Hyaluronic acid: which active ingredients should it be paired with?

The hyaluronic acid and the collagen are closely linked in the extracellular matrix of the dermis.

Indeed, collagen imparts structural integrity and mechanical strength to the skin, while hyaluronic acid occupies intercellular spaces by retaining large quantities of water, thereby maintaining the elasticity of connective tissue. These two components interact: hyaluronic acid creates a hydrated environment conducive to fibroblast activity (the cells responsible for collagen synthesis) and indirectly contributes to the regeneration of the dermal matrix.

When applied topically, the collagen is unable to penetrate deeply into the skin due to its high molecular weight. However, it provides an immediate hydrating effect by forming an occlusive film on the surface of the epidermis. Some formulations use collagen peptides, smaller fragments that can penetrate further and stimulate endogenous collagen synthesis by activating fibroblasts, as shown in several studies in vitro. Meanwhile, low-molecular-weight hyaluronic acid can also stimulate fibroblast activity, while its high-molecular-weight form similarly remains on the surface and forms a hydrating and protective film.

Combining collagen and hyaluronic acid enhances skin hydration at multiple levels and improves its elasticity.

Although no purely cosmetic research has evaluated this combination, a clinical study examined its potential to limit postoperative complications associated with wisdom tooth extraction. Twenty participants were included, each receiving both treatments in a randomized manner: collagen alone on one side and collagen enriched with hyaluronic acid on the other. The authors measured mouth opening and the degree of swelling on the third and seventh postoperative days. The results show a overall reduction in facial swelling more pronounced on the side that received both active agents. This study appears to indicate that adding hyaluronic acid to the collagen-based solution had a soothing effect.

The niacinamide, or vitamin B3, is an active ingredient commonly used in cosmetics. It offers numerous skin benefits and notably helps to strengthen the barrier function of the epidermis, attenuate hyperpigmentation and redness linked to inflammation. Moreover, at the cellular level, niacinamide reduces free radical production and limits the activation of the SASP (senescence-associated secretory phenotype), a biomarker linked to premature skin aging. Studies in vitro have demonstrated that it slows the entry of cells into senescence, extends fibroblast lifespan, and stimulates keratinocyte proliferation, thereby delaying the onset of wrinkles.

The combination of hyaluronic acid and niacinamide is particularly beneficial for hydrating the skin and caring for mature skin.

This combination was evaluated in a series of experiments ex vivo conducted on human skin explants obtained after abdominoplasty. A formulation containing 6% niacinamide and 0.2% hyaluronic acid distributed between high molecular weight (>1 MDa) and intermediate fragments (≈120 kDa) was applied for three days. Alcian blue staining revealed a notable densification of the dermal matrix, with a 52% increase in glycosaminoglycans compared to untreated explants. Moreover, under UVA irradiation (20 J/cm² over three days), explants treated with hyaluronic acid and niacinamide showed marked protection against dermal collagen degradation, whereas irradiated untreated explants displayed disruption of the collagen network.

These promising results were confirmed in vivo in a clinical study involving 44 women aged 38 to 55. Over an eight-week period, they applied a daily formulation containing 5% niacinamide and 0.2% hyaluronic acid. After just one month, significant improvements were observed : 64% of participants exhibited smoother skin and their complexion was, on average, 21% more radiant. After two months, the effects were even more pronounced: all volunteers reported a brighter complexion (+44% radiance on average), 95% exhibited visibly smoother skin (+39%) and firmer, plumper skin (+39%). Finally, wrinkle depth decreased by an average of 20%.

The combination of hyaluronic acid and vitamin C ranks among the most widely used in cosmetics. These two molecules act at different levels, yet synergistic : vitamin C primarily functions as an antioxidant and helps to even out skin tone, while hyaluronic acid helps maintain hydration and the integrity of the skin’s barrier function.

The combination of hyaluronic acid and vitamin C enables the simultaneous targeting of multiple aspects of skin aging: oxidative stress, inflammation, loss of radiance, wrinkles, and hyperpigmented spots...

This synergy was explored in a study in vitro published in 2017. It focused on the effects of hyaluronic acid and vitamin C on chondrocytes, the cells of articular cartilage, under inflammatory stress simulated by interleukin-1β, a proinflammatory cytokine. The researchers evaluated the effects of hyaluronic acid (100 µg/mL) and vitamin C as ascorbic acid (50 µg/mL) on these cells separately and in combination. In chondrocytes subjected to inflammation, the dual treatment enabled a significant restoration of cell morphology and viability, slightly surpassing the results seen with each compound alone. This improvement was accompanied by a marked reduction in IL-1β-induced cytotoxicity, suggesting a protective effect against inflammatory stress.

