Review Article | Volume: 12, Issue: 7, July, 2022

A review of the cosmetic use and potentially therapeutic importance of hyaluronic acid

Lidia K. Al-Halaseh Nariman A. Al-Jawabri Shahed K. Tarawneh Wasan K. Al-Qdah Maha N. Abu-Hajleh Ali M. Al-Samydai Mai A. Ahmed   

Open Access   

Published:  Jul 05, 2022

DOI: 10.7324/JAPS.2022.120703
Abstract

Hyaluronic acid (HA) is an endogenous substance detected and isolated from various tissues and biological fluids. Owing to its physicochemical properties, HA contributes to many biological processes at intra- and extracellular levels, such as skin hydration, joints lubrication, and wound healing, besides its anti-inflammatory and antioxidant effects. The current review highlights the employment of exogenous HA in many aesthetic and dermatological aspects. Also, it aims to clarify the skin rejuvenating activity by compensating for the biological loss of HA with advanced age. Other positive impacts of HA on hair, nail, and overall health status were also revised. Cosmetics and cosmeceuticals that contain HA, among other active ingredients, are commercially available in different dosage forms such as gels, creams, intradermal injections, and fillers. Aesthetic enhancement is achieved via soft tissue augmentation, skin hydration level increasing, grooves refilling, and collagen and elastin biosynthesis stimulation. HA contributes to various therapeutic approaches such as gingivitis, stomatitis, ulceration, and osteoarthritis. Additionally, it has beneficial uses in dentistry due to its antioxidant and anti-inflammatory properties. The recent implication of HA following the claims that it has a rejuvenating power for the skin and many therapeutic benefits has to be thoroughly investigated and delivered by a trained expert to avoid undesirable effects.


Keyword:     Hyaluronic acid dermatology cosmeceuticals hyaluronan skincare filler


Citation:

Al-Halaseh LK, Al-Jawabri NA, Tarawneh SK, Al-Qdah WK, Abu-Hajleh MN, Al-Samydai AM, Ahmed MA. A review of the cosmetic use and potentially therapeutic importance of hyaluronic acid. J Appl Pharm Sci, 2022; 12(07):034–041.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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INTRODUCTION

Hyaluronic acid (HA) or hyaluronan is chemically derived from the mucopolysaccharides glycosaminoglycans (Vasvani et al., 2020). HA is a natural component detected in the intra- and the extracellular matrixes in the skin, articular cartilage, synovial fluid, vitreous humor, and mammalian bone marrow (Hascall et al., 2004). The physicochemical properties of HA are responsible for its vital biological and physiological functions. The properties of biological importance include high viscoelasticity, biocompatibility, hygroscopicity, and moisture retention abilities (Gupta et al., 2019; Hascall et al., 2004). Skin hydration ability, lubrication, and diminishing aging symptoms are among the physiological functions of our interest.

Since the late 50s, when the first therapeutic application of HA in eye surgery was introduced, HA and its derivatives have been incorporated wi dely into many health aspects, including the medical, pharmaceutical, dietary, aesthetic, and cosmetic fields (Necas et al., 2008). Moreover, the drug delivery system has used HA to optimize and enhance drug particles activities (Arshad et al., 2021).

Regarding skincare products, HA has a clinically approved efficacy in fighting aging symptoms and counteracting the negative impact of skin chronic exposure to exposomes, external environmental challenges, such as sunrays, tobacco smoking, and pollution (Gueniche et al., 2022).

Nowadays, HA and derivatives are the most popular cosmetic agents with promising aesthetic results. Delivering HA in variable routes of administrations such as topical, internal, and injectable showed confirmed antiwrinkles properties, skin hydration, aging marks reversal, and grooves filling. Additionally, there are clinical pieces of evidence on its ability to reduce hallow marks, boost nail strength, and rejuvenate hair fibers, among many other therapeutic aspects (Fagien et al., 2012; Monheit and Coleman, 2006; Peng et al., 2022 ; Schwartz and Park, 2012).


