Abstract
Convection-enhanced delivery (CED) is a method used to increase transport of therapeutics in and around brain tumors. CED works through locally applying a pressure differential to drive fluid flow throughout the tumor, such that convective forces dominate over diffusive transport. This allows therapies to bypass the blood brain barrier that would otherwise be too large or solely rely on passive diffusion. However, this also drives fluid flow out through the tumor bulk into surrounding brain parenchyma, which results in increased interstitial fluid (IF) flow, or fluid flow within extracellular spaces in the tissue. IF flow has been associated with altered transport of molecules, extracellular matrix rearrangement, and triggering of cellular motility through a number of mechanisms. Thus, the results of a simple method to increase drug delivery may have unintended consequences on tissue morphology. Clinically, prediction of dispersal of agents via CED is important to catheter design, placement, and implementation to optimize contact of tumor cells with therapeutic agent. Prediction software can aid in this problem, yet we wonder if there is a better way to predict therapeutic distribution based simply on IF flow pathways as determined from pre-intervention imaging. Overall, CED based therapy has seen limited success and we posit that integration and appreciation of altered IF flow may enhance outcomes. Thus, in this manuscript we both review the current state of the art in CED and IF flow mechanistic understanding and relate these two elements to each other in a clinical context.
Highlights
Convection-enhanced delivery (CED) is a technique that harnesses increased flow of fluid to increase transport of large molecules and drugs throughout a tissue
We hope to describe these flows in the context of both the natural flow in the brain and the changes in interstitial fluid (IF) flow that may be attributed to the technique of CED
Catheter placement, tumor location, tumor size, infusion rate, infusion frequency, drug type and concentration, and brain anatomy can all contribute to differential CED responses
Summary
Convection-enhanced delivery (CED) is a technique that harnesses increased flow of fluid to increase transport of large molecules and drugs throughout a tissue. This technique has been implemented for decades but has not been adopted widely in the clinic. The ability of this therapy to move drugs around is useful, there are a number of factors that can inhibit or obstruct the ability of this method to work appropriately. Fluid flow in the brain (healthy or diseased) is a constant force and it can affect the transport of drugs and molecules throughout the tumor and surrounding tissue, and cause changes to tumor cells and surrounding cells that could worsen or alter disease progression.
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