Hyaluronic Acid for Eyes and Wound Healing

Table of Contents

1. 1. Hyaluronan in the Vitreous and on the Eye’s Surface
2. 2. How Hyaluronic Acid Eye Drops Work
3. 3. Dry Eye Meta-Analyses: What the Pooled Trials Found
4. 4. Dry Eye After Cataract Surgery
5. 5. Hyaluronan as a Surgical Tool in Eye Operations
6. 6. The Role of Hyaluronan in Wound Repair
7. 7. Large Molecules, Small Fragments and Inflammation
8. 8. Chronic Wounds and Diabetic Foot Ulcers: The Reviews
9. 9. Healing After Sinus Surgery and Tooth Extraction
10. 10. Open Questions in Eye and Wound Research
11. Key Research Papers
12. Connections

1. Hyaluronan in the Vitreous and on the Eye’s Surface

Hyaluronan is found in every vertebrate tissue and body fluid, according to a classic review by Fraser, Laurent and Laurent. Unlike most large molecules in the body it is not built inside the cell and exported; it is spun out at the cell’s outer membrane by enzymes called hyaluronan synthases, using sugars the body makes from glucose. It is a long, unbranched chain of two alternating sugars — glucuronic acid and N-acetylglucosamine, a close relative of glucosamine.

The vitreous: where hyaluronan was discovered

Meyer and Palmer’s 1934 paper isolated the substance from the vitreous humor. A 2018 review of hyaluronan research by Fallacara and colleagues reports that the source was cow (bovine) eyes and gives the concentration of hyaluronan in the vitreous as about 0.1 mg per mL — far lower than in joint fluid (3–4 mg/mL) or the umbilical cord (about 4 mg/mL). Low as that is, hyaluronan chains are so long that they tangle into a network even at dilute concentrations; Laurent and colleagues describe entangled networks below 1 mg/mL, which give hyaluronan solutions their unusual flow properties. In the eye that network helps hold the vitreous gel in shape.

A molecule that is constantly replaced

Hyaluronan is not a permanent fixture. Fraser’s review gives tissue half-lives ranging “from less than 1 to several days”; hyaluronan that leaves a tissue travels in lymph to the lymph nodes, which break much of it down, and what reaches the blood is cleared within minutes, mainly by the liver. Fallacara’s review cites estimates of about 24–36 hours for hyaluronan in the eye in general and about 70 days in the vitreous — figures it quotes from earlier work, so they are best read as one review’s estimates rather than measured constants.

Because the eye already makes and uses hyaluronan, it was a natural candidate for products applied to the eye’s surface and used inside the eye during surgery — the subjects of the next sections.

Back to Table of Contents

2. How Hyaluronic Acid Eye Drops Work

Dry eye disease is a family of conditions in which the tear film is too scant or evaporates too quickly, leaving the surface of the eye irritated and, in more severe cases, damaged. Artificial tears try to replace or thicken the tear film. Many contain sodium hyaluronate; others use cellulose derivatives, carbomer gels, polyvinyl alcohol or plain saline. The site’s Dry Eye Disease page covers the condition itself.

Water holding and viscoelasticity

Two properties of hyaluronan underlie its use on the eye. First, it binds large amounts of water, which is why it is described across the literature as the body’s water-holding molecule. Second, its tangled chains make its solutions viscoelastic — part liquid and part elastic gel. Fallacara’s review credits Endre Balazs with producing the first pharmaceutical-grade hyaluronan, in 1979, from rooster combs and umbilical cords. The aim of a viscoelastic drop is a film that stays on the eye longer than a watery one.

What the trials measure

Dry eye trials use a handful of standard tests, and they are worth knowing because the reviews below report results test by test:

• Schirmer test — a strip of paper tucked under the lower lid measures how much tear fluid is produced in a set time.
• Tear break-up time (TBUT) — how many seconds the tear film stays intact after a blink before dry spots appear.
• Surface staining — a dye such as fluorescein shows damaged spots on the cornea and conjunctiva.
• Symptom scores — questionnaires such as the Ocular Surface Disease Index record grittiness, burning and blurred vision.

