CAMBRIDGE, Mass.—Patient compliance is a leading issue in the industry, not just in clinical trials but also in regular medicine administration. And when the delivery method consists of multiple injections, such as with diabetes, compliance can be even worse.
But there might be a way around that now. A team from the Massachusetts Institute of Technology (MIT) recently shared news of a 3D fabrication method capable of designing novel drug-carrying particles that can enable multiple doses of a compound to be administered over time from a single injection.
The microparticles are like tiny cups made of a biocompatible, FDA-approved polymer that can be made to degrade at a set time: PLGA [poly(lactic-co-glycolic acid)], which is currently used in implants, sutures and prosthetic devices. The cups can be filled with a compound—either a drug or a vaccine—and sealed off, then degrade at their given times to release their contents. The amount of time it takes for a particle to degrade is based on the molecular weight of the PLGA polymer and the structure of the polymer molecules' “backbone,” according to an MIT press release by Anne Trafton. The work was published in a paper titled “Fabrication of fillable microparticles and other complex 3D microstructures,” which appeared in Science.
“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,” said Robert Langer, the David H. Koch Institute Professor at MIT and senior author of the paper.
In addition to designing these new microparticles, the team also needed a new way to fabricate them, as standard 3D printing techniques were not sufficient given the material and size needed. Instead, the researchers used photolithography to create silicon molds for the cups and lips. Roughly 2,000 molds are fitted onto a glass slide and used to shape the cups—which are actually cubes—and lids. Once the cups are formed, they're filled with a custom-built, automated dispensing system, then the lids are attached and both are heated slightly until cups and lids fuse together.
According to Ana Jaklenec, a research scientist at MIT’s Koch Institute for Integrative Cancer Research and another senior author of the Science paper, “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.”
This method was also tested with actual biologics payloads, including ovalbumin, a protein in egg whites commonly used as a model antigen to trigger an immune response, and the trivalent inactivated polio vaccine (IPV). A formulation consisting of IPV and other substances was loaded into cups, which were then sealed to assess if the heat of the sealing process affected stability. They found that the IPV D-antigenicity “remained statistically similar before and after the sealing process,” according to the paper, and “the stability of the biologic during sealing in PLGA1 was much higher than what is typically reported for microsphere encapsulation with an emulsion-based process, likely due to the elimination of organic solvents, emulsification stressors and washing, which can lead to substantial losses.”
“Particles composed of PLGA1, PLGA2 or PLGA3 released in vitro at 10 ± 0, 15 ± 0 and 34 ± 1 days, respectively. No measurable leakage was observed prior to release, indicating that this platform releases its contents as a sharp pulse after degradation of the polymer barrier. A similar trend was observed when particles were subcutaneously injected into mice, as PLGA1, PLGA2 and PLGA3 particles released after 9 ± 2, 20 ± 1 and 41 ± 3 days in vivo, respectively, as indicated by an ~50-fold increase in fluorescence upon release,” the authors noted in the paper.
Jaklenec and colleagues have also engineered particles that last for hundreds of days after injection before degrading. To fully take advantage of them, however, the paper notes that compounds such as IPV might need to be stabilized “against thermal and acidic pH stressors that it will encounter during long-term storage in the body. To achieve very long time points with this system, it may be necessary to use PLGA with different end groups, copolymer ratios and/or molecular weights.”