Many neurological diseases are potentially treatable through pharmacologic approaches, but current clinical therapies are limited by our inability to deliver agents at a controlled rate over a prolonged period to a specified target location in the brain. This problem is magnified in the brain, in comparison with other organs, because of the blood-brain barrier, which renders brain cells inaccessible to agents in the bloodstream unless very high (often toxic) levels are applied. We propose to develop general technology for releasing controlled quantities of agents into the brain in association with microfabricated materials that are commonly used for brain recording and stimulation. These new technologies would permit the coupling of precisely controlled pharmacologic interventions to electrical recording and/or stimulation Once developed, this controlled delivery technology will be useful in a variety of settings including 1) real-time study of the influence of pharmacologic agents on the response of the brain during recording or stimulation and 2) when coupled with signal recording capability, will provide the opportunity to adjust the controlled delivery mechanism in response to a biological effect in the tissue. In the present application, we propose to examine two different, but potentially complementary, delivery techniques: controlled release and microfluidics. We will design and build delivery systems for four different neuroactive agents, which represent the spectrum of agents that are of interest in treating disease in the brain (neurotransmitter, dopamine; anti-inflammatory agent, dexamethasone; protein growth factor, BDNF; and gene therapy vector, plasmid DNA). To develop a complete,quantitative, and predictive understanding of these two delivery technologies, we propose a series of inter-related specific aims, including 1) development and characterization of delivery systems; 2) studies of agent delivery to the brain using both systems; 3) dynamic studies of agent transport in tissue using live brain slice and two-photon laser scanning microscopy.
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