Convection-Enhanced Delivery of Macromolecules to the Brain Using Electrokinetic Transport
Alec Valenta, Stephen Weber, Amir Faraji, Yanguang Ou, Andrea Jaquins-Gerstl
Introduction: Pressure-driven infusion of molecules into the brain has historically been limited in clinical practice by the inability to control infusion flow paths or by tissue distortion at the cannula tip. Electrokinetic convection-enhanced delivery (ECED) has the potential to infuse local areas of the brain with improved directional control along electrical current paths, thus leading to better clinical target coverage.
Objective: To demonstrate in vivo infusions using ECED, describe how infusions move along electrical current paths, and devise a semi-empirical computational model to predict transport in the brain.
Methods: Our protocol was approved by the University of Pittsburgh IACUC committee. Bilateral craniotomies were performed in anesthetized male rats and 100 μm inner diameter cannulas were used for ECED experiments with currents ranging from 25 to 75 μA. Three fluorophores were infused with varying molecular weights, electrophoretic mobilities, and fluorescence characteristics. Rat brains were collected post-infusion, serially sliced, and imaged to determine volumes of distribution. COMSOL software was used to develop a semi-empirical computational model to predict transport in brain tissue.
Results: The infusate contained a fluorescent dextran, 10 kDa BODIPY10 or 70 kDa TR70, or Ru(bpy)32+. The volumes of distribution were 1.71 ± 0.12 µL (N = 3), 0.62 ± 0.04 µL (N = 4), and 13.0 ± 2.0 µL (N = 4) respectively. Infusions moved along tissue connections and the electrical current path. No tissue deformation, edema, or cell death was observed. COMSOL Computational modeling corroborated our experimental data.
Conclusions: ECED represents a new and powerful methodology to locally-deliver agents to the brain with improved directional control as compared to pressure-driven infusions. ECED can augment existing drug delivery methods and may ultimately improve clinical outcomes in diseases requiring intraparenchymal infusions.