Harvard Researchers Using Bacterial Hydrogels as Intestinal Band-Aids

A group of Harvard researchers has recently created a probiotic hydrogel that can function as a Band-Aid-like seal for internal wounds. External wounds like cuts on the skin can easily be covered by an adhesive patch, however, mucus layers within the body make this solution impractical for abrasions on surfaces such as the gut. With this innovation from Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS), physicians may soon have a new internal wound healing solution. This work was published on August 12 in Advanced Materials.

This solution involves probiotic hydrogels made from the mucoadhesive nanofibers of an engineered gut bacterium. These gels are easily generated from cultures of bacteria and can be applied as both self-regenerating “live gels” that live for long periods and “cell-free gels” which live for a shorter duration. These gels can be applied to the intestinal surfaces using a spray, syringe, or endoscopic procedure to cover a desired region.

“This new type of engineered living material with its ease of production and storability, biocompatibility, and mucoadhesive properties could be a door-opener for bioactive wound healing strategies for use inside the human gut lumen,” said Neel Joshi, a faculty member at the Wyss Institute and associate professor at SEAS. “We can essentially program the normal nanofiber-producing molecular machinery of nonpathogenic E. coli to produce hydrogels that have a viscosity strongly resembling that of mucus, and with mucoadhesive capabilities built into them; and their modularity could allow us to tune them to match specific sections of the gastrointestinal tract with their individual mucus compositions and structures.”

Previous research from Joshi and others has utilized strains of E. Coli to create biofilm-forming nanofibers. These bacteria samples have also been used to produce pharmaceuticals, other chemicals, and substances that can engineer the CsgA protein. This protein self-assembles into curli nanofibers outside of the cell, which provide adhesion to surfaces. CsgA has been modified to allow for various functions, including the performance of a reaction that creates a drug or chemical. These curli nanofiber solutions are still yet to be used in therapeutic applications.

“Naturally produced biofilms are known to hinder wound healing processes up to a point where they need to be actively managed by health care practitioners,” said first author Anna Duraj-Thatte, a postdoctoral fellow at the Graduate School of Arts and Sciences. “We have essentially hacked one of the core machineries that produces them with the long-term goal to do exactly the opposite, to produce materials that could support wound healing in an environment that is inaccessible by other materials.” Duraj-Thatte is also a member of Joshi’s research team.

Creating the Hydrogels

Joshi and colleagues programmed a non-harmful strain of E. Coli to synthesize a CsgA curli protein variant that is fused to a domain group of the human trefoil factors (TFFs). These TFFs are created by the cells that create mucus to both protect the mucosal epithelia and help them repair. The researchers created the live gels by extracting the live bacteria that contain the hydrogel, and the cell-free gels undergo an extra step to kill the bacteria with drug treatment.

“We think that the presence of the TFF domains enable different curli fibers to crosslink to each other and form a water-storing mesh, and demonstrated that the exact hydrogel properties depend on the type of TFF used,” explained Duraj-Thatte.

A collaborative study between Joshi’s team, Jeffrey Karp, and Yuhan Lee tested this hydrogel’s tissue-adhesion ability with a goat colon tissue sample. These researchers found that the hydrogel correctly oriented to the sample, adhering to the mucosal surface when the TFFs were presented on the hydrogel and the serosal side of the sample when fibronectin protein was bound. Fibronectin is found on the outward-facing (serosal) surface of the colon, therefore these hydrogels showed specificity to each side of the colon tissue.

These live gels were able to survive the digestive conditions of the stomach and digestive tract when given orally to mice and are hopeful that this solution could eventually become a valuable therapy for patients with gastrointestinal issues.

“Since hydrogels with different TFF domains can be easily sprayed onto tissue surfaces with controllable adhesion and functional activity, we envision their potential use in endoscopic procedures to treat intestinal disorders, like a spray-on bandage,” said Karp, who is a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital.