Verwendung von schneckenschleim in der hautpflege

https://onlinelibrary.wiley.com/doi/10.1111/jocd.16269

 Abstract

Background
Snail mucin is becoming increasingly popular for its wide range of ingredients and potential benefits. Snail extract's widespread appearance in cosmetic formulations encourages an investigation into the medical and cosmetic benefits.

Aims
This study aims to explore current literature on the variety of snail mucin applications. Specifically, we present a review of the uses, global market estimates and projects, and limitations to snail mucin.

Methods
A literature search was conducted on PubMed reviewing snail mucin and their application in medical and dermatologic fields examining their uses. Economic reports were also investigated for Global Market estimates.

Results
The therapeutic use of snail mucin in medical fields has been studied as antimicrobial agents, drug delivery vehicles, antitumor agents, wound healing agents, and biomaterial coatings among others. Additionally, the use in cosmetic fields includes antiaging, hydrating, anti-acne, scarring, and hyperpigmentation treatments. It is important to highlight that most studies conducted were preclinical or small clinical studies, stressing the need for additional large-scale clinical trials to support these claims. Investigations into the global market found estimates ranging from $457 million to $1.2 billion with upward projections in the upcoming decade. Limitations include ethical habitats for collection, allergy investigation, and missing clinical studies.

Conclusions
The findings presented here emphasize the expanding uses of snail mucin and its ingredients alongside a growing market cosmetic industry should consider. We also emphasize the need for appropriate clinical trials into the stated benefits of snail mucin to ensure consumer safety and ethical extraction of mucin.

1 INTRODUCTION
Snail mucin and extract has gained popularity in several areas of dermatologic care ranging from usage to expedite healing in burn patients to daily skincare for its claimed antiaging and anti-acne benefits. The fascination behind snail mucin is rooted in its animal origin and collection methods, yet the full possibilities of its ingredients are actively still being explored. This review aims to discuss the multifaceted functions of snail mucin, economic projections of the field, limitations to their use and more.

The composition of snail mucin having multiple trusted skincare ingredients such as growth factors, antioxidants, and hyaluronic acid, made for an easy transition of snail mucin into skincare.1 Other ingredients found in snail mucin include glycosaminoglycans, glycoproteins, allantoin, glycolic acid, lactic acid, collagen, and elastin.2 This makes snail mucin an incredibly unique natural product, offering a rare combination of ingredients not found in nature otherwise. Snail slime is a clear liquid with light yellow pigment that has a pH around 4.80 and density of 102 g/mL.3 Snail mucin has existed globally for centuries dating back to Ancient Greece, where Hippocrates mentioned its use in relieving inflamed skin. Historic records also note Chilean snail farmers found snail mucin to help heal skin lesions without scarring, and the Han Dynasty in China documented its use in children's tetanus, insect bites, and hemorrhoids.4-6 Throughout time, numerous functions have been proposed for snail mucin and extract including antimicrobial agents, drug delivery vehicles, antitumor agents, wound healing agents, biomaterial coatings, and antiaging and anti-acne skincare.

2 FUNCTIONS OF SNAIL MUCIN IN MEDICINE
The antimicrobial properties of snail mucin is also a prospective way in which anti-acne treatments can be utilized. In one study, the mucus of Achatina fulica inhibited the growth of S. aureus while the mucus from Helix aspersa had a strong antibacterial effect on multiple strains of P. aeruginosa with only minimal effect on S. aureus.7 An extracted protein containing Apextrin C-terminal (ApeC) from the snail Biomphalaria glabrata revealed a high affinity to the Lys-type peptidoglycan recognition protein (PGN) of S. aureus, suggesting one way in which mucus binds to bacteria.8 Semi-purified fractions of Achatina fulica mucus targeted the virulence factors of alpha-hemolysin, coagulase, and biofilm formation of S. aureus to inhibit growth.9 Other research using Achatina fulica Férussac mucus found antibacterial activity against B. subtilis, S. aureus, E. coli, P. aeruginosa, S. mutans, and A. actinomycetemcomitans using the paper-disc method.10, 11 Additional antibiotic activity included the inhibition of both S. aureus and S. epidermidis when snail mucus from Achatina fulica was integrated into the wound dressings of mice.12 Another snail species, Achatina reticulata, had antimicrobial activity against E. coli, S. aureus, K. pneumoniae, and P. aeruginosa that was comparable to conventional antibiotics.13 The snail species Cornu aspersum exhibited antibacterial activity against B. laterosporus, E. coli, and the anerobic bacterium Clostridium perfringens.14 Snail mucin when digested can also affect the bacteria of the gut microbiome as it was found to ameliorate symptoms of loperamide-induced constipation in rats. Here, snail mucin increased the bacteria belonging to the phyla Actinobacteria and Frimicutes and reduced the bacteria belonging to phyla Bacteriodetes and Verrucomicrobia.15 This resulted in a statistically significant decrease of constipation, alluding to yet another way in which snail mucin can be used in medicine.

