This project is concerned with characterizing and improving the delivery of pharmacologic and diagnostic agents to the central nervous system. Characterization of the infusate backflow that occurs along the shafts of infusion catheters at high volumetric rates was improved. Scaling laws were developed for both rat and human giving the absolute length of backflow along the catheter as a function of the volumetric infusion rate and catheter radius. The relative magnitude of the contributions to transport of axial and radial flow components in brain tissue was assessed: axial flow is negligible for infusion rates above 0.5 microliter/min and becomes progressively more important as the flow rate drops to 0.1 microliter/min. Below 0.1 microliter/min, infusate transports with spherical symmetry. The ratio of gray to (average) white matter hydraulic conductivity was computed from experimental data describing the distribution of radiolabelled albumin in brain as a function of inflow rate and found to be 0.16; 10-fold lower values as reported elsewhere do not appear likely because they imply such a low gray matter conductivity that a 4 microliter infusion into the center of the caudate at 0.5 microliter/min would overflow the caudate into the corpus callosum, a prediction in disagreement with observation. Efforts to describe the backflow-associated solute distribution in infused tissue by finite element methods have been initiated. Finite element modeling of the spinal cord has also been initiated and preliminary results show anisotropic distribution of macromolecules within the white fiber tracts that may be useful for drug delivery. The movement of viral-sized particles by high flow interstitial infusion has been investigated using autoradiography, dynamic light scattering, and capillary electrophoresis. Albumin-coated 100nm (and smaller) polystyrene microspheres were found capable of movement through the interstitium, as was adenovirus. Larger microspheres became progressively retarded. - infusion, brain, mathematical modeling, pallidotomy, lesioning