A drop can help one measure and not another, which is exactly what the pooled evidence shows.

Back to Table of Contents

3. Dry Eye Meta-Analyses: What the Pooled Trials Found

Two systematic reviews with meta-analyses have compared hyaluronic acid drops with drops that do not contain it.

The 2017 Singapore review

Ang and colleagues reviewed 18 studies comparing sodium hyaluronate with non-hyaluronate artificial tears, published up to May 2016. Most of the individual studies favoured hyaluronate for surface staining and symptoms. When the randomized trials were pooled, hyaluronate gave a greater improvement in the Schirmer test (7 trials, 979 eyes; standardized mean difference 0.24) but a smaller improvement in tear break-up time (9 trials, 1,109 eyes; standardized mean difference −0.57). The authors’ summary was that “neither preparation was shown to be consistently superior across all outcome measures”, and that the differences on both tests were not clinically significant.

The 2021 Korean review

Yang and colleagues searched eight databases, including Korean ones, up to September 2020, and pooled 19 studies with 2,078 cases. Hyaluronic acid drops improved tear production compared with non-hyaluronate drops, with a small pooled effect (standardized mean difference 0.18). In a subgroup comparing hyaluronate with plain saline, both the Schirmer test and tear break-up time improved more with hyaluronate. The authors concluded that hyaluronate drops “may be superior” to non-hyaluronate drops, and called for further research by age, treatment length, dry eye severity and dose.

Reading the two together

Both reviews found a small advantage for hyaluronate on tear production. They differ on tear break-up time: against other artificial tears it was worse in the 2017 review, while against saline it was better in the 2021 subgroup. Part of the difference is the comparison drop — saline is a weak comparator, while modern cellulose or carbomer tears are themselves thickened. The overall picture in these reviews is that hyaluronate drops perform at least as well as other artificial tears, with modest differences that depend on the test and the comparison.

Back to Table of Contents

4. Dry Eye After Cataract Surgery

Wen and colleagues open their review by noting that the incidence of dry eye after cataract surgery is high. The site’s Cataracts page describes the operation itself.

A 2020 meta-analysis by Wen and colleagues pooled 24 randomized trials, with 2,177 eyes, in which sodium hyaluronate was added to conventional anti-inflammatory treatment after cataract surgery and compared with conventional treatment alone. The review drew on English-language and Chinese-language databases. After one month:

• the “total effective rate” was 1.33 times higher with added hyaluronate (12 trials);
• dry eye symptom scores were lower (10 trials; standardized mean difference −2.98);
• tear break-up time was longer (17 trials; mean difference 2.06);
• fluorescein staining scores were lower (16 trials); and
• Schirmer test wetting was greater (8 trials; mean difference 1.50).

In the older patients analysed separately, tear break-up time again improved, but staining and the Schirmer test did not differ. The authors described hyaluronate on top of conventional treatment as “highly effective”, while noting that the available studies were small and that “high-quality studies are warranted” to look further at safety. Heterogeneity between the trials was high (for symptom scores, I² = 92%), which means the individual studies disagreed considerably on the size of the effect — a reason for caution about the large pooled numbers.

Back to Table of Contents

5. Hyaluronan as a Surgical Tool in Eye Operations

Inside the eye, hyaluronan’s best-established use is not as a treatment but as a tool. During cataract surgery the clouded lens is broken up with ultrasound (phacoemulsification) and removed through a tiny opening, and a new plastic lens is folded in. Throughout, the surgeon fills the front chamber of the eye with a clear, thick gel called an ophthalmic viscosurgical (or viscoelastic) device. The gel keeps the chamber from collapsing, holds tissues apart, and protects the delicate tissues of the eye during the operation.

In a short 2008 review, Endre Balazs — whose work produced the first purified hyaluronan for medical use — described hyaluronan viscoelastic devices as used in cataract, vitreoretinal, glaucoma and corneal transplant surgery. The molecule’s viscoelasticity is what makes it suited to the job: thick enough to hold space when still, yet able to flow through a fine cannula and to be rinsed out at the end of the operation.

