Chronic wounds caused by diseases such as diabetic foot have a lifetime risk of developing incurable ulcers. However, the current treatment of chronic wounds is still not ideal, and there is a lack of ideal wound dressings that integrate rapid dressing change, long-term treatment and high efficacy.

In view of this, Prof. Fan Yubo and Prof. Niu Xufeng from Beihang University proposed a synergistic separable microneedle (MNs) with a double-layer structure, which can be programmed through a disposable dressing. The microneedles are made of chitosan (CS) hydrogel as the tip and Mg-containing polyvinylpyrrolidone (PVP) as the base. The synergistic separation was achieved by dissolving the Mg/PVP substrate within minutes due to the enhanced Mg response to the inflammatory microenvironment due to the locally moist environment of the needle tip (Fig. 1). The combined treatment of Mg and needle-loaded Panax notoginseng saponins (PNS) achieves antibacterial, neovascularization, and activation of benign immune responses, thereby achieving a dynamic balance between the three overlapping periods of inflammation, tissue proliferation, and tissue remodeling in wound healing. Related work was published in Advanced Healthcare Materials under the title "SynergisTIcally Detachable Microneedle Dressing for Programmed Treatment of Chronic Wounds".


Microneedle Preparation

In order to prepare microneedles, the researchers dissolved CS and PNS in acetic acid solution in turn and vacuum-cast them into needle tips, then soaked in NaOH solution to remove acid and cross-linked CS, then deposited Mg particles on CS, and added PVP to prepare PVP -Mg substrate. During the preparation process, in order to prevent the reaction of Mg in the acidic solution, the entire mold was immersed in an aqueous NaOH (10% w/v) solution and the CS was cured.


Figure 1 Double-layer microneedle

Collaborative separation

Compared with CS/PVP MNs, CS/Mg-PVP MNs produced a large number of air bubbles after being inserted into the simulated wound (Fig. 2), the substrate disintegrated rapidly, and the dye permeability increased. This is attributed to Mg reacting with the inflammatory microenvironment to generate H₂, which promotes tip-base separation and increases drug permeability. At the same time, the microneedle base was removed after piercing the simulated wound for 5 minutes, and it was found that the base separation rate of CS/Mg-PVP MNs (87.5%) was significantly higher than that of the control group (29.3%) and other experimental groups (Fig. 3a), indicating that Mg can Effectively improve the needle tip separation rate and realize the coordinated separation of needle tips.


Figure 2 In vitro separation test of microneedles

Drug burst and sustained release

The researchers used bovine serum albumin (BSA) as a biomacromolecule drug and rhodamine B (RhB) as a small molecule drug to study the programmable multi-stage drug release of microneedles. It was found that when the drug was loaded on the PVP substrate, the Mg reaction produced a large number of H₂ bubbles and formed cavities in the substrate. The cavity can increase the reaction area and accelerate the dissolution of PVP, resulting in a burst release of the drug (Fig. 3b). When the drug release amount was ~90%, both BSA (40min→9min) and RhB (30min→9min) release times were reduced in CS/Mg-PVP MNs compared with CS/PVP MNs (Fig. 3c). However, both microneedles with and without Mg showed long-lasting drug release when the drug was loaded on the CS needle tip (Fig. 3d).


Figure 3 Drug release curve

Diabetic wound healing with Staphylococcus aureus infection

The in vivo study of SD rats found that after 10 days of treatment for S. aureus-infected rats, the wound area in the PNS-CS/Mg-PVP MNs group (6.34%) was much smaller than that in the control group (Control) (34.43%) (Fig. 4b,c), its granulation tissue thickness (1271.7 μm) was also much larger than that of the Control group (437.4 μm), CS/PVP MNs group (606.4 μm) and CS/Mg-PVP MNs group (838.3 μm) (Fig. 4d), and PNS Can promote cell re-epithelialization (Figure 5). The results of MTS showed that blood scabs formed in the Control group (Figure 6), and abnormal columnar epithelial accumulation and epithelial cell proliferation appeared under the blood scabs, indicating abnormal wound healing and hypertrophic scars caused by bacterial infection. However, there was almost no blood scab formation in the experimental group, and the newly generated fibroblasts of PNS-CS/Mg-PVP MNs could promote collagen deposition and achieve the healing of chronic wounds caused by bacterial infection. At the same time, quantitative analysis of platelet-endothelial cell adhesion molecule (CD31) showed that PNS-CS/Mg-PVP MNs could promote angiogenesis by prolonging the release of PNS, and the amount of new blood vessels (8.51%) in the control group (2.27%) %) 3.75 times. In terms of inflammation, the treatment of both PNS-CS/Mg-PVP MNs and CS/Mg-PVP MNs down-regulated wound tissue inflammatory factors IL-6 and TNF-a, which was attributed to their release of Mg²⁺ inhibiting the secretion of inflammatory factors, Reduce wound inflammation. The degree of inflammation in the two groups was very similar, indicating that the main inflammatory regulator in the entire drug delivery system was Mg²⁺. In addition, the Mg²⁺ released by the two groups can also promote the transformation of macrophages from M1 type to M2 type, which reduces the pro-inflammatory effect of the wound and makes the wound transition from the initial inflammatory stage to the tissue proliferation and remodeling stage.

In conclusion, we developed a facile two-layer detachable microneedle strategy to achieve programmed treatment of bacterially infected chronic wounds, and the inclusion of Mg in the substrate can synergistically accelerate needle tip separation, which can be achieved by a one-time insertion. Multistage drug release at programmed time points. Furthermore, microneedles can kill bacteria, promote neovascularization in chronic wounds, and regulate macrophage phenotype switching to reduce inflammation. This bilayer detachable microneedling is an innovative programmed therapy and shows great promise for improving skin wound treatment.

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