molecules Review Advantages of Hyaluronic Acid and Its Combination with Other Bioactive Ingredients in Cosmeceuticals Anca Maria Juncan 1,2,3,* , Dana Georgiana Moisă 3,*, Antonello Santini 4 , Claudiu Morgovan 3,* , 3 3 1 Luca-Liviu Rus , Andreea Loredana Vonica-T, incu and Felicia Loghin 1 Department of Toxicology, Faculty of Pharmacy, “Iuliu Hat, ieganu” University of Medicine and Pharmacy, 6 Pasteur Str., 400349 Cluj-Napoca, Romania; fl[email protected] 2 SC Aviva Cosmetics SRL, 71A Kövari Str., 400217 Cluj-Napoca, Romania 3 Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 2A Lucian Blaga Str., 550169 Sibiu, Romania; [email protected] (L.-L.R.); [email protected] (A.L.V.-T, .) 4 Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy; [email protected] * Correspondence: [email protected] or [email protected] (A.M.J.); [email protected] (D.G.M.); [email protected] (C.M.) Abstract: This study proposes a review on hyaluronic acid (HA) known as hyaluronan or hyaluronate and its derivates and their application in cosmetic formulations. HA is a glycosaminoglycan consti- tuted from two disaccharides (N-acetylglucosamine and D-glucuronic acid), isolated initially from the vitreous humour of the eye, and subsequently discovered in different tissues or fluids (especially Citation: Juncan, A.M.; Mois˘a,D.G.; in the articular cartilage and the synovial fluid). It is ubiquitous in vertebrates, including humans, and Santini, A.; Morgovan, C.; Rus, L.-L.; it is involved in diverse biological processes, such as cell differentiation, embryological development, Vonica-T, incu, A.L.; Loghin, F. inflammation, wound healing, etc. HA has many qualities that recommend it over other substances Advantages of Hyaluronic Acid and used in skin regeneration, with moisturizing and anti-ageing effects. HA molecular weight influences Its Combination with Other Bioactive its penetration into the skin and its biological activity. Considering that, nowadays, hyaluronic Ingredients in Cosmeceuticals. acid has a wide use and a multitude of applications (in ophthalmology, arthrology, pneumology, Molecules 2021, 26, 4429. https:// rhinology, aesthetic medicine, oncology, nutrition, and cosmetics), the present study describes the doi.org/10.3390/molecules26154429 main aspects related to its use in cosmetology. The biological effect of HA on the skin level and its potential adverse effects are discussed. Some available cosmetic products containing HA have Academic Editors: María De La Luz Cádiz-Gurrea, Antonio been identified from the brand portfolio of most known manufacturers and their composition was Segura-Carretero and David evaluated. Further, additional biological effects due to the other active ingredients (plant extracts, Arráez-Román vitamins, amino acids, peptides, proteins, saccharides, probiotics, etc.) are presented, as well as a description of their possible toxic effects. Received: 7 June 2021 Accepted: 20 July 2021 Keywords: hyaluronic acid; cosmeceuticals; biological activity; skin health; moisturising effect; Published: 22 July 2021 anti-ageing effect; bioactive compounds; molecular weight; hyaluronan derivates Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Hyaluronic acid (HA) is a polysaccharide belonging to the glycosaminoglycans, made up of disaccharide units constituted of N-acetylglucosamine and D-glucuronic acid (Figure1) . It is a component of the connective, epithelial, and neural tissues and it represents a substantial constituent of the extracellular matrix (ECM) [1–6]. HA was Copyright: © 2021 by the authors. discovered for the first time in the vitreous humour of the eye in 1934, and in 1964 it was Licensee MDPI, Basel, Switzerland. synthesized in vitro [7–9]. HA has a wide range of molecular weights ranging from 2 × 105 This article is an open access article to 107 Da [10–13]. The HA average molecular weight can influence its physico-chemical distributed under the terms and properties [3,14]. conditions of the Creative Commons Among the many biological effects, HA is involved in cell differentiation, embry- Attribution (CC BY) license (https:// ological development, inflammation, wound healing, viscoelasticity, etc. [15]. As it has creativecommons.org/licenses/by/ been observed, the molecular mass and the mode of its synthesis or degradation define 4.0/). Molecules 2021, 26, 4429. https://doi.org/10.3390/molecules26154429 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 4429 2 of 43 the HA biological effects [3,16,17]. By a passive mechanism, high molecular weight HA (HMW-HA) permits the tissue hydration, contributes to the osmotic balance, and stabilizes the ECM structure. On the other hand, HA interacts