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Diabetic wounds can be difficult to heal because several biological problems occur at the same time. High levels of oxidative stress can damage cells, inflammation can remain active for too long, and the growth of new blood vessels can be impaired. Together, these conditions can prevent injured tissue from repairing itself normally.
Researchers at Nanchang University have developed a treatment that combines engineered extracellular vesicles with a hydrogel microneedle patch.
Extracellular vesicles, or EVs, are small membrane-bound particles released by cells. They can transport proteins, RNA, lipids, and other molecules between cells, making them useful candidates for delivering therapeutic materials.
Combining extracellular vesicles with ALDH2
The researchers used extracellular vesicles derived from human amniotic mesenchymal stem cells. These EVs were combined with liposomes carrying aldehyde dehydrogenase 2, or ALDH2, an enzyme involved in protecting cells from oxidative damage.
The resulting hybrid particles, called ALDH2@Lipo/EV, were designed to combine the natural biological properties of extracellular vesicles with delivery of ALDH2.
Laboratory experiments showed that the engineered EVs promoted angiogenesis, the formation of new blood vessels. Restoring blood vessel growth is particularly important in diabetic wounds because damaged circulation can limit the delivery of oxygen and nutrients needed for tissue repair.
Reducing oxidative stress and inflammation
The engineered extracellular vesicles also affected macrophages, immune cells that play an important role in inflammation and wound healing.
ALDH2@Lipo/EV reduced oxidative damage and inflammatory activity by influencing pathways involved in mitochondrial health. The treatment inhibited activation of a protein called Drp1, which regulates mitochondrial division, while promoting activity in the PINK1/Parkin pathway.
The PINK1/Parkin pathway helps cells identify and remove damaged mitochondria through a process called mitophagy. Maintaining healthier mitochondria may reduce oxidative stress and help immune cells shift toward conditions that support tissue repair.
The researchers also observed changes in macrophage polarization. Macrophages can adopt different functional states, including inflammatory states that help fight injury or infection and repair-associated states that support healing. Better regulation of this balance could help resolve the persistent inflammation commonly associated with diabetic wounds.
Delivering EVs with microneedles
Getting therapeutic extracellular vesicles into damaged tissue efficiently can be challenging. To improve delivery, the researchers incorporated ALDH2@Lipo/EV particles into a methacrylated gelatin, or GelMA, hydrogel microneedle patch.
Microneedles are extremely small projections that can penetrate the outer layers of tissue without using a conventional injection needle. In this system, they helped deliver the engineered EVs directly into the wound at a controlled depth.
This approach may help overcome limitations associated with applying extracellular vesicles only to the wound surface, where penetration into deeper tissue can be limited.
Improving wound healing in mice
The researchers tested the microneedle system in a mouse model of diabetic wound healing.
Wounds treated with the ALDH2@Lipo/EV microneedle patches showed improved healing and tissue reconstruction. The treatment addressed several processes that contribute to chronic wounds, including poor blood vessel formation, oxidative stress, mitochondrial dysfunction, and prolonged inflammation.
These results illustrate the potential benefit of combining biological delivery systems with engineered materials. Extracellular vesicles provide a biologically active carrier, liposomes deliver ALDH2, and the hydrogel microneedles help place the treatment directly into the wound.
Further research will be needed to determine whether the same approach is safe and effective in humans. However, integrating engineered extracellular vesicles with microneedle delivery provides a promising strategy for addressing several biological barriers to diabetic wound healing at the same time.
