Epidermal growth factor in aesthetics and regenerative medicine: Systematic review

Abstract

INTRODUCTION In recent years, Epidermal Growth Factor (EGF) has been an important innovation.[1] It is a mitogenic polypeptide that is responsible for the maintenance and protection of the epithelia.[2] Thanks to genetic recombination, effective and clinically safe recombinant EGF (rhEGF) is available. On the other hand, there are striking similarities between oxidative events that promote skin aging and the oxidation seen in delayed wound healing. In both cases, the skin’s repair mechanisms are overwhelmed, as the production of growth factors slows down, including the production of EGF.[3] In both cases, it is necessary to biostimulate fibroblasts and keratinocytes, inducing the replacement of collagen and elastin and the extracellular matrix.[3] The success of the use of growth factors as a strategy to reverse photoaging lies in understanding its role in wound healing.[4] Therefore, the new cosmetic assets with recombinant growth factors as the rhEGF pursue this restructuring.[567] The rhEGF has been investigated in the past decade as a treatment of facial photoaging.[8] However, the literature review revealed that there are no systematic reviews, in Spanish or English, about the efficacy of rhEFG as facial and regenerative therapy. Given the lack of this information and the clinical potential of this factor, this systematic review aims at describing the current state of facial aesthetic and regenerative medicine treatments in which rhEGF has been effectively used with an emphasis on cutaneous restructuring. MATERIALS AND METHODS Search strategy The search was started in health databases: Medline (via PubMed), Lilacs (via Bireme), Science Direct, Cochrane Library Virtual Health Library (VHL), SciELO, Medigraphic, and Google Scholar. To delimit the number of papers to select, the search was filtered by preferred languages (English and Portuguese) and the period 2001–2019 (since the information published in the past five years was not enough). The logical AND operator was used to combine the following descriptors for the search: — English (MeSH): facial antiaging therapeutics; skin rejuvenation; EGF recombinant; epidermal growth factor; tissue regeneration; EGF, rhEGF. — Portuguese: Fator crescimento ou recombinant epidermal carcinoma; rejuvenescimento gives peel; redensificação dermal; com faciais therapies fatores of crescimento; EGF, rhEGF. Selection of clinical studies The following inclusion criteria were considered: — Preclinical and clinical trials related to the use of the rhEGF in skin disorders or skin aging — Texts that undergo a rigorous evaluation process (peer-reviewed publications and texts from renowned publishers) Duplicated publications were removed. Literature reviews, case reports, incomplete publications or those did not comply with methodological rigor criteria (e.g. biases selection of participants or biases analysis of information), clinical treatment guidelines, and other irrelevant studies were excluded. By utilizing skimming and scanning as analysis strategies for information, irrelevant items were discarded by title and abstract. Once the exhaustivity of the search had been confirmed (by depletion of publications of each source consulted), the veracity of the information was confirmed by each author by methodological analysis and the content analysis of each publication. RESULTS Seven sources of information were consulted, resulting in 75,986 publications that included the descriptors; of these, only 133 articles were directly related to the subject and they were examined by their title and abstract, and 73 articles were excluded because they did not meet the selection criteria. After reading the full text of the remaining 60 articles, taking into consideration the analysis criteria, 11 articles were removed, leaving a total of 49 articles [Figure 1] with a total sample of 821 patients.Figure 1: Flowchart of literature search. Source: Prepared by the authors from the study resultsThe results indicate that most of the publications on rhEGF applications were led by Korea, followed by the United States and Japan. The years in which it was most published in this regard were 2015 and the period between 2017 and 2019. Publications were classified according to the information source where they were located [Table 1]. Medline via Pubmed was the source that hosted major related scientific evidence.Table 1: Corpus according to sources and number of papers selectedLikewise, 46 studies corresponded to original research articles, and they are predominantly clinical trials (24 articles) over preclinical trials and case series; also, 13 articles are review articles, 9 are traditional reviews, 2 are systematic reviews, and 2 are meta-analyses [Table 2].Table 2: Corpus according to the type of study and number of articles foundEpidermal growth factor has been used basically in two major areas: regenerative medicine and aesthetic medicine. In aesthetics, there are three emerging categories: its application in hyperpigmentation, skin restructuring, and facial rejuvenation. The rhEGF in regenerative medicine Growth factor promotes wound healing,[910] employing the intralesional administration of 75mg lyophilized powder thrice per week; gel 150g / g or spray rhEGF topically twice a day until complete healing.[11] Of the 21 publications in regenerative medicine, only 14 are clinical or preclinical trials [Table 3]. Korea is the country that has most investigated rhEGF in regeneration and the year in which it was most published was 2013.Table 3: Research designs under which rhEGF studies were conducted in the area of regenerative medicineThe main clinical uses of rhEGF in regenerative medicine include the treatment of alopecia and dermatitis after chemotherapy, burns, diabetic foot ulcers, postsurgical ulcers, oral mucositis, pharyngeal ulcers, and tympanic membrane perforation. This evidence is summarized in [Table 4] next.Table 4: Applications of the rhEGF in regenerative medicineIn alopecia treatment, the topical EGF-liposomal solution by transfollicular route favored primary hair recovery via the dystrophic anagen pathway.[12] In this regard, the mechanism of action consists of EGF, promotes the proliferation and migration of hair follicle outer root sheath cells, and modulates the expression of several follicle-regulatory genes via Wnt/β-catenin signaling.[13] The rhEGF in aesthetic medicine From fibroblast cell cultures with rhEGF, it was determined that rhEGF promotes the migration and contractility of aged fibroblasts[10] and increases the production of hyaluronic acid and the synthesis of collagen.[11] Hence, it possesses potential as a regenerator of skin aging. Peptides with rhEGF that penetrate the skin when applied topically have been developed[11]; cosmeceuticals with rhEGF that prevent or improve rhytids and hydrate the skin without significant side effects are being formulated.[26] Of the 28 publications in Aesthetic Medicine, 23 are clinical or preclinical trials [Table 5] with a higher level of evidence in aesthetics than in regenerative medicine. The country that has researched this matter the most is Korea, followed by the United States, and the periods of greatest publication were 2015 and 2017.Table 5: Research designs under which rhEGF studies were conducted in the area of aestheticsThe rhEGF to treat hyperpigmentation The EGF is a noninvasive and effective treatment for melasma. Topical serum twice a day for 8 weeks decreased melasma in 73.4% cases of the experimental group without any side effects.[27] The EGF acts on the melanocytes by reducing the expression of melanogenesis‐associated proteins (e.g. tyrosinase/MITF microphthalmia-associated transcription factor), in consequence inhibiting or regulating melanin synthesis.[28] It is also effective in preventing postinflammatory hyperpigmentation after fractional carbon dioxide laser treatment; its daily application resulted in significant stimulation of healing with slight pruritus.[29] Other research confirmed that rhEGF prevents inflammatory hyper pigmentation by laser treatment at 3, 7, and 35 days after its use.[30] The rhEGF for restructuring the skin The EGF contributes to restructuring the skin tissue; it improves facial acne, both inflammatory and noninflammatory, when it is applied as an rhEGF cream for 6 weeks. It also decreases sebum production and increases hydration, whereby the topical rhEGF may be an effective and safe adjuvant treatment option for mild to moderate vulgar acne.[31] The EGF also restructures the skin with stretch marks; it is being used as a complementary treatment to the ablative fractional carbon dioxide laser, twice a day until one month after the last session, showing significant improvements in stretch marks. Skin biopsy revealed an increased epidermal thickness and a decrease in elastic fragmentation.