This project is concerned with characterizing and improving the delivery of pharmacologic and diagnostic agents to the brain. A previously developed theory of microinfusion based on flow in porous media, microvascular transport, and brain metabolism was used to predict large penetration and relatively even dosing of tissue for high-flow microinfusion of macromolecules. We confirmed multi-centimeter macromolecular penetration of white matter in the cat brain via autoradiography, as well as flat concentration profiles and expected spread in the gray matter of rats. We performed a SPECT study in primates and phantoms, thus demonstrating this technique's ability to monitor delivery and characterize tissue spread, clearance, and effects on blood flow. Model computations were invoked to screen the ability of available contrast agents (iopamidol and Gd-DTPA-albumin) to track macromolecular agents in normal and tumorous brain. Based on porous media flow and deformation theory, a mathematical model of backflow of infusate along catheter shafts was developed as a function of flow rate, catheter diameter, and tissue parameters. This included the development of a new nondimensional scalar that is useful for selecting optimal catheter diameter and flow-rate combinations. To ascertain optimal infusion parameters for excitotoxin pallidotomy of Parkinson's disease, we also developed a mathematical model of quinolinic acid infusion into small gray matter nuclei.
