Hyaluronic acid (HA), a naturally occurring glycosaminoglycan (GAG), has emerged as a pivotal bioactive ingredient in modern cosmeceuticals due to its remarkable biocompatibility, hydrophilicity, and multifunctional dermatological benefits. This review explores the structural, pharmacological, and therapeutic dimensions of HA, particularly in the context of skin hydration, repair, and anti-aging. HA's molecular weight (MW) plays a critical role in its bioactivity. High molecular weight (HMW) HA offers surface-level hydration and anti-inflammatory effects, while low MW-HA penetrates deeper to promote collagen synthesis and tissue regeneration. Topical formulations, injectable dermal fillers, and advanced delivery systems such as nanoparticles and microneedles have broadened HA’s clinical utility and consumer appeal. Mechanistically, HA interacts with receptors such as cluster of differentiation 44 (CD44) and the receptor for hyaluronic acid-mediated motility (RHAMM), influencing the functions of keratinocytes and fibroblasts, while also regulating immune responses through Toll-like receptors 2 and 4 (TLR2/TLR4). These receptor-mediated pathways enhance skin elasticity, accelerate wound healing, and mitigate oxidative stress. Recent advances include cross-linked and bioengineered HA derivatives with improved stability and prolonged activity. Moreover, combination therapies incorporating HA with peptides, retinoids, or vitamins exhibit synergistic benefits in anti-aging and scar treatments. Safety assessments affirm HA’s excellent tolerability, reinforcing its dominant role in both cosmetic and therapeutic dermatology. Emerging frontiers in personalized HA-based skincare and its potential role in regulating the skin microbiome signal forward-looking strategies for innovation. Overall, HA continues to redefine cosmeceutical science by offering multifunctional, evidence-based solutions for skin health and rejuvenation.

Keywords: anti-aging, extracellular matrix, collagen synthesis, Cosmeceuticals, dermal fillers, nanoparticles, transdermal delivery, artificial intelligence

HA, hyaluronic acid; GAG, glycosaminoglycan; MW, molecular weight; HMW, high molecular weight; CD 44, cluster of differentiation 44; RHAMM, receptor for hyaluronic acid-mediated motility; TLR2/TLR4, toll-like receptors 2 and 4; ECM, extracellular matrix; TEWL, trans-epidermal water loss; LMW, low molecular weight; AI, artificial intelligence

The global cosmeceutical industry has undergone a significant transformation in recent years, driven by growing consumer demand for scientifically backed, multifunctional skincare products.¹ Cosmeceutical products that lie at the fusion of cosmetics and pharmaceuticals offer both aesthetic and therapeutic benefits. Among the many active ingredients used in modern formulations,² hyaluronic acid, also known as Hyaluronan, has emerged as one of the most prominent and widely researched biomolecules.^3,4 Originally discovered in the 1930s, HA was initially valued for its unique viscoelastic and hydrophilic properties, but it is now recognized for its broad applicability in dermatology, particularly in the areas of skin hydration, repair, and anti-aging interventions.^5,6 The rise of HA in cosmeceutical formulations is rooted in both its biological relevance and its exceptional pharmacological profile.⁷ As a naturally occurring GAG found in the extracellular matrix (ECM) of human connective tissue, skin, and synovial fluid, HA plays a vital role in maintaining skin structure, moisture balance, and cellular signaling.⁸ The concentration of HA in the dermis decreases significantly with age and environmental stressors, contributing to common signs of skin aging such as dryness, loss of elasticity,⁹ and the formation of fine lines and wrinkles.¹⁰ This physiological decline has led to the widespread incorporation of HA in both topical and injectable skincare products aimed at restoring hydration and youthful appearance.¹¹ In the context of dermato-pharmacology, HA is of particular interest due to its dual function as both a passive moisturizer and an active modulator of skin physiology. Its high biocompatibility, non-immunogenic nature, and ability to interact with specific cell surface receptors such as CD44 and RHAMM make it an ideal candidate for therapeutic use.¹² Furthermore, advancements in formulation technology, ranging from nanocarriers and cross-linked gels to multi-molecular weight systems, have enhanced HA's bioavailability and penetration into different skin layers, thereby expanding its clinical efficacy, market, and consumer demand.¹³ These innovations have positioned HA not only as a cosmetic agent but also as a key pharmacological tool in managing skin aging and related dermatological conditions.¹⁴ Given its multifunctional roles, increasing clinical validation, and consumer preference for effective, science-driven skincare, HA continues to redefine the landscape of modern cosmeceuticals.¹⁶ This study aims to provide a comprehensive analysis of the structural, pharmacological, and therapeutic dimensions of HA, with a focus on its application in skin health, anti-aging strategies, and recent innovations in delivery technologies.

Chemical structure and physicochemical properties

HA is a linear polysaccharide composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine, linked by alternating β-1,4 and β-1,3 glycosidic bonds.¹⁷ Its strong hydrophilicity, viscoelastic nature, and MW-dependent bioactivity contribute to its multifunctional role in skin hydration, elasticity, and anti-aging therapy.¹⁸

Molecular structure

HA is a naturally occurring, unbranched linear polysaccharide composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine.¹⁹ These monomers are alternately linked by β-1,3 and β-1,4 glycosidic bonds, forming the backbone structure of the polymer. The general repeating unit can be denoted as [→4) β-D-GlcA (1→3) β-D-GlcNAc (1→]ₙ,²⁰ where GlcA refers to glucuronic acid and GlcNAc to N-acetylglucosamine (Figure 1).²¹ Unlike other GAGs, HA is non-sulfated and not covalently bound to a protein core, which distinguishes it structurally and functionally.²² The presence of multiple hydroxyl, carboxyl, and acetamido functional groups imparts strong hydrophilicity and enables HA to form a highly hydrated, gel-like matrix within the extracellular space. This molecular configuration plays a critical role in the maintenance of skin hydration, viscoelasticity, and tissue homeostasis, and serves as the basis for its significant use in topical, injectable, and transdermal cosmeceutical formulations.²³

Figure 1 Molecular structure of HA, composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine linked via alternating β-1,4 and β-1,3 glycosidic bonds.^24,25

Hydrophilicity and viscoelasticity

HA is highly hydrophilic due to the presence of multiple hydroxyl, carboxyl, and acetamido groups capable of forming strong hydrogen bonds with water molecules. This characteristic allows it to absorb and retain large amounts of water up to 1000 times its weight, making it an ideal natural moisturizing agent in dermatology and cosmetology.²⁶ Its viscoelastic properties are another defining physicochemical feature, enabling HA to behave as a viscous fluid under low shear conditions and as an elastic solid under high shear stress.²⁷ These rheological behaviors depend on concentration, MW, and polymer entanglement. In synovial fluid, for example, these properties contribute to shock absorption and lubrication, while in skin care, they help in enhancing texture and application feel, and maintaining skin tone.²⁸

