An evaluation of the relationships between catheter design and tissue mechanics in achieving high-flow convection-enhanced delivery.

Convection-enhanced delivery (CED) is a rational technique for the direct intracranial administration of a range of therapeutic agents. CED critically depends on the use of a catheter with a narrow outer diameter and low infusion rate. Failure to adhere to these requirements can lead to reflux of infusate along the catheter-brain interface and damage at the catheter-tip. In this study we have tested the hypothesis that the relationship between infusion parameters and infusate distribution, including reflux, is critically dependent on the occurrence of tissue damage. The relationship between catheter outer diameter and the extent of blood-brain barrier disruption and subsequent tissue oedema was evaluated following catheter insertion into the striatum of rats. Three patterns of infusate distribution were observed: (1) Reflux restricted to the traumatised tissue around the catheter site. (2) Distribution in the white matter beyond the area of tissue trauma. (3) Widespread distribution in the striatum, which occurred only with catheters of an outer diameter of 0.35 mm or less. Extensive tissue damage occurred with a 0.2mm outer diameter catheter. This damage was completely prevented by rounding the catheter-tip. Infusions into pig brain demonstrated that high-flow CED could be performed in a large brain in both grey and white matter using a 0.2mm outer diameter catheter, with minimal reflux or MRI-evidence of tissue damage. This study demonstrates that by minimising tissue damage from catheter design and insertion, high flow-rate CED can be utilised to distribute therapeutic agents over large volumes of brain within clinically practical timescales.