The Promising Hydrogel Candidates for Preclinically Treating Diabetic Foot Ulcer: A Systematic Review and Meta-Analysis

Significance: Diabetic foot ulcer (DFU) causes high amputation rates owing to its aberrant wound healing. Traditional dressings cannot effectively contribute to DFU healing. Functional hydrogels have been proposed as a promising novel dressing to treat DFU in future, but the evidence for various hydrogels to heal DFU is still ambiguous. Recent Advances: In accordance with PRISMA and CONSORT guidelines, a meta-analysis was performed to evaluate the efficacy of functional hydrogels. Four electronic databases and one website were used for data searching. Twenty-four animal studies and six clinical trials met the inclusion criteria with a total of 399 diabetic murine models and 278 patients with DFU. Critical Issues: Functional hydrogels accelerated the healing progress for DFU and relieved symptoms in patients. According to their characteristics, the functional hydrogels were divided into antioxidant hydrogel (AOH), antibacterial hydrogel (ABH), multifunctional hydrogel (MFH), proangiogenic hydrogel, and hydrogel promoting proliferation (PPH). By network meta-analysis, AOH and MFH were considered the premium options for treating wounds of diabetic patients at whole stage. Future Direction: Functional hydrogels effectively accelerate healing rates in wounds of diabetic animals. Hydrogels of AOH and MFH might become the ideal candidates for clinical trials on DFU treatment, based on the meta-analyses from the reported work. Early treatment with AOH followed a week later with ABH, which might become an advanced strategy for DFU in future. This information is very important for researchers or/and physicians in taking consideration for alternate application of hydrogel dressings. Scope and Significance: The treatment of DFU imposes a huge burden on medical workers. If DFU is not treated properly, patients will have to suffer from amputation and from spiritual agony. Although various topical dressings have been designated for DFU, the healing ability of those dressings is still unknown well. In this review and meta-analysis, we quantitatively evaluated the reported outcomes of functional hydrogels, pure scaffolds, and controls in 2-week interval. Healing ability of various kinds of functional hydrogels was also assessed in different stages of wound, aiming to screen promising candidates for DFU treatment. This information is valuable in designing smart dressings for researchers or/and physicians in future. Translational Relevance: Considering many external factors like formation of bacterial film and internal factors like hyperglycemia, the progress during DFU healing could involve many biochemical aspects. Persistent inflammation, oxidation stress, and impaired angiogenesis lead to prolonged wound healing and even lethal outcomes. Thus, improvement of topical conditions and inhibition of adverse factors will lead to the alleviated morbidity and even mortality. Clinical Relevance: DFU brings about great burden on patients and medical staffs because of high morbidity and poor prognosis. Improper and powerless treatment might induce high rates of amputation and mortality. Functional hydrogels, mimicking extracellular matrices, would provide the tissue with suitable media and functions to promote DFU healing. The application of various types of hydrogels could be a promising solution to heal DFU and reduce adverse events and costs.