Molecular weight implications

The biological and pharmacological activities of HA are strongly influenced by its MW, which can range from 5 kDa to over 10,000 kDa. Based on MW,²⁹ HA can be categorized into three types:

High molecular weight (>1000 kDa)

Exhibits anti-inflammatory and immunosuppressive effects. It forms a protective film on the skin surface and prevents trans-epidermal water loss (TEWL), making it ideal for surface hydration and skin barrier reinforcement in topical applications.³⁰

Medium molecular weight (~250-1000 kDa)

Provides moderate skin penetration and hydration. It balances the properties of HMW and low molecular weight (LMW), often used in formulations targeting both surface and mid-layer skin hydration.³¹

Low molecular weight (<250 kDa)

Penetrates deeper into the epidermis, potentially stimulating cell proliferation, collagen synthesis, and wound healing. However, extremely LMW (<50 kDa) may occasionally exhibit pro-inflammatory effects, necessitating careful optimization in product formulations.³² The ability to engineer HA at specific MW or combine multiple weights in one formulation has allowed the development of multifunctional cosmeceuticals that hydrate, protect, and biologically stimulate the skin at multiple levels.³³

Pharmacokinetics and pharmacodynamics

 HA, though primarily known for its topical and injectable use in dermatological and cosmetic medicine, exhibits a complex pharmacokinetic and pharmacodynamic profile that underpins its biological effectiveness in cosmeceuticals and therapeutic applications.³⁴

Absorption, distribution, metabolism, and excretion

HA is absorbed based on its route of administration, with topical forms acting locally and injectables reaching deeper tissues. It is distributed in connective tissues, is metabolized by hyaluronidases (HYAL1 and HYAL2), and is excreted via the lymphatic system and kidneys (Figure 2).^35,36

Figure 2 Pharmacokinetic pathway of HA (HA’s absorption (topical/injectable), distribution in connective tissues, enzymatic metabolism by HYAL1 & HYAL2, and excretion via the lymphatic system and kidneys).

Absorption

The route of administration significantly affects HA’s absorption. Topically applied HA, especially HMW forms, primarily exerts effects on the stratum corneum and upper layers of the epidermis due to its large size and limited skin permeability. However, recent advances in LMW-HA formulations, nano-encapsulation, and chemical modifications have improved dermal penetration and enhanced systemic and localized effects. Injectable forms, such as dermal fillers or intra-articular injections, bypass epidermal barriers and are directly delivered to target tissues.³⁷
Distribution

Once absorbed or injected, HA distributes predominantly in the ECM of connective tissues, including the skin, synovial fluid, and vitreous body. Its distribution is dependent on its MW; smaller fragments are more readily distributed systemically, whereas larger polymers remain localized at the injection site and serve as a scaffold or hydrating reservoir.³⁸

Metabolism

HA is metabolized primarily through enzymatic degradation by hyaluronidases (HYAL1 and HYAL2), which break the glycosidic bonds between the disaccharide units. HYAL2, located on the cell surface, initiates HA breakdown into intermediate-size fragments, which are subsequently internalized and further degraded in lysosomes by HYAL1. In tissues, oxidative stress and reactive oxygen species can also contribute to non-enzymatic depolymerization of HA.³⁹

Excretion

The metabolic byproducts of HA are cleared predominantly via the lymphatic system and kidneys. Small oligosaccharides resulting from degradation are excreted in the urine.⁴⁰ The systemic half-life of HA is relatively short, ranging from minutes to a few hours, depending on molecular size and route of administration. In contrast, cross-linked HA (used in dermal fillers) may persist in tissues for several months due to its resistance to enzymatic breakdown.⁴¹

Cluster of Differentiation 44

A widely expressed transmembrane glycoprotein involved in cell adhesion, migration, proliferation, and inflammation. Binding of HA to CD44 influences keratinocyte function, fibroblast activity, and immune modulation, making it central to skin repair and anti-aging effects.⁴²

Receptor for hyaluronic acid-mediated motility

This receptor is associated with cytoskeletal remodeling, cell motility, and wound healing. HA-RHAMM interactions promote fibroblast migration and tissue regeneration, contributing to HA’s effectiveness in rejuvenation therapies.⁴³

Toll-like receptors 2/4

LMW-HA fragments may act as danger-associated molecular patterns and bind to TLRs, regulating immune responses and influencing inflammation. This dual role is size-dependent: while HMW-HA is anti-inflammatory, LMW-HA can be pro-inflammatory under certain conditions.⁴⁴

Mechanism of action in skin physiology

HA hydrates the skin by retaining water, stimulates collagen synthesis via fibroblast activation, and supports epidermal barrier repair through enhanced keratinocyte function. It also exhibits antioxidant and anti-inflammatory effects, protecting skin from oxidative stress and promoting regeneration (Figure 3).⁴⁵

Figure 3 HA’s role in skin health: promoting hydration, enhancing collagen synthesis, providing antioxidant and anti-inflammatory effects, and supporting epidermal barrier repair.

Hydration and water retention

HA plays a vital role in maintaining skin hydration due to its unique ability to bind and retain up to a thousand times its weight in water.⁴⁶ This hydrophilic nature allows HA to form a viscoelastic, gel-like matrix in the extracellular space, enhancing skin tone and hydration level, smoothness, and elasticity. It acts as a reservoir for moisture, particularly in the stratum corneum and dermis, maintaining optimal hydration levels essential for barrier integrity and cell viability.⁴⁷

Stimulation of collagen synthesis

HA contributes indirectly to collagen production by creating a hydrated environment that supports fibroblast function and ECM remodeling. HA-CD44 interactions stimulate fibroblasts to synthesize type I and III collagen, crucial for skin firmness and elasticity. This regenerative property is further amplified by cross-linked HA used in cosmetic procedures, which prolongs fibroblast activation and dermal matrix reinforcement.⁴⁸

Antioxidant and anti-inflammatory effects

HMW-HA exhibits antioxidant activity by scavenging reactive oxygen species, thereby protecting skin cells from oxidative stress and UV-induced damage.⁴⁹ It also suppresses inflammatory pathways by down regulating pro-inflammatory cytokines and inhibiting the activity of enzymes like matrix metalloproteinases, which degrade collagen. Conversely, LMW-HA fragments may stimulate a transient inflammatory response beneficial for wound healing and tissue renewal.⁵⁰

Epidermal barrier repair

HA aids in restoring the epidermal barrier by promoting keratinocyte proliferation, migration, and differentiation. It strengthens cell-cell junctions and enhances the expression of tight junction proteins,⁵¹ leading to improved barrier function and reduced TEWL. HA also accelerates re-epithelialization and facilitates the repair of microdamage, making it a key agent in formulations aimed at treating dry, irritated, or aging skin.⁵²

Formulation strategies in Cosmeceuticals

Cosmeceutical formulation strategies encompass a range of innovative delivery systems designed to optimize the efficacy of active ingredients. Topical formulations such as creams, gels, and serums are widely employed to provide hydration and deliver targeted skin benefits.⁵³ Injectable formulations, notably dermal fillers composed of HA, offer long-lasting effects in restoring volume and reducing the appearance of wrinkles. Advanced delivery technologies, including liposomes, nanoparticles, and microneedles, enhance the penetration and bioavailability of active ingredients,⁵⁴ overcoming the barrier function of the stratum corneum.⁵⁵ The MW of compounds, particularly HA, plays a pivotal role in determining their cutaneous absorption, biological activity, and depth of action within the skin layers.⁵⁶

Topical delivery systems

Creams, gels, and serums are among the most widely used vehicles in cosmeceutical formulations. Creams and lotions, typically emulsions of oil and water, provide excellent moisturization and are ideal for delivering HMW ingredients like HA that act on the skin surface to retain moisture and protect the barrier.⁵⁷ Gels, on the other hand, are non-greasy and suitable for oily or sensitive skin types, allowing better incorporation of low to medium MW active ingredients. Serums are lightweight and fast-absorbing aqueous formulations designed for deeper penetration of active ingredients like peptides, antioxidants, and LMW-HA. Their minimal base and high concentration of active ingredients make them highly effective for targeted skin benefits such as hydration, brightening, and anti-aging.⁵⁸

Injectable formulations

The dermal fillers based on HA have gained popularity in cosmetic dermatology. These formulations often consist of cross-linked HA, which provides viscoelasticity and volumizing effects when injected into the dermis or subcutaneous tissue.⁵⁹ The degree of cross-linking and particle size determine the filler’s viscosity, longevity, and suitability for different facial areas. These injectables can last from six months to over a year, offering temporary but significant improvement in facial wrinkles, volume loss, and contouring.⁶⁰ The minimally invasive nature and immediate results make dermal fillers a preferred choice for non-surgical facial rejuvenation.⁶¹

Advanced delivery methods

Liposomes, nanoparticles, and microneedles are revolutionizing the effectiveness of cosmeceuticals by enhancing skin penetration and targeted delivery of active ingredients. Liposomes, which are phospholipid vesicles, encapsulate both hydrophilic and lipophilic actives and merge with skin membranes to release contents effectively.⁶² Nanoparticles, including solid lipid nanoparticles and nanostructured lipid carriers, offer controlled release, improved stability, and better penetration of active ingredients into deeper skin layers. Microneedles are another cutting-edge technology that creates microchannels in the skin, facilitating the transdermal delivery of macromolecules like peptides, growth factors, and even HMW-HA, which would otherwise have limited permeability through the stratum corneum.⁶³

Role of molecular weight (Low vs High) in efficacy

The MW of active ingredients, especially HA, plays a crucial role in determining their efficacy and depth of action. HMW-HA (>1000 kDa) remains on the skin surface, forming a hydrating and protective film, reducing TEWL, and providing anti-inflammatory effects. In contrast, LMW-HA (<100 kDa) penetrates deeper into the epidermis and dermis, where it can interact with cellular receptors such as CD44 and stimulate biological responses like collagen synthesis, tissue repair, and skin rejuvenation. Therefore, a combination of different MWs in a single formulation can offer both immediate surface hydration and long-term dermal benefits.⁶⁴

Therapeutic and cosmetic applications of hyaluronic acid

HA plays a pivotal role in both therapeutic and cosmetic dermatology due to its exceptional hydrating, regenerative, and biocompatible properties (Figure 4).⁶⁵ It enhances skin hydration and elasticity by retaining moisture in the epidermis, thereby improving suppleness and reducing dryness. HA-based dermal fillers are widely used to minimize fine lines and wrinkles by restoring volume and stimulating collagen synthesis.⁶⁶ Additionally, HA promotes wound healing and scar reduction by controlling inflammation and supporting tissue repair. In acne and photo damage management, HA soothes irritated skin, reduces inflammation, and aids in skin regeneration, making it an essential ingredient in anti-aging and regenerative skincare regimens (Table 1).^67–69

Figure 4 Broad-spectrum applications of HA and its derivatives across various medical and therapeutic domains.

Skin hydration and elasticity improvement

HA’s high water-binding capacity helps retain moisture in the epidermis, improving skin tone and elasticity. It reinforces the skin’s natural barrier, leading to increased elasticity and a rejuvenated appearance. Topical formulations and injectable HA (dermal fillers) are commonly used for deep moisturization and volumizing effects.⁷⁰

Reduction of fine lines and wrinkles

HA-based dermal fillers (such as non-crosslinked or crosslinked HA) are widely used in aesthetic dermatology to fill wrinkles and restore lost facial volume. HA smoothens the skin surface by attracting and holding water in the dermis, providing an immediate lifting effect and long-term structural support through stimulation of collagen production.⁷¹

Wound healing and scar treatment

HA modulates inflammation, promotes fibroblast migration, and supports re-epithelialization. These properties accelerate tissue regeneration and healing. HA-containing dressings and gels are used for treating chronic wounds, burns, and surgical scars by maintaining a moist environment and reducing scar formation.⁷²

Acne and photodamage management

In acne treatment, HA hydrates and soothes irritated skin, reduces post-inflammatory hyperpigmentation, and enhances skin repair. For photodamaged skin, HA improves texture and tone by restoring moisture, reducing oxidative stress, and assisting in dermal remodeling. It is often combined with antioxidants or retinoids for synergistic benefits.⁷³

Innovations and recent advances

Recent innovations and advances in cosmeceutical science have significantly enhanced the functionality and versatility of HA-based products. One of the breakthroughs is the development of cross-linked HA technologies, which involve chemically modifying HA to form a stable 3D network.⁷⁴ This cross-linking improves the viscoelastic properties, resistance to enzymatic degradation, and durability of HA in dermal filler applications. In addition, the advent of bioengineered HA and synthetic derivatives has enabled the production of highly pure, tailored MW-HA with enhanced biocompatibility and targeted biological activity. These novel forms provide better control over hydration, anti-aging effects, and tissue regeneration. Furthermore, combination therapies incorporating HA with bioactive molecules such as peptides, vitamins (vitamin C and E), and growth factors have shown synergistic effects, promoting collagen synthesis, cellular repair, and skin rejuvenation.⁷⁵ These multi-functional formulations address multiple signs of aging and skin damage more effectively than HA alone. Complementing these innovations are smart delivery systems and sustained-release platforms, including hydrogel matrices, nanocarriers, and pH or temperature-responsive vehicles. These systems ensure controlled and prolonged delivery of HA and other active ingredients, minimizing dosing frequency while maximizing therapeutic outcomes and patient compliance.⁷⁶

Safety, tolerability, and adverse effects

HA is widely regarded as a safe and biocompatible substance in both clinical and cosmetic applications due to its natural presence in the human body. Clinical data have consistently shown that HA-based topical and injectable products exhibit excellent tolerability, with minimal risk of skin irritation, sensitization, or allergic reactions. Most adverse events are mild and temporary, such as localized erythema, swelling, or tenderness at the injection site in dermal filler applications. Allergic responses are rare, particularly with non-animal stabilized HA preparations.⁷⁷