MECHANISM OF ACTION

Clinical studies demonstrate several physiological effects of exogenous HA. Studies on osteoarthritic cartilage using in vitro articular chondrocytes in a hydrogel culture system revealed its significant stimulatory effect on the metabolic activity of chondrocytes which explains its longer term protective effect on articular cartilage (Liu et al., 2022). This effect is associated with inhibition of immune complex adherence to polymorphonuclear cells, scavenging of free radicals, and inhibition of leucocyte and macrophage migration and regulation of fibroblast proliferation (Akmal et al., 2005). Moreover, it was found that combinational treatment of HA and platelet-rich plasma (PRP) in intra-articular injection exerts a synergistic effect in both regenerative and anti-inflammatory potentials on osteoarthritis compared to either HA or PRP alone (Whitmire et al., 2012).

Topically, HA is well known for its hydrophilic nature. The high water-binding capacity is attributed to the high density of negative charges from the carboxyl groups in its structure, which causes the osmotic pressure and draws the water molecules into the tissues (Valachová et al., 2022). The exact moisturizing mechanism varies with HA molecular weight. For this reason, the choice of HA fragment for cosmetic formulation should be carefully considered in context with the intended reason of use and application. Generally, the larger the molecular weight, the more predominant the physicochemical properties, while biological properties will be overcome in the case of smaller-molecular-weight fragments (Smejkalova et al., 2015; Snetkov et al., 2020). The biological activity of HA was conducted through its interaction with several receptors, such as CD44 and the receptor for hyaluronic acid-mediated motility (RHAMM), as shown in Figure 1 (Jensen et al., 2020).


DERIVATIZATION OF HYALURONAN FOR COSMETOLOGY

As mentioned earlier, HA is highly susceptible to degradation by the hyaluronidases, which means a high rate of in vivo turnover. Thus, chemical modifications are required for cosmetic or pharmaceutical applications. These modifications are either chemical attachment of groups to decrease HA hydrophilicity, so it can be easily blended with the hydrophobic ingredients typically found in cosmetics, or cross-linking to form insoluble HA derivatives or hydrogels (Smejkalova et al., 2015).

Figure 1. The interaction between HA and CD44 receptor and RHAMM receptor. Each acts differently to elicit cell behavior (Jensen et al., 2020 ).

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THE USE OF HYALURONAN IN COSMETOLOGY

In skincare products

Skin moisturizing is one of the primary goals of commercially available skincare products. HA possesses an exceptional capacity to bind and retain water molecules and, hence, contribute to skin moisturization, elasticity improvement, skin hydration, collagen and elastin stimulation, and face volume restoration showing promising results in skin tightness and wrinkles reduction (Juncan et al., 2021; Papakonstantinou et al., 2014).

Sunscreen products

Sunscreen products containing HA can maintain firmer skin besides their UV-radiation protection activity. The sun protection activity refers to its antioxidant properties. Additionally, adding HA to sunscreens provides extra protection against type B ultraviolet (UVB) radiation by prohibiting mutation in the HA synthase, decreasing the release of proinflammatory mediators. Accordingly, the anti-inflammatory effect is an added value (Hašová et al., 2011).

Dermal fillers

Injectable dermal fillers containing cross-linked HA have become a desirable aesthetic procedure. Patients are looking to rejuvenate the skin and compensate for the age-related loss and, overall, diminish age-related symptoms. This procedure is not invasive and needs to be performed by an expert specialist (Aziz et al., 2019).

After Food and Drug Administration approval, the cosmetic industry field commenced HA use in various cosmetic products, including dermal fillers. The high safety profile and promising aesthetic enhancement properties make it the component of choice in cosmeceuticals. Adding HA to dermal fillers aims to increase the augmentation of the soft tissue and to hydrate skin compartments. Hydrating skin takes part by attracting water molecules to compensate for the loss of natural components at the cellular level. Therapy supports the collagen and elastin fibers that diminish and lose their function partially by advanced age. Due to the noninvasive method of treatment and the quick observed results, injecting HA into the dermis would minimize the hallmarks of aging and boost the skin volume and elasticity (Kontis and Rivkin, 2009; Rohrich et al., 2019; Zerbinati et al., 2018).

