Hyaluronic Acid as an Antioxidant: Forms, Absorption and Safety

Table of Contents

1. 1. Is Hyaluronic Acid an Antioxidant? The Short Answer
2. 2. Test-Tube Evidence of Radical Scavenging
3. 3. Hyaluronan as a Target of Reactive Oxygen in Inflamed Joints
4. 4. Why Molecular Weight Changes the Picture
5. 5. Why Hyaluronic Acid Is Not Classed With Classic Antioxidants
6. 6. Does Swallowed Hyaluronic Acid Reach the Body? Animal Studies
7. 7. Forms Compared: Injections, Creams, Capsules, Drops and Surgical Gels
8. 8. Safety Findings Across the Forms
9. 9. The Body’s Own Production and Food Sources
10. Key Research Papers
11. Connections

1. Is Hyaluronic Acid an Antioxidant? The Short Answer

An antioxidant, in the everyday sense, is a molecule that neutralises reactive oxygen species (often called free radicals) before they damage fats, proteins and DNA. Classic examples are vitamin C, vitamin E and glutathione, which the body uses, recycles and regulates for exactly that purpose.

Hyaluronic acid does react with reactive oxygen, but the research describes it in a different way. The evidence falls into four groups:

• Test-tube studies show that HA reacts with the hydroxyl radical and can protect cultured cells from hydroxyl-radical damage (Presti and Scott 1994), and that low-molecular-weight HA preparations scavenge several radicals in a dish (Ke and colleagues 2011).
• One mouse study found that orally given low-molecular-weight HA raised the activity of antioxidant enzymes in immunosuppressed mice (Ke and colleagues 2011).
• Joint research shows that in inflamed joints HA is itself broken down by reactive oxygen — it is consumed, not recycled (Sołtés and colleagues 2006; Yamazaki and colleagues 2003).
• No human trial measuring HA as an antioxidant was found while preparing this article.

Older overviews listed free-radical scavenging among the possible jobs of HA in the joint, but the authors themselves called that list “more or less well documented hypotheses” (Laurent and colleagues 1996). The broad 2018 review by Fallacara and colleagues put it most plainly: the antioxidant role “has only been hypothesized, as it is not sufficiently supported by experimental data.”

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2. Test-Tube Evidence of Radical Scavenging

The 1994 fibroblast experiment

Presti and Scott exposed cultured tendon fibroblasts to hydroxyl radicals made by an enzyme system, with and without HA in the medium. HA protected the cells, and the protection grew with HA concentration. The largest HA tested (1,218 kilodaltons) protected much better than smaller preparations of 176 and 668 kilodaltons. HA also competed with benzoate, a standard hydroxyl-radical “catcher,” showing that it was reacting with the radical directly. Interestingly, when the researchers measured the raw speed of the chemical reaction with pulse radiolysis, that rate did not depend on molecular size — so the better protection by long chains did not come from faster chemistry; the abstract does not settle what explains it.

The 2011 low-molecular-weight study

Ke and colleagues broke a 1,050-kilodalton HA into two smaller fractions of 145 and 45 kilodaltons. In test-tube assays these fractions inhibited lipid peroxidation, scavenged the hydroxyl radical strongly, and scavenged the DPPH radical and superoxide moderately. The 145-kilodalton fraction was the strongest. Note that this points in the opposite direction from Presti and Scott, who found larger HA more protective — the two studies used different assays and different endpoints, and they have not been reconciled.

Surgical gels in the eye

During phacoemulsification cataract surgery, the ultrasound probe generates hydroxyl radicals inside the eye. Maugeri and colleagues tested several HA-based ophthalmic viscosurgical gels in a Fenton-reaction assay and found that all of them showed “marked hydroxyl radical scavenging activity.” This is a laboratory measurement of the gels themselves, not a measurement of outcomes in patients.

Taken together, these studies establish that HA can react with reactive oxygen in a dish. They do not show that HA acts as an antioxidant in the living human body.

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3. Hyaluronan as a Target of Reactive Oxygen in Inflamed Joints

Healthy synovial fluid — the lubricant inside joints — is rich in very large HA molecules, about 3–4 mg per millilitre according to the Fallacara review. Those long chains give the fluid its slippery, shock-absorbing thickness. In inflamed joints, white blood cells release reactive oxygen species, and those species attack HA.

Yamazaki and colleagues showed that the hydroxyl radical, produced in a Fenton system, cuts HA into smaller pieces, and they related this to the smaller HA found in the joint fluid of people with arthritis. Sołtés and colleagues reviewed the chemistry in detail: reactive oxygen degrades the high-molecular-weight HA of synovial fluid so reliably that the loss of molecular weight and viscosity is used in laboratories as a marker of oxidative damage — and as a test system for measuring how well other antioxidants protect HA.