A note on free radicals during surgery

Ultrasound breaking up the lens generates hydroxyl radicals, among the most reactive oxygen species. In a 2007 test-tube study, Maugeri and colleagues measured hydroxyl-radical scavenging by several hyaluronan-based surgical gels in a Fenton-reaction assay and reported “marked” scavenging activity for all of them. This is laboratory evidence, not a measurement inside human eyes; the site’s companion page on hyaluronic acid as an antioxidant looks at the wider evidence on that question.

Back to Table of Contents

6. The Role of Hyaluronan in Wound Repair

Wound healing runs through overlapping stages: bleeding and clotting, inflammation, the building of new tissue (granulation, new blood vessels and skin cells migrating across the gap), and finally remodelling into a scar. The body’s own hyaluronan is present at every stage. The site’s animated wound-healing visualization shows the stages in motion.

A 2016 review in the journal Wounds by Litwiniuk and colleagues describes how hyaluronan acts on cells through surface receptors such as CD44, influencing inflammation, cell migration and the growth of new blood vessels (angiogenesis). The review also discusses hyaluronan’s antioxidative properties in the wound setting.

The 2023 Cochrane review of hyaluronic acid dressings states the reasoning behind applying it to wounds from outside: it has been suggested that hyaluronan may promote healing by keeping the wound environment moist, which helps cells migrate across the wound bed. This is the same principle behind modern moist-wound dressings generally, which may help explain why trials comparing hyaluronan with other moist dressings (section 8) find smaller differences than trials comparing it with an inert vehicle.

The body’s own production

The natural thread here is the body itself: skin, connective tissue and the eye all make hyaluronan continuously, and Stern’s work on hyaluronan turnover describes the body building and breaking down a large share of its supply every day. Dressings and gels supply extra hyaluronan from outside, but the healing process they aim to support is one the tissues already run on their own hyaluronan. Other nutrients the site covers for wound repair — such as zinc — act on different steps of the same process.

Back to Table of Contents

7. Large Molecules, Small Fragments and Inflammation

One of the central findings of hyaluronan biology is that the molecule’s size changes what it does. Stern, Asari and Sugahara’s 2006 review describes hyaluronan as “an information-rich system”:

• Large, intact polymers are space-filling, and are described as anti-angiogenic and immunosuppressive — they calm the tissue.
• Smaller fragments are inflammatory, immune-stimulating and angiogenic; they can act as endogenous “danger signals” that tell the body tissue has been injured.
• Very small pieces, down to four-sugar units, have still other effects, including protecting cells from programmed cell death.

Litwiniuk’s wound review summarises the same pattern for healing: high-molecular-weight hyaluronan tends to be anti-inflammatory, low-molecular-weight hyaluronan pro-inflammatory. In an injury, enzymes called hyaluronidases and reactive oxygen species break the large native molecule into fragments, and those fragments help start the inflammatory and blood-vessel-building phases.

For products, this means “hyaluronic acid” is not one thing. Dressings, gels and eye drops use hyaluronan of different chain lengths, sometimes chemically modified, and the reviews below pool products that may not behave alike. Several of the review authors list this variation among the limits of the evidence.

Back to Table of Contents

8. Chronic Wounds and Diabetic Foot Ulcers: The Reviews

The 2023 Cochrane review

Roehrs and colleagues updated the Cochrane review of hyaluronic acid dressings and topical agents for chronic wounds, with searches to February 2022. They included 12 trials with 1,108 participants (average age about 70), covering 896 leg ulcers, 178 pressure ulcers and 54 diabetic foot ulcers. The comparisons were split many ways, and most were small. The key results:

• Against a neutral vehicle (the same base without hyaluronan): hyaluronic acid “probably improves complete ulcer healing” (risk ratio 2.11, 95% confidence interval 1.46 to 3.07; 4 studies, 526 participants; moderate-certainty evidence), may slightly reduce pain, and may slightly increase the shrinkage of ulcers over 45 days. Whether it changes the rate of infection was uncertain.
• Against other active dressings (hydrocolloid, paraffin gauze, dextranomer, collagen, conventional dressings): the evidence was very low certainty, so the reviewers could not say whether hyaluronic acid differed from them.
• Pressure ulcers and diabetic foot ulcers: the authors concluded there is currently insufficient evidence to determine whether hyaluronic acid dressings help these wounds heal.

