MIT engineers have created 3D microstructures that could improve drug delivery by encapsulating therapeutic agents inside a protective but slowly degrading shell. They say this invention will allow multiple doses of a drug or vaccine to be delivered over an extended time period with just one injection. The work was published in Science yesterday.
"We are very excited about this work because, for the first time, we can create a library of tiny, encased vaccine particles, each programmed to release at a precise, predictable time, so that people could potentially receive a single injection that, in effect, would have multiple boosters already built into it. This could have a significant impact on patients everywhere, especially in the developing world where patient compliance is particularly poor," says Robert Langer, the David H. Koch Institute Professor at MIT, and senior author on the paper.
Langer has previously developed polymer particles with drugs embedded throughout the particle, allowing them to be gradually released over time. However, for this project, the researchers wanted to come up with a way to deliver short bursts of a drug at specific time intervals, to mimic the way a series of vaccines would be given.
In order to do this, they developed a sealable polymer cup made from PLGA, a biocompatible polymer that has already been approved for use in medical devices. PLGA can also be designed to degrade at different rates, allowing for the fabrication of multiple particles that release their contents at different times.
Conventional 3D printing was not suitable so they created silicon molds for the cups and the lids using photolithography. Once the polymer cups (cubes with edge lengths of a few hundred microns) were formed, they were filled with a drug. After the cups were filled, the cup and lid were fused together, sealing the drug inside.
"Each layer is first fabricated on its own, and then they're assembled together," Ana Jaklenec, a research scientist at MIT's Koch Institute for Integrative Cancer Research and another senior author on the paper, explains. "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 3D 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 3D microfluidic devices."
The molecular weight of the PLGA polymer and the structure of the polymer molecules' "backbone" determine how fast the particles will degrade after injection. The degradation rate determines when the drug will be released. By injecting many particles that degrade at different rates, the researchers can generate a strong burst of drug or vaccine at predetermined time points.
In mice, the researchers showed that particles release in sharp bursts, without prior leakage, at 9, 20, and 41 days after injection. They then tested particles filled with ovalbumin. Using a combination of particles that released ovalbumin at 9 and 41 days after injection, they found that a single injection of these particles was able to induce a strong immune response that was comparable to that provoked by two conventional injections with double the dose.