and atrophy.[1]

Furthermore, collagen and elastic fibers become damaged as the aging process progresses, and over time, advancing age and photodamage cause type I collagen to become more fragmented.[2] Fibroblasts respond with increased production of metalloproteases and decreased production of collagen, creating a vicious cycle of increasing collagen loss and subsequent thinning of the skin.[3] Lines are visible lateral to the eye (“crow’s feet”), generally by the sixth decade of life and extend from the lower eyelids to the malar cheeks.

The dark circles surrounding the eyes (periorbital hyperpigmentation) are due to thinning of the skin, atrophy of malar fat, and enlargement of the orbital bony space resulting in an increasingly hyperpigmented concavity at the medial border of the eyelid and cheek known as the tear trough deformity.[4] Roh et al[5] described additional causative factors of infraorbital dark circles as thin translucent lower eyelid skin overlying the orbicularis oculi muscle, shadowing due to the tear trough deformity, and skin laxity.[5] The authors discussed environmental etiologies, such as sun exposure, drug ingestion, post-inflammatory changes, and exacerbation due to atopic or allergic contact dermatitis. Lastly, it has been postulated that the pigmentation can also be due to venous stasis with hemosiderin deposition.[6]

According to Goldberg et al,[7] the formation of lower eyelid bags is a similar complex series of anatomic changes, including lower lid skin elasticity, orbital fat prolapse, eyelid fluid accumulation, orbicularis prominence, a prominent malar mound, and formation of the tear trough deformity.

Eyelid skin is unique as it is the thinnest skin in the body, measuring 0.2mm in thickness in some patients.[8] The thin nature of this area contributes to its vulnerability to environmental damage and photodamage. Caution must be used around the periorbital region due to the thin nature of the skin and the close proximity to the eye. In conclusion, aging of the delicate periorbital region is a complex series of physiological and anatomic changes resulting from multiple etiological factors.

Topicals

Topical therapy may be divided by the route at which their micro and macromolecules enter into the skin, which include the following: 1) the intercellular pathway, through the lipid matrix occupying the intercellular spaces of the keratinocytes, 2) the transcellular pathway, through the keratinocytes, and 3) transappendageal pathway, via hair follicles, sebaceous glands, and sweat glands.[9] From the conventional classification for periorbital rejuvenation, topical products are considered “adjunctive.” An important consideration is whether they can be as efficacious as monotherapy.

In comparison, from a marketing point of view, the labeling of cosmetic products is often formulated to advertise its ability for “moisturizing and lifting,” “anti-wrinkle and firming,” or “skin toning and brightening.” The term “active ingredients” is also used to communicate to the consumer which substances are used in the product to create local biological effects that would not be elicited from its vehicle alone.[10] When applied to the skin, most substances will show some activity or effect, so there is a blurred line between the validity of an “active” and “inert” ingredient. The term is mostly used for advertisement purposes, as regulatory limitations only allow companies to report appearance-based product claims.

Nevertheless, these “active” ingredients, which we will now simply term “ingredients,” may be considered by their origin and their purported activity as described by Lintner et al.[10] The origin of these products may be classified into four different types: 1) manufactured synthetic (peptides, ceramides, most vitamins); 2) extracted/purified from natural sources (botanicals herb extracts); 3) obtained by biotechnology, such as fermentation and cell culture (enzymes and cofactors, polysaccharides, and proteins); or 4) extracted from animal sources.10 The activity or efficacy of these ingredients may be analyzed using the combination of Klingman’s three golden rules of cosmeceuticals: 1) Can the active ingredient penetrate the stratum corneum and be delivered in sufficient concentrations to its intended target in the skin over a time course consistent with its mechanism of action? 2) Does the active ingredient have a specific biochemical mechanism of action in the target cell or tissue in human skin? 3) Are there published peer-reviewed, double-blinded, placebo-controlled, statistically significant, clinical trials to substantiate the efficacy claims?[11]

INGREDIENTS

Retinoids. Topical retinoids are the cornerstone of treatment for photodamaged skin. The class of retinoids encompasses both naturally occurring and synthetic derivatives of vitamin A. Retinoic acid is a prescription retinoid with substantial clinical evidence starting in 1986, when Klingman et al[12] demonstrated the effects of tretinoin on photodamaged skin. Dehydrogenases in human keratinocytes enzymatically convert retinol into retinaldehyde and subsequently retinaldehyde into retinoic acid.[13] Since retinol and retinaldehyde are ultimately converted to trans-retinoic acid, these cosmeceuticals are postulated to have similar clinical effects as retinoic acid.

