Engineered Bacteria Hydrogels Designed for Gut Repair

Nanofiber network produced by genetically engineered E. coli bacteria (Wyss Institute, Harvard University)

12 Aug. 2019. Biomedical engineers genetically altered bacteria that when added to gel materials can be applied like a spray or ointment to help heal intestinal surfaces. Researchers from labs at Harvard University and its affiliated Brigham and Women’s Hospital in Boston describe their discoveries in today’s issue of the journal Advanced Materials (paid subscription required).

A team from the Harvard lab of Neel Joshi that studies biologically fabricated materials, part of the Wyss Institute for Biologically Inspired Engineering, is seeking better techniques for healing wounds in the gut. Layers of mucous line the insides of the human gut that resist normal adhesives, making it difficult for even surgically-applied materials to stick to internal wounds. In addition, the complex nature of the human gut requires a solution that can be adjusted to work with surfaces other than mucous membranes, having different properties.

Joshi’s lab studies properties of bacteria, including the millions of strains living in the gut that can be adapted to produce living materials with therapeutic characteristics, rather than pathogens. One of those materials is the lab’s biofilm-integrated nanofiber display, or Bind, that genetically engineers E. coil bacteria to produce biofilms with nanoscale fibers having desired properties. E. coli and biofilms are usually associated with food poisoning and antibiotic-resistant bacteria, but when genetically altered, they can perform helpful functions rather than have harmful effects.

In this case, Joshi and colleagues genetically engineered E. coli to express nanoscale fibers called curli, part of the cell framework produced by some bacteria to form biofilms, particularly for adhering to other cell surfaces. The bacteria were also engineered to bind to human trefoil factors, peptides secreted by mucous cells to protect the intestinal surface tissue layer. The researchers added these curli- and trefoil factor-engineered bacteria to hydrogels, water-based and biocompatible polymer gels that can be administered with syringes or endoscopes into the gut.

In tests with samples of gut tissue from goats, the researchers found hydrogels with the altered E. coli expressing trefoil factors adhered to the mucous-lined surfaces in that tissue. In further tests with goat colon tissue, the team engineered E. coli to express fibronectin proteins found on serous membranes, a protective layer in the gut and other organs. In these tests, the hydrogels adhered to the serous layer, but not mucous-lined tissue.

In tests with lab mice, hydrogels with live cells — the researchers call them Live Gels — could be taken orally, survive the harsh stomach environment, and reach the entry to large intestine with the engineered live bacteria intact. Also, bacteria designed for a particular type of trefoil factor or TFF, were retained in the mice colons. “The presence of bacteria in Live Gels prolonged their residency times in the gut from one day to at least five days,” says Joshi in a Wyss Institute statement, “due to the bacteria’s ability to continuously regenerate the curli fiber networks that are decorated with TFFs, without affecting the health of mice in any obvious way.”

Co-author Jeffrey Karp, a biomedical engineering professor at Brigham and Women’s Hospital adds, “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 a spray-on bandage.”

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