Diabetic foot ulcer (DFU) is the most serious and costly complication of diabetes (1). It plays a very important role in the occurrence of vascular disease, neuropathy, and infection of diabetes. In severe cases, amputation is required, which significantly affects the patients’ quality of life.

Wound dressing plays an important role in the clinical treatment of DFU. A kind of dressing with good hemostatic maintenance ability, anti-infection and promoting repair ability may be suitable for diabetic wound (2). In recent years, several studies have reported satisfactory results after the treatment of chronic complex wounds, with advanced dressings, including gauze, films, foams or, hydrocolloid-based dressings as well as polysaccharide- and polymer-based dressings (3).

Hyaluronic acid (HA) is a major component of the extracellular matrix that possesses desirable properties such as biocompatibility, biodegradability, and hydrophilicity (4). It has been found to be a promising candidate to promote wound healing by stimulating the proliferation of fibroblast, keratinocyte migration, and remodeling of the extracellular matrix (5). A recent Cochrane review by Roehrs et al. (6) evaluated the effects of HA and its derivatives on the healing of chronic wound, and found that HA probably improves complete ulcer healing and may increase change in ulcer size when compared with neutral vehicle. In particular, the effect of HA on diabetic wound remains unclear. Therefore, we presented a systematic review and meta-analysis to evaluate the effectiveness of HA and its derivatives on wound healing in DFU.

The systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 guidelines (7). It was registered at PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024588743).

The electronic databases included PubMed, BIOSIS, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar internet. The final search was updated on Aug 31, 2024. No restriction of language was performed in this study. The following combination of search terms was used: (hyaluronic acid, or hyaluronate) AND (diabetic foot, diabetic wound, or DFU). We reviewed references from the original trials, grey literatures, and review articles to identify potential eligible articles. Two reviewers conducted literature searches independently and resolved differences through discussion with the third author.

A total of 82 primary studies were identified from online databases prior to Aug 2024. The process of study selection is reported in Figure 1 . According to the inclusion and exclusion criteria, seven RCTs involving 444 patients and 456 ulcers were included in our study (11–17). All were published in English. The sample ranged from 25 to 160. Three articles were published in Italy, three were from Korea, and one was from Bulgaria. Detailed of included RCTs are presented in Table 1 . The outcomes of included studies are reported in Table 2 . The qualities of included studies are shown in Figure 2 .

Seven trials reported the outcome of ulcer healing rate. The study showed a higher ulcer healing rate in the HA group compared with the control group (OR 3.92, 95% CI 1.74 to 8.81, I² = 62%). There was a significant heterogeneity among these studies (I² = 62%, P = 0.02) ( Figure 3A ). Results gave a pooled rate of 62.76% (150/239) in the HA group and of 40.09% (87/217) in the control. We performed a sensitivity analysis and the result showed that summary results were not significantly influenced by any single study ( Figure 4 ). In addition, we performed a subgroup analysis based on the HA intervention (HA alone and HA plus autograft). Subgroup analysis indicated that the rate of complete ulcer healing varied with the HA intervention (HA alone OR = 5.03, 95% CI 1.76 to 14.39, P = 0.61; HA plus autograft OR = 3.51, 95% CI 1.13 to 10.89, P = 0.005) ( Figure 3B ). Regarding HA intervention, I² changed from 0% for HA alone group to 77% for HA plus autograft group. Different HA intervention might not account for the heterogeneity.

Four studies reported the data of time to healing. A lower wound healing duration was found in the HA group compared with the control group (SMD = -0.83, 95% CI -1.13 to -0.53, I² = 28%). There was no between-study heterogeneity among these studies (P = 0.24, I² = 28%) ( Figure 3C ).

Five trials reported the outcome of adverse events. 31/194 participants (15.98%) in the HA group experienced an adverse event compared with 35/171 (20.47%) in the control group. The overall pooled data showed no significant difference (OR = 0.79, 95% CI 0.46 to 1.35, P = 0.31, I² = 16%) ( Figure 3D ).

The funnel plot in the meta-analysis showed no evidence of publication bias in relation to risk of ulcer healing rate ( Figure 5 ). It was also proved by Egger’s test (P = 0.222) and Begg’s test (P = 0.368).

This meta-analysis evaluated the effect of HA and its derivatives on wound healing in DFU. When compared with standard treatment, HA and its derivatives significantly improved the complete ulcer healing rate, shorten healing time, without increasing incidence of adverse events.

Hyaluronic acid is a straight chain, glycosaminoglycan polymer of the extracellular matrix composed of repeating units of the disaccharide (18). Previous studies have reported its significant role in promoting wound healing and regulating immune inflammatory response (19, 20). A meta-analysis on the effect of HA on the healing of burns, epithelial surgical wounds, and chronic wounds reported improved healing when compared with traditional therapies or placebo (21). In the early stage of wound healing, cells secrete a large amount of HA, which can promote wound contraction, increase the activity of neutrophils, and accelerate the phagocytosis of necrotic tissue and bacteria (22). HA can also induce cell aggregation and promote the formation of blood vessels within the collagen and fibrin matrix, thus promoting wound healing (23). With its inherent biocompatibility, viscoelastic properties, biodegradability, and non-immunogenicity, HA make it an excellent candidate for diabetic wound dressing components (24).

In 2014, a meta-analysis by Chen et al. (25) reported the effectiveness of HA for treating diabetic foot. The authors suggested that HA was beneficial in treating diabetic foot by increasing the rate of wound healing. This meta-analysis only included four trials, and studies did not reported the outcome of time to complete healing. In this present study, we included three extra trials and performed an updated meta-analysis of RCTs. In addition to the result of ulcer healing rate, we compared the clinical outcomes on time to healing and incidence of adverse events. More comparison of outcomes can help us make better clinical decisions.

Different HA-based wound dressing are used in our study. It can either be placed directly on the wound or used as a substrate for future autologous tissue grafts. Three trials used hyaluronic acid based scaffold (Hyalograft3D) plus autograft. One study used hyaluronic acid sheet plus autograft. The other three studies used HA gel, HA dressing, and Zinc hyaluronate, respectively. We further performed a subgroup analysis. Both the two subgroup results revealed a significant difference in favor of HA for the healing rate (OR = 5.03, 95% CI 1.76 to 14.39, P = 0.61; OR = 3.51, 95% CI 1.13 to 10.89, P = 0.005). HA alone or in combination with other compounds has a positive wound healing effect in DFU. In recent years, different methods of HA for the production of different types of wound dressing, including hydrogels, films, scaffolds, foams, and topical formulations, and nanoformulations, have been widely used for wound management (26). An extensive investigation will be needed to develop and optimize these novel wound dressings.

Some limitation should be noted. First, we only included seven studies, and the sample size in most of the studies were small. Secondly, some trials did not report the clinical characteristics of the individuals included and ulcer type and stage, which might cause potential bias in the selection of participants. Thirdly, this review found moderate inter-study heterogeneity (I² = 62%). We performed a sensitivity analysis by investigating the effect of each individual study on the pooled effect size, and the summary results were comparatively reliable. Each trial varied in terms of demographic factors, patient profile, ulcer size, location method of adding HA to the dressing material, and duration of use, which might contribute to the heterogeneity. In future, more RCTs are needed to support these findings.

In conclusion, HA and its derivatives could be a potentially beneficial therapy for DFU treatment that promotes the complete ulcer healing rate, shortens healing time, without increasing incidence of adverse events. The use of different HA-based wound dressing methods should be further assessed. In addition, high quality of RCTs are needed in the future.