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 ). [Click here to view] |
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. [Click here to view] |
 | Table 1. Reported cases of undesirable effects after HA administration. [Click here to view] |
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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