Healing biomaterials activate immune system for stronger skin

Researchers at Duke University and the University of California, Los Angeles have developed a biomaterial that dramatically reduces scar formation after injury, leading to more efficient healing of the skin. This new material, which quickly degrades once the wound is closed, demonstrates that activating an adaptive immune response can trigger regenerative healing, leaving healed skin stronger and healthier.

This work builds on the team’s previous research with hydrogel scaffolds, which create structure to support tissue growth, accelerating wound healing. In their new study, the team showed that a modified version of this hydrogel activates a regenerative immune response, which can potentially help heal skin injuries such as burns, cuts, diabetic ulcers, and other healing wounds. normally with large scars which are more likely to be injured. .

This research appears online November 9, 2020 in the journal Materials from nature.

“The body forms scar tissue as quickly as possible to reduce the risk of infection, reduce pain and, in larger wounds, prevent water loss through evaporation,” said Maani Archang, first author of the article and doctor of medicine. .RE. student in Scumpia and Di Carlo laboratories at UCLA. “It’s a natural wound healing process.”

Current healing hydrogels available for clinical use sit on the wound surface, where they act as a dressing and help prevent the wound from drying out. This in turn helps the wound to heal faster, usually through the formation of scars.

In their 2015 Materials from nature paper, the research team, led by Tatiana Segura of Duke and Dino Di Carlo of UCLA, developed annealed microporous particle (MAP) hydrogels, which are a microparticle-based biomaterial that can integrate into the wound rather than sitting on the surface of the skin. The beads in the MAP gel bind together but leave open spaces, creating a porous structure that provides support for cells as they grow at the wound site. When the wound closes, the gel slowly dissolves, leaving healed skin.

Although MAP hydrogels allowed for rapid cell growth and faster repair, the team noticed that the scarred skin had limited complex structures like hair follicles and sebaceous glands. The team were curious if they could modify their biomaterial to improve the quality of healed skin.

“Previously, we had seen that when the wound started to heal, the MAP gel started to lose its porosity, which limited the growth of tissue through the structure,” says Don Griffin, assistant professor at the University of Virginia who is a first author on paper and a former postdoctoral fellow at Segura Lab. “We hypothesized that slowing the rate of degradation of the MAP scaffold would prevent the pores from closing and provide additional support to the tissue as it grows, which would improve the quality of the tissue.”

Rather than creating an entirely new gel with new materials, the team instead focused on the chemical binder that allowed the scaffold to be naturally broken down by the body. In their original MAP gels, this chemical linker is made up of an amino acid sequence taken from the body’s own structural proteins and arranged in a chemical orientation called L chirality. Since this peptide sequence and orientation is common throughout everything. the body, this helps the gel to avoid triggering a strong immune response, but also allows easy breakdown thanks to naturally occurring enzymes.

“Our body has evolved to recognize and degrade this amino acid structure, so we hypothesized that if we returned the structure to its mirror image, which is chirality, the body would have a harder time degrading the scaffold. Said Segura, a professor of biomedical engineering at Duke. “But when we put the hydrogel in a mouse wound, the updated gel ended up doing the exact opposite.”

The updated material integrated into the wound and supported the tissue as the wound closed. But instead of lasting longer, the team found that the new gel was almost entirely gone from the wound site, leaving only a few particles.

However, the scarred skin was found to be stronger and included complex skin structures that are usually absent from scars. Upon further investigation, the researchers found that the reason for the stronger healing – despite the lack of longevity – was a different immune response to the gel.

After a skin injury, the body’s innate immune response is immediately activated to ensure that all foreign substances that enter the body are quickly destroyed. If substances can escape this first immune response, the body’s adaptive immune response kicks in, which identifies and targets the invading material with more specificity.

Because the original MAP gel was made with the common L peptide structure, it generated a mild innate immune response. But when the team placed the reformulated gel in a wound, the foreign D chirality activated the adaptive immune system, which created antibodies and activated cells, including macrophages, that targeted and cleared the gel more quickly after the wound closure.

“There are two types of immune responses that can occur after injury: a destructive response and a milder regenerative response,” said Scumpia, assistant professor in the division of dermatology at UCLA Health and West Los Angeles VA Medical Center. . “When most biomaterials are placed in the body, they are isolated by the immune system and ultimately degraded or destroyed. But in this study, the immune response to the gel induced a regenerative response in the healed tissue.”

“This study shows us that activating the immune system can be used to tip the balance from wound healing from tissue destruction and scar formation to tissue repair and skin regeneration,” Segura said.

Working with Maksim Plikus, a regenerative tissue expert at the University of California at Irvine, the team also confirmed that key structures, like hair follicles and sebaceous glands, formed correctly on the scaffold. When the team explored the mechanism, they found that cells of the adaptive immune system are needed for this regenerative response.

As the team continues to study the regenerative immune response to its gel, it is also exploring the possibility of using the new hydrogel MAP as an immunomodulatory platform. “The team is currently exploring how best to release immune signals from the gel to either induce skin regeneration or develop the hydrogel as a vaccine platform,” said Scumpia.

“I am excited about the possibility of designing materials that can directly interact with the immune system to support tissue regeneration,” Segura said. “It’s a new approach for us.”