3D Printing of Microcontainers for Oral Delivery of Drugs and Probiotics

Microcontainers (MCs), as innovative oral delivery microdevices, have already been validated to successfully deliver drugs through the gastrointestinal (GI) tract. The MCs protect the delivered content against the harsh environment in the stomach and provide a unidirectional drug release in the intestine, resulting in an overall increase in drug absorption. At the same time, the MCs have the potential to successfully deliver probiotics to the intestinal mucosa in a more efficient way than the current technologies today. However, the MCs do not achieve optimal delivery since the MCs have limited retention time during the transit process through the GI tract. Besides, the release orientation of MCs is uncontrollable, limiting the delivery rate. One potential strategy to extend retention and control orientation is via manipulating mucoadhesion of the MCs. This thesis focuses on improving the geometry structure of MCs to enhance mucoadhesion, resulting in controlled orientation and overall extended intestinal retention.
To realize innovative geometry design, we custom-built a 3D printer with micro/nanoscale printing resolution and centimeter-scale printing volume. This printer allows more design and fabrication freedom for microscale features embedded in the design of the MCs. The 3D printer integrates an HD-DVD optical pickup unit (originally designed for Xbox game console) as a core optical module to solidify photopolymer. The 3D printer achieves the highest printing resolution of 385 nm along the lateral direction. Hence, MCs with overhanging structures and additive features can be realized.
Investigation of the mucoadhesive forces of the MCs provides a preliminary understanding for proofing the concept of geometry design. Nevertheless, the current technique lacks an experienced and suitable instrument to quantify mucoadhesive forces under the micro-newton scale (the range in which MCs normally behave). Therefore, the mucoadhesive force of a single MC is difficult to detect. To overcome the force measuring gap, we repurposed a DVD optical pickup unit for constructing a broad range force analyzer. Within a novel design of a cantilever force transducer, the force analyzer implements high sensitive force measurement of force range from 1.1 N to 40 nN, while the force resolution is 0.99 nN.
With the proposed high-resolution 3D printer and broad range force analyzer, we realized MCs with novel geometry followed by mucoadhesive forces measurement of a single MC. Three design strategies were implemented to enhance intestinal mucoadhesion. First, we designed an asymmetrical structure of MCs to increase the probability of facing the drug release side to the mucus layer. Then, additive micro-pillars were printed on the MCs to enhance mucoadhesion. Besides, we designed a multiple arrows structure on the side of MCs to provide a hook for deeper entanglement into the mucus layer. An ex vivo tensile strength experiment provided a preliminary investigation of MCs mucoadhesive forces, verifying the designed geometry structure. To trace the MCs along the GI tract in an in vivo study in rats, we fabricated radiopaque MCs with embedded BaSO4 nanoparticles using the 3D printer. Planar X-ray scanning showed the distribution of MCs through the GI tract of the rats at various time points, 0.5, 1, 2, and 3 h. The results indicated that while most MCs passed the small intestine after 3 h, approximately 40 % of MCs equipped with micro-pillars stayed in the distal intestine. Besides, the spatial dynamics of MCs during the transit process were captured by CT scans. CryoSEM observed the mucosa interaction of MC, showing the mucus layer embedment of MC with specific orientation, sideway and facing release-side to the mucosa. Lastly, the 3D printed MCs were loaded with the model drug, furosemide, and the cavity was coated with a pH-sensitive polymer of Eudragit® L100. An in vitro drug release study proved the concept of controlling the drug release.
Finally, the in vivo result implied that the micro-pillars might have a slight trend of improved mucoadhesion, but no statistically significant enhancement was found through all of these three designs. However, in this project, we demonstrated that the proposed micro and nanoscale 3D printer is the most suitable tool to realize the innovative geometry of MCs, especially from the aspect of printing resolution, printing volume, and economic benefit. Simultaneously, the broad range force analyzer provides reliable ex vivo measurement of MCs mucoadhesive forces. The procedure of 3D printed microdevices incorporated with BaSO₄ particle allows obtaining comprehensive mucoadhesive information via in vivo study. Within all these complete and powerful tools, other designs of MCs with “crazy” geometry shapes can be realized to improve the retention time in the intestine in the future.