NEURAL DRUG DELIVERY: NOVEL MICROFLUIDIC DELIVERY DEVICES AND STUDIES OF TRANSPORT PHENOMENA

Abstract

There are many promising pharmacological treatments for neurological disorders whose efficacies are limited by difficulties in delivering therapeutics to disease afflicted tissue. The work in this dissertation addresses some of the issues associated with neural drug delivery through three main investigative routes: development of new and more effective delivery devices, comprehension of drug transport mechanisms, and improvement in pre-clinical testing models for new therapeutics. A major focus of this work is convection enhanced delivery (CED). In CED, drugs are infused directly into tissue through a needle or catheter, and therefore are able to penetrate deeper into tissue than diffusion mediated delivery. A novel implantable microfluidic device was fabricated and characterized for chronic convection enhanced delivery protocols. The device consists of a flexible parylene microfluidic channel that is supported during tissue insertions by a biodegradable poly(DL-lactide-co-glycolide) scaffold. The device was able to reproducibly inject fluid into neural tissue with final infusate distributions that closely approximate delivery from an ideal point source. Also, real-time studies of drug transport through tissue were carried out using 2-photon excited fluorescence microscopy to monitor the movement of fluorescent nanoparticles in the rat cortex during delivery via CED. We found that perivascular spaces can drastically affect the distribution of therapeutic constructs larger than approximately 50nm by providing a high permeability conduit for transport through neural tissue. Finally, a new endovascular microcatheter was developed that allows for selective intra-arterial injections in the rat brain. The device consists of a 169?m outer-diameter polyimide tube that has laser machined fluid delivery side-ports in the distal tip. A 450?m diameter by 1mm long poly(dimethyl siloxane) cylinder is attached to the distal end of the catheter to block blood flow in the carotid artery, to simulate an ischemic stroke. This device shows great promise for testing intra-arterial delivery of novel therapeutics in rat models.