The effects of retinoic acid on mottled hyperpigmentation, fine lines, and skin texture are well-known; however, there is less clinical research available for cosmeceutical retinoids.[12],[14] Retinol 1.6% when compared to 0.025% retinoic acid produced less erythema while inducing epidermal thickening and enhancing expression of cellular retinoic acid-binding protein (CRABP-II mRNA) and cellular retinol binding protein (CRBP mRNA), similar to retinoic acid.[14] Retinaldehyde has been shown to be significantly efficacious in reducing fine lines and improving skin roughness when compared to retinoic acid.[13] Levin et al[15] identified sufficient evidence of cutaneous penetration and supported the use of retinaldehyde and retinol to decrease fine lines and wrinkles.

When identifying the ideal topical agent for periorbital rejuvenation, skin irritation is an important consideration. Retinol and retinaldehyde have similar irritation potential, whereas esters have less documented irritation than retinol.[16],[17] Although esters have minimal irritation potential, they have both a weaker efficacy and require a higher dose (2%) to observe an effect.[18]

Skin irritation may be the limiting factor in the use of products for periorbital rejuvenation. There is often hesitation to apply the product close to the eye for fear of ocular damage or resultant periorbital erythema. Conjunctival irritation can occur when applied directly to the eye at high doses, as shown in the studies using all-trans-retinoic acid for its cytostatic effect on ocular surface dysplasia.[19] Retinoids have also been shown to cause corneal toxicity.[20] Based on this data, retinaldehyde has the best efficacy of the topical retinoid cosmeceutical agents, with less irritation potential than prescription retinoic acid.

Antioxidants. Reactive oxygen species (ROS) are highly unstable and reactive molecules generated from oxygen found within the skin after exposure to ultraviolet (UV) light.[21] ROS have a multitude of detrimental effects on aging skin by damaging deoxyribonucleic acid (DNA), cell membranes, proteins, and collagen.[22] It was first shown in 1958 that ROS play a key role in aging.[23] Free radicals also lead to inflammation, which is another factor implicated in the aging process.[24] Antioxidants are substances that delay or prevent oxidative damage caused by the presence of ROS. Our body’s antioxidant defense system includes endogenous (enzymatic and nonenzymatic) antioxidants and exogenous antioxidants. There are many exogenous sources that have been studied and shown to have topical effects. However, there is a paucity of studies for antioxidant agents that have been utilized around the periorbital skin specifically.

Vitamin C. Vitamin C or L -ascorbic acid is an efficient water-soluble antioxidant that is able to neutralize free radicals both intracellularly and extracellularly.[25] Although humans are unable to synthesize vitamin C like most animals and plants, it is the most abundant antioxidant in human skin.[26] Functioning in the aqueous compartment of the cell, vitamin C not only neutralizes free radicals, it also donates electrons and protects intracellular structures from oxidative stress.[22] L-ascorbic acid has been documented to protect porcine skin from ultraviolet A (UVA) phototoxic injury and UVB-induced erythema and sunburn cell formation.[27]

Vitamin C is notorious for its essential role in collagen biosynthesis. It is a cofactor for both lysyl and prolyl hydroxylase, which hydroxylate lysine and proline in collagen, creating the triple helical structure.[28] Collagen synthesis is also directly stimulated by increased transcription and stabilization of procollagen messenger ribonucleic acid (mRNA) of collagen type I and type III.[29] L-ascorbic acid dually inhibits the enzymes responsible for collagen degradation.[30] The anti-inflammatory effect of vitamin C is resultant from suppressed activation of nuclear factor ?? (NF-??) by inhibition of tumor necrosis factor alpha (TNF-?).[31] Ascorbic acid also provides lightening benefits via inhibition of tyrosinase.[32]

Traikovich designed a three-month, randomized, double-blind, vehicle-controlled study to determine the efficacy of topical vitamin C in photodamaged skin.[33] Subjects blindly applied vitamin C cream to one side of the face and the control vehicle to the other side. Results were measured by clinical and self-assessment, optical profilometry image analysis, and photographic assessment. Clinical assessment showed significant improvement in many features, including fine wrinkles, tactile roughness, laxity, and tone. Self-assessment questionnaire demonstrated that 84.2 percent of the subjects preferred the side treated with vitamin C to the control side. Photographic assessment showed vitamin C treated skin to have 57.9 percent greater improvement compared to control. Optical profilometry analysis demonstrated improvement of the crow’s feet with active treatment up to 73.7 percent greater than control.

