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Keratinocytes

Evaluation of a Broad-Molecular-Weight Hyaluronic Acid Complex Using Human Skin Models

/ by Lifeline® Cell Technology

Psoriasis Action Month

Psoriasis is a chronic inflammatory skin disease that causes skin cells to multiply too quickly, resulting in dry, itchy, scaly plaques. In addition to inflammation, the skin barrier is often compromised, leading to increased transepidermal water loss (TEWL) and reduced moisture retention. While moisturizers and barrier-supporting ingredients do not treat psoriasis itself, maintaining skin hydration is an important part of supporting overall skin barrier function.

One of the most widely used ingredients for skin hydration is hyaluronic acid (HA). HA is a naturally occurring polysaccharide that attracts and retains water, helping to maintain skin hydration and support epidermal barrier function. However, not all HA performs the same. Its biological activity depends largely on molecular weight (MW), which influences how deeply it penetrates the skin and how it interacts with different layers of the epidermis.

A recent study evaluated a broad-molecular-weight hyaluronic acid complex using advanced human skin models to better understand how combining multiple HA molecular weights may enhance hydration, barrier function, and overall skin performance.

HA20: Assessing the Multi-Functional Activity of Broad-Spectrum Hyaluronic Acid

The relationship between HA MW and biological activity is complex. Higher-MW HA primarily remains at the skin surface to support hydration, reinforce the skin barrier, and maintain tissue homeostasis, whereas lower- and intermediate-MW HA fractions can penetrate more deeply into the skin to activate cellular repair mechanisms. Because each molecular weight range contributes unique biological benefits, combining multiple HA sizes into a broad-spectrum formulation may provide more comprehensive skin support and protection than a single MW alone.

Wang et al. evaluated HA20, an optimized broad-spectrum hyaluronic acid complex with a MW distribution of approximately 10–1000 kDa (~200 kDa), to test this idea. In this model, the low MW fractions penetrate the deep dermis to repair UVA-induced damage, whereas the intermediate-MW fractions remain in the viable epidermis to trigger a structural repair program. To evaluate these effects, the researchers used LifeLine®’s Normal Human Dermal Fibroblasts (NHDFs), Normal Human Epidermal Keratinocytes (NHEKs), and FibroLife® Serum-Free Medium, together with a 3D reconstructed human epidermis (RHE) model. These physiologically relevant human skin models enabled the team to investigate HA20’s biological activity.

First, HA20 was evaluated for safety and compatibility in NHEKs using the CCK-8 assay. HA20 was well tolerated across the tested concentration range (0.0001–0.1%), with cell viability remaining comparable to untreated controls. Based on these results, 0.1% HA20 was selected for subsequent functional studies.

At the dermal level, HA20 demonstrated protective and regenerative effects associated with maintaining skin structure and reducing signs of aging. In NHDFs, HA20 increased production of type I collagen and elastin, essential components of the extracellular matrix (ECM) responsible for skin strength and elasticity. HA20 also reduced levels of Nε-(carboxymethyl)lysine (CML), an advanced glycation end-product (AGE) that stiffens the collagen-elastin in the ECM network, resulting in loss of skin elasticity over time. Additionally, HA20 restored mitochondrial function following UVA exposure by increasing mitochondrial membrane potential back to control levels, suggesting protection against photoaging-related cellular stress.

In the epidermis, HA20 can modulate epidermal inflammation by specifically suppressing the expression of Th2-driven pruritus-associated keratinocyte markers. HA20 reduced the expression of neurogenic itch markers (NELL2, CAII) in NHEKs triggered by IL4/IL3 cytokines. To further assess barrier protection, the team exposed the RHE model to severe dryness stress. Untreated tissues showed disruption of the stratum corneum, including separation and loss of the outer protective layer. In contrast, HA20-treated tissues maintained a more organized and intact stratum corneum structure, like the control group. Gene expression analysis showed activation of the PI3K-AKT and focal adhesion pathways, which are associated with epidermal repair, barrier integrity, and lipid metabolism, supporting the role of HA20 in maintaining skin structure under stress conditions.

Overall, these findings demonstrate that HA20 provides multi-functional skin defense against environmental stressors by combining the complementary activities of different molecular weight HA fractions. The mix of molecule sizes helps to protect and repair different layers of the skin by targeting glycation, photo-oxidation, neurogenic inflammation, and dehydration together to provide broad-spectrum skin defense.

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