[32] The rhEGF to treat skin aging Most clinical trials reported the efficacy of rhEGF to reverse signs of skin aging,[3334] such as rhytids, grooves, hyper pigmentation and other senile pigmentations, hydration loss, and a decrease in epidermal and dermal thickness; test topical formulations such as cream, serum, and gel, either as a single therapy applied daily at home or as a complementary treatment after other treatments for facial rejuvenation such as the ablative laser. Only a few recent publications have studied its incorporation with classic injections of mesotherapy or through the use of patches with microspicles for the transdermal release of the factor.[3536] Clinical applications of the EGF factor in facial aesthetics are shown in [Table 6].Table 6: Applications of the rhEGF in aesthetic medicineDISCUSSION A skin wound is similar to skin aged by inflammation mediated by reactive oxygen species.[48] Besides, in wound healing there is angiogenesis and replacement of extracellular matrix, leading to re-epithelialization, but it is in the final phase that the collagen fibers are remodeled and elastin is restructured.[49] This last phase is characterized by antiaging treatments, and the use of growth factors evokes such dermal restructuring.[50] When topical or injectable growth factors are administered, the depleted levels are replenished and the activity of the cells responsible for dermal remodeling is regulated, reversing skin aging.[4851,52] The rhEGF replenishes this balance and facilitates wound healing and dermatological conditions, as evidenced in some studies.[53] In 1972 Savage et al.[54] completed the sequentiation of EGF for the first time. In 1995 Parries et al.[55] they worked into their isolation and purification. Since this, the mass production of rhEGF has become a formidable task. From 2002, a heterologous protein such as EGF with an adequate molecular size (6kDa) started being produced in large quantities based on recombinant DNA technology. This placed an increased impetus on the development of more effective and economical methods for industrial purposes.[5657] Taking advantage of this technology, in the past two decades, the EGF has been produced and exploited in the cosmetic industry for the purpose of skin treatment.[58] For some authors, it is controversial that a growth factor that is applied topically can rejuvenate the skin; however, due to its large molecular size (> 15,000Da), its ability to penetrate the stratum corneum and to reach viable keratinocytes in the basal stratum is limited.[5960] This limitation was overcome from 2002 onward, because since then the majority of dermatologically and cosmetically commercialized formulations contain an rhEGF of 6kDa (or 6,000Da) with excellent potential for topical penetration into the stratum corneum.[6162] The rhEGF entry into the skin is through hair follicles and sweat glands. Also, it may be possible to improve their penetration by chemical modification with lipophilic molecules or by facilitating their diffusion by compromised skin, for example, after using microneedling or laser resurfacing,[63] as observed in all studies cited earlier, in which the EGF exhibits a low molecular size. The evidence is clear as to the success or effectiveness of rhEGF for facial rejuvenation; however, quasi-experimental, uncontrolled, or randomized clinical trials still abound. The studies assessed its effects while it was applied topically, but the greatest efficiency of the EFG was obtained intradermally, with a greater reduction of rhytids, folds, and a longer response over time. Besides, to guarantee its effectiveness, a possible route of entry for this molecular size is through intradermotherapy. In regenerative medicine, the EGF has been studied under preclinical trials and clinical trials, mostly quasi-experimental ones that are not uniform in terms of the route of administration, dose, and therapeutic regimen, which indicates the need to shield studies in this area by promoting the control and randomization to give more precise results on the resounding efficacy of the factor in wound regeneration. CONCLUSIONS Products with EGF are an important topical therapeutic modality to treat aging skin efficiently and to treat hyper-pigmentation, rhytids, dryness, and laxity. The EGF is effective in the advanced healing of skin wounds, according to the results of multiple investigations in severe cases, although studies are required to establish concentrations and indications of use for each case. Injected rhEGF exerts a higher antiaging effect, inducing collagen, elastin, and hyaluronic acid, which are responsible for skin elasticity and turgor. However, more controlled, randomized, and long-term follow-up clinical trials are needed to specify the dose and therapeutic protocol to ensure its efficacy. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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