Haircare products

Recently, manufacturers of cosmetic haircare products have tended to incorporate HA into their formulas for its claimed efficacy in the revitalization of hair follicles. Researchers interested in hair cosmetology confirmed the efficacy of the compound of our interest combined with a range of amino acids in promoting the anabolic process of the dermal papilla cells. These biological processes include the synthesis of needed proteins and the production of intracellular matrix components (Matarasso et al., 2006). Moreover, HA contributes to counteracting the oxidative stress of the hair follicles triggered by various internal and external factors. The main external trigger is exposure to type A ultraviolet (UVA) and UVB radiation. Formulas enriched with HA participate in reducing the inflammatory responses by decreasing the inflammatory marker IL-8 and the keratinocytes’ vascular growth factors. This biological activity was confirmed after in vitro testing using a human follicle dermal papilla cell line (Zerbinati et al., 2021a).

Nail care products

Nails are considered one of the cosmetologist and manufacturer target tissues. Nail cosmetic products and cosmeceuticals are designed either to beautify the nails or for therapeutic purposes. Fragile periungual tissues could result from environmental factors or excessive cuticle removal. Nail care products have incorporated HA derivatives to add strength to brittle nails. According to the results obtained by Leah and Schmidt, an aqueous solution containing a mixture of mastic tree extract, Pistacia lentiscus, and HA has shown an improvement in nail plate strength after 6 months of regular topical application. Softening rough nail plates and minimizing distal breakage would positively influence wholescale nail resistance and appearance. Because HA has a good surface adherence property, it would enhance the deep moisturizing of nail compartments (Zerbinati et al., 2021b). The adhesion property refers to the ionic interaction between the positively charged acid and the nail surface. This characteristic allows a desirable spreading of the formula, extends the contact time, and delivers the active ingredient more efficiently (Piraccini et al., 2020).

Nutraceuticals and other food supplements containing HA have clinically significant positive effects on the health of nails, hair, and skin after regular intake for 8 weeks. Other adjuvant components include peptides, fatty acids, and collagen (Uyttendaele et al., 2003).


THE THERAPEUTIC ACTIVITY OF HA IN DERMATOLOGICAL CONDITIONS

Dry skin

Several internal and external factors contribute to dry skin conditions. These include UV radiation, nutrition, heredity, and aging. Due to aging, the amount of natural moisturizing factors stored in the phospholipids’ envelopes of the stratum corneum decreases. This reduction disturbs the skin barrier mechanism and limits its resistance to external stimuli (Engelke et al., 1997; Rogers et al., 1996; Sunwoo et al., 2006; Yagoda and Gan, 2014).

Applying topical moisturizers is recommended to avoid dry skin complications such as bruising and open cuts. Unfortunately, topical application is not convenient for all patients, especially those of advanced age and who live alone. On the other side, a dietary supplement containing HA, at a minimum daily dose of 120 g, would help moisturize the skin and reduce the complications of chronic rough skin cases (Di Cerbo et al., 2015; Sato et al., 2002).

Dry skin is also associated with atopic dermatitis and xerosis; these dermatological conditions also benefit from HA consumption. Treatment reduces pruritus accompanied by a dry skin condition (Kawada et al., 2014).

Oily skin

Overactivity of the skin sebaceous gland leads to a condition known as oily skin. The experimental and clinical studies outputs found that HA has an essential role in reducing lipid synthesis, therefore decreasing secretion from the sebaceous gland (Jung et al., 2017). Intradermal injection of the acid reduces the size of the sebaceous gland and limits lipid production. At the molecular level, downregulation of the HA binding receptors (CD44) occurs which affect the lipid and sebum biosynthesis as well. In general, formulas with HA would effectively address oily skin (Kawada et al., 2014).

