Hyaluronic acid (HA) is a naturally occurring substance found in the skin and other tissues, playing crucial roles in hydration, lubrication, and protection. Low-molecular-weight hyaluronic acid (LMW-HA), a smaller form of HA, exhibits enhanced skin penetration and possesses a range of potential benefits, including antioxidant, anti-tumor, and angiogenic properties. A recent review comprehensively examined the current scientific understanding and clinical applications of LMW-HA in dermatology, encompassing its use in medical conditions such as wounds, rosacea, and scars, as well as in cosmetic applications like addressing skin aging and enhancing hydration. The review analyzed research published from 2003 to 2023, identifying promising applications for LMW-HA in various dermatological procedures. 

LMW-HA Safety

LMW-HA exhibits a favorable safety profile for topical and oral applications. Numerous studies have demonstrated its safety and effectiveness in wound healing, skin conditions, and cosmetic procedures. However, in filler applications, LMW-HA released from the breakdown of higher molecular weight (HMW) HA injectable filler may contribute to the formation of nodules or granulomas, and induce the expression of pro-inflammatory cytokines, particularly TNF-α. 

Impact of Size on Skin Penetration

LMW-HA's smaller molecular size, compared to HMW-HA, allows it to penetrate the skin more effectively. The outermost layer of the skin, the stratum corneum, acts as a protective barrier, regulating the passage of substances into and out of the skin. This barrier is composed of tightly packed cells and lipids, creating a challenging obstacle for molecules to cross. The size of a molecule significantly influences its ability to penetrate the skin. Smaller molecules, in general, have a better chance of navigating the spaces between skin cells and passing through the lipid layers.

HMW-HA, due to its larger molecular weight, primarily sits on the surface of the skin, providing hydration and supporting barrier function. In contrast, LMW-HA's smaller size allows it to penetrate more deeply into the skin layers. Farwick et al. (2008) demonstrated that LMW-HA had greater penetrative ability compared to HMW-HA in an in vitro study. Essendoubi et al. (2016) used Raman spectroscopy to probe the penetration of HA molecules of different sizes into human skin. They found that smaller HA molecules penetrated more deeply. Nashchekina and Raydan (2018) also focused on the penetration of HA into the skin. The authors found that LMW-HA with a size of 5 nm could penetrate the epidermal barrier.

The ability to penetrate the skin makes LMW-HA a promising candidate for drug delivery systems. It can potentially be used to transport other beneficial molecules, such as antioxidants or anti-inflammatory agents, into the skin. The depth of penetration also influences the biological activity of HA. Once LMW-HA reaches deeper skin layers, it can interact with cells and trigger various processes, such as collagen synthesis or the production of signaling molecules involved in wound healing.

The ability of LMW-HA to penetrate the skin, attributed to its smaller molecular size, distinguishes it from HMW-HA and opens up a wide range of potential applications in dermatology.

Applications of LMW-HA in Dermatology

In wound healing, LMW-HA has been shown to be effective in treating both acute and chronic wounds. It activates toll-like receptors 2 and 4, which promote the production of beta-defensin-2, an important molecule for the skin's defense against microbes. Additionally, it decreases TNF-ɑ, IL-1β, and IL-6, promotes angiogenesis, collagen expression, and wound healing. Studies have also shown that wound dressings containing LMW-HA can facilitate wound healing. A case report documented LMW-HA contributing to the healing of a difficult-to-treat venous ulcer.

Studies have shown that LMW-HA is safe and effective for treating seborrheic dermatitis, rosacea, and scars. LMW-HA has also shown promise in improving signs of skin aging, such as wrinkles and loss of elasticity. It can increase Type I collagen, decrease matrix metalloproteinase-1, and increase laminin-332 and fibrillin-1 in the dermoepidermal junction. Topical LMW-HA at 50 kDa has been shown to decrease roughness and the appearance of wrinkles.

LMW-HA plays a role in post-procedure healing after cosmetic and surgical procedures, including promoting healing after ingrown toenail surgery and improving recovery time after chemical peels.

Studies have shown that LMW-HA can increase the expression of filaggrin, a protein that plays a vital role in maintaining skin hydration and barrier function. By supporting filaggrin production, LMW-HA contributes to a healthier and more hydrated skin barrier. Further LMW-HA itself has a remarkable ability to bind and retain water molecules, helping to keep the skin plump and hydrated. These hydrating properties make LMW-HA a valuable ingredient in various cosmetic products designed to address dry skin.

Conclusion

LMW-HA exhibits significant potential in various dermatological applications due to its enhanced skin penetration compared to HMW-HA. Its ability to penetrate deeper skin layers allows it to interact with cellular processes, influencing collagen synthesis, modulating inflammation, and promoting wound healing. With an excellent safety profile in topical and oral applications, LMW-HA demonstrates promise as a valuable tool in modern dermatology, offering potential benefits for wound healing, skin aging, and the management of various skin conditions. NeuLuna Day and Night Cream features a patented delivery system that increases the skin absorption of LMW-HA. Learn more here.

Reference

Waggett, S., Lyles, E., & Schlesinger, T. (2024). Update on low-molecular weight hyaluronic acid in dermatology: A scoping review. EMJ Dermatology, 12(1), 134-146. https://doi.org/10.33590/emjdermatol/CCHB4701