No trial reported quality of life or whether wounds came back. The authors downgraded the evidence for risk of bias, imprecision or both, and called for larger, blinded trials.

Diabetic foot ulcers: an older meta-analysis

A smaller 2014 meta-analysis by Chen, Hung and Lin pooled four randomized trials with 328 patients with diabetic foot ulcers. Complete healing at 12 weeks was more likely with hyaluronan (overall odds ratio 1.71; 95% confidence interval 1.01 to 2.90; p = 0.047), and the authors wrote that the findings support its use. The result only just reached statistical significance, and the later Cochrane review — with stricter grading — rated the diabetic foot evidence very low certainty and found it insufficient to judge. The two reviews are therefore not in full agreement, and the Cochrane assessment is the more cautious and more recent of the two. The site’s diabetic foot page covers the wider condition.

Back to Table of Contents

9. Healing After Sinus Surgery and Tooth Extraction

Hyaluronan is also applied to fresh surgical wounds, where the aim is smoother healing rather than closing a chronic ulcer.

Sinus surgery

After endoscopic sinus surgery for chronic rhinosinusitis, the raw surfaces inside the nose can heal into adhesions (synechiae) — bands of scar tissue that bridge the nasal passages. A 2017 systematic review by Fong and colleagues gathered 13 studies with 501 patients in which hyaluronic acid was applied in the nasal cavity after surgery. In the pooled data, adhesions formed in 42 of 283 cases with hyaluronic acid and 81 of 282 controls (risk ratio 0.52; 95% confidence interval 0.37 to 0.72). Hyaluronic acid was not associated with any significant adverse events. The authors described it as clinically safe and well tolerated and possibly useful early after surgery to limit adhesions, and called for larger randomized trials looking at outcomes reported by patients. The site’s Sinusitis page covers the underlying condition.

Tooth extraction

A 2023 systematic review by Domic and colleagues looked at hyaluronic acid placed in the tooth socket, or used as a spray or mouthwash, after extraction. It included 5 animal studies and 22 clinical studies (1,062 patients at final evaluation). In the animal studies every individual study saw more new bone with hyaluronan, but the meta-analysis did not confirm that effect. In people:

• after surgical removal of lower wisdom teeth, hyaluronan reduced pain at 7 days compared with no treatment or a placebo/carrier;
• early post-operative pain, jaw stiffness (trismus) and swelling were not affected;
• after simple extraction of normally erupted teeth, it may help soft-tissue healing, but did not reduce pain; and
• it did not appear to reduce the shrinking of the jaw ridge after extraction.

The authors reported no competing interests.

Back to Table of Contents

10. Open Questions in Eye and Wound Research

Across eyes and wounds the research leaves several questions open, most of which the review authors raise themselves:

• Which comparison matters. Hyaluronan looks clearly better than an inert vehicle or saline in several reviews, but differences shrink or disappear when it is compared with other active artificial tears or modern moist dressings.
• Product variation. Chain length, concentration, cross-linking and the other ingredients in a drop or dressing vary between trials. Given how strongly size changes hyaluronan’s biology, pooling products may hide real differences.
• Trial size and quality. The Cochrane wound review downgraded every comparison for bias or imprecision; the post-cataract dry eye review found high heterogeneity; the sinus review called for larger randomized trials.
• Outcomes people care about. No chronic-wound trial in the Cochrane review measured quality of life or recurrence, and dry eye reviews rely heavily on test scores that do not always track how the eye feels.
• The antioxidant question. Hyaluronan gels scavenge hydroxyl radicals in test tubes, but whether that matters during eye surgery or in a healing wound has not been measured in people.

