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doctoral thesis

Microfabrication of lipids for drug delivery applications

Park, Jongeon  
2025

All living organisms contain lipids because lipids are the essential components of cell membranes, which preserve the integrity and functionality of cells by protecting their organelles from the external environment. Lipids can also be found easily in our daily life in different forms such as oils or waxes, in cooking, and packaging. In biomedical engineering, lipids have found significant applications in drug delivery systems due to their high biocompatibility, biodegradability, and ability to encapsulate drugs that are poorly soluble in water or sensitive to hydrolysis. Lipids are employed in various delivery systems, including lipid nanoparticles, lipid implants, and self-emulsifying drug delivery systems. The most known and successful example of a lipid drug delivery system is mRNA lipid nanoparticles for COVID-19 vaccination. So far, the design and dimensions of the lipid-based drug delivery devices are limited to sphere shapes at the nanoscale and simple cylinders or cubes at the millimeter or centimeter scales. Microfabricating lipids into complex designs could offer significant advantages over existing nanoscale and macroscale devices, such as controlled drug release from drug implants, minimal invasiveness, and targeted functionality from lipid nanoparticles. Additionally, designing it to specific shapes could add additional functionalities such as enhancing the interaction of these devices with their surrounding environment and locomotion. However, the poor mechanical properties of lipids, their thermolability, and their incompatibility with organic solvents hinder applying the conventional microfabrication process for shaping lipids. This thesis aims to develop a novel microfabrication method for structuring lipids at various dimensions and into complex shapes, from simply dispensing molten lipids in microcavities to creating complex 3D microstructures. Each lipid microstructure, uniquely developed with different designs and dimensions, has been applied to drug delivery applications, advancing the field by utilizing the distinct properties of lipids for drug delivery. First, dispensing precise amounts of molten lipids into microcavities by inkjet printing has been developed for encapsulating drug solutions in micro reservoirs. Lipids serve as a good sealing layer due to their hydrophobic and water-impermeable properties. Fabricated devices could release the encapsulated drug solution on demand and at multiple selected time points by magnetic field iv exposure. In vitro validation in tissue phantoms and on cells showed the feasibility of drug solution encapsulating microdevices as drug implants. 2.5D patterning of lipids is achieved by the thermal imprinting using water-soluble PVA molds, followed by the selective dissolution of PVA in an aqueous solution. Honeycomb lipid microstructures were fabricated and used for sublingual administration of poorly water-soluble drugs by lipid-based self-emulsifying drug delivery (SEDDS) composites, exploiting the high solubility of poorly water-soluble drugs into lipids and lipid's self-assembly properties in water by hydrophobicity. The lipid microstructure increases the dissolution rate by increasing the surface area to volume ratio and improves the poor mechanical properties of the lipid, which is a necessary feature for the sublingual administration. An in vivo investigation using mice models successfully showed the device's feasibility for delivering poorly water-soluble drugs.

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