Properties of convective delivery in spinal cord gray matter: laboratory investigation and computational simulations.

Abstract

OBJECT Convection-enhanced delivery (CED) is a method for distributing small and large molecules locally into the interstitial space of the spinal cord. Delivering these molecules to the spinal cord is otherwise difficult due to the blood-spinal cord barrier. Previous research has proven the efficacy of CED for delivering molecules over long distances along the white matter tracts in the spinal cord. Conversely, the characteristics of CED for delivering molecules to the gray matter of the spinal cord remain unknown. The purpose of this study was to reveal regional distribution of macromolecules in the gray and white matter of the spinal cord with special attention to the differences between the gray and white matter. METHODS Sixteen rats (F344) underwent Evans blue dye CED to either the white matter (dorsal column, 8 rats) or the gray matter (ventral horn, 8 rats) of the spinal cord. The rates and total volumes of infusion were 0.2 μl/min and 2.0 μl, respectively. The infused volume of distribution was visualized and quantified histologically. Computational models of the rat spinal cord were also obtained to perform CED simulations in the white and gray matter. RESULTS The ratio of the volume of distribution to the volume of infusion in the gray matter of the spinal cord was 3.60 ± 0.69, which was comparable to that of the white matter (3.05 ± 0.88). When molecules were injected into the white matter, drugs remained in the white matter tract and rarely infused into the adjacent gray matter. Conversely, when drugs were injected into the gray matter, they infiltrated laterally into the white matter tract and traveled longitudinally and preferably along the white matter. In the infusion center, the areas were larger in the gray matter CED than in the white matter (Mann-Whitney U-test, p < 0.01). In computational simulations, the aforementioned characteristics of CED to the gray and white matter were reaffirmed. CONCLUSIONS In the spinal cord, the gray and white matter have distinct characteristics of drug distribution by CED. These differences between the gray and white matter should be taken into account when considering drug delivery to the spinal cord. Computational simulation is a useful tool for predicting drug distributions in the normal spinal cord.