What is well established is the biology: the eye and healing tissues make and use hyaluronan themselves, the molecule’s size changes its signals, and its water-holding, viscoelastic properties are what made it useful first in the operating theatre and later in drops and dressings. The other pages in this wing cover skin, joints, and antioxidant activity, forms and safety.

Back to Table of Contents

Key Research Papers

1. Meyer K, Palmer JW. The polysaccharide of the vitreous humor. J Biol Chem. 1934;107(3):629-634. DOI: 10.1016/S0021-9258(18)75338-6
2. Fraser JR, Laurent TC, Laurent UB. Hyaluronan: its nature, distribution, functions and turnover. J Intern Med. 1997;242(1):27-33. PubMed PMID: 9260563
3. 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
4. Stern R, Asari AA, Sugahara KN. Hyaluronan fragments: an information-rich system. Eur J Cell Biol. 2006;85(8):699-715. PubMed PMID: 16822580
5. Fallacara A, Baldini E, Manfredini S, Vertuani S. Hyaluronic Acid in the Third Millennium. Polymers (Basel). 2018;10(7):701. PubMed PMID: 30960626
6. Ang BCH, Sng JJ, Wang PXH, Htoon HM, Tong LHT. Sodium Hyaluronate in the Treatment of Dry Eye Syndrome: A Systematic Review and Meta-Analysis. Sci Rep. 2017;7(1):9013. PubMed PMID: 28827614
7. Yang YJ, Lee WY, Kim YJ, Hong YP. A Meta-Analysis of the Efficacy of Hyaluronic Acid Eye Drops for the Treatment of Dry Eye Syndrome. Int J Environ Res Public Health. 2021;18(5):2383. PubMed PMID: 33804439
8. Wen Y, Zhang X, Chen M, Han D. Sodium hyaluronate in the treatment of dry eye after cataract surgery: a meta-analysis. Ann Palliat Med. 2020;9(3):927-939. PubMed PMID: 32434354
9. Balazs EA. Hyaluronan as an ophthalmic viscoelastic device. Curr Pharm Biotechnol. 2008;9(4):236-8. PubMed PMID: 18691081
10. 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
11. 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
12. Stern R. Hyaluronan catabolism: a new metabolic pathway. Eur J Cell Biol. 2004;83(7):317-25. PubMed PMID: 15503855
13. Roehrs H, Stocco JG, Pott F, Blanc G, Meier MJ, Dias FA. Dressings and topical agents containing hyaluronic acid for chronic wound healing. Cochrane Database Syst Rev. 2023;7(7):CD012215. PubMed PMID: 37497805
14. Chen CP, Hung W, Lin SH. Effectiveness of hyaluronic acid for treating diabetic foot: a systematic review and meta-analysis. Dermatol Ther. 2014;27(6):331-6. PubMed PMID: 25039587
15. Fong E, Garcia M, Woods CM, Ooi E. Hyaluronic acid for post sinus surgery care: systematic review and meta-analysis. J Laryngol Otol. 2017;131(S1):S2-S11. PubMed PMID: 28164779
16. Domic D, Bertl K, Lang T, Pandis N, Ulm C, Stavropoulos A. Hyaluronic acid in tooth extraction: a systematic review and meta-analysis of preclinical and clinical trials. Clin Oral Investig. 2023;27(12):7209-7229. PubMed PMID: 37963982

PubMed Topic Searches

1. Hyaluronic acid and dry eye
2. Hyaluronan ophthalmic viscosurgical devices
3. Hyaluronic acid and chronic wound healing
4. Hyaluronan fragments, inflammation and wounds

Back to Table of Contents

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 as an Antioxidant: Forms, Absorption and Safety
• Dry Eye Disease
• Cataracts
• Wound Healing
• Wound Healing (Animation)
• Diabetic Foot Care and Ulcer Prevention
• Sinusitis
• Glucosamine