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Does Low Molecular Weight Hyaluronic Acid Cause Inflammatory Reactions?

One of the most well-known functions of hyaluronic acid (HA) is moisturization. Additionally, HA can help reduce wrinkles and accelerate wound healing. However, some believe that while high molecular weight HA has anti-inflammatory effects, low molecular weight HA may trigger inflammatory reactions. But is this really true?

Low Molecular Weight Hyaluronic Acid Penetrates Deep into the Epidermis

In skincare, low molecular weight hyaluronic acid has long been considered more effective due to its excellent transdermal absorption, allowing it to penetrate deep into the basal layer of the epidermis. Researchers used Raman imaging to study the penetration of HA of different molecular weights into human skin tissue.[1] They found that among HA with molecular weights of 1000–1400 kDa, 100–300 kDa, and 20–50 kDa:

• 20–50 kDa HA can penetrate deep into the epidermis;
• 100–300 kDa HA can reach the stratum lucidum;
• Large molecular weight HA (1000–1400 kDa) remains only in the stratum corneum (at a depth of 25 μm).

Even smaller oligomeric hyaluronic acid can penetrate further into the dermis. This gives low molecular weight HA greater potential in moisturizing, repairing, and anti-aging.

Fig 1. High molecular weight vs. low molecular weight hyaluronic acid

Does Low Molecular Weight Hyaluronic Acid Cause Skin Inflammation?

It is widely known that hyaluronic acid is naturally present in the human body. In fact, the process of wound repair in the body involves the degradation and regeneration of HA:

1. High molecular weight HA aggregates to clear necrotic tissue and bacteria.
2. During the inflammation stage, high molecular weight HA degrades into low molecular weight HA, inducing cytokine production.
3. Angiogenesis and cell migration occur.
4. Fibroblast proliferation completes the repair process.

Fig 2. Involvement of hyaluronic acid in the wound-healing process[2]

In this process, low molecular weight hyaluronic acid does mediate certain inflammatory responses, such as immune cell aggregation and cytokine expression. However, this is a normal part of the repair mechanism and should not be simply viewed as a negative effect.

Multiple studies have shown that exogenous hyaluronic acid has beneficial effects on wound healing. Topical application of hyaluronic acid has been proven to accelerate skin wound healing in rats and hamsters. Other studies indicate that both high and low molecular weight Hyaluronic acid have anti-inflammatory effects in UVB-induced keratinocyte inflammation.[3]

Although some studies suggest that low molecular weight HA may cause increased inflammatory responses, the mechanism behind this phenomenon remains unclear. Some scholars argue that the inflammation observed in experiments may be due to contaminants in the samples. For example, FDA-related experiments showed that even HA with a molecular weight as low as 4.77 KDa did not cause inflammatory reactions in mouse macrophages.

The studies on the pro-inflammatory effects of LMW-HA have only been discussed in the context of injury, with no mention of its implications in daily skincare routines.

What Are the Functions of Low Molecular Weight Hyaluronic Acid?

In skincare, the greatest advantage of low molecular weight HA lies in its ability to be absorbed transdermally, providing deep moisturization. However, beyond moisturizing, low molecular weight HA has many other functions:

1. Promotes Cell Proliferation and Wound Healing

LMW-HA is widely present in the dermis, epidermis, and subcutaneous tissues of human skin, with the highest concentration in the dermis. It helps maintain skin structural stability by regulating moisture, osmotic pressure, and ion flow, and facilitates substance exchange. When tissue is injured, macrophages in the body gather at the wound site and secrete hyaluronidase. This enzyme breaks down endogenous high-molecular-weight hyaluronic acid into low-molecular-weight fragments. These small fragments act like an “alarm signal,” attracting immune cells and endothelial cells to migrate toward and accumulate at the injury site. During this process, endothelial cells proliferate and new blood vessels form, supplying oxygen and nutrients to the damaged tissue, thereby accelerating the repair process.

2. Anti-Photoaging

Skin aging is a complex process, and photoaging caused by ultraviolet (UV) radiation is a significant external factor. Studies show that under UVB exposure, the content of HA in the skin increases, with a notable rise in the proportion of low molecular weight HA. Thus, it can be said that LMW-HA participates in the skin’s anti-photoaging process and helps reduce photodamage.

Conclusion

There is currently insufficient evidence to suggest that low molecular weight HA used in skincare products causes harmful inflammation. On the contrary, it demonstrates significant efficacy in moisturizing, repairing, and anti-aging.

For other questions about HA, you can check our previous articles. If you are looking for sodium hyaluronate powder for use in cosmetics, eye drops, wound dressings, or medical devices, Stanford Chemical Company (SCC) is a good option.

• Is Hyaluronic Acid Antibacterial? Mechanisms and Applications
• How Hyaluronic Acid is Absorbed and Degraded in the Human Body
• What is Hyaluronic Acid Powder? Benefits and Usage
• Why Hyaluronic Acid is an Ideal Material for Wound Healing
• Hyaluronic Acid, Sodium Hyaluronate, Hydrolyzed Sodium Hyaluronate: What Are the Differences
• How is Hyaluronic Acid Powder Made

Reference:

[1] Essendoubi M, Gobinet C, Reynaud R, Angiboust JF, Manfait M, Piot O. Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy. Skin Res Technol. 2016 Feb;22(1):55-62. doi: 10.1111/srt.12228. Epub 2015 Apr 16. PMID: 25877232.

[2] Bibire, Tudor & Yılmaz, Onur & Ghiciuc, Cristina & Bibire, Nela & Dănilă, Radu. (2022). Biopolymers for Surgical Applications. Coatings. 12. 211. 10.3390/coatings12020211.

[3] Liuying Hu, Satoshi Nomura, Yasunari Sato, Kyoko Takagi, Tsuyoshi Ishii, Yoichi Honma, Kenji Watanabe, Yoichi Mizukami, Jun Muto, Anti-inflammatory effects of differential molecular weight Hyaluronic acids on UVB-induced calprotectin-mediated keratinocyte inflammation, Journal of Dermatological Science, Volume 107, Issue 1, 2022, Pages 24-31, ISSN 0923-1811,https://doi.org/10.1016/j.jdermsci.2022.06.001.