Alcoholic-skin damage

Skincare formulas contain alcohol for its disinfectant properties or as a vehicle to dissolve other ingredients. Unfortunately, alcohol, in particular, ethanol, harms skin health and induces skin cytotoxicity and inflammatory responses (Lachenmeier, 2008; Neuman et al., 2011; Pershing et al., 1990; Rotter et al., 1998). Cutaneous erythema, for example, is among the most common allergic reactions after topical ethanol application (Haddock and Wilkin, 1982).

Neuman et al. (2010) confirmed that HA at a concentration range of 2%–4% could repair skin damage induced by ethanol (Neuman et al., 2010).

Antiaging effect

HA is a natural skin component, its biosynthesis and production diminishing with advanced age. A lower concentration is associated with wrinkle formation and dryer, thinner skin (Lee et al., 2016). Because hyaluronan can preserve water content in skin cells, the decrease in its concentration would ultimately dehydrate the skin (Prasathkumar and Sadhasivam, 2021). In normal healthy skin, HA is continuously renewed after its degradation. Unfortunately, the rate of renewal tends to decrease with age. The decrease would be greater if combined with other external factors such as exposure to UV radiation. The optical concentration of HA at the cellular level is essential to retard aging symptoms (Bucay, 2021; Fraser et al., 1997; Olejnik et al., 2012). Not only does HA has an ability to retain moisture, but it also influences the keratinocytes’ growth rate; besides, HA confers antioxidant properties due to the attached units of d-glucuronic acid (Fallacara et al., 2018;Haeusler., 2015; Manuskiatti and Maibach, 1996; Pavicic et al., 2011; Witting et al., 2015).


THERAPEUTIC USES OF HA

Oral ulcers and aphthous stomatitis

Our acid of interest and its salt, sodium hyaluronate, are effective after topical administration to address oral mucosa ulceration. The active component works by applying a protective coat around the cavity, promoting hydration, and eventually accelerating the healing process (Nolan et al., 2006). The gel dosage form containing 0.2% of HA showed a good response and alleviates oral ulcers after topical administration in clinical studies (Lee et al., 2008). Mucosal protection effects result from the physical barrier formed over the ulceration after gel application (Abo-shady et al., 2020; Casale et al., 2017). Repeated administration is recommended to keep the infected area covered and to obtain better healing activity (Casale et al., 2017; Koray et al., 2016).

Dentistry

Hyaluronan has been incorporated into dentistry as a potential remedy for minor oral diseases. It can accelerate periodontal tissue healing, attenuate gingivitis symptoms, and promote wound healing (Al-Khateeb and Olszewska-Czyz, 2020). An HA derivative could have a synergistic effect with other topical medicines in minor oral operations such as implants, sinus lifts, and surgical extraction. Other potential benefits include delivering a high concentration of the chemical drugs topically and promoting tissue regeneration (Casale et al., 2016).

Osteoarthritis

External HA provides viscoelasticity to the joints because it compensates for the loss in the endogenous HA in the synovial fluid. Due to its anti-inflammatory activities, HA contributes to the relief of arthritic conditions. The anti-inflammatory mechanisms involve cytokines suppression and multiple effects on other inflammatory mediators (Yang et al., 2012). The anti-inflammatory activity of the HA derivatives largely depends on their molecular weight, oligosaccharide chain length, and affinity toward the CDD4 receptors (Campo et al., 2010; Higman et al., 2014; Termeer et al., 2002; Wolny et al., 2010). HA for treating arthritis is delivered via an intra-articular route either as a single component or combined with other drugs such as steroids or nonsteroidal anti-inflammatory drugs (Euppayo et al., 2017; Gomes et al., 2022).

Intra-articular injection of corticosteroids has short-term effects (about 4 weeks) while injecting HA via the same route has an elongated effect for up to 26 weeks (Bannuru et al., 2009).

Rosacea

Rosacea is a common dermatological condition characterized by erythema, flushing, and papules. The disease pathogenesis is mainly affected by genetic factors which are exacerbated by reverse environmental conditions. Recently, dermatologists confirmed the positive effect of treating rosacea with HA. By reinforcing the skin’s natural antioxidant capability, HA was found to minimize the severity of rosacea symptoms. For example, improvement in erythema and increased skin tightness was observed in addition to a total decrease in the basal sensitivity scores (Berardesca et al., 2020; Schlesinger and Powell, 2013). The implications of HA and its derivatives in medicines and cosmetics are summarized in Figure 2.


