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

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

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

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

Combining collagen with hyaluronic acid enhances skin hydration on multiple levels, as well as its elasticity.

Although no purely cosmetic research has evaluated this combination, a clinical trial investigated its potential to limit postoperative complications associated with wisdom tooth extraction. Twenty participants were enrolled, each receiving both treatments in a randomised manner: collagen alone on one side and collagen enriched with hyaluronic acid on the other. The authors measured mouth opening and the extent of swelling on the third and seventh days following the intervention. The results show an overall reduction in facial swelling that was more pronounced on the side treated with both active agents. This study suggests 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 benefits for the skin, notably helping to strengthen the barrier function of the epidermis, diminish hyperpigmentation and reduce redness associated with inflammation. Moreover, at the cellular level, niacinamide decreases free radical production and limits activation of the SASP (senescence-associated secretory phenotype), a biomarker linked to premature skin ageing. Studies in vitro have shown that it slows cellular entry into senescence, extends fibroblast lifespan and stimulates keratinocyte proliferation, thereby delaying the onset of wrinkles.

The combination of hyaluronic acid and niacinamide is particularly effective 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 over three days. Alcian blue staining revealed a notable densification of the dermal matrix, with a 52% increase in glycosaminoglycans compared with untreated explants. Moreover, under UVA irradiation (20 J/cm² over three days), explants treated with hyaluronic acid and niacinamide exhibited marked protection against dermal collagen degradation, whereas untreated irradiated explants displayed a disorganisation of the collagen network.

These promising results have been confirmed in vivo in a clinical trial involving 44 women aged 38 to 55 years. Over eight weeks, they applied the formulation containing 5% niacinamide and 0.2% hyaluronic acid daily. As early as one month, significant improvements were observed : 64% of participants had smoother skin and their complexions were on average 21% more radiant. By the end of two months, the results were even more marked: all volunteers reported a brighter complexion (+44% radiance on average), 95% exhibited visibly smoother skin (+39%) and increased plumpness (+39%). Finally, wrinkle depth decreased by an average of 20%.

The association between hyaluronic acid and vitamin C is among the most commonly used in cosmetics. These two molecules act on different yet synergistic levels: vitamin C primarily functions as an antioxidant and helps to even out skin tone, while hyaluronic acid supports 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 ageing: oxidative stress, inflammation, loss of radiance, wrinkles and pigmentation spots...

This synergy was explored during a study in vitro published in 2017. It examined the effects of hyaluronic acid and vitamin C on chondrocytes, the cells of articular cartilage, under simulated inflammatory stress induced by interleukin-1β, a pro-inflammatory cytokine. The researchers evaluated separately and then jointly the impact of hyaluronic acid (100 µg/mL) and vitamin C as ascorbic acid (50 µg/mL) on these cells. In inflamed chondrocytes, the combination of both agents led to a significant restoration of cell morphology and viability, slightly surpassing the effects observed with each compound alone. This improvement was accompanied by a marked reduction in IL-1β-induced cytotoxicity, suggesting a protective effect against inflammatory stress.

Moreover, the researchers observed a significant decrease in the expression of the matrix metalloproteinases MMP-3 and MMP-9, enzymes that degrade the extracellular matrix. Antioxidant activity was also strengthened, with a rise in superoxide dismutase expression (SOD), an enzyme that traps free radicals produced by metabolism. These results, although not obtained with skin cells, support the notion that the combination of hyaluronic acid and vitamin C could mitigate oxidative stress and inflammation in the skin, thereby helping to preserve dermal integrity.

The vitamin E, or tocopherol, is a naturally occurring lipid-soluble antioxidant present in the superficial layers of the epidermis. It plays a vital role in neutralising free radicals generated by repeated UV exposure and environmental pollution. By reducing membrane lipid oxidation, vitamin E helps maintain the skin barrier. It is also present in sebum where it protects its constituents from oxidation, notably squalene which, when oxidised to squalene peroxide, becomes comedogenic. That is why vitamin E is sometimes regarded as a marker of acne severity. It is also known for its soothing and anti-inflammatory properties. Vitamin E is widely used in cosmetic products, and it is often combined with hyaluronic acid.

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

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

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

A study published in 2021 assessed 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 and hyaluronic acid combination, and a final group treated with silver sulphadiazine 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.

