Repair of chronic wounds, caused by trauma, surgery or diabetes, for example, can be challenging. When the skin is cut or torn, the body works to heal itself, via a complex process involving blood clotting, elimination of any bacterial invaders, regrowth of damaged blood vessels and tissue remodelling.

Techniques are available that can help heal wounds, such as applying bandages or stitches to stop bleeding, or using antibiotics to prevent infection. But now, researchers in China have developed a wound-healing ink that aims to actually accelerate the body’s natural healing process, called “portable bioactive ink for tissue healing”, or PAINT. The ink, described in ACS Applied Materials & Interfaces, is made from extracellular vesicles (EVs) embedded in hydrogel and can be painted directly into wounds of any shape using a 3D-printing pen.

EVs secreted from white blood cells such as macrophages play an important role in promoting blood vessel formation and reducing inflammation during healing. To create their PAINT platform, the research team – headed up by Dan Li from Nanjing University, and Xianguang Ding and Lianhui Wang from Nanjing University of Posts and Telecommunications – mixed bioactive EVs derived from M2 macrophages (the type associated with tissue repair) with biocompatible sodium alginate hydrogels. Within minutes, this mixture forms a sturdy EV_M2-gel ink that can be applied to wounds in situ.

The researchers first tested the effect of exposing human endothelial cells to various concentrations (0, 100, 200 and 300 µg/ml) of EV_M2. In particular, they examined the impact on angiogenesis (the formation of new blood vessels), an essential factor in wound healing.

Cells incubated with EV_M2 formed more capillary tubes than untreated controls, with angiogenesis increasing with EV_M2 concentration and over time. Optical microscopy showed that the total blood vessel length, vessel percentage area and total number of junctions all increased significantly after 6 h incubation, demonstrating that EV_M2 can promote angiogenesis in vitro.

Next, the team incubated macrophages with the three concentrations of EV_M2. Macrophages are a vital part of the immune system: they respond to and resist the invasion of foreign substances and play a key role in the repair and regeneration of inured tissues. Polarization of macrophages from the M1 (pro-inflammatory) to the M2 (pro-healing) phenotype is an effective approach for promoting wound healing. Compared with the control group, the ratio of M2 to M1 macrophages significantly increased in the EV_M2 groups, indicating that EV_M2 promoted polarization to the M2 phenotype in a concentration-dependent manner.

Finally, the researchers assessed the therapeutic effect of PAINT in vivo on injured mice. For this, they developed a 3D-printing pen that internally mixes EV_M2 with hydrogel precursors to form the EV_M2-gel ink at the surface of the skin. This application process can be adapted to match the size and shape of any wound.

Following the creation of a 9 mm circular wound on the back of mice, the animals were treated with EV_M2-gel ink containing 100 or 300 µg/ml concentrations of EV_M2, or no gel. Fluorescence imaging 6 and 12 h after administration showed that the ink continuously released EV_M2 into the wound.

Compared with the control group, mice treated with EV_M2-gel experienced significantly accelerated wound healing. On day 12, wound areas were reduced to 21.22, 12.87 and 6.73% of the original size, for the control, 100 and 300 µg/ml groups respectively. Histology indicated that the EV_M2-gel ink significantly increased epidermal thickness and promoted collagen fibre formation, essential factors in remodelling newly formed tissues.

Smart stitches could prevent infections at surgical sites

Consistent with the in vitro findings, the ink also significantly increased the average microvessel density in the wound area and polarized macrophages to the M2 phenotype. By day 14, scarring gradually decreased and wounds of mice in the 300 µg/ml group were almost completely healed.

The researchers say that this work could help heal a wide variety of cuts quickly and easily, without the need for complex procedures. “Our study demonstrates the high potential of bioactive EV ink in biomedical applications,” they conclude. While the PAINT platform has not yet been tested in human subjects, ultimately, the team plans to work towards clinical translation, Ding tells Physics World.

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• Source: https://physicsworld.com/a/paintable-bioactive-ink-heals-wounds-of-any-shape-or-size/