SAFETY PROFILE AND LIMITATION OF USE

Generally, HA is considered safe to use as it is a natural component of the skin. After oral ingestion of the acid and derivatives, no clinical observation was noticed according to published data. Also, no food interaction or clinical or pathological effects were found (Kawada et al., 2014; Lee et al., 2017).

This is not always the case with filler injection containing HA or derivatives. Unfortunately, Lee et al. (2018) reported a case of blepharoptosis, skin necrosis, and a decrease in visual acuity after injection with hyaluronidase in the filler component. These serious adverse effects were due to accidental injection of the acid into the blood vessels. Physicians refer the complications to the high vascularity around the nose area combined with a large filler injection volume (Lee et al., 2017). Caution has to be taken when injecting fillers containing HA and derivatives, and it should be done by a trained specialist. Examples of reported cases of undesirable side effects following HA administration either for aesthetic purposes or for therapeutic efficacy are summarized in Table 1.

Figure 2. The implications of HA and its derivatives in medicines and cosmetics.

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Table 1. Reported cases of undesirable effects after HA administration.

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CONCLUSION

Innovative formulas for aesthetic appearance and diminishing aging symptoms have become the main interest of manufacturers, the cosmetic sector, and even pharmaceutical companies. Recently, HA and its derivatives have become trendy compounds in cosmeceuticals for their claimed effects of beautifying, hydrating, regenerating, and compensating the natural loss by advanced age. The efficacy of HA, and its derivatives, is confirmed due to its antioxidant and anti-inflammatory activities. Moreover, these compounds have desirable physicochemical properties. Accordingly, in-depth investigation to introduce HA in the treatment protocols of age-related deformations is much encouraged.

Enhancing the bioavailability and efficacy after noninvasive routes of administration is recommended to attain customers’ compliance and to avoid undesirable consequences of the injectable routes.


ACKNOWLEDGMENT

The authors would like to acknowledge the staff members of Mutah University, the Faculty of Pharmacy, and the supporting librarian for providing the needed resources.


AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.


FUNDING

There is no funding to report.


CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.


ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.


DATA AVAILABILITY

All data generated and analyzed are included within this research article.


PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.


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Piraccini BM, Granger C, Alessandrini A, Brandi N, Bruni F, Mandel VD, Pellacani G, Starace M. Clinical and instrumental objective evidence of the efficacy of a new water-based nail-strengthening solution containing Pistacia lentiscus and hyaluronic acid applied for up to 6 months to improve the appearance of weak, Brittle Nails. Dermatol Ther (Heidelb), 2020; 10(1):119–31. CrossRef

Prasathkumar M, Sadhasivam S. Chitosan/hyaluronic acid/alginate and an assorted polymers loaded with honey, plant, and marine compounds for progressive wound healing—Know-how. Int J Biol Macromol, 2021; 186:656–85. CrossRef

Rogers J, Harding C, Mayo A, Banks J, Rawlings A. Stratum corneum lipids: the effect of ageing and the seasons. Arch Dermatol Res, 1996; 288(12):765–70. CrossRef

Rohrich RJ, Bartlett EL, Dayan E. Practical approach and safety of hyaluronic acid fillers. Plast Reconstr Surg Glob Open, 2019; 7(6):e2172. CrossRef

Rotter ML, Simpson RA, Koller W. Surgical hand disinfection with alcohols at various concentrations: parallel experiments using the new proposed European standards method. Infect Control Hosp Epidemiol, 1998; 19(10):778–81. CrossRef

Sato T, Sakamoto W, Odanaka W, Yoshida K, Urushibara O. Clinical effects of dietary hyaluronic acid on dry, rough skin. Aesthet Dermatol, 2002; 12:109–20.

