Nonsurgical system for controlled delivery of antibiotics to treat aggressive periodontitis in adolescents

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Aggressive periodontitis is a severe type of gum infection that causes the destruction of ligament and bone and can lead to tooth loss in otherwise healthy individuals. Traditional treatment typically involves deep cleaning and antibiotics.

Lehigh University researcher Angela Brown and her team were recently awarded a grant from the National Institutes of Health (NIH) to pursue a novel treatment alternative.

Brown, an associate professor of chemical and biomolecular engineering in Lehigh's P.C. Rossin College of Engineering and Applied Science, received an Exploratory/Development Research Grant Award (R21) to develop a nonsurgical drug delivery system that will enable the controlled delivery of antibiotics to treat aggressive periodontitis in adolescents. According to the NIH, R21 grants are meant to encourage research in high risk/high reward areas that could lead to significant breakthroughs or yield novel techniques, methods, and applications that will benefit biomedical, behavioral, or clinical research.

The way these infections are typically treated is by scaling and planing, which essentially means scraping off the bacteria, and then prescribing oral antibiotics. And while that tends to work, sometimes the bacteria come back, and then you have to start the course of antibiotics all over again. The more frequently you take antibiotics, the greater the chances the bacteria will become resistant to them."

Angela Brown, Researcher, Lehigh University

Antibiotic resistance is indeed a growing problem. According to the Centers for Disease Control and Prevention, more than 2.8 million antimicrobial-resistant infections occur every year in the U.S., and more than 35,000 people die as a result.

In previous work, Brown and her team have shown that antibiotics can be encapsulated in liposomes-;tiny, round vesicles that contain one or more membranes and can be used as a delivery mechanism. They've also shown that the toxin released by the periodontitis-causing bacteria, called leukotoxin, triggers the release of the antibiotics.

"Leukotoxin fights the body's immune response by binding with cholesterol in the membrane of white blood cells, disrupting the membrane and killing the cells," she says. "So we're creating a liposome that has cholesterol, and we're hoping that all or most of the toxin will bind onto the liposome instead of the host cells," says Brown. "When the toxin binds to the liposome, it should cause a release of the antibiotics, killing the disease-causing bacteria."

This grant will support the cell culture work her lab will perform to determine if the approach can protect the host cells from the toxin while simultaneously killing the bacterial cells. They will do this using a "co-culture" model, in which human immune cells and bacterial cells are grown together.

The ultimate goal, she says, is to provide an alternative method of delivering antibiotics to treat aggressive periodontitis.

"We'd also like to continue showing the advantages of using controlled delivery strategies for antibiotics," she says. "And because this toxin we're working with is closely related to those that cause diseases like whooping cough and cholera and E. coli infections, this approach could be useful against a range of bacteria."

Brown has been working with leukotoxins since she was a postdoctoral student. At that time, she was focusing on how the toxin interacted with the cell membrane. Her research team found that when they encapsulated fluorescent dye inside a cell, the toxin caused the release of the dye.

"Because I'm an engineer, I had this thought, Okay, now that we know the toxin has that effect, how can we use that?" she says. "It was just a vague idea back then, but I was thinking about how cool it would be if we could encapsulate antibiotics inside cells."

Years later, the vague idea became real. One of her master's students, Ziang Li-;now a PhD student co-advised by both Brown and Professor Steve McIntosh, who chairs Lehigh's chemical and biomolecular engineering department-;wanted to research drug delivery mechanisms.

"At the time, it wasn't something our lab was doing, but I said to him, 'I have this crazy idea, do you want to try it?'"

With significant support from a Lehigh Faculty Innovation Grant, Li was able to collect the preliminary data that ultimately led to the NIH funding.

"Looking at different delivery strategies for antibiotics represents a new direction for my lab," she says. "This is our first externally funded project to do this work, and it validates the idea that this approach has a lot of potential to solve problems with both disease and with antibiotic resistance."

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