Biocompatibility studies indicate that HA does not typically induce immunogenic responses and is generally well-accepted by skin and connective tissues. High-purity, bioengineered forms of HA further minimize the risk of contamination and endotoxin-related reactions. For long-term use, data support the safety of HA in repeated applications, although monitoring is advised in sensitive individuals or those with a history of dermal allergies.⁷⁸

From a regulatory perspective, HA-based products are subject to oversight by agencies such as the United States Food and Drug Administration (U.S. FDA), European Medicines Agency (EMA), and Central Drugs Standard Control Organization in India. Topical HA formulations are typically classified as cosmetics or over-the-counter products, requiring only basic safety evaluations. In contrast, injectable HA fillers are regulated as medical devices (Class III in the U.S.) or combination products and must meet safety, efficacy, and manufacturing standards, including preclinical and clinical trial data submission.⁷⁹ Overall, HA remains one of the most biocompatible and clinically validated ingredients in dermatology and cosmetic medicine, with a favorable safety profile across diverse formulation types and usage scenarios. Nonetheless, adherence to good manufacturing practices, patient screening, and post-market surveillance is crucial to maintaining safety and public trust in HA-based products.⁸⁰

Comparative efficacy with other Cosmeceutical agents

HA holds a unique position among cosmeceutical ingredients due to its exceptional water-binding capacity, viscoelastic properties, and compatibility with various skin types. However, when compared to other widely used agents like collagen, retinoids, peptides, and Niacinamide, the distinct mechanisms and benefits of each compound underscore the value of both individual and combined use in advanced skincare formulations.⁸¹

Collagen vs hyaluronic acid

Both collagen and HA are naturally occurring components of the ECM and play vital roles in skin structure and hydration. While collagen provides structural support and mechanical strength, it has poor skin penetration due to its HMW when applied topically.⁸² HA, on the other hand, particularly in LMW forms, penetrates deeper into the skin and significantly improves hydration, skin firmness, and elasticity. Injectable collagen has become less favored due to allergenicity risks, while HA-based dermal fillers have largely replaced it because of superior safety and prolonged effectiveness.⁸³

Retinoids vs hyaluronic acid

Retinoids, including retinol and tretinoin, are vitamin A derivatives known for promoting cellular regeneration, reducing wrinkles, and treating acne. However, they can cause dryness, irritation, and photosensitivity. HA serves as an excellent complementary agent by counteracting the dehydration and irritation commonly associated with retinoid use. While retinoids actively remodel the skin at a cellular level, HA passively supports this process by maintaining moisture and barrier integrity.⁸⁴

Peptides vs hyaluronic acid

Peptides, especially signal peptides and carrier peptides, stimulate collagen synthesis, enhance skin firmness, and support wound healing. Their action complements HA's hydrating function by promoting structural protein regeneration. When used in combination, HA ensures an optimal microenvironment for peptide function by maintaining hydration and facilitating deeper skin penetration.⁸⁵

Niacinamide vs hyaluronic acid

Niacinamide (Vitamin B3) is known for its anti-inflammatory, brightening, and barrier-repair properties. It regulates sebum production, improves pigmentation, and reduces redness. Unlike HA, which hydrates passively, niacinamide actively enhances the skin barrier and reduces TEWL. Combined use of niacinamide and HA provides comprehensive skin benefits: hydration from HA and barrier repair, plus anti-aging effects from niacinamide.⁸⁶

Synergistic effects and combination use

Recent formulation trends focus on synergistic blends of HA with these cosmeceuticals to target multiple skin concerns. For instance, HA-retinoid serums are increasingly popular for anti-aging regimens, as HA offsets the irritation of retinoids while maintaining hydration.⁸⁷ Similarly, HA-peptide serums promote skin strength and hydration simultaneously, while HA-niacinamide formulations balance moisture retention with anti-inflammatory benefits. These combinations not only enhance the efficacy of each active but also improve user tolerability and compliance.⁸⁸

Market trends and consumer perspectives

The global demand for HA in cosmeceuticals is rising rapidly, driven by its anti-aging and hydrating benefits. Consumers increasingly prefer scientifically backed, transparent formulations, but challenges remain in standardized labeling and substantiated marketing claims.⁸⁹

Global hyaluronic acid cosmeceutical market growth

The global cosmeceutical market, particularly products featuring HA, has experienced exponential growth in recent years. As of the latest market estimates, the global HA-based skincare market is valued at over USD 9 billion, with projections suggesting it will surpass USD 15 billion by 2030, driven by increased demand for anti-aging, hydrating, and minimally invasive aesthetic solutions.^90,91 The rise in the aging population, greater awareness of skin health, and the growing popularity of non-surgical cosmetic procedures have contributed significantly to this expansion. HA is a flagship ingredient in serums, moisturizers, facial masks, and injectable dermal fillers, making it a key driver in the cosmeceutical and aesthetic dermatology industries across North America, Europe, and the Asia-Pacific region (Figure 5).^92–94

Figure 5 The global market growth of HA in Cosmeceuticals (2018 to 2030). The trend highlights a gradual increase in market size, projected to reach approximately USD 15.8 billion by 2030.

Consumer preferences and formulation transparency

Modern consumers are increasingly educated and selective about the ingredients in their skincare products. There is a strong preference for clean, scientifically backed, and sustainably sourced ingredients. HA fits this profile, especially when labeled as non-animal derived or bio-fermented, which appeals to vegan and cruelty-free markets. Consumers also value the MW of HA, often seeking products with a blend of HMW and LMW-HA for both surface hydration and deeper penetration.⁹⁵

Formulation transparency has become a priority. Shoppers demand clear ingredient lists, knowledge about product sourcing, and evidence-based efficacy claims. Brands that disclose the type of HA used, concentration, and clinical benefits gain higher consumer trust. Additionally, the demand for minimalist, multifunctional formulations has led to the rise of combination products where HA is paired with peptides, vitamins, or plant-based antioxidants for comprehensive skin benefits.⁹⁶

Challenges in product labeling and claims

Despite its popularity, the cosmeceutical market faces challenges related to regulatory standards, labeling, and marketing claims. In many countries, including the U.S. and India, cosmeceuticals fall into a regulatory gray area not classified as either pure cosmetics or drugs, allowing room for ambiguous or exaggerated marketing claims.⁹⁷ Products often label HA-containing formulations as clinically proven or anti-aging, without substantiating these claims with robust clinical trials.⁹⁸

Furthermore, the lack of standardization in labeling HA types (sodium hyaluronate vs hydrolyzed HA vs cross-linked HA) creates confusion among consumers and limits informed decision-making. Regulatory agencies like the U.S. FDA and EMA do not require pre-approval for cosmetic formulations, which sometimes leads to misleading representations of product efficacy, MW impact, or HA concentration.⁹⁹ To address these challenges, there is a growing push for harmonized regulations, clinical validation of claims, and greater industry accountability in HA cosmeceutical labeling and promotion.¹⁰⁰

