Diabetic wounds (DWs) are a common and severe complication of diabetes mellitus, which imposes a tremendous health and economic burden worldwide. DWs are often characterised by reactive oxygen species (ROS) accumulation, disordered inflammation, and infection. ROS accumulation impacts the whole course of wound healing (haemostasis, inflammation, cell migration and proliferation, angiogenesis, and remodelling) by increasing cell apoptosis, senescence, lipid peroxidation, protein modification, and DNA damage. Wound healing requires tight orchestration of cell migration, proliferation, matrix deposition and remodelling, alongside inflammation and angiogenesis. Hyperglycaemia in the microenvironment causes undesirable impairments to the orchestration, leading to abnormal wound healing, reduced tensile strength of the skin, and wound recurrence.

Objective

Asiaticoside (AC), a natural compound, offers antioxidant, anti-inflammatory, and tissue repair benefits for wound healing. However, traditional delivery is ineffective in penetrating biofilms and maintaining local concentration. In the present study, AC was loaded into Hyaluronic acid Methacryloyl (HAMA) to fabricate a hydrogel microneedle (MN) patch as a multifunctional dressing to treat infectious DWs. 

The premix hydrogel solution of AC and HAMA was filtered and exposed to UV light to construct the hydrogel microneedle patch. The physical properties, drug release profile, degradation analysis and antioxidant capacity of the AC@MN were evaluated in the study. The efficacy of antibacterial and biofilm removal was also tested in the study. The ROS scavenging, in vitro anti-inflammatory and macrophage phenotype regulatory capacities of the MN were evaluated. An infectious diabetic wound model was used to evaluate the influence of the AC@MN patch on in vivo activities. Data were depicted as means ± standard deviation (x̅ ± s). Two-tailed p values < 0.05 were considered significant.

A hydrogel MN patch fabricated with 10% (w/v) HAMA and 0.5% (w/v) AC was maintained in the present experiments and referred to as AC@MN, which showed superior mechanical characteristics. In vitro investigations indicated that AC@MN possessed a superior cytocompatibility and ROS scavenging capacity on RAW 264.7 cell lines under hydrogen peroxide H2O2 or lipopolysaccharides (LPS) stimulation. In addition, using MN as a drug delivery vehicle, the AC@MN hydrogel showed a moderate antioxidative capacity to modulate OS throughout the whole course of wound healing. Meanwhile, the MN patch inhibited expressions of several cytokines, such as interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and inhibited NLRP3 inflammasome activation. It also manipulated M1/M2 macrophage polarisation in an inflammatory microenvironment. Additionally, the patch exhibited excellent antibacterial activity against Escherichia coli and Staphylococcus aureus in vitro. Animal experiments discovered that the AC@MN patch significantly promoted wound healing with preferable re-epithelialisation, angiogenesis and collagen deposition.

The AC@MN system effectively delivers asiaticoside, penetrating biofilms and modulating macrophage polarisation from pro-inflammatory M1 to anti-inflammatory M2. As noted, macrophage polarisation dysfunction in DWs is associated with impaired wound closure, poor angiogenesis, and decreased collagen deposition. This action reduces oxidative stress, suppresses inflammatory pathways, and accelerates infectious DWs healing through improved microenvironment and tissue repair. In conclusion, this AC@MN patch ameliorated undesirable microenvironments in DWs and offered a promising therapeutic strategy for wound management in clinical practice. The AC@MN patch showed preferable OS attenuation and immunoregulatory properties in vivo and contributed to DW healing acceleration by modulating inflammation and promoting collagen deposition and angiogenesis.