The greatest challenge with vitamin C administration is product stability and adequate penetration. As L-ascorbic acid is water soluble, it is prone to oxidation in solution, resulting in the by-product dehydroascorbic acid. It was identified that L-ascorbic acid must be formulated at pH levels less than 3.5 to enter the skin and the maximal concentration for optimal percutaneous absorption was 20 percent.[34] Esterified derivatives of L-ascorbic acid, such as magnesium ascorbyl phosphate and ascorbyl-6-palmitate, have been used to improve stability.[35] Fitzpatrick et al[36] demonstrated the benefit of a combination of anhydrous ascorbic acid and lipid soluble tetrahexyldecyl (THD) ascorbate. The penetration of THD at the same concentration of ascorbic acid is three times greater, with a superior penetration rate even when ascorbic acid is 25 times higher than THD ascorbate.[37]

Vitamin E. ?-tocopherol is a lipophilic antioxidant that serves as a protective agent for the cell membrane and the stratum corneum lipid bilayer.[38] A four-month facial study with 5% topical vitamin E showed improvement in periorbital wrinkling and reduction of post-UV inflammation.[39] Vitamin E decreases UVB-induced photodamage, inhibits human metalloproteinases that degrade elastin, and inhibits UV-induced tumor formation.[40],[41] Lin et al[42] reported the combination of 15% L-ascorbic acid and 1% ?-tocopherol provided a fourfold photoprotection for the skin against erythema and sunburn cell formation. The synergistic photoprotection is resultant from combining the hydrophilic and lipophilic antioxidants to create a stabilized formulation, in which L-ascorbic acid is available to regenerate ?-tocopherol whenever it is oxidized.[42] Another publication identified that ferulic acid, a ubiquitous plant antioxidant, doubled photoprotection via increased stability to the combination of vitamin C and E by providing additional protection against thymine dimer formation and reduced apoptosis within keratinocytes.[4]3

Niacinamide. Niacinamide (vitamin B3) is an essential vitamin that is commonly used in cosmeceutical products due to the wide array of cutaneous effects. It is a precursor to the nicotinamide adenine dinucleotide [NAD(P)] family of endogenous enzyme cofactors, which serve as co-enzymes to many biochemical reactions in the skin. The reduced forms of these cofactors [NAD(P)H] have anti-oxidant properties.[26] It has been effectively demonstrated that niacinamide has significant penetration through the stratum corneum.[44] To further support this data, studies have illustrated increased levels of NAD with cutaneous application of niacinamide.[45] In addition to the antioxidant effects of niacinamide, it has also been well-documented to reduce skin yellowing, hyperpigmentation, erythema and blotchiness, as well as improving the epidermal barrier and reducing fine lines and wrinkles.[46–49] Bissett et al[46] validated that niacinamide is well-tolerated, easily formulated, and chemically stable, making it an ideal agent to formulate cosmeceutical products.

The beneficial qualities of niacinamide specifically for periorbital rejuvenation include improvement of skin texture, fine lines, and reduction of hyperpigmentation. Cutaneous pigment is reduced via inhibition of melanosome transfer from melanocytes to keratinocytes.[47] The improvement of rhytides is postulated to be due to the increase in collagen production as shown in fibroblast cultures and the reduction of excess dermal glycosaminoglycans (GAGs) that is characteristic of photodamaged or wrinkled skin.[14],[50],[51] Lastly, niacinamide increases both the lipid and protein components of the stratum corneum subsequently reducing transepidermal water loss (TEWL) and increasing the skin’s barrier properties.[49] Levin et al[15] summarized niacinamide as one of the best studied cosmeceutical ingredients for anti-aging.

