There’s some bullcrap on social media promulgated by a physician who wasn’t trained as a dermatologist and lost his mecidal license, saying that low molecular weight hyaluroic acid (HA) is bad for the skin. Little could be further from the truth. Let’s explore the benefits of low molecular weight hyaluronic acid, and even HA nanoparticles. The benefits are huge.

HA is a type of glycosaminoglycan (GAG), and is found in many parts of the body, including the skin. In the skin, HA retains and evenly distributes water, thus preserving the volume of the skin and its elastic and flexible properties.. HA also plays a protective role as an inhibitor of free radicals, generated upon exposure to solar radiation. HA has been reported to be about one third of the total amount of both the dermis (±0.5 mg/g wet tissue) and the epidermis (±0.1 mg/g wet tissue. In the epidermis, the HA is metabolized and actively participates in many regulatory processes, such as cell proliferation, migration, and differentiation. In the dermis, it fills the extracellular spaces

The benefits of using topical low molecular weight hyaluronic acid (LMHA) in your skincare routine are many. Here are a few key benefits that make this ingredient a must-have in your skincare routine:

• Deep Hydration: LMHA delivers moisture deep into the skin layers, ensuring that your skin remains hydrated for a longer period.
• Reduced inflammation: LMHA has been found to decrease inflammatory cytokines in the skin
• Improved Skin Texture: Regular use of LMHA can lead to a smoother and softer skin texture, thanks to its ability to boost collagen production.
• Reduced Signs of Aging: LMHA can help minimize the appearance of fine lines and wrinkles, giving your skin a youthful glow.
• Enhanced Skin Barrier: By providing deep hydration, LMHA strengthens the skin’s barrier function, protecting it from environmental stressors.

Let’s look at some of the evidence:

Hyaluronic acid nanoparticles (HA-NPs) have recently been found to exhibit significant efficacy in treating psoriasis, one of the inflammatory skin diseases (ISDs) (Lee et al, 2022). HA particles were able to penetrate deep into the skin and were hyaluronidase (HYAL) resistant. Furthermore, the HA particles exhibited receptor-mediated targeting of pro-inflammatory M1 type macrophages in inflamed skin. This macrophage-targeting ability of HA-NPs has also been observed in other inflammatory diseases such as type 2 diabetes, atherosclerosis, and IBD.  

Indeed, low molecular weight HA, not just nanoparticles, have been found to penetrae the skin (Essendoubi et al, 2016) and be beneficial to a number of skin conditions, Seborrheic Dermatitis, UVB-induced inflammation, dry skin and disrupted barrier formation, rosacea, atopic dermatitis, leg ulcers,

LMHA Penetrates the Stratum Corneum

Low-molecular-weight hyaluronan (LMHA) is obtained by changing the molecular weight or modifying the functional groups of HA. In contrast to the stratum corneum impermeability of high-molecular-weight HA (1000–1400 kDa), the LMHA (20–300 kDa) has been reported to pass through the stratum corneum by Raman spectroscopy (Essendoubi et al, 2016).

Positive Effects of LMHA

Increases NMF. Low molecular weight HA and nano-particles of HA have been found to provide many benfits to the skin. For example, evidence suggests that topical application of LMHA resulted in an increase in natural moisturizing factor and promote moisturization of the stratum corneum (Hashimoto and Maeda (2021).

Increases CASP14 and stratum Corneum Formation. Proteolytic activation of CASP14 is associated with stratum corneum formation, implicating CASP14 in terminal keratinocyte differentiation and cornification When LMHA was applied topically to the 3D epidermis model, the mRNA level of CASP14 was increased, and the activity of CASP14 was increased in the stratum granulosum and stratum corneum (Hashimoto and Maeda, 2021). They found that HA of molecular weights of 10 kDa or less can penetrate deep into the stratum corneum, affecting FLG-degrading enzymes in the stratum granulosum and mucopolysaccharides in the basal layer of epidermis.

 LMW-HA-induced activation of keratinocytes that is not accompanied by an inflammatory response, because no production of IL-8, TNF-α, IL-1β, or IL-6 was observed (Gariboldi et al, 2007).. 

 500-kDa HMW-HA protects macrophages from LPS-induced inflammation, i.e. inflammatory cytokines, through an interaction between HMW-HA/CD44 and LPS/TLR4 signals (Muto et al, 2009).

Both LMW-HA and HMW-HA have inhibitory effects on TLR-mediated macrophage inflammation, therefore HA has a high capacity to suppress TLR4-related keratinocyte inflammation (Hu et al, 2022).

Highly expressed IL-6 in psoriatic skin stimulates abnormal keratinocyte proliferation, and IL-6 inhibition by HA (Hu et al, 2022) is helpful in maintaining skin homeostasis in conditions such as psoriasis

Low MW HA inhibits Th1 mediated inflammatory immune response (Zheng et al, 2022).

Topical LMHA significantly contributes to wrinkle resuction (Pavicic et al, 2011).

Topical application of nano-HA decreases wrinkles (Jegasothy et al, 2014)

LMHA influences the expression of various genes including those contributing to keratinocyte differentiation and formation of intercellular tight junction complexes without showing proinflammatory activity (Farwick et al, 2022).

LMHA can promote wound healing by accelerating epithelization through the HIF-1α/VEGF pathway (Liu et al, 2024).

 LMHA, 35 kDa low molecular weight hyaluronan fragment (HA35) has been found to alleviate pain when applied subcue (Zhang et al, 2024), thus it may have similar effects when applied to the skin.

LMHA when applied with amino acids, increased fibroblast activity resulting in the production of Type III reticular collagen, as well as an increased number of blood vessels and epidermal thickness (Scarano et al, 2024). 

LMHA is better than high MWHA (HMHA) in mosituring the skin of aged people (Muhammad et al, 2024).

Low molecular weight hyaluronic acid prevents oxygen free radical damage to granulation tissue during wound healing (Trabucchi et al, 2002).

LMHA inhibits inflammation through inhibition of leukocytes (Jia et al, 2023)

Butyrate conjugated forms of HA (one of the forms of HA that NeoGenesis uses) have been found to be anti-inflammatory by modulating cytokine expression and increasing lymph flow, thus preventing chronic wounds of all kinds from entering a chronic inflammatory state (Gao et al, 2019).

Summary

If you’re not using topical LMHA in your skin care routine, you’re likely to realize sub-optimal results.