Schwartz SR, Park J. Ingestion of BioCell Collagen®, a novel hydrolyzed chicken sternal cartilage extract; enhanced blood microcirculation and reduced facial aging signs. Clin Interv Aging, 2012; 7:267–73. CrossRef

Schlesinger TE, Powell CR. Efficacy and tolerability of low molecular weight hyaluronic acid sodium salt 0.2% cream in rosacea. J Drugs Dermatol, 2013; 12(6):664–7.

Smejkalova D, Huerta Angeles G, Ehlova T, Dobrouc D. Hyaluronan (hyaluronic acid): a natural moisturizer for skin care. 9th edition, pp 605–22, vol. 2, 2015.

Snetkov P, Zakharova K, Morozkina S, Olekhnovich R, Uspenskaya M. Hyaluronic acid: the influence of molecular weight on structural, physical, physico-chemical, and degradable properties of biopolymer. Polymers, 2020; 12(8):1800. CrossRef

Sunwoo Y, Chou C, Takeshita J, Murakami M, Tochihara Y. Physiological and subjective responses to low relative humidity. J Physiol Anthropol, 2006; 25(1):7–14. CrossRef

Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, Miyake K, Freudenberg M, Galanos C, Simon JC. Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med, 2002; 195(1):99–111. CrossRef

Trignano E, Baccari M, Pili N, Serra PL, Rubino C. Complications after breast augmentation with hyaluronic acid: a case report. Gland Surg, 2020; 9(6): 2193–7. CrossRef

Uyttendaele H, Geyer A, Scher R. Brittle nails: pathogenesis and treatment. J Drugs Dermatol, 2003; 2(1):48–9.

Valachová K, El Meligy MA, Šoltés L. Hyaluronic acid and chitosan-based electrospun wound dressings: problems and solutions. Int J Biol Macromol, 2022; 206:74–91. CrossRef

Vasvani S, Kulkarni P, Rawtani D. Hyaluronic acid: a review on its biology, aspects of drug delivery, route of administrations and a special emphasis on its approved marketed products and recent clinical studies. Int J Biol Macromol, 2020; 151:1012–29. CrossRef

Whitmire RE, Wilson DS, Singh A, Levenston ME, Murthy N, García AJ. Self-assembling nanoparticles for intra-articular delivery of anti-inflammatory proteins. Biomaterials, 2012; 33(30):7665–75. CrossRef

Witting M, Boreham A, Brodwolf R, Vavrova K, Alexiev U, Friess W, Hedtrich S. Interactions of hyaluronic acid with the skin and implications for the dermal delivery of biomacromolecules. Mol Pharm, 2015; 12(5):1391–401. CrossRef

Wolny PM, Banerji S, Gounou C, Brisson AR, Day AJ, Jackson DG, Richter RP. Analysis of CD44-hyaluronan interactions in an artificial membrane system: insights into the distinct binding properties of high and low molecular weight hyaluronan. J Biol Chem, 2010; 285(39):30170–80. CrossRef

Yagoda M, Gans E. A nutritional supplement formulated with peptides, lipids, collagen and hyaluronic acid optimizes key aspects of physical appearance in nails, hair and skin. J Nutr Food Sci, 2014; 5:2. CrossRef

Yang C, Cao M, Liu H, He Y, Xu J, Du Y, Liu Y, Wang W, Cui L, Hu J, Gao F. The high and low molecular weight forms of hyaluronan have distinct effects on CD44 clustering. J Biol Chem, 2012; 287(51):43094–107. CrossRef

Zerbinati N, Lotti T, Damiano Monticelli VM, Cipolla G, D’Este E, Calligaro A, Mocchi R, Maccario C, Sommatis S, Lotti J, Wollina U. In vitro evaluation of the sensitivity of a hyaluronic acid PEG cross-linked to bovine testes hyaluronidase. Open Access Maced J Med Sci, 2018; 6(1):20–4. CrossRef