Furthermore, the researchers observed a significant decrease in the expression of metalloproteinases MMP-3 and MMP-9, enzymes that degrade the extracellular matrix. Antioxidant activity was also enhanced, with an increase in the expression of superoxide dismutase (SOD), an enzyme that scavenges free radicals produced by metabolism. These results, even though they were not obtained in skin cells, support the idea that the combination of hyaluronic acid and vitamin C could limit oxidative stress and inflammation on the skin, thereby helping to preserve the integrity of the dermis.

The vitamin E, or tocopherol, is a lipid-soluble antioxidant naturally present in the superficial layers of the epidermis. It plays an essential role in neutralizing free radicals generated by repeated UV exposure and pollution. By reducing the oxidation of membrane lipids, vitamin E contributes to preserving the skin barrier. It is also present in sebum, where it protects its constituents from oxidation, notably squalene, which, when oxidized to squalene peroxide, becomes comedogenic. That is why vitamin E is sometimes considered a marker of acne severity. It is also known for its soothing and anti-inflammatory properties. Vitamin E is widely used in cosmetic formulations and is often paired with hyaluronic acid.

Combining vitamin E with hyaluronic acid helps protect the skin from dehydration and oxidative stress.

The aloe vera is a medicinal plant known for its richness in polysaccharides, notably acemannan, and for its moisturizing, anti-inflammatory, and healing properties. When applied to the skin, aloe vera gel primarily acts by forming a protective film that limits water evaporation, soothes irritation, and promotes the regeneration of keratinocytes and fibroblasts. Aloe vera is particularly used to care for the skin after exposure to the sun and to support the healing of superficial wounds. It is suitable for all skin types, even the most sensitive.

Combining hyaluronic acid with aloe vera enhances skin hydration while soothing sensitive skin.

A study published in 2021 evaluated the effect of a gel combining aloe vera and hyaluronic acid (AV-HA) on the healing of superficial burns in 54 rabbits. Four groups were established: an untreated group, a group treated with hyaluronic acid alone, another with the aloe vera–hyaluronic acid combination, and a final group treated with silver sulfadiazine (SSD) cream, a compound often used to soothe burns. The products were applied once daily for 21 days. After 21 days, the reduction in burn area was significantly greater in the AV-HA group (1.12 ± 0.07 cm²) compared with hyaluronic acid alone (1.56 ± 0.05 cm²), SSD (1.64 ± 0.06 cm²), and the untreated group (2.65 ± 0.09 cm²), as shown in the table below. These results suggest a synergy between aloe vera and hyaluronic acid in accelerating skin repair.

Organized into intercellular lipid bilayers, ceramides ensure cohesion of corneocytes and limit transepidermal water loss, thus maintaining the hydrolipid barrier and contributing to supple, resilient skin against external aggressors. When applied topically, ceramides are able to restore an impaired barrier, particularly in cases of xerosis or atopic dermatitis. The ceramides also possess wound-healing properties. Indeed, some studies have shown that these agents can modulate eicosanoid levels, molecules involved in regulating inflammation and the healing process.

Combining ceramides with hyaluronic acid is particularly beneficial for dry and dehydrated skin.

The retinoids are a family of vitamin A derivatives. There are several forms, including tretinoin (retinoic acid), retinol, retinaldehyde, and retinyl esters, each with different potency and tolerability. Retinol, for example, must be oxidized to retinal and then to retinoic acid to become active at the cellular level, making it less irritating but also less potent than tretinoin. Retinoids primarily act by binding to nuclear RAR and RXR receptors, thereby modulating the expression of genes involved in keratinocyte proliferation, epidermal differentiation, and collagen synthesis. They promote cell turnover, improve pigment uniformity, stimulate type I collagen production, and decrease metalloproteinase activity, which makes them a reference against photoaging.

Combining retinoids with hyaluronic acid enhances their effects on signs of aging while minimizing the risk of irritation through improved skin hydration.

A large study involving 1,462 participants assessed the efficacy of combining retinaldehyde (RAL 0.05%) with intermediate-sized hyaluronic acid fragments (HAFi, 0.5–1%) to mitigate signs of photoaging. Three groups were formed: group 1 (cream with RAL 0.05% and HAFi 0.5%), group 2 (anti-wrinkle concentrate with RAL 0.05% and HAFi 1%), and group 3 (combination of both products). The formulations were applied daily for 90 days. At the end of the study, all three groups showed a significant improvement in the photoaging score, with marked reductions in forehead wrinkles (–19%), nasolabial folds (–20%), crow’s feet (–27%), and perioral lines (–34%). Meanwhile, skin elasticity improved by 32–33%, and hyperpigmentation decreased by more than 30%.