Green tea. For thousands of years the tea plant, Camellia sinensis, has been cultivated to produce green tea. The different forms of tea (green, black, and white) are distinguished by the amount of oxidation that occurs during the extraction process. Green tea contains the highest concentration of tea polyphenols due to the unique withering and steaming process, which prevents oxidation and preserves the composition.[52] The four major polyphenols (catechins) found in green tea include epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and epigallocatechin-3-gallate (EGCG), the latter of which is the most abundant, physiologically active, and thus the most applied form.[53]

It is well-documented that green tea exhibits anti-oxidant, anti-inflammatory, and anticarcinogenic properties.[54] The anti-aging benefits of green tea are postulated as a result of its photoprotective benefits and its effect on collagen synthesis. Elmets et al[55] confirmed the photoprotective effect on human skin by demonstrating that the topical application of green tea extract resulted in dose-dependent inhibition of erythema response evoked by a 2 minimal erythema dose solar simulated radiation. EGCG and ECG provided the most UV protection, both of which contain a galloyl group at the 3 position. The photoprotective effects were further illustrated on histological examination, which revealed the green tea application protected epidermal Langerhans cells from UV damage and reduced the number of sunburn cells.[55] EGCG is a powerful free-radical scavenger that has been shown to reduce UVA-induced sun damage and UVB-induced lipid peroxide, to downregulate UV-induced expression of AP-1 and NF-??, to inhibit expression of collagenase in cultured human fibroblasts, and to prevent collagen cross-linking in hairless mice.[56]

The anti-aging mechanisms of EGCG are remarkably promising, although the clinical application remains a challenge due to its lack of stability and epidermal penetration. Hsu54 described EGCG as a highly reactive compound that is easily oxidized in the environment. The hydrophilic nature of EGCG also limits its epidermal penetration in human skin. Recent research indicates an oil-in-water emulsion is the most effective vehicle to achieve percutaneous penetration.[57] A glycosylated form of EGCG has also been shown to be more efficacious for targeting keratinocytes and maximizing antioxidant activity.[58]

Overall, much skepticism still exists for the use of topical EGCG as the only randomized, double-blind, controlled clinical study found no statistically significant clinical improvement.[59] Amidst the skepticism, if the major challenge of stability and penetration can be addressed, the benefits of green tea for the human skin could become a powerful adjunct in our cosmeceutical armamentarium.

Peptides. Short chains of amino acid sequences, known as peptides, are the building blocks of proteins. The human body utilizes peptides to communicate between cells. Fields et al[60] further identified that peptides are involved in the modulation of protein synthesis, protein regulation, cell proliferation, cell migration, inflammation, angiogenesis, and melanogenesis. Some of the most studied peptides include palmitoyl-lysine-threonine-threonine-lysine-serine (pal-KTTKS), acetyl-glutamate-glutamate-methionine-glutamine-arginine-arginine (Ac-EEMQRR), and the tripeptide copper glycine-histadine-lysine (Cu-GHK).[61] KTTKS is a fragment of procollagen I, which has been shown to stimulate dermal matrix production in fibroblast cultures.[62] Palmitoyl, a fatty acid fragment, was added to this hydrophilic peptide to improve cutaneous penetration. In a 12-week, double-blind, placebo-controlled, split-face study, topical 3 parts/million pal-KTTKS was well- tolerated and demonstrated significant improvement in the appearance of facial rhytides.[63] Collagen synthesis and matrix mellatoproteinases may be stimulated when GHK, a collagen fragment, is complexed with copper to form Cu-GHK.[64] The hexapeptide Ac-EEMQRR has been postulated to have inhibitory effects on neurotransmitter release, with documented improvement of facial wrinkle depth with the application of topical 10% Ac-EEMQRR for 30 days of treatment.[65] There are indefinite modifications that can be made to the amino acid sequences comprising peptide molecules; however, as the amino acid residues increase so does the cost and difficulty of skin penetration. This technology will continue to evolve in the future and will play an integral role in the cosmeceutical industry.