The protein moiety of snail mucin is the main contributor to its antibacterial properties, as when the mucin was broken down via a proteinase, the antimicrobial effects were lost.4 This antibacterial glycoprotein factor was able to be isolated via DEAE-Toyopearl 650 M ion exchange chromatography.16 An additional cysteine-rich antimicrobial peptide from Achatina fulica has been isolated named mytimacin-AF which exhibited antimicrobial activity against gram positive and gram negative bacteria in addition to the fungal species C. albicans.17 Antiviral properties have also been seen by the glycosaminoglycans produced by Achatina fulica. The heparin-like sulfated polysaccharide named acharan sulfate was able to inhibit the binding of SARS-CoV-2 spike protein to the ACE2 receptor, preventing the virus's ability to infect cells.18

The location where mucus from a snail exits can also impact its antibacterial properties. One study found that the mucus from the mantle of snails showed higher amounts of the antibacterial protein achacin than the mucus from the foot in both Lissachatina fulica and Hemiplecta distincta species.19 Achacin is a glycoprotein derived from snail mucus that provides bacteriostatic but not bactericidal activity against negative bacteria in the growth-phase stage through exhibiting L-amino oxidase activity and attacking the cytoplasmic membrane of the cell.20, 21 It is crucial to continue identifying the natural antimicrobial properties of snail mucin as antibiotic resistance emerges and drug-resistant bacterial species continue to develop.

Snail mucin also has been successfully incorporated in drug delivering vehicles, particularly via patches due to its bioadhesive properties and assistance with diffusion across membranes.22 The mucin from Archachatina maginata was integrated into a transdermal ibuprofen patch with efficacious drug diffusion in rats.23 Snail mucin was also integrated into a gelatin-based film that successfully delivered fluconazole and was effective against clinical isolates of C. albicans.24 Snail mucin was also able to prevent drug recrystallization over time, prolonging the half-life and efficacy of a medication. The combination of snail mucin and polyethylene glycol (PEG) in a 3:1 ratio has been successful in creating an extended release metformin hydrochloride formulation.25 This unique combination of PEG and snail mucin in a matrix allows for several advantages to the pharmokinetics of potentially hundreds of medications through increasing both drug release and gastrointestinal mucosal absorption and prolonging half-life. Mucins have been proposed to be a foundational building block for biomaterials, and deriving mucins from snails shows promising results.26

Another potential for drug delivery via snails is rooted in the mating process. Male snails shoot a dart of protein-containing mucus into a female snail that penetrates tissue and increases the female snail's fertility.27 This process has been studied extensively and noticed that an increase in sperm competition with multiple male snails of similar and different species results in an increase of mucus production and transport via a male's darts.28 This dart-delivering technology that naturally occurs in snails suggests another possible use of repurposing snail mucin mating to increase mucus production and potentially drug delivery.

