Hyaluronic acid for chronic wound healing

What is the aim of this review?

The aim of this review was to evaluate the effects of hyaluronic acid on the healing of chronic wounds. Hyaluronic acid is a naturally occurring molecule present in human cells. Chronic wounds are wounds that take a long time to heal. They include pressure ulcers, foot ulcers, and leg ulcers.

Key messages

We cannot be certain whether dressings and topical agents containing hyaluronic acid are more effective for healing pressure ulcers or foot ulcers in people with diabetes than other dressings and topical agents. When used in people with leg ulcers and compared with the inactive substance included in the dressing to serve as a means of delivering hyaluronic acid (neutral vehicle), hyaluronic acid probably improves complete ulcer healing and may slightly decrease pain and increase change in ulcer size. There was not enough information to be sure how dressings and topical agents containing hyaluronic acid compare with other dressings and topical agents in terms of potential side effects.

What was studied in the review?

Chronic wounds are hard-to-heal wounds that arise for a variety of reasons, including in response to an underlying disease. Treatment includes different types of wound dressing or topical agents with a variety of purposes, including: maintenance of a moist healing environment; reduction of bacteria present in the wound; and prevention of infection.

What did we do?

We searched the medical literature for studies that evaluated the effects of hyaluronic acid compared with other dressings. We compared the data obtained, summarised the results, and rated our confidence in the evidence, based on factors such as study methods and sizes. We only included randomised controlled trials, a type of study where people are assigned at random to receive different treatments, because they provide the most reliable health evidence.

What are the main results of the review?

We found 12 studies involving a total of 1108 participants. Sex was reported for 1022 participants (57.24% female). Mean age corresponded to 69.60 years. Dressings containing varying concentrations of hyaluronic acid, or containing hyaluronic acid in combination with another treatment, were compared with other dressing types.

It is uncertain whether hyaluronic acid is better or worse at healing pressure ulcers or foot ulcers in people with diabetes. It is also uncertain if there is any difference in effect between hyaluronic acid and other dressings on adverse events and pain in these types of wounds. This is due to scarcity of data to analyse or because of study limitations such as small sample sizes and methodological problems.

In leg ulcers, hyaluronic acid probably improves complete ulcer healing when compared with neutral vehicle (4 studies, 526 participants), and may slightly reduce pain (3 studies, 337 participants) and slightly increase change in ulcer size (2 studies, 190 participants). It is uncertain whether hyaluronic acid is better or worse at healing leg ulcers when compared with hydrocolloid (an agent that forms a gel when exposed to wound fluids), paraffin gauze, or dextranomer (a type of dressing that promotes wound healing).

No trial reported health-related quality of life or wound recurrence.

What limited our confidence in the evidence?

Most studies were small (fewer than 100 participants), and most (9 out of 12) used methods that were likely to have introduced errors in their results. Follow-up duration was short (9 out of 12 studies followed participants for 60 days or less), and studies were not designed to assess time to complete healing (only 1 study followed participants until complete healing).

How up-to-date is the review?

We searched for studies published up to February 2022.

Authors' conclusions: 

There is currently insufficient evidence to determine the effectiveness of hyaluronic acid dressings in the healing of pressure ulcers or foot ulcers in people with diabetes. We found evidence that hyaluronic acid probably improves complete ulcer healing and may slightly decrease pain and increase change in ulcer size when compared with neutral vehicle. Future research into the effects of hyaluronic acid in the healing of chronic wounds should consider higher sample size and blinding to minimise bias and improve the quality of evidence.

Read the full abstract...
Background: 

Hyaluronic acid is synthesised in plasma membranes and can be found in extracellular tissues. It has been suggested that the application of hyaluronic acid to chronic wounds may promote healing, and the mechanism may be due to its ability to maintain a moist wound environment which helps cell migration in the wound bed.

Objectives: 

To evaluate the effects of hyaluronic acid (and its derivatives) on the healing of chronic wounds.

Search strategy: 

We used standard, extensive Cochrane search methods. The latest search date was February 2022.

Selection criteria: 

We included randomised controlled trials that compared the effects of hyaluronic acid (as a dressing or topical agent) with other dressings on the healing of pressure, venous, arterial, or mixed-aetiology ulcers and foot ulcers in people with diabetes.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach.

Main results: 

We included 12 trials (13 articles) in a qualitative synthesis, and were able to combine data from four trials in a quantitative analysis. Overall, the included trials involved 1108 participants (mean age 69.60 years) presenting 178 pressure ulcers, 54 diabetic foot ulcers, and 896 leg ulcers. Sex was reported for 1022 participants (57.24% female).

Pressure ulcers

It is uncertain whether there is a difference in complete healing (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.58 to 2.35); change in ulcer size (mean difference (MD) 25.60, 95% CI 6.18 to 45.02); or adverse events (none reported) between platelet-rich growth factor (PRGF) + hyaluronic acid and PRGF because the certainty of evidence is very low (1 trial, 65 participants). It is also uncertain whether there is a difference in complete healing between lysine hyaluronate and sodium hyaluronate because the certainty of evidence is very low (RR 2.50, 95% CI 0.71 to 8.83; 1 trial, 14 ulcers from 10 participants).

Foot ulcers in people with diabetes

It is uncertain whether there is a difference in time to complete healing between hyaluronic acid and lyophilised collagen because the certainty of evidence is very low (MD 16.60, 95% CI 7.95 to 25.25; 1 study, 20 participants). It is uncertain whether there is a difference in complete ulcer healing (RR 2.20, 95% CI 0.97 to 4.97; 1 study, 34 participants) or change in ulcer size (MD −0.80, 95% CI −3.58 to 1.98; 1 study, 25 participants) between hyaluronic acid and conventional dressings because the certainty of evidence is very low.

Leg ulcers

We are uncertain whether there is a difference in complete wound healing (RR 0.98, 95% CI 0.26 to 3.76), percentage of adverse events (RR 0.79, 95% CI 0.22 to 2.80), pain (MD 2.10, 95% CI −5.81 to 10.01), or change in ulcer size (RR 2.11, 95% CI 0.92 to 4.82) between hyaluronic acid + hydrocolloid and hydrocolloid because the certainty of evidence is very low (1 study, 125 participants). It is uncertain whether there is a difference in change in ulcer size between hyaluronic acid and hydrocolloid because the certainty of evidence is very low (RR 1.02, 95% CI 0.84 to 1.25; 1 study, 143 participants). We are uncertain whether there is a difference in complete wound healing between hyaluronic acid and paraffin gauze because the certainty of evidence is very low (RR 2.00, 95% CI 0.21 to 19.23; 1 study, 24 ulcers from 17 participants).

When compared with neutral vehicle, hyaluronic acid probably improves complete ulcer healing (RR 2.11, 95% CI 1.46 to 3.07; 4 studies, 526 participants; moderate-certainty evidence); may slightly increase the reduction in pain from baseline (MD −8.55, 95% CI −14.77 to −2.34; 3 studies, 337 participants); and may slightly increase change in ulcer size, measured as mean reduction from baseline to 45 days (MD 30.44%, 95% CI 15.57 to 45.31; 2 studies, 190 participants). It is uncertain if hyaluronic acid alters incidence of infection when compared with neutral vehicle (RR 0.89, 95% CI 0.53 to 1.49; 3 studies, 425 participants). We are uncertain whether there is a difference in change in ulcer size (cm2) between hyaluronic acid and dextranomer because the certainty of evidence is very low (MD 5.80, 95% CI −10.0 to 21.60; 1 study, 50 participants).

We downgraded the certainty of evidence due to risk of bias or imprecision, or both, for all of the above comparisons. No trial reported health-related quality of life or wound recurrence. Measurement of change in ulcer size was not homogeneous among studies, and missing data precluded further analysis for some comparisons.