Convection-Enhanced Delivery: Connection to and Impact of Interstitial Fluid Flow

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.

Keywords: CED; brain; cancer; drug delivery; fluid flow; glioma; transport.

Figure 1

Fluid flows throughout the brain in bulk flow pathways and in interstitial space within the cellular environment. (A) Bulk flow pathways include CSF through the ventricles and subarachnoid space, blood through the arteries and veins, and lymph through the meningeal lymphatics. Flow direction is shown by arrows. (1) CSF to cribriform plate (2) CSF to venous sinus through arachnoid villi (3) CSF to spinal cord. (B) Interstitial flow moves from cerebral arterioles to venules through the endothelial cells, crossing through extracellular matrix and cells such as neurons, astrocytes, and microglia. Figure not to scale.

Figure 2

Overview of CED into brain tumors. (A) CED is performed through catheters placed either intratumorally or intraparenchymally. The infusate profile will change depending on region of delivery (shown in orange). (B) Some example catheter designs that have been used to deliver CED.

Figure 3

Illustration of fluid flow resulting from tumor (blue arrows) and potential effects on flow when introducing CED (orange arrows). Without CED, the tumor causes interstitial flow from its border into the surrounding parenchyma, affecting cells located there. With CED, this interstitial flow will be increased but it is not known if this will create new pathways of flow or just increase existing ones, or what the downstream impact of this increased flow will be on the resident cells. Figure not to scale.