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Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue

BACKGROUND: Convection enhanced delivery (CED) is emerging as a promising infusion toolto facilitate delivery of therapeutic agents into the brain via mechanically controlled pumps. Infusion protocols and catheter design have an important impact on delivery. CED is a valid alternative for systemic a...

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Autores principales: Miranpuri, Gurwattan, Hinchman, Angelica, Wang, Anyi, Schomberg, Dominic, Kubota, Ken, Brady, Martin, Raghavan, Raghu, Bruner, Kevin, Brodsky, Ethan, Block, Walter, Grabow, Ben, Raschke, Jim, Alexander, Andrew, Ross, Chris, Simmons, Heather, Sillay, Karl
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Indian Academy of Neurosciences 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117126/
https://www.ncbi.nlm.nih.gov/pubmed/25206026
http://dx.doi.org/10.5214/ans.0972.7531.200306
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author Miranpuri, Gurwattan
Hinchman, Angelica
Wang, Anyi
Schomberg, Dominic
Kubota, Ken
Brady, Martin
Raghavan, Raghu
Bruner, Kevin
Brodsky, Ethan
Block, Walter
Grabow, Ben
Raschke, Jim
Alexander, Andrew
Ross, Chris
Simmons, Heather
Sillay, Karl
author_facet Miranpuri, Gurwattan
Hinchman, Angelica
Wang, Anyi
Schomberg, Dominic
Kubota, Ken
Brady, Martin
Raghavan, Raghu
Bruner, Kevin
Brodsky, Ethan
Block, Walter
Grabow, Ben
Raschke, Jim
Alexander, Andrew
Ross, Chris
Simmons, Heather
Sillay, Karl
author_sort Miranpuri, Gurwattan
collection PubMed
description BACKGROUND: Convection enhanced delivery (CED) is emerging as a promising infusion toolto facilitate delivery of therapeutic agents into the brain via mechanically controlled pumps. Infusion protocols and catheter design have an important impact on delivery. CED is a valid alternative for systemic administration of agents in clinical trials for cell and gene therapies. Where gel and ex vivo models are not sufficient in modeling the disease, in vivo models allow researchers to better understand the underlying mechanisms of neuron degeneration, which is helpful in finding novel approaches to control the process or reverse the progression. Determining the risks, benefits, and efficacy of new gene therapies introduced via CED will pave a way to enter human clinical trial. PURPOSE: The objective of this study is to compare volume distribution (Vd)/ volume infused (Vi) ratios and backflow measurements following CED infusions in ex vivo versus in vivo non-human primate brain tissue, based on infusion protocols developed in vitro. METHODS: In ex vivo infusions, the first brain received 2 infusions using a balloon catheter at rates of 1 μL/min and 2 μL/min for 30 minutes. The second and third brains received infusions using a valve-tip (VT) catheter at 1 μL/min for 30 minutes. The fourth brain received a total of 45 μL infused at a rate of 1 μL/min for 15 minutes followed by 2 μL/min for 15 minutes. Imaging was performed (SPGR FA34) every 3 minutes. In the in vivo group, 4 subjects received a total of 8 infusions of 50 μL. Subjects 1 and 2 received infusions at 1.0 μL/min using a VT catheter in the left hemisphere and a smart-flow (SF) catheter in the right hemisphere. Subjects 3 and 4 each received 1 infusion in the left and right hemisphere at 1.0 μL/min. RESULTS: MRI calculations of Vd/Vi did not significantly differ from those obtained on post-mortem pathology. The mean measured Vd/Vi of in vivo (5.23 + /-1.67) compared to ex vivo (2.17 + /-1.39) demonstrated a significantly larger Vd/Vi for in vivo by 2.4 times (p = 0.0017). CONCLUSION: We detected higher ratios in the in vivo subjects than in ex vivo. This difference could be explained by the extra cellular space volume fraction. Studies evaluating backflow and morphology use in vivo tissue as a medium are recommended. Further investigation is warranted to evaluate the role blood pressure and heart rate may play in human CED clinical trials.
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spelling pubmed-41171262014-09-09 Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue Miranpuri, Gurwattan Hinchman, Angelica Wang, Anyi Schomberg, Dominic Kubota, Ken Brady, Martin Raghavan, Raghu Bruner, Kevin Brodsky, Ethan Block, Walter Grabow, Ben Raschke, Jim Alexander, Andrew Ross, Chris Simmons, Heather Sillay, Karl Ann Neurosci Research Article BACKGROUND: Convection enhanced delivery (CED) is emerging as a promising infusion toolto facilitate delivery of therapeutic agents into the brain via mechanically controlled pumps. Infusion protocols and catheter design have an important impact on delivery. CED is a valid alternative for systemic administration of agents in clinical trials for cell and gene therapies. Where gel and ex vivo models are not sufficient in modeling the disease, in vivo models allow researchers to better understand the underlying mechanisms of neuron degeneration, which is helpful in finding novel approaches to control the process or reverse the progression. Determining the risks, benefits, and efficacy of new gene therapies introduced via CED will pave a way to enter human clinical trial. PURPOSE: The objective of this study is to compare volume distribution (Vd)/ volume infused (Vi) ratios and backflow measurements following CED infusions in ex vivo versus in vivo non-human primate brain tissue, based on infusion protocols developed in vitro. METHODS: In ex vivo infusions, the first brain received 2 infusions using a balloon catheter at rates of 1 μL/min and 2 μL/min for 30 minutes. The second and third brains received infusions using a valve-tip (VT) catheter at 1 μL/min for 30 minutes. The fourth brain received a total of 45 μL infused at a rate of 1 μL/min for 15 minutes followed by 2 μL/min for 15 minutes. Imaging was performed (SPGR FA34) every 3 minutes. In the in vivo group, 4 subjects received a total of 8 infusions of 50 μL. Subjects 1 and 2 received infusions at 1.0 μL/min using a VT catheter in the left hemisphere and a smart-flow (SF) catheter in the right hemisphere. Subjects 3 and 4 each received 1 infusion in the left and right hemisphere at 1.0 μL/min. RESULTS: MRI calculations of Vd/Vi did not significantly differ from those obtained on post-mortem pathology. The mean measured Vd/Vi of in vivo (5.23 + /-1.67) compared to ex vivo (2.17 + /-1.39) demonstrated a significantly larger Vd/Vi for in vivo by 2.4 times (p = 0.0017). CONCLUSION: We detected higher ratios in the in vivo subjects than in ex vivo. This difference could be explained by the extra cellular space volume fraction. Studies evaluating backflow and morphology use in vivo tissue as a medium are recommended. Further investigation is warranted to evaluate the role blood pressure and heart rate may play in human CED clinical trials. Indian Academy of Neurosciences 2013-07 /pmc/articles/PMC4117126/ /pubmed/25206026 http://dx.doi.org/10.5214/ans.0972.7531.200306 Text en Copyright © 2013, Annals of Neurosciences
spellingShingle Research Article
Miranpuri, Gurwattan
Hinchman, Angelica
Wang, Anyi
Schomberg, Dominic
Kubota, Ken
Brady, Martin
Raghavan, Raghu
Bruner, Kevin
Brodsky, Ethan
Block, Walter
Grabow, Ben
Raschke, Jim
Alexander, Andrew
Ross, Chris
Simmons, Heather
Sillay, Karl
Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue
title Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue
title_full Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue
title_fullStr Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue
title_full_unstemmed Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue
title_short Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue
title_sort convection enhanced delivery: a comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117126/
https://www.ncbi.nlm.nih.gov/pubmed/25206026
http://dx.doi.org/10.5214/ans.0972.7531.200306
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