In this picture HA behaves like a sacrificial target. When it “scavenges” a radical, the chain is broken; it is not restored the way vitamin C is regenerated in the body. Hyaluronidase enzymes and reactive oxygen are the two main routes by which HA is degraded (Fallacara and colleagues 2018).

A hypothesis about joint oxygen

In 2014 Juranek, Stern and Šoltés published a paper in the journal Medical Hypotheses proposing that oxygen-consuming peroxidation of HA is part of normal joint function: in their view it helps keep oxygen tension low inside the joint, and they suggested that indiscriminate use of antioxidants could interfere with this. The paper presents an idea to be tested, not experimental findings, and it is labelled here as a hypothesis for that reason.

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4. Why Molecular Weight Changes the Picture

HA is not one molecule but a family of chains of very different lengths. In the body, chains can reach millions of daltons; Stern and colleagues cite lengths up to 2 × 10⁴ kilodaltons. Size changes what HA does:

• Large polymers are space-filling and, according to reviews by Stern and colleagues, anti-inflammatory, anti-angiogenic and immunosuppressive.
• Small fragments act very differently: they are inflammatory, immune-stimulating and angiogenic, and can behave as endogenous “danger signals” that tell the body tissue has been injured (Stern and colleagues 2006).
• Wound-biology reviews describe the same split: high-molecular-weight HA anti-inflammatory, low-molecular-weight HA pro-inflammatory (Litwiniuk and colleagues 2016).

This matters for the antioxidant question. When reactive oxygen cuts long HA in an injured or inflamed tissue, the resulting fragments are not neutral leftovers — they can amplify inflammation (Stern and colleagues 2006). So the very reaction that looks like “scavenging” in a dish can, in tissue, produce molecules that keep inflammation going.

The two main test-tube studies also disagree on which size is “better.” Presti and Scott found long chains protected cells more; Ke and colleagues found a mid-sized fragment scavenged radicals best. Any claim that one size of HA is “the antioxidant form” goes beyond what this research shows.

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5. Why Hyaluronic Acid Is Not Classed With Classic Antioxidants

The site’s Antioxidants section covers molecules such as vitamin C, vitamin E and the endogenous redox molecules in Redox Cofactors and Endogenous Antioxidants. Compared with them, HA differs in several ways the research makes clear:

• Main job. HA’s known functions are structural: holding water, filling space, lubricating joints and shaping how cells move (Fraser and colleagues 1997; Laurent and colleagues 1996). Radical scavenging is a side reaction.
• No recycling. Classic antioxidants are regenerated by enzyme systems. HA that reacts with a hydroxyl radical is broken, as described in section 3.
• Side effects of the reaction. The fragments produced can be pro-inflammatory (Stern and colleagues 2006).
• Evidence level. The antioxidant findings are from test tubes and one mouse model; no human antioxidant trial was found, and the 2018 Fallacara review called the role hypothesized rather than established.

A wound-healing review by Litwiniuk and colleagues does discuss “antioxidative properties” of HA alongside its many receptor-driven effects, which shows the idea is taken seriously in research. But in the scientific literature as a whole, HA is classed as a glycosaminoglycan — a structural sugar polymer — rather than as an antioxidant nutrient.

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6. Does Swallowed Hyaluronic Acid Reach the Body? Animal Studies

Oral HA is sold for skin and joints, so a basic question is whether a swallowed HA molecule ever reaches those tissues. The evidence comes only from animals, and the studies disagree. No human pharmacokinetic study was found while preparing this article.

Studies reporting uptake

• Balogh and colleagues (2008), rats and dogs. High-molecular-weight HA labelled with radioactive technetium was given by mouth. Between 86.7% and 95.6% of the radioactivity was recovered, almost all in the faeces — yet radioactivity also appeared in tissues from 15 minutes to 48 hours, concentrated in joints, vertebrae and salivary glands at 4 hours, and imaging showed it in skin, bone and joints.
• Oe and colleagues (2014), rats. Using carbon-14-labelled HA, about 90% of the label was absorbed from the gut, peaked in plasma at 8 hours, and was higher in skin than in blood at 24 and 96 hours; more than 90% left the body in exhaled air or urine. Because the carbon label follows the carbon atoms, “absorbed” here may mean breakdown products used for energy, not intact HA.
• Kimura and colleagues (2016), rats. HA was not broken down by artificial stomach or intestinal juice but was broken down by gut bacteria from the caecum into small oligosaccharides, which passed through the wall of the large intestine. After oral 300-kilodalton HA, HA fragments of several sizes were found in skin.