Future directions in research and development

The future of HA in cosmeceuticals is marked by exciting advancements. Next-generation HA derivatives, such as thiolated or PEGylated HA, are being designed for enhanced stability, targeted delivery, and prolonged skin effects. Personalized cosmeceuticals are emerging, where artificial intelligence (AI) driven diagnostics and genetic profiling allow formulation of HA products tailored to individual skin types and needs.¹⁰¹ Additionally, HA is being investigated for its role in regulating the skin microbiome, offering potential for formulations that support skin health through microbiota balance. These innovations will shape more effective, science-driven, and consumer-responsive HA-based skincare.¹⁰²

Next-generation HA derivatives

The future of HA research lies in the development of next-generation derivatives that offer enhanced bioactivity, stability, and targeted performance. Scientists are engineering HA molecules through chemical modifications such as sulfation, acetylation, and cross-linking with biodegradable polymers.¹⁰³ These modifications create HA variants with controlled degradation rates, improved skin penetration, and targeted receptor interactions. One notable innovation is thiolated-HA, which forms disulfide bonds and exhibits superior muco-adhesion and antioxidative properties. Another advancement includes HA-polyethylene glycol conjugate copolymers, which extend the half-life and allow for sustained release in topical and injectable applications.¹⁰⁴ These novel derivatives are being integrated into advanced formulations for wound healing, anti-aging, pigmentation control, and transdermal delivery systems, opening doors to multifunctional skincare and therapeutic platforms.¹⁰⁵

Personalized cosmeceuticals

The concept of personalized cosmeceuticals is revolutionizing skincare by aligning HA-based products with individual skin biology, genetics, lifestyle, and environmental exposure. Advances in skin microbiome sequencing, gene expression profiling, and AI-driven diagnostics enable the creation of HA formulations that are customized for specific skin concerns such as dehydration, sensitivity, or premature aging.¹⁰⁶ Companies are beginning to utilize smart diagnostic tools (mobile apps, skin scanners, and deoxyribonucleic acid kits) to assess individual skin profiles and deliver optimized HA-based products with precise MW, concentration, and added bioactive compounds. Personalized cosmeceuticals not only improve efficacy but also enhance consumer satisfaction and compliance. The integration of machine learning and big data analytics into dermatology is expected to significantly shape the next phase of HA-based skincare innovations.^107,108

Role of hyaluronic acid in skin microbiome regulation

Emerging studies suggest that HA may play a pivotal role in regulating the skin microbiome, a critical factor in maintaining skin health and barrier function.¹⁰⁹ HA can serve as a prebiotic, promoting the growth of beneficial skin flora while reducing pathogenic colonization. Its moisturizing effects help maintain an optimal skin pH and hydration, which are essential for a balanced microbiota. Some modified HAs have been shown to enhance the production of antimicrobial peptides and improve epithelial immunity, thereby indirectly supporting a healthy microbial environment (Figure 6).^110,111 Current research is exploring the synergy between HA and probiotic or postbiotic ingredients, leading to the development of microbiome-friendly HA formulations aimed at conditions like atopic dermatitis, acne, and rosacea.¹¹² This area holds significant promise for the formulation of next-generation dermo-cosmetics that target not just the skin but its living ecosystem.¹¹³

Figure 6 The skin functions as a dynamic ecosystem where the microbiome, metabolome, and phenome are closely interconnected. (Blue box) Diverse substances, derived from the host (stratum corneum, skin appendages, and plasma), environment (xenobiotics) and microbial metabolism, cover the skin surface, forming the micro-environment for skin microbiota;¹¹⁴ (Green box) occupation of ecological niches by self-adaptation and microbe-microbe interactions, promoting commensals or inhibiting pathogens; (Yellow box) the skin microbes, by their structures or bioactive molecules, reshape the host skin phenotypes.¹¹⁵

HA has emerged as a key component in modern cosmeceuticals due to its exceptional hydrating properties, biocompatibility, and multifunctional biological activity. This review compiles substantial evidence that highlights HA's essential role in maintaining skin hydration, promoting collagen synthesis, controlling inflammation, and supporting epidermal barrier repair. Its ability to interact with specific cellular receptors, such as CD44 and RHAMM, enables it to actively participate in skin regeneration and anti-aging processes. Recent advances in formulation science, including MW engineering, nanocarriers, cross-linking, and microneedle technologies, have substantially improved HA’s bioavailability and efficacy. Furthermore, HA’s synergy with other cosmeceutical agents like peptides, retinoids, and niacinamide enhances the scope of its therapeutic benefits, making it a central ingredient in both topical and injectable skincare products. Innovations such as next-generation HA derivatives and personalized cosmeceuticals driven by AI and genomic profiling signal a transformative advancement in HA-based skincare. Additionally, HA’s potential role in regulating the skin microbiome opens new frontiers in dermatological therapy. Given its robust safety profile, proven clinical benefits, and evolving technological capabilities, HA continues to redefine standards in cosmetic dermatology and therapeutic skincare. Future research should focus on personalized formulations, standardized labeling, and expanded clinical validation to further establish HA’s position in evidence-based cosmeceutical development.

None.

The authors declare that there is no conflict of interest.

None.

