Journal September 26, 2026 5 min read

How Does Hyaluronic Acid Work?

Hyaluronic acid (HA) is a high-molecular-weight glycosaminoglycan. This page outlines its mechanism of action and summarises laboratory and clinical research on HA-containing formulations.

peptides-pro Editorial

What is hyaluronic acid?

Hyaluronic acid (HA), also known as hyaluronan, is a naturally occurring linear glycosaminoglycan composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine. It is a high-molecular-weight polymer, with molecular weights typically ranging from 10⁵ to 10⁷ Da depending on source and method of preparation. In its native form, HA is a key component of the extracellular matrix and is noted for its water retention capacity and biocompatibility [2].

Research into HA centres on its interactions with cell-surface receptors, particularly the CD44 receptor family, and its role in modulating the extracellular environment. The studies summarised below examine HA in diverse contexts, from joint health to wound healing and drug delivery.

Research Studies

Oral hyaluronic acid and knee pain in human subjects

A clinical trial is evaluating the effect of an oral hyaluronic acid drink (A+HA Premium) on relieving knee pain [1]. The study is designed to assess functional outcomes in participants consuming the drink. This is a human interventional study; results are not yet available.

Ergothioneine and the stability of hyaluronic acid-based wound-healing materials

HA-based hydrogels are widely used as wound-healing materials and topical delivery systems due to their biocompatibility, water retention, and ability to promote cell migration. However, HA is susceptible to oxidative chain scission, which reduces molecular weight and compromises formulation stability [2]. A study evaluated ergothioneine (EGT) as a candidate antioxidant stabilising excipient in a model HA-based wound-healing material. Using CCK-8 assays in L929 mouse fibroblasts, the biocompatibility of EGT was assessed after 24 hours of exposure. The study also employed a stress-screening framework including Fenton oxidation and high-temperature/high-humidity conditions [2].

Ectoine and IL-1β-induced inflammation in chondrocytes and a rat osteoarthritis model

Ectoine, a natural osmoprotectant, was investigated for its effects on NF-κB signalling in osteoarthritis (OA). In primary rat chondrocytes pretreated with ectoine (0–3.0% w/v) and stimulated with IL-1β (10 ng/mL), cell viability was evaluated, and RT-qPCR and Western blot analyses were performed [3]. The study also assessed whether ectoine mitigates OA progression in a rat model. This research is preclinical, using cell culture and animal models.

Niacinamide-enriched hyaluronic acid dermal filler and collagen stimulation

A study evaluated a niacinamide-enriched cross-linked hyaluronic acid dermal filler (HAR) for its biostimulatory, antimicrobial, anti-inflammatory, and safety profiles compared to untreated controls and Belotero Balance® [4]. The research context notes that biological skin aging involves flattening of the epidermal-dermal junction and reduced collagen types I and III, and that modern aesthetic medicine is shifting toward regenerative dermal fillers. Niacinamide is known to stimulate collagen synthesis, modulate inflammation, and inhibit bacterial growth [4]. This is a preclinical evaluation.

REJENERA® and osteoarthritis in a rat model

REJENERA®, a multi-component bioflavonoid-based formula containing olive leaf bioflavonoids (ZeyEX®, quercetin, luteolin), S-allylcysteine, palmitoylethanolamide, L-proline, hyaluronic acid, and boron, was studied for its efficacy in treating knee OA in a rat model [5]. OA was established by intra-articular injection of monosodium iodoacetate (MIA; 3 mg) into the right knee joint. The study compared REJENERA with ZeyEX, NPROC® (a combination of collagen-rich eggshell membrane and olive leaf extract), and ibuprofen, focusing on the NLRP3-TXNIP-iNOS axis and inflammation [5]. This is an animal study.

Chlorhexidine mouthwash with hyaluronic acid and human gingival fibroblasts

An in vitro study is evaluating the effects of two chlorhexidine-based mouthwash formulations on the survival and function of human gingival fibroblasts (hGFs) [6]. Gingival fibroblasts obtained from discarded tissue during routine dental procedures will be cultured and exposed to a conventional 0.2% chlorhexidine mouthwash and a 0.2% chlorhexidine mouthwash supplemented with N-acetylcysteine (NAC) and hyaluronic acid (HA). Cell viability, apoptosis, migration, and gene expression will be assessed using Trypan Blue exclusion, FACS, scratch assay, and quantitative real-time PCR [6]. This is an in vitro study.

Oral supplement with hyaluronic acid and HPV DNA integration in women

An interventional, single-center, open-label randomized clinical study is evaluating an oral dietary supplement (Pervistop®) in women with persistent Human Papillomavirus (HPV) infection [7]. The supplement combines epigallocatechin gallate (EGCG), folic acid, vitamin B12, and hyaluronic acid. The primary objective is to describe the effect on HPV DNA integration into the host genome by measuring the clearance rate of viral oncoproteins E6 and E7. A total of 42 women aged 25 or older with persistent HPV infection and low-grade cervical lesions will be randomized 1:1 into two groups [7]. This is a human clinical study.

Hyaluronic acid and folic acid-modified mesoporous silica nanoparticles delivering sulforaphane in NSCLC

Sulforaphane (SF) suppresses NSCLC metastasis by modulating miR-616-5p, which is transcriptionally upregulated by SPI1. However, the poor stability of SF limits its clinical application [8]. To address this, researchers developed hyaluronic acid and folic acid-modified mesoporous silica nanoparticles delivering sulforaphane. The study found that SPI1 expression in NSCLC tissues positively correlated with miR-616-5p levels, and that SPI1 transcriptionally regulated miR-616-5p to promote NSCLC cell invasion and migration. SF directly binds SPI1, inhibiting its activity and downregulating miR-616-5p expression, thereby attenuating NSCLC metastasis [8]. This is a preclinical study.

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