A study reporting little or no uptake

• Lazníček and colleagues (2012), rats. After oral technetium-labelled HA (0.1 to 1 megadalton) there was “no significant absorption to the central compartment,” and with carbon-14-labelled HA “only traces” were absorbed.

Kimura and colleagues summed up the state of knowledge in their own words: “the absorption of orally administrated HA remains controversial.” Industry-affiliated researchers were among the authors of at least one of the studies reporting uptake, a fact readers may weigh when comparing them.

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7. Forms Compared: Injections, Creams, Capsules, Drops and Surgical Gels

Hyaluronic acid used in medicine and cosmetics comes from two main industrial sources: historically animal tissues such as rooster combs and umbilical cords, and today largely bacterial fermentation using streptococci (Fallacara and colleagues 2018). It is used in at least six forms, each studied for different purposes. Doses below are those used in the trials cited, reported as trial facts.

• Joint injections (viscosupplementation). HA is injected into the knee or hip to restore joint-fluid thickness. In the Rutjes 2012 meta-analysis, 22 of 89 trials used cross-linked HA, a chemically bonded form designed to last longer. See Joints and Osteoarthritis.
• Dermal fillers. Usually cross-linked HA gels injected into the face (Kyriazidis and colleagues 2024; Zhou and Yu 2025). See Skin and Hydration.
• Topical creams, lotions and serums. In a trial of 36 elderly people with dry skin, a low-molecular-weight HA lotion raised skin moisture readings more than a high-molecular-weight lotion or the plain vehicle at 4 weeks (Muhammad and colleagues 2024).
• Oral capsules and drinks. Skin trials gave 120 mg per day of HA for 12 weeks, in one trial as either 2-kilodalton or 300-kilodalton HA (Oe and colleagues 2017; Hsu and colleagues 2021).
• Eye drops. Sodium hyaluronate artificial tears for dry eye (Ang and colleagues 2017; Yang and colleagues 2021). See Eyes and Wound Healing.
• Surgical gels for the eye. Ophthalmic viscoelastic devices that protect the inside of the eye during cataract, vitreoretinal, glaucoma and corneal transplant surgery, described in a review by Endre Balazs (Balazs 2008), who according to the Fallacara review produced the first pharmaceutical-grade HA in 1979.
• Wound dressings and topical agents for chronic ulcers (Roehrs and colleagues 2023).

Only the eye gels have a laboratory antioxidant measurement attached to the form itself (Maugeri and colleagues 2007, section 2). None of the forms has been tested in people as an antioxidant treatment.

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8. Safety Findings Across the Forms

Joint injections

Two lines of evidence point in different directions, and both are reported here as their authors state them. A safety meta-analysis by Miller and colleagues (2021) pooled 35 randomised trials with 8,078 patients and found no difference between HA and saline injections in adverse events, serious adverse events or withdrawals; non-serious local reactions at the injection site were somewhat more common with HA (14.5% versus 11.7%) and typically resolved within days. By contrast, the Rutjes 2012 meta-analysis reported a higher risk of serious adverse events with viscosupplementation (relative risk 1.41, 95% confidence interval 1.02–1.97), and the 2022 BMJ meta-analysis by Pereira and colleagues, pooling large placebo-controlled trials, found the same direction (relative risk 1.49, 95% confidence interval 1.12–1.98).

Dermal fillers

A systematic review of 48 randomised trials of HA fillers found mostly short-lived injection-site reactions; severe events, such as severe swelling or angioedema, were rare and needed treatment, with hyaluronidase (the enzyme that dissolves HA) among the treatments used (Kyriazidis and colleagues 2024). An expert consensus on late-onset reactions, typically appearing 3–4 months after injection, listed proposed causes as low-molecular-weight HA in the product, infection or biofilm, and an imbalance in the person’s immune response (Baranska-Rybak and colleagues 2024). That paper is expert opinion, not trial data.

Creams and lotions

No side effects were reported in any arm of the elderly dry-skin trial by Muhammad and colleagues (2024).

Oral HA

The oral trials reviewed for this article report no safety signals in their abstracts, and a 2016 review by Oe and colleagues discusses safety. That review was written by researchers connected to an HA manufacturer, and no independent review of oral HA safety was found. The available evidence therefore does not amount to proof that oral HA is safe over long periods; it shows that short trials did not report problems.