The potential for snail mucin to additionally function as antitumor agents has the potential to notably alter treatment approaches for a variety of cancers. Current literature notes this hypothesis stems from the well-known antioxidant properties of snail mucin. In testing the Ereminia desertorum snails' mucus in human colonic adenocarcinoma cells and human hepatoma cell lines, gene expression levels of antioxidant markers were measured to be increased in mucin-treated cells. These genes included antioxidant enzymes of glutathione S-Transferase Alpha 1, catalase, superoxide dismutase, glutathione peroxidase among others. Well-known tumor suppressor genes of p53, Rb, APC, and PTEN were also increased in mucin-treated cell lines.29 Hemocyanins extracted from Rapana thomasiana and Helix pomatia snails inhibited tumor growth, splenomegaly, and lung metastasis while prolonging survival in a murine model of colon carcinoma.30 A prognostic role can also be found within snail mucin. The lecithin known as Helix pomatia agglutin also played a role in identifying oligosaccharides that were associated with poor-prognosis in breast cancers. Here, elevated levels of snail agglutin bound to oligosaccharides of interest had a shorter disease-free interval, indicating better predictions through snail mucin.31

In melanoma, cutaneous melanoma cells treated with snail mucus demonstrated an increase in extrinsic apoptotic cell death and synergistic cytotoxicity with Atezolizumab, an anti PD-1 L antibody.32 Another melanoma cell line treated with Helix aspersa maxima mucus had an increased apoptotic effect through PARP cleavage and a decreased expression of matrix metalloproteinase MMP2, inhibiting invasion.33 Two peptide fractions of snail mucin were isolated and identified to decrease the viability of triple negative breast cancer cells through enhancing the chemotherapeutic activation of the extrinsic apoptotic FAS pathway and suppressing nucleolin.34, 35 Achatina fulica mucus was investigated for potential inhibition of mammary cancers in rats induced with DMBA which demonstrated a significant inhibitory growth rate activity at its greatest dose of 25 mg/kg.36 A biogenically synthesized silver nanoparticle combined with terrestrial snail-mucus mediated anticancer activity with over 15% inhibition of HeLa cells' growth.37 This research has sparked the potential of incorporating snail mucin alongside traditional chemotherapeutic treatments.

Snail mucin has also been successfully incorporated as wound healing agents in full-thickness skin wounds. A biological adhesive derived from snail mucus gel consisting of positively charged protein and polyanionic glycosaminoglycan exhibited acceleration of wounds in normal and diabetic male rats. Additionally, there was a decrease of inflammation in chronic wounds and an improvement in epithelial regeneration and angiogenesis when this adhesive was used.38 Glycoproteins extracted from Achatina fulica mucus when used to treat experimentally burned mice had a significantly faster healing time than the control group as confirmed by histopathological and biochemical analysis.39 For deep partial thickness facial burns, Helix aspersa extract had lower times for eschar detachment and burn surface epithelization in comparison to moist exposure burn ointment.40 Similar to burns, gastric ulcers were also healed at a faster rate when clarithromycin was combined with mucin from the giant African snail.41 In mice with experimentally induced testicular damage and intestinal inflammation via carbon tetrachloride (CCl4), Eremina desertorum snail mucin provided notable antioxidant and anti-inflammatory effects as evidenced by histopathology.42 Airway epithelium has also seen benefit from snail mucin in which helcidine extracted from Helix pomatia was seen to relax the trachea via release of prostaglandin E2, suggesting a potential broncho-relaxant and antitussive agent.43 A new lubricating ophthalmic solution eye product, GlicoPro, includes snail mucus as one of its ingredients for management of dry eye disease. In vitro results elucidated an improvement of corneal wound healing and bio-adhesivity alongside a reduction of inflammatory and ocular damage biomarkers.44 These studies highlight the successful use of snail mucin to expedite wound healing on both cutaneous skin and mucous membranes.

Similar to its use as adhesives in wound healing, snail mucin can also be integrated into biomaterial coatings combining all of its properties. Precoating polyethylene terephthalate medical implants with a mucin-based film showed a reduced IgG and IgM immune response which lowers the likelihood of rejection.45 This allows for the potential of biologically similar snail mucin to comparably be integrated and tested as a biomaterial coating.24 Another successful use of snail mucus extract from Achatina fulica demonstrated a decrease in apoptotic activity of chondrocytes. This promotes a pro-survival effort in cartilage tissue repair using snail mucus glycosaminoglycans (GAGs) and 6-gingerol.46 Similarly, scaffolds generated from both Helix aspersa mucus and slime extract exhibited osteochondral tissue regeneration through mimicking structure.47

