Enhancing particle transport in the brain with oscillatory fluid flows: Models and simulations

Can larger drug distributions (e.g., gene therapy needed for monogenic correction of rare brain diseases) be achieved by supplementing direct delivery of the drug into the brain with sonication, steered and focused to effectively push the infusion away from the infusion catheter? Both better steering towards desired targets and potentially larger distribution volumes with appropriate protocols are desirable goals. These techniques may also enable effective intrathecal delivery which is less invasive than direct infusion. The desired velocities of advection and dispersivities (beyond the usually negligible molecular diffusivities) of the therapeutic particles necessary for clinical significance are quite small (1–10 microns/second, 1000–2000 microns squared/second) but still difficult to attain. The mechanisms involved include streaming and augmented dispersion, both very sensitive to boundary conditions: Further development is needed to correct literature in this field because it has numerous errors and omissions that may invalidate the conclusions therein. We discuss the theory, its subtleties, and three possible applications to enhance drug distributions: (i) intrathecal and (ii) intraparenchymal delivery to the brain and (iii) other intraparenchymal deliveries, e.g., to liver. The calculations offer room for optimism, but the developments needed are considerable. We conclude with a “control diagram” for needed developments.