Zerbinati N, Sommatis S, Maccario C, Capillo MC, Di Francesco S, Rauso R, Protasoni M, D’Este E, Gasperina DD, Mocchi R. In vitro hair growth promoting effect of a noncrosslinked hyaluronic acid in human dermal papilla cells. Biomed Res Int, 2021a; 2021: 5598110. CrossRef

Zerbinati N, Sommatis S, Maccario C, Capillo MC, Di Francesco S, Rauso R, Protasoni M, D’Este E, Dalla Gasperina D, Mocchi R. In vitro evaluation of the effect of a not cross-linked hyaluronic acid hydrogel on human keratinocytes for mesotherapy. Gels, 2021b; 7(1):15. CrossRef

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Peng YP, Lin YW, Yang YY. System strategy to achieve full-face aesthetic with hyaluronic acid fillers: yes-lifting and pyramid-volumized approaches. Adv Oral Maxillofac Surg, 2022; 5:100209. https://doi.org/10.1016/j.adoms.2021.100209

Pershing LK, Lambert LD, Knutson K. Mechanism of ethanolenhanced estradiol permeation across human skin in vivo. Pharm Res, 1990; 7(2):170-5. https://doi.org/10.1023/A:1015832903398

Piraccini BM, Granger C, Alessandrini A, Brandi N, Bruni F, Mandel VD, Pellacani G, Starace M. Clinical and instrumental objective evidence of the efficacy of a new water-based nail-strengthening solution containing Pistacia lentiscus and hyaluronic acid applied for up to 6 months to improve the appearance of weak, Brittle Nails. Dermatol Ther (Heidelb), 2020; 10(1):119-31. https://doi.org/10.1007/s13555-019-00343-0

Prasathkumar M, Sadhasivam S. Chitosan/hyaluronic acid/ alginate and an assorted polymers loaded with honey, plant, and marine compounds for progressive wound healing-Know-how. Int J Biol Macromol, 2021; 186:656-85. https://doi.org/10.1016/j.ijbiomac.2021.07.067

Rogers J, Harding C, Mayo A, Banks J, Rawlings A. Stratum corneum lipids: the effect of ageing and the seasons. Arch Dermatol Res, 1996; 288(12):765-70. https://doi.org/10.1007/BF02505294

Rohrich RJ, Bartlett EL, Dayan E. Practical approach and safety of hyaluronic acid fillers. Plast Reconstr Surg Glob Open, 2019; 7(6):e2172. https://doi.org/10.1097/GOX.0000000000002172

Rotter ML, Simpson RA, Koller W. Surgical hand disinfection with alcohols at various concentrations: parallel experiments using the new proposed European standards method. Infect Control Hosp Epidemiol, 1998; 19(10):778-81. https://doi.org/10.2307/30141424

Sato T, Sakamoto W, Odanaka W, Yoshida K, Urushibara O. Clinical effects of dietary hyaluronic acid on dry, rough skin. Aesthet Dermatol, 2002; 12:109-20.

Schwartz SR, Park J. Ingestion of BioCell Collagen®, a novel hydrolyzed chicken sternal cartilage extract; enhanced blood microcirculation and reduced facial aging signs. Clin Interv Aging, 2012; 7:267-73. https://doi.org/10.2147/CIA.S32836

Schlesinger TE, Powell CR. Efficacy and tolerability of low molecular weight hyaluronic acid sodium salt 0.2% cream in rosacea. J Drugs Dermatol, 2013; 12(6):664-7.

Smejkalova D, Huerta Angeles G, Ehlova T, Dobrouc D. Hyaluronan (hyaluronic acid): a natural moisturizer for skin care. 9th edition, pp 605-22, vol. 2, 2015.

