A biphasic drug-releasing microneedle with ROS scavenging and angiogenesis for the treatment of diabetic ulcers

Oct 3, 2024Acta biomaterialia

A two-stage drug-releasing microneedle that reduces harmful molecules and promotes new blood vessels to treat diabetic ulcers

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Regenerative Health on OpenScience ↗PubMed ↗DOI ↗

Abstract

A biphasic drug-releasing microneedle significantly improves wound healing in diabetic ulcer models.

The microneedle releases cerium dioxide nanoparticles rapidly to clear reactive oxygen species (ROS) during the initial inflammation phase.
Vascular endothelial growth factor is released gradually from the microneedle to enhance blood vessel formation in the later stages of healing.
In vitro and in vivo studies demonstrate increased cell proliferation and migration associated with the use of this microneedle.
The microneedle promotes M2 macrophage polarization, which is linked to improved healing outcomes.
The delivery system may provide a multifunctional approach for treating diabetic ulcers by combining nano-enzymes and growth factors.

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Diabetic ulcers are one of the common complications in diabetic patients. Delayed wound healing is associated with persistent pro-inflammatory M1 polarization, reduced angiogenesis and increased reactive oxygen species (ROS) in the microenvironment. Wound healing consists of multiple phases and therefore requires treatment tailored to each phase. In this study, a biphasic drug-releasing microneedle (MN) was fabricated to achieve early ROS scavenging and late accelerated angiogenesis to promote wound healing. Vascular endothelial growth factor (VEGF) was first encapsulated in methacryloylated sulfonated chitosan (SCSMA) microspheres (V@MP), and then V@MP was loaded into hyaluronic acid (HA) microneedles along with cerium dioxide nanoparticles (CONPs). Rapid dissolution of HA rapidly releases the CONPs to clear ROS, whereas the V@MP stays in the wound. SCSMA slow degradation prolongs the release of VEGF, thereby promoting angiogenesis. In vitro and in vivo studies have shown that this biphasic drug-releasing smart microneedle improves cell proliferation and migration, effectively scavenges ROS, promotes angiogenesis and tissue regeneration, and synergistically promotes M2 macrophage polarization. It provides a new delivery mode for nano-enzymes and growth factors that could be multifunctional and synergistic in the treatment of diabetic ulcers. STATEMENT OF SIGNIFICANCE: In our study, we present a microneedle (V@MP/C@MN) that can release drugs biphasically, which showed good repair ability in diabetic ulcer model. Large amounts of CONPs were rapidly released to alleviate oxidative stress during the inflammation of the wound, and V@MP stayed in the wound for a long period of time to release VEGF and promote angiogenesis in the late stage of wound healing. The results indicated that V@MP/C@MN could promote cell proliferation and migration, effectively scavenge ROS, promote angiogenesis and tissue regeneration, and synergistically promote M2 macrophage polarization, which could play a multifunctional and synergistic role in the treatment of diabetic ulcers.

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A biphasic drug-releasing microneedle with ROS scavenging and angiogenesis for the treatment of diabetic ulcers

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