Fighting Superbugs With Nets And Light Switches

Each year, bacterial infections are responsible for roughly 7.7 million deaths worldwide, with this problem further exacerbated by rising antibiotic resistance. Not only are wound infections increasingly difficult to treat, they also impede healing of the surrounding tissue at the same time. This is because the wound infection causes a misdirected inflammatory reaction in which the immune system is constantly activated, damages healthy tissue and blocks the repair processes required for healing. Antibiotics offer little assistance in such situations, even if they are effective against the underlying bacteria.

How our immune cells' protein nets work

This is the starting point for a new approach, developed by ETH Zurich's Professor Raffaele Mezzenga and his team, in collaboration with researchers from Shanghai University, and recently published in external page Nature Communications .

Their approach is inspired by the net-like protein structures that immune cells release to trap pathogens and render them harmless. These neutrophil extracellular traps (NETs) are a sort of natural snare, preventing infections from spreading throughout the body.

Trials of artificial imitations of these structures have been conducted before. However, the synthetic materials used in past trials turned out to be too unstable, were not sufficiently tolerable or lacked the necessary efficacy against resistant bacteria.

Antibacterial enzyme activated by infrared light

"Unlike many synthetic approaches, we rely on a natural, protein-based system," explains Mezzenga. The gel is made from the whites of hens' eggs and comprises a dense mesh of tiny protein fibres made from lysozyme, which remains inactive in this form. Lysozyme is an antibacterial enzyme that also occurs in the human body. The gel acts as a physical net that settles over the wound and detains the bacteria within.

The decisive step in activating the enzyme is as straightforward as pushing a button: subjecting the gel to near-infrared light - a gentle, relatively minimally invasive method - heats up a thermally responsive molecule integrated for precisely this purpose. The heat generated by this molecule causes part of the protein fibre net to disassemble temporarily and release individual lysozyme molecules. In this form, the lysozyme molecules are biologically active. They attack the bacteria, targeting their cell walls, and kill the pathogen.

Replacing chronic inflammation with healing

In parallel with this, the gel also releases magnesium ions when activated by light. Rather than delivering an antibacterial effect, these ions calm the immune system. They reprogramme pro-inflammatory immune cells into a pro-regenerative phenotype. Consequently, instead of maintaining inflammatory response, the cells now actively support cell repair - and thus promote healing rather than impairing it.

When the light pulse is terminated, the protein fibres reassemble to form a stable net. This means that the gel again provides a framework that provides cells with stability while supporting tissue regeneration.

The hydrogel's key attribute is the reversibility of its fibres, which can be triggered to disassemble and reassemble. "Our technology combines antibacterial and anti-inflammatory effects with wound healing. One day, it could open new possibilities, especially for diabetic patients with chronic wounds and for patients battling with antibiotic resistance," says Qize Xuan of Shanghai University, lead author of the study and former visiting doctoral student in Mezzenga's lab.

Bacterial load in animal models reduced by 95 percent

The hydrogel has already been tested in pre-clinical studies involving mice and pigs. In the murine model, the gel reduced the bacterial load in a wound infected with antibiotic-resistant MRSA by 95 percent. Furthermore, the treated wound closed almost completely within 15 days, while untreated controlled wounds exhibited significantly slower healing. Accelerated wound healing was also identified in the porcine model, along with significantly lower bacterial colonisation. In addition, the material creates a favourable environment for the formation of new bone and soft tissue.

The gel, which is applied directly onto the wound, remains in place throughout the healing process. It is absorbed into the tissue and gradually biodegrades as the tissue regenerates.

However, there is still a long way to go before the gel could reach patients. The next step is clinical trials. "We're now searching for industry partners to assist us," says Mezzenga. "Trials like this are laborious, expensive and only possible in close collaboration with hospitals."