Snetkov P, Zakharova K, Morozkina S, Olekhnovich R, Uspenskaya M. Hyaluronic acid: the influence of molecular weight on structural, physical, physico-chemical, and degradable properties of biopolymer. Polymers, 2020; 12(8):1800. https://doi.org/10.3390/polym12081800

Sunwoo Y, Chou C, Takeshita J, Murakami M, Tochihara Y. Physiological and subjective responses to low relative humidity. J Physiol Anthropol, 2006; 25(1):7-14. https://doi.org/10.2114/jpa2.25.7

Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, Miyake K, Freudenberg M, Galanos C, Simon JC. Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med, 2002; 195(1):99-111. https://doi.org/10.1084/jem.20001858

Trignano E, Baccari M, Pili N, Serra PL, Rubino C. Complications after breast augmentation with hyaluronic acid: a case report. Gland Surg, 2020; 9(6): 2193-7. https://doi.org/10.21037/gs-20-448

Uyttendaele H, Geyer A, Scher R. Brittle nails: pathogenesis and treatment. J Drugs Dermatol, 2003; 2(1):48-9.

Valachová K, El Meligy MA, Šoltés L. Hyaluronic acid and chitosan-based electrospun wound dressings: problems and solutions. Int J Biol Macromol, 2022; 206:74-91. https://doi.org/10.1016/j.ijbiomac.2022.02.117

Vasvani S, Kulkarni P, Rawtani D. Hyaluronic acid: a review on its biology, aspects of drug delivery, route of administrations and a special emphasis on its approved marketed products and recent clinical studies. Int J Biol Macromol, 2020; 151:1012-29. https://doi.org/10.1016/j.ijbiomac.2019.11.066

Whitmire RE, Wilson DS, Singh A, Levenston ME, Murthy N, García AJ. Self-assembling nanoparticles for intra-articular delivery of antiinflammatory proteins. Biomaterials, 2012; 33(30):7665-75. https://doi.org/10.1016/j.biomaterials.2012.06.101

Witting M, Boreham A, Brodwolf R, Vavrova K, Alexiev U, Friess W, Hedtrich S. Interactions of hyaluronic acid with the skin and implications for the dermal delivery of biomacromolecules. Mol Pharm, 2015; 12(5):1391-401. https://doi.org/10.1021/mp500676e

Wolny PM, Banerji S, Gounou C, Brisson AR, Day AJ, Jackson DG, Richter RP. Analysis of CD44-hyaluronan interactions in an artificial membrane system: insights into the distinct binding properties of high and low molecular weight hyaluronan. J Biol Chem, 2010; 285(39):30170-80. https://doi.org/10.1074/jbc.M110.137562

Yagoda M, Gans E. A nutritional supplement formulated with peptides, lipids, collagen and hyaluronic acid optimizes key aspects of physical appearance in nails, hair and skin. J Nutr Food Sci, 2014; 5:2. https://doi.org/10.4172/2155-9600.S5-002

Yang C, Cao M, Liu H, He Y, Xu J, Du Y, Liu Y, Wang W, Cui L, Hu J, Gao F. The high and low molecular weight forms of hyaluronan have distinct effects on CD44 clustering. J Biol Chem, 2012; 287(51):43094-107. https://doi.org/10.1074/jbc.M112.349209

Zerbinati N, Lotti T, Damiano Monticelli VM, Cipolla G, D'Este E, Calligaro A, Mocchi R, Maccario C, Sommatis S, Lotti J, Wollina U. In vitro evaluation of the sensitivity of a hyaluronic acid PEG cross-linked to bovine testes hyaluronidase. Open Access Maced J Med Sci, 2018; 6(1):20-4. https://doi.org/10.3889/oamjms.2018.046

Zerbinati N, Sommatis S, Maccario C, Capillo MC, Di Francesco S, Rauso R, Protasoni M, D'Este E, Gasperina DD, Mocchi R. In vitro hair growth promoting effect of a noncrosslinked hyaluronic acid in human dermal papilla cells. Biomed Res Int, 2021a; 2021: 5598110. https://doi.org/10.1155/2021/5598110

Zerbinati N, Sommatis S, Maccario C, Capillo MC, Di Francesco S, Rauso R, Protasoni M, D'Este E, Dalla Gasperina D, Mocchi R. In vitro evaluation of the effect of a not cross-linked hyaluronic acid hydrogel on human keratinocytes for mesotherapy. Gels, 2021b; 7(1):15 https://doi.org/10.3390/gels7010015

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