Probiotic Hydrogels Designed as Spray-On Bandage for Intestines

Researchers at Harvard have developed probiotic hydrogels that can be used to heal wounds inside human intestines.

Hydrogels are finding their way into medical applications due to their softness and the ease with which they can be made bio-compatible.

One latest use for this type of materials comes from Harvard University, where researchers have developed probiotic hydrogels that can be used to help intestinal wounds heal and promote intestinal health.

This SEM image shows a curli nanofiber network that is continuously produced by genetically programmed non-pathogenic commensal E. coli bacteria, and binds to mucus proteins on the surface of the intestinal wall. The network is found in hydrogels developed by researchers at Harvard University to heal wounds inside the intestines. (Image source: Wyss Institute at Harvard University)

Researchers from Harvard’s Wyss Institute for Biologically Inspired Engineering External and John A. Paulson School of Engineering and Applied Sciences (SEAS) developed the new hydrogels, which the team produced using cells from bacterial cultures, they said. The hydrogels are comprised of muco-adhesive nanofibers and produced by an engineered natural gut bacterium.

“This new type of engineered living material with its ease of production and storability, biocompatibility, and muco-adhesive properties could be a door-opener for bioactive wound-healing strategies for use inside the human gut lumen,” said Neel Joshi, an associate professor at SEAS and core faculty member at the Wyss Institute, in a press statement.

Researchers envision that doctors could apply the two versions of their hydrogels—longer-lived self-regenerating “Live Gels” or shorter-lived “Cell-free Gels”--to intestinal surfaces using syringes, spray, and/or endoscopic techniques to provide a seal to intestinal wounds, they said.

“We can essentially program the normal nanofiber-producing molecular machinery of non-pathogenic E. coli to produce hydrogels that have a viscosity strongly resembling that of mucus, and with muco-adhesive capabilities built into them,” explained Joshi in the press statement.

Moreover, the materials’ “modularity could allow us to tune them to match specific sections of the gastrointestinal tract with their individual mucus compositions and structures,” he said.

Expanding the Scope

The new research stems from previous work by Joshi and other Harvard researchers to use commensal strains of E. coli to create biofilm-forming nanofibers and as living foundations for new chemicals and materials. They achieved this by engineering a protein the bacteria secretes, called CsgA, which self-assembles into “curli” nanofibers in the extracellular environment, researchers said.

In these previous applications, researchers modified CsgA to enable additional enzymatic or structural functions, such as to perform a chemical reaction required to synthesize a drug or chemical. However, the new work now demonstrates the direct use of curli nanofiber-based materials for therapeutics, researchers said.

To achieve this goal and enable the formation of extracellular hydrogels, Joshi’s team programmed a non-pathogenic strain of the gut bacterium E. coli to synthesize a variant of the CsgA curli protein that is fused to a domain called human trefoil factors (TFFs), which can bind to the mucus inside the intestine. TFFs are co-secreted by mucus-producing cells to protect mucosal epithelia found in the intestine and help them repair injuries.

Researchers used a simple filtration to enable the clean separation of the live bacteria-containing hydrogel from the rest of the culture, they said. To create the shorter-lived Cell-free Gels, the team used an additional step to kill the bacteria using a simple chemical treatment.

The TFF domains are what researchers believe is the key to allowing the hydrogels to perform their job within the intestine, Anna Duraj-Thatte, a postdoctoral fellow on Joshi’s team, said in a press statement.

“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,” she said.

Researchers published a paper outlining their work in the journal Advanced Materials.

Tests Point to Uses

Scientists collaborated with researchers at Brigham and Women’s Hospital in Boston to test the specificity of tissue adhesion of their hydrogels. They found that hydrogels containing TFFs enhanced adhesion only to the lumen-exposed mucosal surface of a goat colon tissue sample.

Alternatively, when a material showed binding to fibronectin protein--which is not found on the mucosa, but on the outward-facing serosal surface of the colon--the hydrogels instead showed a preference to stick to the serosal side of the colon tissue sample, researchers said.

Joshi’s team also tested how the hydrogels performed when giving orally to mice. In these tests, the cell-containing Live Gels could withstand the harsh pH and digestive conditions of the stomach and small intestine and reach the cecum with the bacteria intact, researchers found. Another result showed that hydrogels bearing one particular TFF domain, TFF2, enhanced retention of the material in the colon.

Based on these results, researchers envision using the hydrogels in endoscopic procedures to treat intestinal disorders, something akin to a spray-on bandage, they said.

Elizabeth Montalbano is a freelance writer who has written about technology and culture for more than 20 years. She has lived and worked as a professional journalist in Phoenix, San Francisco and New York City. In her free time she enjoys surfing, traveling, music, yoga and cooking. She currently resides in a village on the southwest coast of Portugal.

 

 

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