1. Sundaram H, Cegielska A, Wojciechowska A, et al. Prospective, randomized, investigator-blinded, Split-face evaluation of a topical Crosslinked hyaluronic acid serum for post-procedural improvement of skin quality and biomechanical attributes. J Drugs Dermatol. 2018;17(4):442–450.
2. Bravo B, Correia P, Gonçalves Junior JE, et al. Benefits of topical hyaluronic acid for skin quality and signs of skin aging: From literature review to clinical evidence. Dermatol Ther. 2022;35(12):e15903.
3. Raab S, Yatskayer M, Lynch S, et al. Clinical evaluation of a multi-modal facial serum that addresses hyaluronic acid levels in skin. J Drugs Dermatol. 2017;16(9):884–890.
4. Papakonstantinou E, Roth M, Karakiulakis G. Hyaluronic acid. A key molecule in skin aging. Dermatoendocrinol. 2012;4(3):253–258.
5. Nobile V, Buonocore D, Michelotti A, et al. Anti-aging and filling efficacy of six types hyaluronic acid based dermo-cosmetic treatment: double blind, randomized clinical trial of efficacy and safety. J Cosmet Dermatol. 2014;13(4):276–287.
6. Zhu J, Tang X, Jia Y, et al. Applications and delivery mechanisms of hyaluronic acid used for topical/transdermal delivery a review. Int J Pharm. 2020;578:119127.
7. Ghersetich I, Lotti T, Campanile G, et al. Hyaluronic acid in cutaneous intrinsic aging. Int J Dermatol. 1994;33(2):119–122.
8. Keen MA. Hyaluronic acid in dermatology. 2017;15(6):441–448.
9. Longinotti C. The use of hyaluronic acid-based dressings to treat burns: a review. Burns Trauma. 2014;2(4):162–168.
10. Voigt J, Driver VR. Hyaluronic acid derivatives and their healing effect on burns, epithelial surgical wounds, and chronic wounds: a systematic review and meta-analysis of randomized controlled trials. Wound Repair Regen. 2012;20(3):317–331.
11. Sabadotto M, Theunis J, Black D, et al. In vivo assessment of the effect of a cream containing Avena Rhealba(®) extract and hyaluronic acid on the restoration of the skin barrier in de-epidermised skin produced with an erbium-YAG laser. Eur J Dermatol. 2014;24(5):583–588.
12. Toole BP, Ghatak S, Misra S. Hyaluronan oligosaccharides as a potential anticancer therapeutic. Curr Pharm Biotechnol. 2008;9:249–252.
13. Ragan C, Meyer K. The hyaluronic acid of synovial fluid in rheumatoid arthritis. J Clin Invest. 1949;28:56–59.
14. Fallacara A, Baldini E, Manfredini S, et al. Hyaluronic acid in the third millennium. Polymers. 2018;10(7):701.
15. Necas J, Bartosikova L, Brauner P, et al. Hyaluronic acid (hyaluronan): a review. Vet Med (Praha). 2008;53(8):397–411.
16. Mero A, Campisi M. Hyaluronic acid bioconjugates for the delivery of bioactive molecules. Polymers. 2014;6(2):346–369.
17. Chen WY, Abatangelo G. Functions of hyaluronan in wound repair. Wound Repair Regen. 1999;7(2):79–89.
18. Fraser JR, Laurent TC, Laurent UB. Hyaluronan: its nature, distribution, functions and turnover. J Intern Med. 1997;242(1):27–33.
19. Stern R. Hyaluronidases in cancer biology. Semin Cancer Biol. 2008;18(4):275–280.
20. Cowman MK, Matsuoka S. Experimental approaches to hyaluronan structure. Carbohydr Res. 2005;340(5):791–809.
21. Stern R, Asari AA, Sugahara KN. Hyaluronan fragments: an information-rich system. Eur J Cell Biol. 2006;85(8):699–715.
22. Prestwich GD, Marecak DM, Marecek JF, et al. Controlled chemical modification of hyaluronic acid: synthesis, applications, and biodegradation of hydrazide derivatives. J Control Release. 1998;53(1-3):93–103.
23. Burdick JA, Prestwich GD. Hyaluronic acid hydrogels for biomedical applications. Adv Mater. 2011;23(12):H41–H56.
24. Al-Halaseh LK, Al-Jawabri NA, Tarawneh SK, et al. A review of the cosmetic use and potentially therapeutic importance of hyaluronic acid. J Appl Pharm Sci. 2022;12(07):034–041.
25. Gupta RC, Lall R, Srivastava A, et al. Hyaluronic acid: molecular mechanisms and therapeutic trajectory. Front Vet Sci. 2019;6:192.
26. Haeusler H. Efficacy of a hyaluronic acid gel to improve the skin properties. SOFW J. 2015;141(9):16–18.
27. Michon A. Hyaluronic acid filler delayed inflammatory reaction after COVID-19 vaccination – A case report. J Cosmet Dermatol. 2021;20(9):2684–2690.
28. Snetkov P, Zakharova K, Morozkina S, et al. Hyaluronic acid: The influence of molecular weight on structural, physical, physico-chemical, and degradable properties of biopolymer. Polymers (Basel). 2020;12(8):1800.
29. Juncan AM, Moisă DG, Santini A, et al. Advantages of hyaluronic acid and its combination with other bioactive ingredients in cosmeceuticals. Molecules. 2021;26(15):4429.
30. Yang C, Cao M, Liu H, et al. The high and low molecular weight forms of hyaluronan have distinct effects on CD44 clustering. J Biol Chem. 2012;287(51):43094–43107.
31. Kawada C, Yoshida T, Yoshida H, et al. Ingested hyaluronan moisturizes dry skin. Nutr J. 2014;13:70.
32. Di Cerbo A, Pezzuto F, Palmieri B. A dietary supplement improves facial photoaging and skin hydration. J Photochem Photobiol B. 2015;144:94–103.
33. Narins RS, Brandt F, Leyden J, et al. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg. 2003;29(6):588–595.
34. Kablik J, Monheit GD, Yu L, et al. Comparative physical properties of hyaluronic acid dermal fillers. Dermatol Surg. 2009;35(Suppl 1):302–312.
35. Chylińska N, Maciejczyk M. Hyaluronic acid and skin: its role in aging and wound-healing processes. 2025;11(4):281.
36. 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;151:1012–1029.
37. Dicker KT, Gurski LA, Pradhan-Bhatt S, et al. Hyaluronan: a simple polysaccharide with diverse biological functions. Acta Biomater. 2014;10:1558–1570.
38. Damodarasamy M, Johnson RS, Bentov I, et al. Hyaluronan enhances wound repair and increases collagen iii in aged dermal wounds. Wound Repair Regen. 2014;22:521–526.
39. Huynh A, Priefer R. Hyaluronic acid applications in ophthalmology, rheumatology, and dermatology. Carbohydr Res. 2020;489:107950.
40. Bukhari SNA, Roswandi NL, Waqas M, et al. Hyaluronic acid, a promising skin rejuvenating biomedicine: a review of recent updates and pre-clinical and clinical investigations on cosmetic and nutricosmetic effects. Int J Biol Macromol. 2018;120(Pt B):1682–1695.
41. Master M, Azizeddin A, Master V. Hyaluronic acid filler longevity in the mid-face: a review of 33 magnetic resonance imaging studies. Plast Reconstr Surg Glob Open. 2024;12(7):e5934.
42. Farwick M, Gauglitz G, Pavicic T, et al. Low molecular weight hyaluronic acid: its effects on epidermal gene expression and skin ageing. SOFW J. 2008;134:11.
43. Essendoubi M, Gobinet C, Polesel-Maris J, et al. Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy. Skin Res Technol. 2016;22(1):55–62.
44. Nashchekina YA, Raydan M. Noninvasive penetration of 5 nm hyaluronic acid molecules across the epidermal barrier (in vitro) and its interaction with human skin cells. Skin Res Technol. 2018;24(1):129–134.
45. Ni C, Wu H, Zhan X, et al. Hyaluronic acid and HA-modified cationic liposomes for promoting skin penetration and retention. J Control Release. 2023;357:432–443.
46. Ferguson EL, Duncan R, Denny WA. Evaluation of the physical and biological properties of hyaluronan and hyaluronan fragments. Int J Pharm. 2011;420(1):84–92.
47. Mineo A, Ricci M, Nicoli F, et al. Development of an artificial dermis composed of hyaluronic acid and collagen. J Biomater Sci Polym Ed. 2013;24(6):726-740.
48. Ke C, Sun L, Wang J, et al. Antioxidant activity of low molecular weight hyaluronic acid. Food Chem Toxicol. 2011;49(10):2670–2675.
49. Alaniz L, Cabrera PV, Blanco G, et al. Low molecular weight hyaluronan inhibits colorectal carcinoma growth by decreasing tumor cell proliferation and stimulating immune response. Cancer Lett. 2009;278(1):9–16.
50. Park D, Kim PH, Jin H, et al. Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ. Mol Cells. 2012;33(6):563–574.
51. Gariboldi S, Palazzo M, Zanobbio L, et al. Low molecular weight hyaluronic acid increases the self-defense of skin epithelium by induction of beta-defensin 2 via TLR2 and TLR4. J Immunol. 2008;181(3):2103–2110.
52. Dominika WP, Agnieszka S, Wojciech M. The interactions and release kinetics of sodium hyaluronate implemented in nonionic and anionic polymeric hydrogels, studied by immunoenzymatic ELISA test. Pharmaceutics. 2021;14(1):58.
53. Buckley C, Murphy EJ, Montgomery TR, et al. Hyaluronic acid: a review of the drug delivery capabilities of this naturally occurring polysaccharide. Polymers (Basel). 2022;14(17):3442.
54. Anna L, Jana K, Alena F, et al. Hyaluronic acid: known for almost a century, but still in vogue. Pharmaceutics. 2022;14(4):838.
55. Litwiniuk M, Krejner A, Speyrer MS, et al. Hyaluronic acid in inflammation and tissue regeneration. 2016;28(3):78–88.
56. Fakhari A, Berkland C. Applications and emerging trends of hyaluronic acid in tissue engineering, as a dermal filler and in osteoarthritis treatment. Acta Biomater. 2013;9(7):7081–7092.
57. Jabbari F, Babaeipour V, Saharkhiz S. Comprehensive review on biosynthesis of hyaluronic acid with different molecular weights and its biomedical applications. Int J Biol Macromol. 2023;240:124484.
58. Marinho A, Nunes C, Reis S. Hyaluronic acid: a key ingredient in the therapy of inflammation. 2021;11(10):1518.
59. Iaconisi GN, Lunetti P, Gallo N, et al. Hyaluronic acid: a powerful biomolecule with wide-ranging applications-a comprehensive review. Int J Mol Sci. 2023;24(12):10296.
60. Pavicic T, Gauglitz GG, Lersch P, et al. Efficacy of cream-based novel formulations of hyaluronic acid of different molecular weights in anti-wrinkle treatment. J Drugs Dermatol. 2011;10(9):990–1000.
61. Chudzińska J, Wawrzyńczak A, Feliczak-Guzik A. Microneedles based on a biodegradable polymer-hyaluronic acid. Polymers (Basel). 2024;16(10):1396.
62. Lu Q, Tang X, Tao B, et al. Multifunctional hyaluronic acid microneedle patch enhances diabetic wound healing in diabetic infections. Int J Biol Macromol. 2025;296:139685.
63. Jin AK, Yun KT, Woo KH, et al. Sodium hyaluronate facilitates skin penetration and hydration and improves microflora balance. J Cosmet Dermatol. 2023;22(2):533–539.
64. Baroni A, Buommino E, De Gregorio V, et al. Structure and function of the epidermis related to barrier properties. Clin Dermatol. 2012;30(3):257–262. 
65. Göllner I, Voss W, von Hehn U, et al. Ingestion of an oral hyaluronan solution improves skin hydration, wrinkle reduction, elasticity, and skin roughness: results of a clinical study. J Evid Based Complementary Altern Med. 2017;22(4):816–823.
66. Zhang Y, Wang B, Chen HC, et al. Association of claudin-1 and epidermal barrier function in UV-exposed skin of different ages. J Clin Dermatology. 2014;43:340–343.
67. Punzo A, Perillo M, Silla A, et al. Promising effects of novel supplement formulas in preventing skin aging in 3D human keratinocytes. Nutrients. 2024;16(16):2770.
68. Wyles S, Mehta R, Mannick J, et al. Skin longevity: A paradigm shift in aesthetics. J Cosmet Dermatol. 2024;23(9):2814–2815.
69. Widgerow AD, Ziegler ME, Shafiq F, et al. A re-examination of a previous study relating to topical body formulations: validating gene expression transcription at multiple time points, and protein expression and translation in an ex vivo model. Cosmetics. 2024;11(5):159.
70. Quan C, Cho MK, Perry D, et al. Age-associated reduction of cell spreading induces mitochondrial DNA common deletion by oxidative stress in human skin dermal fibroblasts: implication for human skin connective tissue aging. J Biomed Sci. 2015;22(1):62. 
71. Wilson D, Berardesca E, Maibach HI. In vivo transepidermal water loss and skin surface hydration in assessment of moisturization and soap effects. Int J Cosmet Sci. 1988;10(5):201–211.
72. Yasuoka H, Larregina AT, Yamaguchi Y, et al. Human skin culture as an ex vivo model for assessing the fibrotic effects of insulin-like growth factor binding proteins. Open Rheumatol J. 2008;2:17–22. 
73. Wong QYA, Chew FT. Defining skin aging and its risk factors: a systematic review and meta-analysis. Sci Rep. 2021;11(1):22075. 
74. Politano VT, Api AM. The Research Institute for Fragrance Materials' human repeated insult patch test protocol. Regul Toxicol Pharmacol. 2008;52(1):35–38.
75. Quan T, Fisher GJ. Role of age-associated alterations of the dermal extracellular matrix microenvironment in human skin aging: a mini-review. 2015;61(5):427–434. 
76. Potic J, Mbefo M, Berger A, et al. An in vitromodel of human retinal detachment reveals successive death pathway activations. Front Neurosci. 2020;14:571293.
77. Wurbs A, Karner C, Vejzovic D, et al. A human ex vivo skin model breaking boundaries. Sci Rep. 2024;14(1):24054.
78. Yang S, Kang W, Choi D, et al. Dihydromyrcenol modulates involucrin expression through the akt signaling pathway. Int J Mol Sci. 2024;25(4):2246. 
79. Zhang Z, Cheng B, Du W, et al. The role of nicotinamide mononucleotide supplementation in psoriasis treatment. Antioxidants (Basel). 2024;13(2):186.
80. Wu PY, Lyu JL, Liu YJ, et al. Fisetin regulates Nrf2 expression and the inflammation-related signaling pathway to prevent UVB-induced skin damage in hairless Mice. Int J Mol Sci. 2017;18(10):2118.
