Illustration of how the gel would work in a human ear. Animation: Boston Children's Hospital
A single-application, bioengineered gel squirted in the ear canal could deliver a full course of antibiotic therapy for middle-ear infections and make treatment of this common childhood illness much easier and potentially safer, according to a preclinical study led by Harvard Medical School researchers at Boston Children’s Hospital.
Middle-ear infections, or otitis media, affect 95 percent of children, prompting 12 to 16 million clinical visits per year in the U.S. alone. It’s the number one reason for pediatric antibiotic prescriptions. But as parents know, getting oral antibiotics into young children several times a day for 7 to 10 days is a daunting task.
“Force-feeding antibiotics to a toddler by mouth is like a full-contact martial art,” said Daniel Kohane, HMS professor of anaesthesia at Boston Children’s and senior author of the study.
Children also seem to get better within a few days, so parents often stop treatment too soon. Incomplete treatment and frequent recurrence of otitis media—40 percent of children have four or more episodes—encourage the development of drug-resistant infections. And because high doses are needed to get enough antibiotic to the ear, side effects like diarrhea, rashes and oral thrush are common.
“With oral antibiotics, you have to treat the entire body repeatedly just to get to the middle ear,” said chemical engineer Rong Yang, HMS instructor in anaesthesia in Kohane’s lab and first author on the paper. “With the gel, a pediatrician could administer the entire antibiotic course all at once, and only where it’s needed.”
The gel was tested in chinchillas, rodents that have a hearing range and ear structure similar to those of humans. Further tests will be needed to determine safety and efficacy in humans.
Penetrating the eardrum
Squirted into the ear canal, the gel quickly hardens, stays in place and gradually dispenses antibiotics across the eardrum into the middle ear.
“Our technology gets things across the eardrum that don’t usually get across, in sufficient quantity to be therapeutic,” said Kohane, who is also director of the Laboratory for Biomaterials and Drug Delivery at Boston Children’s.
Previously, the eardrum, also called the tympanic membrane, was an impenetrable barrier. The bioengineered gel gets drugs past it with the help of chemical permeation enhancers (CPEs), compounds that are FDA-approved for other uses.
CPEs are structurally similar to the lipids in the eardrum’s outermost layer, the stratum corneum. The CPEs insert themselves into the membrane, opening molecular pores that allow the antibiotics to seep through.
In the chinchilla tests, the gel dispensed high concentrations of the antibiotic ciprofloxacin in the middle ear and completely cured ear infections due to Haemophilus influenzae in 10 of 10 animals. Ordinary ciprofloxacin ear drops cleared the infection in only 5 of 8 animals by day 7.
There was no observable toxicity, and no antibiotic was detected in the animals’ blood, the authors said. Yang and Kohane observed a slight hearing loss, similar to that caused by earwax. Giving less of the gel alleviated the problem.
“Transtympanic delivery of antibiotics to the middle ear has the potential to enable children to benefit from the rapid antibacterial activity of antimicrobial agents without systemic exposure and could reduce emergence of resistant microbes,” said Stephen Pelton, a pediatric infectious disease physician at Boston Medical Center and a co-author on the paper.
The work recently won a poster competition at the 2016 Massachusetts Life Sciences Innovation Day. Kohane has received a five-year grant from the National Institutes of Health to further the work and an award from the Technology Development Fund at Boston Children’s to move the patented technology toward clinical use. Though further studies are needed, Kohane hopes to form a company that would begin testing the gel in patients in the next few months.
The study was done in collaboration with investigators at Boston Medical Center and Massachusetts Eye and Ear.
Funding was provided by the Center for Integration of Medicine and Innovative Technology (U.S. Army Medical Research Acquisition Activity subcontract #W81XWH-09-2-0001), the Shereta R. Seelig Charitable Foundation Trust, the National Institutes of Health (grant DC015050) and the Department of Anesthesiology at Boston Children’s.