Growth factors. The clinical data supporting the use of growth factors and cytokines in wound healing has incited a novel new anti-aging treatment.[66] Growth factors play an integral role in the repair and remodeling of dermal infrastructure, as specific growth factors and cytokines affect the proliferation of dermal fibroblasts and extracellular matrix production.[67] The rejuvenative effects of growth factors have been confirmed by two studies utilizing a skin cream with a mixture of human growth factors and cytokines that were obtained through a biotechnology process using cultured human fetal fibroblasts, originating from a dedicated cell bank for the development of products in wound healing.[68],[69] Gold et al[68] reported 17-percent improvement of periorbital wrinkles after two months of twice-daily application. Whereas Hussain et al[69] identified a 33-percent improved clinical appearance of periorbital wrinkles after six months of twice-daily application. The authors further postulated that topical application may promote growth of keratinocytes, dermal fibroblasts, and other cells with decreased proliferative capacity due to aging.[69] One clinical trial demonstrated 37-percent increase in grenz-zone collagen and 30-percent increase in epidermal thickness after 60 days of twice-daily application.[70] An alternative to human growth factors is the use of a topical product containing secretions of the snail Cryptomphalus aspersa (SCA), which has been shown to provide significant improvement of periocular rhytides after 12 weeks of use.[71] The large molecular size of growth factors still raises the question of effective skin penetration, although it has been postulated that the effects may be due to penetration via a vertical pathway, such as hair follicles, sweat glands, or microlesions in the interfollicular stratum corneum.[69] Growth factors and cytokines will likely continue to be an emerging area of study for periorbital rejuvenation.

Alpha hydroxyacids. Alpha hydroxyacids (AHAs) have been widely incorporated in therapeutic formulations to rejuvenate photodamaged skin. AHAs are organic carboxylic acids with one hydroxyl group attached to the alpha position of the aliphatic carbon atom.[72] Glycolic acid, lactic acid, mandelic acid, and benzilic acid are all included in the AHA group, with glycolic acid being the smallest molecule.[73] In 1974, the predominant effect of AHAs was identified as decreased corneocyte cohesion above the stratum granulosum, promoting exfoliation of the outer layers of stratum corneum.[74] Ditre et al[75] reported treatment with topical AHAs for six months resulted in 25-percent increase in epidermal thickness with improved synthesis of glycosaminoglycans, collagen, and possibly elastic fibers. Additional findings included reversal of basal cell atypia, dispersal of melanin pigmentation, and return to a more normal rete pattern.[75] It was further demonstrated that glycolic acid and lactic acid up-regulated collagen I and procollagen I levels.[76] These agents can be formulated in daily skin care regimens and higher concentrations may be used for chemical peels. AHAs have been shown to address the crucial issues of periorbital rejuvenation including photoaging and hyperpigmentation.

Hyaluronic acid. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan in the human body, which serves as a major component of the extracellular matrix of the skin.[77] It is considered to be a humectant, which is a substance that attracts moisture. HA is known to bind 1,000 times its volume in water.[78] In the skin, HA helps maintain tissue turgor, elasticity, and hydration.[79] Similar to most cosmeceutical ingredients, the greatest challenge with topical HA is the ability to penetrate the dermis to achieve maximal deposition. Specifically, the diameter and molecular weight of topical HA formulations have been under much investigation. Most over-the-counter HA molecules are 3,000nm in diameter, whereas the intercellular space is only 15 to 50nm.[9] A recent study investigated the efficacy of a nanoproduct (5nm in diameter) and found a statistically significant change in the depth of wrinkles and an increase in moisture and elasticity of the periorbital region.[80] Substances smaller than 500kDa, with sufficient oil solubility and high partition coefficient, can be absorbed into the skin. However, in contrast, larger molecules (molecular weight >500 kDa) cannot pass the cutaneous barrier.[81] A 2011 study showed that twice-daily application of HA at 50 and 130kDa applied for 60 days to the periorbital region significantly decreased wrinkle depth.[82] Pavicic et al[82] postulated the anti-wrinkle properties of HA were due to both the potent water-binding mechanism and the anti-inflammatory effects on the degradation of collagen, elastin, and genuine HA.[82] It is important to be cognizant of both the diameter and molecular weight of a HA formulation.

Ceramides. Ceramides are an essential component of the stratum corneum. Harding et al[83] eloquently described the stratum corneum as a unique sophisticated biosensor, which provides the critical skin barrier function that serves as a prerequisite for terrestrial life itself. The lamellar layers of the intercellular lipids are composed of ceramides, free fatty acids, and cholesterol, with ceramides comprising 50 percent of the lipid content by mass.[83] This intricate lipid interface is essential for maintaining the barrier function and preventing TEWL.[84] Ceramides have gained favor in the cosmeceutical industry as clinical studies have shown ceramides improve skin hydration, reduce TEWL, and increase tolerability of topical tretinoin.[85],[86] The addition of ceramides to any periorbital rejuvenation regimen will provide improvement in overall skin hydration.

Caffeine. Caffeine is a purine alkaloid, which is found in many popular beverages. Azam et al[87] confirmed the antioxidant properties of caffeine by demonstrating its quenching effect on the production of hydroxyl radicals and oxidative DNA breakage by hydroxyl radicals.[87] Caffeine also exhibits anti-inflammatory properties and influences cell migration and proliferation.[87],[88] It has also been proven that caffeine stimulates lipolysis, which Lupo et al[90] postulated may contribute to improvements in lower eyelid sagging and puffiness.[89],[90] Although caffeine is used in many cosmeceutical products, there is still caution for its anti-aging use, as it has been shown to reduce collagen synthesis in human cultured skin fibroblasts.[91]

Chamomile/bisabolol. Chamomile, known as Matricaria recutita L, is an annual herbaceous plant that is a popular ingredient in herbal teas. Studies have shown that chamomile and its main constituent, ?-bisabolol, have moderate antioxidant activities and potent anti-inflammatory action.[92] However, it was shown that topical ?-bisabolol did not show significant anti-irritant effects because it did not reduce irritation from substances greater than the vehicle alone.[93] Further studies need to be performed to clearly demonstrate the role of chamomile in reducing puffiness and irritation of periorbital skin.

Licorice root/glycyrrhizic acid. Glycyrrhetinic acid, the active principle of licorice root, has been elucidated to have anti-inflammatory properties.[94],[95] Licorice root also offers pigment lightening as it contains liquiritin and isoliquertin, which disperse melanin, and glabridin, which inhibits tyrosinase.[96] Licorice root is effective in treating the hyperpigmentation associated with photoaging; however, more studies are needed to examine its role specifically in periorbital hyperpigmentation.[97]

Skin lightening agents. Hydroquinone is the most widely prescribed and most studied agent for the treatment of hyperpigmentation.[5] Hydroquinone functions as a bleaching agent by inhibiting tyrosinase, a critical enzyme in melanin biosynthesis, via selective damage to melanosomes and melanocytes.[98] Per Roberts,[99] the other bleaching agents can be organized by mechanism of action: skin turnover accelerators (hydroxy acid, retinoic acid), premelanin synthesis tyrosinase transcription (tretinoin), tyrosinase inhibitors (azelaic acid, kojic acid, arbuin, soy, peptide), postmelanin synthesis tyrosinase degradation (linoleic acid), postmelanin synthesis melanasome transfer inhibition (soy, niacinamide), and antioxidants that chelate copper ions to reduce dopaquinone (vitamin C).

Invisible Shapewear

A recent advancement in periorbital rejuvenation is the addition of a noninvasive polymer emulsion. This can be applied to the under-eye area with resultant in-situ cross-linking functionality, and formation of an invisible film. Sakamoto et al[100] demonstrated the aesthetic and hydration benefits of this technology in a randomized, split-face study, which identified a one-grade improvement in lower lid bag protrusion and increased epidermal thickness.

Prevention

Benjamin Franklin once quoted “an ounce of prevention is worth a pound of cure.” UV exposure exponentially accelerates the photoaging process. Therefore, this article cannot be complete without addressing the importance of the daily use of a physical blocking sunscreen and sun-protective measures. Included in these measures, specific for the periorbital region, is the daily use of eyewear or sunglasses. Small lenses increase the probability of UV radiation reaching the periorbital skin. Based on this factor, the Australian standard has a minimum requirement of the lens size, which is 28mm for adult and 24mm for children.[101] Behar-Cohen et al[102] developed an eye-sun protection factor (E-SPF) to provide reliable labeling of the protective potential of lenses. Another preventative topic is avoidance of smoking tobacco. Fan et al[103] identified significant changes in temperature, partial pressure of oxygen, and oxyhemoglobin levels in the periocular facial skin after 30 minutes of smoking. Thus, abstaining from smoking tobacco will aid in the prevention of premature skin aging.

Conclusion

The periorbital region is a critical aspect of facial rejuvenation. For patients wishing to utilize a noninvasive topical therapy, there are a multitude of cosmeceutical ingredients that have good scientific data. Due to the thin nature of the periorbital skin and the close proximity to the eye, caution must be taken when choosing the appropriate ingredients. Periorbital treatment options have exponentially grown from extensively studied retinoids, to recent technology, such as growth factors and peptides. Future scientific advances will continue to expand our treatment armamentarium for periorbital rejuvenation.

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