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Investigation of Human Intrathecal Solute Transport Dynamics Using a Novel in vitro Cerebrospinal Fluid System Analog
BACKGROUND: Understanding the relationship between cerebrospinal fluid (CSF) dynamics and intrathecal drug delivery (ITDD) injection parameters is essential to improve treatment of central nervous system (CNS) disorders. METHODS: An anatomically detailed in vitro model of the complete CSF system was...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406265/ https://www.ncbi.nlm.nih.gov/pubmed/37555174 http://dx.doi.org/10.3389/fnimg.2022.879098 |
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author | Seiner, Akari Burla, Goutham Kumar Reddy Shrestha, Dev Bowen, Mayumi Horvath, Joshua D. Martin, Bryn A. |
author_facet | Seiner, Akari Burla, Goutham Kumar Reddy Shrestha, Dev Bowen, Mayumi Horvath, Joshua D. Martin, Bryn A. |
author_sort | Seiner, Akari |
collection | PubMed |
description | BACKGROUND: Understanding the relationship between cerebrospinal fluid (CSF) dynamics and intrathecal drug delivery (ITDD) injection parameters is essential to improve treatment of central nervous system (CNS) disorders. METHODS: An anatomically detailed in vitro model of the complete CSF system was constructed. Patient-specific cardiac- and respiratory-induced CSF oscillations were input to the model in the subarachnoid space and within the ventricles. CSF production was input at the lateral ventricles and CSF absorption at the superior sagittal sinus. A model small molecule simulated drug product containing fluorescein was imaged within the system over a period of 3-h post-lumbar ITDD injections and used to quantify the impact of (a) bolus injection volume and rate, (b) post-injection flush volume, rate, and timing, (c) injection location, and (d) type of injection device. For each experiment, neuraxial distribution of fluorescein in terms of spatial temporal concentration, area-under-the-curve (AUC), and percent of injected dose (%ID) to the brain was quantified at a time point 3-h post-injection. RESULTS: For all experiments conducted with ITDD administration in the lumbar spine, %ID to the brain did not exceed 11.6% at a time point 3-h post-injection. Addition of a 12 mL flush slightly increased solute transport to the brain up to +3.9%ID compared to without a flush (p < 0.01). Implantation of a lumbar catheter with the tip at an equivalent location to the lumbar placed needle, but with rostral tip orientation, resulted in a small improvement of 1.5%ID to the brain (p < 0.05). An increase of bolus volume from 5 to 20 mL improved solute transport to the brain from 5.0 to 6.3%ID, but this improvement was not statistically significant. Increasing bolus injection rate from 5 to 13.3 mL/min lacked improvement of solute transport to the brain, with a value of 6.3 compared to 5.7%ID. CONCLUSION: The in vitro modeling approach allowed precisely controlled and repeatable parametric investigation of ITDD injection protocols and devices. In combination, the results predict that parametric changes in lumbar spine ITDD-injection related parameters and devices can alter %ID to the brain and be tuned to optimize therapeutic benefit to CNS targets. |
format | Online Article Text |
id | pubmed-10406265 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-104062652023-08-08 Investigation of Human Intrathecal Solute Transport Dynamics Using a Novel in vitro Cerebrospinal Fluid System Analog Seiner, Akari Burla, Goutham Kumar Reddy Shrestha, Dev Bowen, Mayumi Horvath, Joshua D. Martin, Bryn A. Front Neuroimaging Neuroimaging BACKGROUND: Understanding the relationship between cerebrospinal fluid (CSF) dynamics and intrathecal drug delivery (ITDD) injection parameters is essential to improve treatment of central nervous system (CNS) disorders. METHODS: An anatomically detailed in vitro model of the complete CSF system was constructed. Patient-specific cardiac- and respiratory-induced CSF oscillations were input to the model in the subarachnoid space and within the ventricles. CSF production was input at the lateral ventricles and CSF absorption at the superior sagittal sinus. A model small molecule simulated drug product containing fluorescein was imaged within the system over a period of 3-h post-lumbar ITDD injections and used to quantify the impact of (a) bolus injection volume and rate, (b) post-injection flush volume, rate, and timing, (c) injection location, and (d) type of injection device. For each experiment, neuraxial distribution of fluorescein in terms of spatial temporal concentration, area-under-the-curve (AUC), and percent of injected dose (%ID) to the brain was quantified at a time point 3-h post-injection. RESULTS: For all experiments conducted with ITDD administration in the lumbar spine, %ID to the brain did not exceed 11.6% at a time point 3-h post-injection. Addition of a 12 mL flush slightly increased solute transport to the brain up to +3.9%ID compared to without a flush (p < 0.01). Implantation of a lumbar catheter with the tip at an equivalent location to the lumbar placed needle, but with rostral tip orientation, resulted in a small improvement of 1.5%ID to the brain (p < 0.05). An increase of bolus volume from 5 to 20 mL improved solute transport to the brain from 5.0 to 6.3%ID, but this improvement was not statistically significant. Increasing bolus injection rate from 5 to 13.3 mL/min lacked improvement of solute transport to the brain, with a value of 6.3 compared to 5.7%ID. CONCLUSION: The in vitro modeling approach allowed precisely controlled and repeatable parametric investigation of ITDD injection protocols and devices. In combination, the results predict that parametric changes in lumbar spine ITDD-injection related parameters and devices can alter %ID to the brain and be tuned to optimize therapeutic benefit to CNS targets. Frontiers Media S.A. 2022-06-23 /pmc/articles/PMC10406265/ /pubmed/37555174 http://dx.doi.org/10.3389/fnimg.2022.879098 Text en Copyright © 2022 Seiner, Burla, Shrestha, Bowen, Horvath and Martin. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroimaging Seiner, Akari Burla, Goutham Kumar Reddy Shrestha, Dev Bowen, Mayumi Horvath, Joshua D. Martin, Bryn A. Investigation of Human Intrathecal Solute Transport Dynamics Using a Novel in vitro Cerebrospinal Fluid System Analog |
title | Investigation of Human Intrathecal Solute Transport Dynamics Using a Novel in vitro Cerebrospinal Fluid System Analog |
title_full | Investigation of Human Intrathecal Solute Transport Dynamics Using a Novel in vitro Cerebrospinal Fluid System Analog |
title_fullStr | Investigation of Human Intrathecal Solute Transport Dynamics Using a Novel in vitro Cerebrospinal Fluid System Analog |
title_full_unstemmed | Investigation of Human Intrathecal Solute Transport Dynamics Using a Novel in vitro Cerebrospinal Fluid System Analog |
title_short | Investigation of Human Intrathecal Solute Transport Dynamics Using a Novel in vitro Cerebrospinal Fluid System Analog |
title_sort | investigation of human intrathecal solute transport dynamics using a novel in vitro cerebrospinal fluid system analog |
topic | Neuroimaging |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406265/ https://www.ncbi.nlm.nih.gov/pubmed/37555174 http://dx.doi.org/10.3389/fnimg.2022.879098 |
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