with different receptor binding pro- teins, and its molecular weight can influence the receptor affinity or its uptake by the cells, leading to opposite effects. For example, HMW-HA inhibits the cell growth (angiogenetic activity) and protects the articular cartilage due to its lubrication properties. Low molecular weight HA (LMW-HA) has angiogenetic activity and can induce tumor progression or presents pro-inflammatory activity [15,16]. Thus, the biological activity of HA is due to its binding to different receptors. For example, the binding HA-CD44 transmembrane receptor mediates cell adhesion and migration in many physiological or pathophysiolog- ical processes: (a) angiogenesis; (b) ECM structure (linking the HA with cytoskeleton); (c) inflammation (upregulation of the receptors overexpresses the interleukin-1); (d) wound healing; (e) malignant tumors (e.g., pancreatic, breast, lung, etc.). The CD-168 receptor (Receptor for Hyaluronan-Mediated Motility, RHAMM) localized on the cell surface has an important relevance in cell migration. When the receptor is situated intracellularly, it affects the activity of the mitotic spindle. As a result, the HA-RHAMM links can influence the inflammation and tissue repair processes. The HARE (Hyaluronan Receptor for En- docytosis) receptors modulate the glycosaminoglycans clearance. The lymph absorption of HA, implicitly the HA turnover, is controlled by LYVE1 (Lymphatic Vessel Endothelial Hyaluronan receptor-1). As a result, HA-LYVE1 interaction influences the tissue biome- chanical properties, including its hydration. Referring to the HA interaction with TLRs (Toll-Like Receptor), it is noticed that LMW-HA has an inflammatory effect, because of its agonist activity on TLR-2 and TLR-4. On the other hand, a high mass of HA decreases the Molecules 2021, 26, x FOR PEER REVIEW 2 of 40 binding capacity to the receptors, forming a dense coat around the cell and covering the receptor surface [15,16,18,19]. FigureFigure 1. 1. ChemicalChemical structure structure of of hyaluronic hyaluronic acid acid (HA). (HA). AmongNowadays, the many there arebiological a lot of studieseffects, conductedHA is involved in order in tocell elucidate differentiation, the mechanism embryo- of logicalaction anddevelopment, the biosynthetic inflammation, pathways ofwound HA, orhealing, to optimize viscoelasticity, its biotechnological etc. [15]. production, As it has beenin order observed, to synthesize the molecular derivatives mass with and superior the mode properties of its synthesis and to improveor degradation its therapeutic define theutilization HA biological [16]. effects [3,16,17]. By a passive mechanism, high molecular weight HA (HMW-HA)The list permits of substances the tissue that hydration, are restricted cont orributes prohibited to the in osmotic the EU balance, for use in and cosmetic stabi- lizesproducts the ECM does structure. not include On hyaluronic the other acid hand, and HA sodium interacts hyaluronate with different (NaHA). receptor As an example,binding proteins,using hyaluronic and its molecular acid, sodium weight hyaluronate, can influence or potassium the receptor hyaluronate affinity or (KHA) its uptake in cosmetics by the cells,is not leading restricted to opposite in Japan [effects.20]. For example, HMW-HA inhibits the cell growth (angio- geneticSome activity) studies and realized protects by the the articular Cosmetic ca Ingredientrtilage due Review to its lubrication (CIR) experts properties. panel, based Low molecularon the application weight HA of cosmetic(LMW-HA) HA has in variousangiogenetic concentrations, activity and showed can induce acute, tumor short-term, pro- gressionor chronic or toxicitypresents [ 20pro-inflammatory]. Additionally, someactivity side [15,16]. tolerable Thus, effects the biological (scaling, erythema,activity of HA and pruritus) were observed, after the use of a topical product with hyaluronic acid (0.01%), is due to its binding to different receptors. For example, the binding HA-CD44 transmem- hydroquinone (4%), and glycolic acid (10%) for melasma treatment [4]. Subsequently, brane receptor mediates cell adhesion and migration in many physiological or pathophys- HA and NaHA can be nebulized and used in cosmetic products which can be applied as iological processes: (a) angiogenesis; (b) ECM structure (linking the HA with cytoskele- ton); (c) inflammation (upregulation of the receptors overexpresses the interleukin-1); (d) wound healing; (e) malignant tumors (e.g., pancreatic, breast, lung, etc.). The CD-168 re- ceptor (Receptor for Hyaluronan-Mediated Motility, RHAMM) localized on the cell sur- face has an important relevance in cell migration.