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Engineers at MIT have developed a novel technique that would allow multiple doses of a drug or vaccine to be delivered over an extended period of time with just one injection.

Current vaccine schedules typically require the patient to return to their doctor multiple times over the course of a few months to receive multiple injections. But in developing nations where access to healthcare facilities is limited, infants are at risk of not receiving full immunizations.

The MIT team is looking to make the immunization process easier and more efficient by creating a new 3-D fabrication method that generates a novel type of drug-carrying particle that allows for multiple doses of a vaccine to be delivered over an extended period of time.

The research began as part of a project funded by the Bill and Melinda Gates Foundation, which focused on identifying ways to ensure babies in developing nations receive all vaccines needed within the first year or two of their lives.

The researchers discovered a way to fill microparticles made of biodegradable polymers with vaccine drugs. The polymers can break down at different points in time (depending on their makeup), which allows specific doses of the drugs to be released at precise times.

The researchers say the microparticles resemble tiny coffee cups, and can be sealed closed with a lid. The particles are made up of a biocompatible, FDA-approved polymer called PLGA, which is already being used in implants, sutures and prosthetics.

PLGA can be designed to degrade at specific times, allowing certain doses to “spill out of the top of the coffee cup.”

As the team explained in a press release on the findings, they created silicon molds for the “cups and lids” using the technique of photolithography. The molds – which look similar to ice cube trays – were fit into a glass slide. Each slide could hold about 2,000 molds.

The molds are then used to shape the PLGA cups and lids. A custom-built, automated dispensing system filled each cup with a designated drug or vaccine. Then, the lids were aligned and lowered onto each cup, and the system was heated until the cup and lid fused together, essentially sealing the drug inside and preventing any leakage.

Each microparticle is about 400 micrometers across.

“Part of the novelty is really in how we align and seal the layers. In doing so we developed a new method that can make structures which current 3-D printing methods cannot. This new method called SEAL (StampEd Assembly of polymer Layers) can be used with any thermoplastic material and allows for fabrication of microstructures with complex geometries that could have broad applications, including injectable pulsatile drug delivery, pH sensors, and 3-D microfluidic devices,” said Ana Jaklenec, a research scientist at MIT’s Koch Institute for Integrative Cancer Research, and senior author of the paper.

The team built upon previous work done by senior author Robert Langer, who developed similar polymer particles that allowed embedded drugs to be released gradually over time. But the main difference with the latest technique is that the particles can deliver short bursts of a drug at specific time intervals, instead of slowly releasing the drug consistently over time.

The dosages can be delivered within a range of a few days after initial injection, to two months later.

The team conducted a series of tests with mice to demonstrate the effectiveness of the technique.

First, they injected mice with microparticles made from one of three different polymers that were filled with a fluorescent substance. The substance was successfully released at nine, 20, and 41 days after injection without any leakage.

The researchers also developed particles that can degrade and release substances hundreds of days after injection. They are now testing these particles with existing vaccines, like the inactivated polio vaccine, as well as new vaccines under development.

“This could have a significant impact on patients everywhere, especially in the developing world where patient compliance is particularly poor,” said Langer, the David H. Koch Institute Professor at MIT.

Yet, challenges still exist with the system. One example is finding a way to ensure the encapsulated vaccine remains stable at body temperature for prolonged periods of time before it is released. Currently, most vaccines are stored in refrigerators.

Additionally, there is no way to modify vaccines between doses, or adjust the timing of vaccine release after the initial injection with this method. For various reasons, doctors may choose to delay a specific vaccine in a patient – for example, if the child has an active viral infection.

The team is currently working on strategies to stabilize the vaccines. The method could potentially be applied to any situation where drugs need to be administered on a regular basis – such as allergy shots or for diabetes patients.

The findings appeared in Science on Sept. 14

An automated dispensing system can be used to load drugs into the 3-D microparticles. Credit: Langer Lab, MIT
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