Quantifying and modeling convection-enhanced delivery in pathological brain states

Convection-enhanced delivery (CED) is an investigational technique in which a cannula is implanted directly into brain tissue and a medication is pressure-driven through the extracellular space of the brain. Direct brain infusion offers several advantages over other drug delivery techniques, including the ability to bypass the blood brain barrier and deliver macromolecular agents to large volumes of the central nervous system (CNS). Many macromolecular agents are being developed to attenuate damage in acute brain injuries, such as stroke and trauma, and to treat brain tumors.; Nearly all forms of acute brain injury and tumors involve significant extracellular space (ECS) alterations and blood flow perturbations. It is therefore likely that infusions in pathological states will be significantly different from those into normal brain. To safely and effectively deliver macromolecular agents in the treatment of these conditions, it is necessary to quantitatively characterize infusion with respect to three principal factors: ECS volume (pore fraction), tissue anisotropy, and tissue infusate clearance (removal of the medication via cerebrospinal fluid or blood flow). Experiments were performed to study infusion distributions in simplified gel phantoms and in animal models of pathological brain states.; These experiments use innovative quantitative MR techniques that could be extended to monitor distribution of appropriately labeled tracers during CED in humans. The experimental focus on the effects of brain pathologies (such as stroke, tumor or traumatic brain injury) on CED is a novel strategy to better understand a promising new therapeutic delivery modality in the CNS. The results from these experiments will be used to elucidate the principal factors involved in the infusion process as well as test and evaluate a three-dimensional mathematical model of medication transport that is designed to account for pathological tissue changes. This approach promises to validate the ability to predict and monitor the distribution of important new molecular therapies being developed for a variety of CNS pathologies.