Convection-Enhanced Drug Delivery: Porous Media Models and Microfluidic Devices

Abstract

Promising treatments of many brain diseases are often thwarted due to their inability to cross the blood-brain barrier. Convection-enhanced drug delivery (CED) uses direct infusion of drug-containing solutions into tissue to circumvent the blood-brain barrier. The aim of this thesis was to combine models of transport in porous media with microfabricated devices to develop novel methods for controlling the distribution of infused drugs. We used a poroelastic model of the brain to explore the effect of infusion induced dilation on transport. We calculated that during infusions at flow rates greater than one microliter/minute, the effective pore size of the extracellular matrix was doubled by dilation from approximately fifty nanometers to one-hundred nanometers. A computational fluid dynamic model of the rat brain determined the perturbation of the flow field between white and gray matter. We found no further perturbation of the flow field when the ratio of permeabilities between white and gray matter exceeded one-hundred. The results of our models suggest that the material properties of a targeted tissue region dictate the transport of infused solutions. To better control and manipulate drug distribution we developed a novel microfluidic platform for delivering drug-solutions at flow rates relevant for CED. The microfluidic devices consisted of parylene channels with a cross-section area of fifty microns by ten microns on a silicon structure with a cross-sectional area of one-hundred microns by one-hundred microns. These probes were tested in the normal rat brain and demonstrated performance advantages over standard needles, including no channel occlusion and attenuation of backflow. We expanded on the simple single channel device to implement more advanced strategies using multiple channels. A two-channel device was fabricated for infusing an enzyme or mannitol solution prior to infusing polystyrene nanoparticles. By pre-treating the targeted tissue region with enzymes or mannitol we increased the effective pore size of the extracellular matrix which resulted in a doubling of the distribution volume of nanoparticles.