(556c) Mechanistic Study of the Intrathecal Drug Dispersion in the Spine Under Different Dosing Parameters and Strategies.

Intrathecal drug (IT) delivery can efficiently target regions in the central nervous system without hindering the blood-brain barrier. This delivery mode is especially promising for novel therapeutics such as enzyme replacement, gene, or antisense oligonucleotide (ASO) therapies for treating neurodegenerative diseases, including Alzheimer’s, Huntington’s disease, and stroke. Due to the high risk to patients and technical limitations of acquiring high-speed cerebrospinal fluid (CSF) flow and bio-distribution data with existing imaging modalities (e.g., MRI, PET) in humans in vivo, the study cannot be performed. A novel, fast, relatively economical, and subject-specific in-vitro method to study the drug bio-dispersion mechanism and optimize IT drug therapies for individual patients is in great need. We have studied this method of drug delivery using experiments, where the bio dispersion process of the tracer was studied with the use of a manufactured in vitro model of the human spine, which is subjected to the effect of pulsation as experienced in the actual human spine, and computational approaches. We present a model design and additive manufacturing process for producing a subject-specific spine that replicates the interaction of the human spine with the CSF, using different parameters such as infusion rate and frequency of pulsation. A numerical solution was developed to solve the 1D diffusion problem to generate and compare the concentration profile with the experimentally obtained concentration profile. Different parameters of the study were performed, which include (1) the intrathecal infusion of the tracer with the effect of CSF production in the spine; (2) the intrathecal infusion of the tracer with the effect of CSF injection to the spine; (3) the long-time inspection of infusion. All these conditions were applied to human, monkey, and rat spines. The results obtained from our model and experiment show that the manufactured spine is functional and can be utilized for optimizing drug dosing guidelines for IT administration before human trials and as a complement or substitute for animal trials. The computational results also provide confidence in the in-vitro experiments as the results are comparable. In addition, the CSF production and CSF injection have the potential to alter the motion of the tracer towards the head.