Polymeric device may reduce risk of infection in developing nations

Key Points

The approach has the potential to benefit patients in developing countries, said Tueng T. Shen, MD, PhD, whose research group, which includes Dr. Shirakawa, a corneal research fellow from the University of Tokyo, at the University of Washington, Seattle, developed the system.

In a rabbit model of induced endoph-thalmitis, sufficient sustained antibiotic concentration was achieved for more than 4 weeks without any external antibiotic treatment; concentrations were above minimum inhibitory concentration (MIC) for the most common bacteria related to endophthalmitis, Dr. Shen said. She is the director of the Refractive Surgery Center at the University of Washington, and she also holds an adjunct position in bioengineering.

The genesis of the device was Dr. Shen's observation during frequent business trips to China that many patients from remote areas face extended hospital stays following cataract surgery. She said that many individuals remain hospitalized primarily because the topical antibiotics used in postoperative prophylaxis are not available in their rural communities. Should individuals develop a complication such as endophthalmitis after their release, the lack of treatment could have devastating consequences, so as a precaution, patients remain hospitalized for about 2 weeks until the risk of infection has passed.

Those hospital stays are expensive and inconvenient, and the plight of such patients, as well as the difficulties the system imposes on physicians and hospitals, motivated Dr. Shen to consult her collaborators about developing a controlled release system that would provide a simple, affordable method of drug delivery. They also wanted a design that would be compatible with current surgical techniques, could be adapted to any three-piece IOL, and would not interfere with postoperative vision.

They concluded that an intraocular delivery method would be more efficient than using topical eye drops for treating postoperative complications because the intraocular medication would penetrate more effectively. The penetration of topical antibiotics averages about 0.035%, Dr. Shen said.

"You can imagine that the socioeconomic impact of better surgeries, faster recovery, and less follow-up is important to consider," she added.

The researchers calculated how much drug was needed; determined the appropriate pellet size for delivery through the injector system; and evaluated various available polymers, looking for those that could be mass produced at a very low cost to make them affordable in developing nations.

The project was designed with a specific product and clinical approach in mind. The research team members looked for the best material to fulfill their requirements rather than having a material and then finding uses for it, Dr. Shen said. She explained that her group manages projects from a multidisciplinary approach, because the members have backgrounds in chemistry, engineering, and other subjects as well as medicine.

"We look at materials in a different way as to what can be translated into practice in different settings," she said.

They chose polyhydroxyethyl-methacrylate (pHEMA) hydrogel as the base polymer for their prototype because the material is widely used and has a good safety profile. The researchers modified the surface of the pHEMA with a coating of C18-ICN to achieve controlled release. The hydroxyl groups of the pHEMA react with the C18-ICN to form a monolayer, and the reaction time determines the release rate.

The researchers then conducted in vitro experiments with norfloxacin as the testing antibiotic, using spectrophotometry to assess drug release patterns. Antibiotic efficacy against Staphylococcus epidermidis then was evaluated using a silicone biofilm model. Norfloxacin-loaded pHEMA was placed with silicone membrane in solution, and the bacterial viability on the membrane was compared with control.

Data from these experiments demonstrated that the desired pattern of antibiotic release could be achieved by optimization of the surface coating. Dr. Shen explained that by changing the density of polymer chains on the surface, the rate of drug release can be customized, a characteristic that could be valuable in using the delivery device with an assortment of medications.

The next step was to conduct in vivo testing using a rabbit model. A control group of New Zealand white rabbits underwent conventional cataract surgery with implantation of an IOL followed by postoperative antibiotics and corticoster-oids. The experiment group received a prototype polymeric drug delivery device, which was inserted with the IOL during surgery. These rabbits received only topical steroids postoperatively. In vivo antibiotic levels were sampled from the anterior chamber for up to 30 days, and clinical outcomes also were evaluated.

In vivo norfloxacin levels in the anterior chamber were above the MIC for bacteria associated with endophthalmitis for more than 4 weeks, and minimal toxicity was observed. Both groups of animals recovered from the surgery with no signs of infection.

The group then pushed the condition even further by challenging the animals with a massive amount of bacteria to induce severe endophthalmitis. The rabbits with the polymer device recovered from this severe infection, whereas the control group, which received topical treatment, did not, according to Dr. Shen.

"These experiments confirmed that the drug delivery device offers better protection for intraocular infection than conventional methods," she said.

Having designed and tested the device, the researchers now are seeking partners who would help with the steps needed to get the product to the target population. Dr. Shen is negotiating with a Seattle-area biotech company and also has met with representatives of academic centers in China to discuss how to introduce the technology. Officials in India have shown interest as well, she said.

Although the primary goal is to reduce the risk of infection after cataract surgery in developing nations, the drug delivery device also could be valuable in certain niche markets in the United States, such as rural or isolated communities, Dr. Shen said.

The research on the drug delivery system was supported by a Walter H. Coulter Foundation Translational Research Partnership Award in Biomedical Engineering.