Hard tissue regeneration has also been proposed using a biomaterial scaffold composed of snail mucus and chitosan where average pore sizes of the scaffold decreased with more snail extract.48 Improvements via increased water barrier, film extensibility, and bioadhesion properties were noted in a mucus percentage-dependent fashion.49 Aloe vera and snail mucin both integrated into a gelatin/chitosan scaffold created an increase of swelling capacity and fluid retention, highlighting an innovative use in tissue engineering.50

3 USE OF SNAIL MUCIN IN SKIN
The overwhelming media popularity surrounding snail mucin lies in its role in skincare for benefits toward antiaging, acne, scarring, hyperpigmentation, and hydration among others.51

3.1 Antiaging
The antiaging benefits of snail mucin have been alluded to through multiple ways. Certain glycoproteins and peptides have been identified to stimulate fibroblast production of collagen and elastin, which the body naturally decreases production of as it ages.52 The aging process of skin has been extensively studied and is attributed in part to an increase in matrix metalloproteinase expression and decrease of glycosaminoglycans and proteoglycans comprising skin.53, 54 This allows for an increased youthful, firm appearance with increased skin elasticity. Additionally, snail mucin purified from Helix aspera muller mucus, a common species used in cosmetic products, was created to form a HelixComplex preparation. This HelixComplex, when introduced to fibroblast cultures, helped protect cells from apoptosis and both directly and indirectly signaled for fibroblast proliferation via cytokine release and the reorganization of the cytoskeleton.52 A similar induction of fibroblasts via maintenance of the actin cytoskeleton and metalloproteinase activity regulation was also seen via mucin from the other common snail species Cryptomphalus aspersa, referred to as SCA.55 Mucin from this species in a 25-patient study noted an improvement of coarse periocular and fine facial rhytides when used daily at both 8 and 12 weeks of use.56 An improvement in skin texture was also noted from the silicone skin impressions prior to and after use. Another study testing on human skin involved 10 subjects where a cream composed of 80% snail mucin was applied to the lateral epicanthal and left cheek twice daily for 4 weeks which found statistically significant changes of dermal density, skin elasticity, and wrinkles as measured by surveys.2 Cryptomphalus aspersa (SCA) secretion was combined with antioxidant ingredients (ectoine, coffeeberry oil, and olive oil) into different formulations of either a lipid-free serum or a cream found to decrease signs of skin aging in 125 females aged 40–65 years, the commonly targeted antiaging population. After 45 days of use, cutometry measured an improved firmness and elasticity at the dermal level.57 Patients that underwent photoaging treatment with a nonablative laser and were then treated with SCA 40% noted an accelerated repair, reduction of erythema, tightness and burning sensation, and increased elasticity by 11%.58

In vitro studies using the water-soluble albumen gland protein extract from snails have observed a decrease in age-related oxidative stress and percentage of erythrocyte hemolysis of human blood samples. Similarly, in rats treated with these snail derived proteins, greater antioxidant enzymes such as catalase and superoxide dismutase were seen when compared to untreated aged mice.59 In the oral form when snail mucin was digested by mice, a suppression of metalloproteinase-1/13 was noted which restored greater amounts of collagen in skin and reduced the depth of wrinkles induced by UVB photodamage.60 Additionally, the intake of snail mucin orally did not appear to have any negative systemic effects with no change in organ size or liver enzymes.54

3.2 Hydration
The presence of hyaluronic acid, a powerful humectant, in snail mucin highlights its ability to retain moisture in skin.24 Hyaluronic acid is a glycosaminoglycan with a unique helical coil that allows it to hold 1000-fold its weight in water, stabilizing the extracellular matrix and holding hydration.61 Mucin from H. aspera was studied in healthy Caucasian female subjects for its hydration properties via measurement of trans epidermal water loss (TEWL) using a TEWAMETER and corneometer probe and found decreased TEWL immediately after application, at 1 h, and at 24 h.62

