A Scalable Platform for Fabricating Biodegradable Microparticles with Pulsatile Drug Release

Abstract Pulsatile drug delivery systems have the potential to improve patient adherence and therapeutic efficacy by providing a sequence of doses in a single injection. Herein, a novel platform, termed Particles Uniformly Liquified and Sealed to Encapsulate Drugs (PULSED) is developed, which enables the high‐throughput fabrication of microparticles exhibiting pulsatile release. In PULSED, biodegradable polymeric microstructures with an open cavity are formed using high‐resolution 3D printing and soft lithography, filled with drug, and sealed using a contactless heating step in which the polymer flows over the orifice to form a complete shell around a drug‐loaded core. Poly(lactic‐co‐glycolic acid) particles with this structure can rapidly release encapsulated material after delays of 10 ± 1, 15 ± 1, 17 ± 2, or 36 ± 1 days in vivo, depending on polymer molecular weight and end group. The system is even compatible with biologics, releasing over 90% of bevacizumab in its bioactive form after a two‐week delay in vitro. The PULSED system is highly versatile, offering compatibility with crystalline and amorphous polymers, easily injectable particle sizes, and compatibility with several newly developed drug loading methods. Together, these results suggest that PULSED is a promising platform for creating long‐acting drug formulations that improve patient outcomes due to its simplicity, low cost, and scalability.