Enhanced intrathecal drug dispersion achieved by high volume injection and natural micromixing

Abstract

AbstractBackgroundTraditionally, there is a widely held belief that drug dispersion after intrathecal (IT) delivery is confined locally near the injection site. We posit that high volume infusions can overcome this perceived limitation of IT administration.MethodsTo test our hypothesis, subject-specific deformable phantom models of the human central nervous system were manufactured so that tracer infusion could be realistically replicated in vitro over the entire physiological range of pulsating cerebrospinal fluid (CSF) amplitudes and frequencies. Dispersion of IT injected tracers was studied systematically with high-speed optical methods to determine the relative impact of injection parameters including infusion volume, flow rate, catheter configurations and natural CSF oscillations.ResultsOptical imaging analysis of high-volume infusion experiments showed that tracer spreads quickly throughout the spinal subarachnoid space (SAS), reaching the cervical region in less than ten minutes. The experimentally observed biodispersion is much faster than suggested by prior theories (Taylor-Aris-Watson TAW dispersion). Our experiments indicate that micro-mixing patterns induced by oscillatory CSF flow around microanatomical features such as nerve roots significantly accelerate solute transport. Strong micro mixing effects due to anatomical features in the spinal subarachnoid space were found to be active in intrathecal drug administration but were not considered in prior dispersion theories. Their omission explains why prior models developed in the engineering community are poor predictors for IT delivery.ConclusionOur experiments support the feasibility of targeting large sections of the neuroaxis or brain utilizing high-volume IT injection protocols. The experimental tracer dispersion profiles acquired with an in vitro human CNS analog informed a new predictive model of tracer dispersion as a function of physiological CSF pulsations and adjustable infusion parameters. The ability to predict spatiotemporal dispersion patterns is an essential prerequisite for exploring new indications of IT drug delivery that targets specific regions in the central nervous system (CNS) or the brain.