3.3 Anti-acne
The anti-acne benefits associated with snail mucin are attributed partially to their antibacterial and anti-inflammatory effects already discussed. The creation of combination serum consisting of snail secretion filtrate, Calendula officinalis, and Glycyrrhiza glaba root extract was tested on patients with mild-to-moderate "maskne", the term for acne induced by wearing masks. After 12 weeks, there was a greater percent reduction in inflammatory acne lesions in the treatment group though no changes in erythema score, noninflammatory lesions, and sebum levels were noted.63 Exfoliative acids found in snail mucin, such as glycolic acid and lactic acid, can also help to unclog pores and reduce the sebum production involved in acne pathogenesis.64

3.4 Scarring and hyperpigmentation
Similar to wound healing, cosmetic applications of snail mucin target scars often left behind from prior acne blemishes or skin damage. Snail mucin from Cryptomphalus Aspersa was found to increase the proliferation and migration of human keratinocytes and fibroblasts in both a time- and dose-dependent fashion. An increase in the expression of adhesion proteins E-cadherin, β-catenin, vinculin, and β1-integrin was also observed, suggesting the likely pathophysiology of scar healing.65 Another ingredient commonly used to treat scars includes exfoliative alpha-hydroxyacids such as lactic acid, which works through loosening connections between desmosomes in the epidermis and allows other products to penetrate deeper. Lactic acid and glycolic acid, while not primary ingredients, are also found as a minor component of snail mucin, proposing a way to treat scars.64, 66 Glycolic acid works to target atrophic acne scars and post-inflammatory hyperpigmentation through its keratolytic properties and promotion of new skin cell development.67, 68

4 GLOBAL MARKET ESTIMATES AND PROJECTIONS FOR THE FUTURE
The demand for snail mucin products and increased need for research into its potential uses provides an economic market that is projected to expand in upcoming years. One snail beauty product market analysis valued the global market to be $457.50 million in the year 2021with projections of reaching $982.70 million by the year 2031.69 The estimated compound annual growth rate is 8.3% was estimated with all product types, applications, and distribution channels. The regions of distribution are separated into North America, Europe, Asia-Pacific, and LAMEA (Latin America, Middle East, and Africa). The Asia-Pacific is by far the largest regional product for the snail beauty products market, with South Korea playing a major stake. The key market players include several companies overarching popular skincare lines such as Kao Corporation, InnoVactiv Inc., Tonymoly Co. Ltd, Clariant AG, Kenra Professional LLC, Murad LLC, Croda International plc, SkinCeuticals, COSRX Official, and Mizon Ltd. Product types included in this report include multifunction cream, cell renewal cream, antiaging cream, antiaging cream, anti-acne cream, and others. The antiaging cream segment is the product projected to dominate the market by 2031. Among all the distribution outlets for snail mucin products, the E-commerce segment was the most significant contributor and is estimated to reach $265.1 million by 2031 as online shopping helps connect global regions easily.68

Another report analyzing the snail beauty products market valued the global industry at $1.2 billion in 2021 with a compound annual growth rate of 5.8% from 2022 to 2031, ultimately reaching a $2.1 billion in 2031.70 This prediction is partially rooted based off the investments of snail farming in Europe causing market expansion. William Reed Ltd. reports that the company Guerdon sells 25 million baby snails per year to farmers in France.71 This report also notes that emerging evidence into new applications of snail mucin ranging from treating razor bumps and stretch marks to flat warts and scars is increasing the breadth that snail mucin products can be targeted toward.72 A separate report estimates the global value of snail beauty products of $559.9 million in 2022, with a 10.47% compound annual growth rate reaching a projected $1232.7 million in 2030.73 While these projects vary slightly by report, it remains consistent that the market of snail mucin products will only continue to increase in value. This highlights the promising value of the market and the need for continued research into the variety of potential uses behind snail mucin.