The bakuchiol is a plant-derived compound extracted from the seeds of Psoralea corylifolia. It is often presented as a natural alternative to retinoids due to its similar effects on the skin. Studies have shown that bakuchiol stimulates collagen production, reduces the activity of metalloproteinases, and improves skin tone uniformity. Bakuchiol is nevertheless better tolerated than retinoids, as it does not cause irritation or peeling, making it particularly appealing for sensitive skin. Furthermore, bakuchiol exhibits antioxidant and anti-inflammatory properties, helping to protect the skin from oxidative stress and environmental aggressors.

Combining bakuchiol with hyaluronic acid could enhance their firming and hydrating effects. To date, no scientific study has evaluated this combination, but their complementary mechanisms suggest a potential benefit.

Glycolic acid is an alpha-hydroxy acid (AHA) primarily obtained from sugarcane. Due to its small molecular size, it penetrates the epidermis efficiently. Glycolic acid functions mainly as a keratolytic agent by promoting exfoliation of dead cells in the stratum corneum. It also stimulates cellular turnover and enhances skin radiance. Glycolic acid is especially used to correct pigmentation irregularities, smooth fine lines, and diminish the acne scars.

While few products are formulated with both glycolic acid and hyaluronic acid, these two active ingredients are very often used in the same skincare routine: one to smooth and the other to rehydrate after exfoliation.

A clinical study conducted on 100 patients with melasma evaluated the efficacy and tolerability of various combinations of active agents. Participants were divided into five groups: group 1 (hydroquinone alone), group 2 (hydroquinone + glycolic acid), group 3 (hydroquinone + hyaluronic acid), group 4 (hydroquinone + glycolic acid + hyaluronic acid), and group 5 (placebo). After daily application for twelve weeks, groups 1, 3, and 4 showed a significant improvement in MASI scores, indicating a clear reduction in hyperpigmentation. In terms of side effects, the addition of hyaluronic acid (group 4) helped mitigate them compared with the same formulation without hyaluronic acid (group 2). These results suggest that hyaluronic acid could enhance skin tolerance to glycolic acid.

Salicylic acid is a beta-hydroxy acid (BHA) primarily recognized for its keratolytic, comedolytic, and anti-inflammatory properties. Being lipophilic, it has the ability to penetrate the sebaceous glands and unclog pores by dissolving the lipid bonds between corneocytes. Therefore, salicylic acid is highly valued for oily or acne-prone skin.

Even though there are no known contraindications for the combination of salicylic acid with hyaluronic acid, clinical studies on this combination are almost non-existent to date.

That being said, it seems plausible that hyaluronic acid, owing to its moisturizing and soothing properties, could mitigate the potentially drying or irritating effects of salicylic acid, particularly in individuals with combination skin that tends to be dehydrated or sensitive.

Lactic acid is an alpha-hydroxy acid (AHA) naturally found in the skin as a component of the natural moisturizing factor (NMF). It is used in cosmetics for its gentle keratolytic and moisturizing properties. Less irritating than other AHAs, like glycolic acid, it works by weakening the bonds between corneocytes, thereby facilitating their exfoliation and cellular renewal. It also helps to improve skin texture, reduce pigmentation spots, and stimulate the production of ceramides in the epidermis, which supports the barrier function. At low concentrations (< 5%), it has a moisturizing effect, while at higher doses, it is used for its exfoliating action.

Associating lactic acid with hyaluronic acid could theoretically enhance skin hydration while providing gentle exfoliation. However, there is currently no study on this combination.

Finally, mandelic acid is another AHA derived from bitter almonds. It has a relatively high molecular weight, allowing it to penetrate the skin slowly, and is generally better tolerated than glycolic acid. Like lactic acid, it exhibits mild keratolytic action. Mandelic acid is distinguished by its antibacterial effects, particularly against Escherichia coli, Proteus mirabilis, Klebsiella pneumonia , and Staphylococcus aureus, which are useful for rebalancing the skin microbiome.

The combination of mandelic acid and hyaluronic acid is based on the same principle as that of lactic acid and hyaluronic acid: providing the skin with gentle exfoliation and enhanced hydration. However, there are no studies validating this combination.

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