81. Zoio P, Ventura S, Leite M, et al. Pigmented full-thickness human skin model based on a fibroblast-derived matrix for long-term studies. Tissue Eng Part C Methods. 2021;27(7):433–443.
82. Yang F, Zhou Z, Guo M, et al. The study of skin hydration, anti-wrinkles function improvement of anti-aging cream with alpha-ketoglutarate. J Cosmet Dermatol. 2022;21(4):1736–1743.
83. Seok J, Hong JY, Choi SY, et al. A potential relationship between skin hydration and stamp-type microneedle intradermal hyaluronic acid injection in middle-aged male face. J Cosmet Dermatol. 2016;15(4):578–582.
84. Yoshioka H, Yamada T, Hasegawa S, et al. Senescent cell removal via JAG1-NOTCH1 signalling in the epidermis. Exp Dermatol. 2021;30(9):1268–1278. 
85. Wang F, Garza LA, Kang S, et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol. 2007;143(2):155–163.
86. Turlier V, Delalleau A, Casas C, et al. Association between collagen production and mechanical stretching in dermal extracellular matrix: in vivo effect of cross-linked hyaluronic acid filler. A randomised, placebo-controlled study. J Dermatol Sci. 2013;69(3):187–194.
87. Paliwal S, Fagien S, Sun X, et al. Skin extracellular matrix stimulation following injection of a hyaluronic acid-based dermal filler in a rat model. Plast Reconstr Surg. 2014;134(6):1224–1233.
88. Franchi G, Neiva-Vaz C, Picard A, et al. Facial injections of hyaluronic acid- based fillers for malformations. Preliminary study regarding scar tissue improvement and cosmetic betterment. Ann Chir Plast Esthet. 2018;63(3):197–204.
89. Few J, Cox SE, Paradkar-Mitragotri D, et al. A multicenter, single-blind randomized, controlled study of a volumizing hyaluronic acid filler for midface volume deficit: patient-reported outcomes at 2 years. Aesthet Surg J. 2015;35(5):589–599.
90. Baumann L, Narins RS, Beer K, et al. Volumizing hyaluronic acid filler for midface volume deficit: results after repeat treatment. Dermatol Surg. 2015;41(Suppl 1):S284–S292.
91. Zonari A, Brace LE, Al-Katib K, et al. Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models. NPJ Aging. 2023;9(1):10.
92. Glaser DA, Kenkel JM, Paradkar-Mitragotri D, et al. Duration of effect by injection volume and facial subregion for a volumizing hyaluronic acid filler in treating midface volume deficit. Dermatol Surg. 2015;41(8):942–949.
93. Jones D, Murphy DK. Volumizing hyaluronic acid filler for midface volume deficit: 2- year results from a pivotal single-blind randomized controlled study. Dermatol Surg. 2013;39(11):1602–1612.
94. Yokota M, Kamiya Y, Suzuki T, et al. Trehangelins ameliorate inflammation-induced skin senescence by suppressing the epidermal YAP-CCN1 axis. Sci Rep. 2022;12(1):952. 
95. Bertucci V, Lin X, Axford-Gatley RA, et al. Safety and effectiveness of large gel particle hyaluronic acid with lidocaine for correction of midface volume loss. Dermatol Surg. 2013;39(11):1621–1629.
96. Weiss RA, Moradi A, Bank D, et al. Effectiveness and safety of large gel particle hyaluronic acid with lidocaine for correction of midface volume deficit or contour deficiency. Dermatol Surg. 2016;42(6):699–709.
97. Zorina A, Zorin V, Kudlay D, et al. Molecular mechanisms of changes in homeostasis of the dermal extracellular matrix: both involutional and mediated by ultraviolet radiation. Int J Mol Sci. 2022;23(12):6655. 
98. Philipp-Dormston WG, Hilton S, Nathan M. A prospective, open-label, multicenter, observational, postmarket study of the use of a 15 mg/mL hyaluronic acid dermal filler in the lips. J Cosmet Dermatol. 2014;13(2):125–134.
99. Zhuo F, Abourehab MAS, Hussain Z. Hyaluronic acid decorated tacrolimus-loaded nanoparticles: Efficient approach to maximize dermal targeting and anti-dermatitis efficacy. Carbohydr Polym. 2018;197:478–489.
100. Dong J, Tao L, Abourehab MAS, et al. Design and development of novel hyaluronate-modified nanoparticles for combo-delivery of curcumin and alendronate: fabrication, characterization, and cellular and molecular evidences of enhanced bone regeneration. Int J Biol Macromol. 2018;116:1268–1281.
101. Zimbler MS, Kokoska MS, Thomas JR. Anatomy and pathophysiology of facial aging. Facial Plast Surg Clin North Am. 2001;9(2):179–187.
102. Prockop DJ, Kivirikko KI, Tuderman L, et al. The biosynthesis of collagen and its disorders (second of two parts). N Engl J Med. 1979;301(2):77–85. 
103. Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18–28.
104. Rao NV, Rho JG, Um W, et al. Hyaluronic acid nanoparticles as nanomedicine for treatment of inflammatory diseases. Pharmaceutics. 2020;12(10):931. 
105. Zhang K, Shi Z, Zhou J, et al. Potential application of an injectable hydrogel scaffold loaded with mesenchymal stem cells for treating traumatic brain injury. J Mater Chem B. 2018;6(19):2982–2992. 
106. Mauro N, Utzeri MA, Drago SE, et al. Hyaluronic acid dressing of hydrophobic carbon nanodots: A self-assembling strategy of hybrid nanocomposites with theranostic potential. Carbohydr Polym. 2021;267:118213.
107. Kamdem AF, Parmentier AL, Mauny F, et al. Assessment of care protocol using hyaluronic acid dressing in second-degree skin burns in children. Burns Open. 2021;5(3),118–124.
108. Jin R, Teixeira LS, Dijkstra PJ, et al. Enzymatically-crosslinked injectable hydrogels based on biomimetic dextran-hyaluronic acid conjugates for cartilage tissue engineering. Biomaterials. 2010;31(11):3103–3113.
109. Ratajczak P, Maciejak O, Kopciuch D, et al. Directions of hyaluronic acid application in cosmetology. J Cosmet Dermatol. 2023;22:862–871.
110. Bojarczuk K, Lewicki M, Morshed K, et al. Comparison of differences in knowledge about skincare between young women and men. J Educ Health Sport. 2017;7(8):1026–1038.
111. Olejnik A, Gościańska J, Nowak I. Significance of hyaluronic acid in cosmetic industry and aesthetic medicine. Chem. 2012;66(2):129–135.
112. Kononowicz WS, Malara B. Post-treatment physiological effects, adverse effects and complications after the selected aesthetic treatments. Review of the literature. Aesth Cosmetol Med. 2021;10(5):211–216.
113. Allemann IB, Baumann L. Hyaluronic acid gel (Juvéderm™) preparations in the treatment of facial wrinkles and folds. Clin Interv Aging. 2008;3:629–634.
114. Philipp-Dormston WG, Bergfeld D, Sommer BM, et al. Consensus statement on prevention and management of adverse effects following rejuvenation procedures with hyaluronic acid-based fillers. J Eur Acad Dermatol Venereol. 2017;31(7):1088–1095.
115. Wronowska L, Rodak I. Assessment of women's awareness of the skin ageing process and treatment options in a cosmetology salon. Aesth Cosmetol Med. 2020;9(3):319–328.