5 LIMITATIONS AND CONSIDERATIONS BEHIND SNAIL MUCIN
The vast methodology behind extracting mucus from snails presents a variety of unknowns and ethical considerations. The most natural method of mucus collection includes natural secretion where snails are placed in a particular cage or glass slide and the snails secrete mucus at a normal rate of production.74 The mucus is then subsequently collected and purified, which results in a long collection time with lower yield but does not induce any stress on the snail. Another method commonly used includes low voltage electrical stimulation where the snails are placed alongside distilled water in a separate device, then stimulated via electricity, and then returned to their breeding site.66, 75 The voltage is often done at short intervals and never exceeds 1000 volts, but this still induces stress on snails which requires them to be fed and hydrated prior to subsequent extraction.9, 14, 17 Using objects such as glass rods, cotton swabs, syringes, droppers, sticks, or needles have also been used to induce blunt force upon a snail which doubles its yield of mucus.5 Snails can also be stimulated via a water jet spray onto the snails body which produces large quantities of mucus.76 Another similar method utilizes a salt solution with NaCl osmotically drawing out a snail's hydration and prompting the generation of mucus.37, 77 Lastly, through cracking the shell of a snail, the soft body of the snail is induced to create more mucus.34, 78 Less common methods include vibrational stimulation, ozone-assisted stimulation, and ultrasonic stimulation. These methods are less favored as snails often die easily.5 The increased demand for snail mucin creates increased pressure on collection methods, explaining why the need for ethical habitats for their collection is crucial. Certain countries, such as South Korea, have strict laws in place against animal testing. This could potentially serve as a nidus for other countries to replicate if they wish to produce products with snail mucin. Since the quality of the mucin collected can be impacted by what snails eat, the environment they are kept in, and how the slime is extracted, the most natural habitat appears to be the strongest, most ethical form of collection.79 No external stress should be applied to the snails or topically to the mesh that snails roam around in.

While snail mucin has showed several promising benefits in vitro and in both animal and preliminary human studies, the application of these in modern medicine will require clinical studies to validate these effects. The different collection methods can also result in a different composition of collected mucus, and future studies should compare how the snail mucus collected under stress versus the natural composition changes its beneficial effects. Furthermore, the positive results seen from animal models in the oral consumption of snail mucin in reducing moisture loss and wrinkle depth must be thoroughly studied in other animals and humans prior to its integration as a supplement. Proper research for the potential negative consequences of snail mucin consumption will prevent any long-term consequences or creation of new problems. Other clinical research must be conducted that looks into the legitimacy of snail mucin products being an effective treatment for razor bumps, flat warts, and rosacea among others as these claims do not presently have any literature to support them. Additionally, larger scale double-blind studies involving thousands of patients should be conducted in order to support the claims initially established by preliminary laboratory and animal studies.

Other potential limitations to the widespread promotion of snail mucin products includes the proper marketing and counseling on how to prevent adverse reactions and irritation. Additionally, allergies or skin sensitivity can potentially be seen with snail mucin products. The pathophysiology behind allergies to snail mucin is hypothesized to have a protein that shares a structural similarity to the protein causing dust mite allergies.80 While the exact protein has not been isolated, there is evidence that house dust mites and shrimp tropomyosin have a high sequence homology with demonstrated cross-reactivity.81 Additionally, patients with allergies to shellfish such as crustaceans or shrimp have a greater likelihood to develop an irritation to snail mucin products.82 Similarly, patients with co-existing asthma, allergic rhinitis, or eczema commonly correlate with having increased skin sensitivity to new products and should be educated on patch testing prior to widespread use.83, 84 Another potential route to irritation is how the foreign proteins of snail mucins can induce an allergic contact dermatitis.85 While these limitations should not prevent the beneficial use of snail mucin in appropriate populations, it will require additional effort from skincare lines and dermatologists to advise proper usage and prevent adverse reactions.

6 CONCLUSION
Snail mucin is a promising product whose benefits are exponentially being examined and integrated into cosmetic and medical products. The unique composition of ingredients and bioadhesive structure is unmatched by other naturally occurring substances. Economic projections accentuate the opportunity for cosmetic manufacturers and scientists alike to consider snail mucin into product inclusion. The need for ethical extraction, proper counseling and management by healthcare providers, and clinical studies to validate effects are the next steps the snail mucin field must tackle prior to widespread use.

CONFLICT OF INTEREST STATEMENT
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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