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9. The Body’s Own Production and Food Sources

How the body makes HA

The body is its own main source. An adult of 70 kg carries about 15 grams of hyaluronan, of which about 5 grams is broken down and replaced every day (Stern 2004). Three enzymes called hyaluronan synthases (HAS1, HAS2 and HAS3) build the chain at the inner face of the cell membrane from two activated sugars made from glucose: UDP-glucuronic acid and UDP-N-acetylglucosamine (Itano and colleagues 1999). The N-acetylglucosamine half links HA to glucosamine. HAS2 makes the largest chains, and the three enzymes differ in speed and product size. When HA is broken down, the pieces are recycled: glucuronic acid and a glucosamine derivative are released for other metabolic cycles (Stern 2004).

Vitamin C is often mentioned alongside HA in skin products, but its known role is in building collagen (see Vitamin C and Collagen Synthesis), not in making HA.

Food sources

HA occurs in animal connective tissues; rooster combs were the classic source for extraction (Fallacara and colleagues 2018). Bone broth made from chicken and vegetables contains a fraction holding both HA and chondroitin sulfate. In a study by Seki and colleagues (2024), that broth and its HA-plus-chondroitin fraction raised bone mineral density in rats with bone loss caused by removal of the ovaries, and the fraction slowed the formation of bone-resorbing cells in culture. That study was about bone in rats; it did not measure how much HA a serving of broth contains or whether HA from broth reaches human skin or joints.

No source found while preparing this article gives the HA content of any food, and none shows a food that raises the body’s own HA production. For now, food HA is best described qualitatively: it is present in animal connective tissues and in broths made from them.

