title: Convection Enhanced Delivery: A Comparison of infusion characteristics in ex vivo and in vivo non-human primate brain tissue.
abstract: 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.
  
  
  OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurological Surgery, School of Medicine and Public Health ; Kinetics Foundation.
authors.forename: Gurwattan
authors.initials: G
authors.lastname: Miranpuri
authors.affiliation: Department of Neurological Surgery, School of Medicine and Public Health.
authors.forename: Angelica
authors.initials: A
authors.lastname: Hinchman
authors.affiliation: Department of Neurological Surgery, School of Medicine and Public Health ; Department of Biomedical Engineering at the University of Wisconsin-Madison.
authors.forename: Anyi
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Neurological Surgery, School of Medicine and Public Health.
authors.forename: Dominic
authors.initials: D
authors.lastname: Schomberg
authors.affiliation: Kinetics Foundation.
authors.forename: Ken
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Therataxis.
authors.forename: Martin
authors.initials: M
authors.lastname: Brady
authors.affiliation: Therataxis.
authors.forename: Raghu
authors.initials: R
authors.lastname: Raghavan
authors.affiliation: Wisconsin National Primate Research Center.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bruner
authors.affiliation: Department of Biomedical Engineering at the University of Wisconsin-Madison.
authors.forename: Ethan
authors.initials: E
authors.lastname: Brodsky
authors.affiliation: Department of Biomedical Engineering at the University of Wisconsin-Madison.
authors.forename: Walter
authors.initials: W
authors.lastname: Block
authors.affiliation: Department of Biomedical Engineering at the University of Wisconsin-Madison.
authors.forename: Ben
authors.initials: B
authors.lastname: Grabow
authors.affiliation: Kinetics Foundation.
authors.forename: Jim
authors.initials: J
authors.lastname: Raschke
authors.affiliation: Weismann Center at the UW Madison, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Alexander
authors.affiliation: Engineering Resources Group Inc.
authors.forename: Chris
authors.initials: C
authors.lastname: Ross
authors.affiliation: Wisconsin National Primate Research Center.
authors.forename: Heather
authors.initials: H
authors.lastname: Simmons
authors.affiliation: Department of Neurological Surgery, School of Medicine and Public Health ; Department of Biomedical Engineering at the University of Wisconsin-Madison.
authors.forename: Karl
authors.initials: K
authors.lastname: Sillay
keywords: Backflow; Convection enhanced delivery (CED); Neurocatheter; Non-human primate; Volume distribution volume infused ratio (Vd/Vi)