Top-down Fabrication of Microparticles for Drug Delivery and Cell Tracking

Microparticles are widely used and studied for biomedical applications and can be fabricated by bottom-up and top-down techniques. While the top-down techniques are superior to the bottom-up techniques in controlling particle geometry, structure and composition, they are limited by high cost, use of harsh processing conditions, or lack of versatility in composition and structure control. We intend to solve this problem by developing a novel top-down technique for fabricating microparticles for drug delivery and cell tracking applications. The first chapter introduces the background information for this work. It reviews key characteristics of microparticles for biomedical applications and major top-down methods for particle fabrication. The second chapter reports research on establishing our technique for microparticle fabrication. The technique integrates microcontact printing (µCP), layer-by-layer (LbL) assembly and a particle release method, and is used to generate microparticles composed of multilayered polyelectrolytes with various two-dimensional shapes and sizes. The structural stability of the microparticles in water increases with layer number and can be enhanced via chemical crosslinking of component polyelectrolytes. In addition to the simple multilayered structure, microparticles with complex structures and a microparticle array consisting of four different types of microparticles are fabricated. Finally, stable microparticle-cell complexes are produced to demonstrate the feasibility of using the microparticles for cell-based biomedical applications. The third chapter presents research on extending the above method to generate a novel type of microparticles, each of which consists of a pad-like multilayered polyelectrolyte film and a dot-like thermoplastic particle located on the center of the pad. Fabrication of the dot-on-pad microparticles relies on the use of the discontinuous dewetting method in addition to LbL and µCP. The lateral size and shape of the pads can be varied by using stamps with different surface features. The size of the dots can be controlled by varying the dewetting condition or concentration of thermoplastic solution. Moreover, the microparticles can be prepared by using completely biodegradable materials desirable for in vivo applications. Finally, a novel usage of the microparticles for unidirectional drug delivery to single cells is proposed and studied. The fourth chapter is dedicated to the fabrication and characterization of microparticles for cell tracking using the methods developed in the previous two chapters. Each of the microparticles consists of a multilayer of gold nanoparticles and a polycation, and is thus called gold nanoparticle-stuffed microdisk. Optical microscopy, atomic force microscopy, and UV-Vis extinction spectroscopy are employed to characterize the microdisks as well as to estimate quantity of gold nanoparticles within the microdisks. Three types of Raman reporter molecules are loaded into the microdisks and their characteristic Raman signals are generated using 785 nm wavelength laser as the excitation light. The surface-enhanced Raman scattering effect induced by the gold nanoparticles is qualitatively confirmed. Moreover, detection of Raman signals from the microdisks from a 4 cm sample-lens distance and tagging a microdisk to a live cell are demonstrated. Finally, hybrid microparticles each composed of a gold nanoparticle-stuffed microdisk pad and a biodegradable thermoplastic dot are fabricated to demonstrate the capability of this technique for producing multifunctional microdevices. The fifth chapter summaries the major conclusions of the above studies.