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Key Research Papers

1. Fallacara A, Baldini E, Manfredini S, Vertuani S. Hyaluronic Acid in the Third Millennium. Polymers (Basel). 2018;10(7):701. PubMed PMID: 30960626
2. Presti D, Scott JE. Hyaluronan-mediated protective effect against cell damage caused by enzymatically produced hydroxyl (OH.) radicals is dependent on hyaluronan molecular mass. Cell Biochem Funct. 1994;12(4):281-8. PubMed PMID: 7834818
3. Ke C, Sun L, Qiao D, Wang D, Zeng X. Antioxidant acitivity of low molecular weight hyaluronic acid. Food Chem Toxicol. 2011;49(10):2670-5. PubMed PMID: 21787831
4. Maugeri F, Maltese A, Ward KW, Bucolo C. Hydroxyl radical scavenging activity of a new ophthalmic viscosurgical device. Curr Eye Res. 2007;32(2):105-11. PubMed PMID: 17364743
5. Soltés L, Mendichi R, Kogan G, Schiller J, Stankovska M, Arnhold J. Degradative action of reactive oxygen species on hyaluronan. Biomacromolecules. 2006;7(3):659-68. PubMed PMID: 16529395
6. Yamazaki K, Fukuda K, Matsukawa M, Hara F, Yoshida K, Akagi M, Munakata H, Hamanishi C. Reactive oxygen species depolymerize hyaluronan: involvement of the hydroxyl radical. Pathophysiology. 2003;9(4):215-220. PubMed PMID: 14567924
7. Juranek I, Stern R, Soltes L. Hyaluronan peroxidation is required for normal synovial function: an hypothesis. Med Hypotheses. 2014;82(6):662-6. PubMed PMID: 24655797
8. Laurent TC, Laurent UB, Fraser JR. The structure and function of hyaluronan: An overview. Immunol Cell Biol. 1996;74(2):A1-7. PubMed PMID: 8724014
9. Stern R, Asari AA, Sugahara KN. Hyaluronan fragments: an information-rich system. Eur J Cell Biol. 2006;85(8):699-715. PubMed PMID: 16822580
10. Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T. Hyaluronic Acid in Inflammation and Tissue Regeneration. Wounds. 2016;28(3):78-88. PubMed PMID: 26978861
11. Fraser JR, Laurent TC, Laurent UB. Hyaluronan: its nature, distribution, functions and turnover. J Intern Med. 1997;242(1):27-33. PubMed PMID: 9260563
12. Balogh L, Polyak A, Mathe D, Kiraly R, Thuroczy J, Terez M, Janoki G, Ting Y, Bucci LR, Schauss AG. Absorption, uptake and tissue affinity of high-molecular-weight hyaluronan after oral administration in rats and dogs. J Agric Food Chem. 2008;56(22):10582-93. PubMed PMID: 18959406
13. Oe M, Mitsugi K, Odanaka W, Yoshida H, Matsuoka R, Seino S, Kanemitsu T, Masuda Y. Dietary hyaluronic acid migrates into the skin of rats. ScientificWorldJournal. 2014;2014:378024. PubMed PMID: 25383371
14. Kimura M, Maeshima T, Kubota T, Kurihara H, Masuda Y, Nomura Y. Absorption of Orally Administered Hyaluronan. J Med Food. 2016;19(12):1172-1179. PubMed PMID: 27982756
15. Laznicek M, Laznickova A, Cozikova D, Velebny V. Preclinical pharmacokinetics of radiolabelled hyaluronan. Pharmacol Rep. 2012;64(2):428-37. PubMed PMID: 22661195
16. Rutjes AW, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med. 2012;157(3):180-91. PubMed PMID: 22868835
17. Pereira TV, Jüni P, Saadat P, Xing D, Yao L, Bobos P, Agarwal A, Hincapié CA, da Costa BR. Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis. BMJ. 2022;378:e069722. PubMed PMID: 36333100
18. Miller LE, Bhattacharyya S, Parrish WR, Fredericson M, Bisson B, Altman RD. Safety of Intra-Articular Hyaluronic Acid for Knee Osteoarthritis: Systematic Review and Meta-Analysis of Randomized Trials Involving More than 8,000 Patients. Cartilage. 2021;13(1_suppl):351S-363S. PubMed PMID: 31735075
19. Kyriazidis I, Spyropoulou GA, Zambacos G, Tagka A, Rakhorst HA, Gasteratos K, Berner JE, Mandrekas A. Adverse Events Associated with Hyaluronic Acid Filler Injection for Non-surgical Facial Aesthetics: A Systematic Review of High Level of Evidence Studies. Aesthetic Plast Surg. 2024;48(4):719-741. PubMed PMID: 37563436
20. Baranska-Rybak W, Lajo-Plaza JV, Walker L, Alizadeh N. Late-Onset Reactions after Hyaluronic Acid Dermal Fillers: A Consensus Recommendation on Etiology, Prevention and Management. Dermatol Ther (Heidelb). 2024;14(7):1767-1785. PubMed PMID: 38907876
21. Muhammad P, Novianto E, Setyorini M, Legiawati L, Yusharyahya SN, Menaldi SL, Budianti WK. Effectiveness of topical hyaluronic acid of different molecular weights in xerosis cutis treatment in elderly: a double-blind, randomized controlled trial. Arch Dermatol Res. 2024;316(6):329. PubMed PMID: 38829483
22. Oe M, Sakai S, Yoshida H, Okado N, Kaneda H, Masuda Y, Urushibata O. Oral hyaluronan relieves wrinkles: a double-blinded, placebo-controlled study over a 12-week period. Clin Cosmet Investig Dermatol. 2017;10:267-273. PubMed PMID: 28761365
23. Balazs EA. Hyaluronan as an ophthalmic viscoelastic device. Curr Pharm Biotechnol. 2008;9(4):236-8. PubMed PMID: 18691081
24. Stern R. Hyaluronan catabolism: a new metabolic pathway. Eur J Cell Biol. 2004;83(7):317-25. PubMed PMID: 15503855
25. Itano N, Sawai T, Yoshida M, Lenas P, Yamada Y, Imagawa M, Shinomura T, Hamaguchi M, Yoshida Y, Ohnuki Y, Miyauchi S, Spicer AP, McDonald JA, Kimata K. Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem. 1999;274(35):25085-92. PubMed PMID: 10455188
26. Seki Y, Ohkuma RC, Miyakawa Y, Karakida T, Yamamoto R, Yamakoshi Y. Hyaluronan and chondroitin sulfate in chicken-vegetable bone broth delay osteoporosis progression. J Food Sci. 2024;89(3):1791-1803. PubMed PMID: 38317402

PubMed Topic Searches

1. PubMed: hyaluronan hydroxyl radical scavenging
2. PubMed: hyaluronan reactive oxygen species degradation in synovial fluid
3. PubMed: oral hyaluronan absorption
4. PubMed: hyaluronic acid molecular weight and inflammation
5. PubMed: hyaluronic acid adverse events, systematic reviews

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Connections

• Hyaluronic Acid: The Body’s Water-Holding Molecule
• Hyaluronic Acid Benefits: What the Research Shows
• Hyaluronic Acid for Skin: Hydration, Wrinkles and Aging
• Hyaluronic Acid for Joints: Injections, Oral Forms and Osteoarthritis
• Hyaluronic Acid for Eyes and Wound Healing
• Redox Cofactors and Endogenous Antioxidants
• Antioxidants
• Oxidative Stress
• Glucosamine
• Collagen
• Osteoarthritis
• Bone Broth