Rapidly Dissolvable PRINT Microneedles for the Transdermal Delivery of Therapeutics

In recent years, microneedle devices have become an attractive method to overcome the diffusion-limiting epidermis and effectively transport therapeutics to the body. Microneedles are arrays of micron-sized projections that pierce the skin to administer drugs, manually creating channels for the passage of a therapeutic. Biodegradable or water-soluble microneedles are of high interest due to their safety, low device complexity, and ability to deliver agents of nearly any size. The main limitation of biodegradable microneedles is their arduous manufacturing, requiring long vacuum and centrifugation steps to fill a mold. The fabrication of microneedles via the highly scalable and reproducible Particle Replication in Non-wetting Templates (PRINT®) platform has great promise to expand this growing field by eliminating these obstacles to clinical translation. Herein, the fabrication of 100% water-soluble PRINT microneedles on flexible substrates is demonstrated. The ability of these devices to load therapeutics of nearly any size, shape, and surface charge - while maintaining the function of the cargo throughout - has been shown through the encapsulation of small molecule dyes, proteins, and hydrogel nanoparticles. PRINT microneedle devices were seen to pierce skin and transport cargo in both ex vivo and in vivo studies. Utilizing optical coherence tomography, it was seen that flexible microneedle patches increase the depth and reproducibility of needle penetrations (as compared to rigid patches). The permeation kinetics of the small molecule, protein, and particulate drug surrogates through full thickness murine skin were investigated; microneedles greatly increased the delivered dose of small molecules when compared to topical formulations. Both proteins and nanoparticles were seen to deposit in the skin after application with PRINT microneedles, but the permeation kinetics through this tissue slowed as cargo size increased. PRINT microneedle device application in vivo was optimized on nude murine models, and it was shown that these devices efficaciously deliver small molecule drug surrogates to living tissue. The ability of the PRINT microneedles pierce excised human skin was shown, highlighting the capability of the technology to transition into a clinically-relevant product. Finally, PRINT microneedle devices were adapted to two therapeutically-relevant systems: the delivery of butyrylcholinesterase as a countermeasure against nerve gas overexposure, and the treatment of skin-invading breast cancers by introducing chemotherapeutics via microneedles. Therefore, efficacious water-soluble microneedle devices have been made reproducibly and quickly via PRINT technology, advancing the field of transdermal drug delivery as a whole.Doctor of Philosoph