Organised into intercellular lipid bilayers, ceramides ensure the cohesion of corneocytes and limit insensible water loss, thereby preserving the hydrolipidic barrier and contributing to supple, resilient skin in the face of external aggressions. When applied topically, ceramides are capable of restoring a compromised barrier, particularly in cases of xerosis or atopic dermatitis. These ceramides also possess wound-healing properties. Indeed, some studies have shown that these active compounds can modulate eicosanoid concentrations, molecules involved in regulating inflammation and the healing process.

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

The retinoids are a family of vitamin A derivatives. Several forms can be distinguished, including tretinoin, or retinoic acid, retinol, retinaldehyde and retinyl esters, each with differing potency and tolerability. Retinol, for example, must be oxidised to retinal and then to retinoic acid to become active at the cellular level, making it less irritating than tretinoin but also less potent. Retinoids primarily act by binding to the nuclear receptors RAR and RXR, thereby modulating the expression of genes involved in keratinocyte proliferation, epidermal differentiation and collagen synthesis. They promote cell turnover, improve pigment homogeneity, stimulate type I collagen production while reducing that of metalloproteinases, which makes them a benchmark against photoageing.

Combining retinoids with hyaluronic acid potentiates their effects on signs of ageing while limiting the risk of irritation thanks to improved skin hydration.

A large-scale study involving 1,462 participants evaluated the efficacy of combining retinaldehyde (RAL 0.05%) with intermediate‐size hyaluronic acid fragments (HAFi, 0.5 to 1%) to mitigate signs of photoageing. 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 (the combination of both products). The products were applied daily for 90 days. At the end of the study, all three groups showed a significant improvement in photoageing score, with marked reductions in forehead wrinkles (−19%), nasolabial folds (−20%), crow’s feet (−27%) and perioral wrinkles (−34%). Concurrently, skin elasticity improved by 32–33% and hyperpigmentation decreased by over 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 matrix metalloproteinase activity and enhances skin tone uniformity. It is, however, better tolerated than retinoids, causing neither irritation nor flaking, which makes it particularly suitable for sensitive skin. Moreover, bakuchiol possesses antioxidant and anti-inflammatory properties, helping to protect the skin from oxidative stress and environmental aggressors.

Combining bakuchiol with hyaluronic acid could reinforce their tightening and moisturising 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 derived from sugar cane. Thanks to its low molecular weight, it effectively penetrates the epidermis. Glycolic acid mainly acts as a keratolytic agent by promoting the exfoliation of dead cells in the stratum corneum. It also stimulates cell renewal and enhances skin radiance. Glycolic acid is particularly employed to correct pigment irregularities, smooth fine lines and reduce acne scarring.

Although few products are formulated with both glycolic acid and hyaluronic acid, these two active ingredients are very often used in the same skincare routine: the former to smooth the skin, the latter to rehydrate it after exfoliation.

A clinical study conducted on 100 patients with melasma assessed the efficacy and tolerability of various active-ingredient combinations. Participants were allocated 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 exhibited a significant improvement in MASI score, indicating a marked reduction in hyperpigmentation. As for side effects, the addition of hyaluronic acid (group 4) mitigated them compared with the same formulation without hyaluronic acid (group 2). These findings suggest that hyaluronic acid could improve the cutaneous tolerability of glycolic acid.

The salicylic acid is a beta-hydroxy acid (BHA) best known for its keratolytic, comedolytic, and anti-inflammatory properties. Being lipophilic, it has the ability to penetrate the sebaceous glands and unclog pores by dissolving lipid bridges between corneocytes. Thus, salicylic acid is highly valued by individuals with oily or acne-prone skin.

Even though there are no known contraindications to 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 moisturising and soothing properties, could modulate the potentially drying or irritating effects of salicylic acid, particularly in individuals with combination skin that is prone to dehydration or sensitivity.

Lactic acid is an alpha-hydroxy acid (AHA) naturally present in the skin as a component of the natural moisturising factor (NMF). It is used in cosmetics for its gentle keratolytic and hydrating properties. Less irritating than other AHAs, such as glycolic acid, it works by weakening the bonds between the 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, enhancing the barrier function. At low concentration (< 5%), it has a moisturising effect, while at higher doses, it is used for its exfoliating action.

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

Finally, mandelic acid is another AHA derived from bitter almonds. With a relatively high molecular weight, it penetrates the skin slowly and is generally better tolerated than glycolic acid. Like lactic acid, it has a gentle keratolytic effect. Mandelic acid is notable for its antibacterial effects, particularly against Escherichia coli, Proteus mirabilis, Klebsiella pneumonia , and Staphylococcus aureus, which are beneficial 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: to provide gentle exfoliation and improved hydration for the skin. However, there are currently no studies validating this combination.

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