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

Abstract

BackgroundConvection 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.PurposeThe 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.MethodsIn 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.ResultsMRI 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).ConclusionWe 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.

Comparative Morphometry of the Wisconsin Miniature Swine^TM Thoracic Spine for Modeling Human Spine in Translational Spinal Cord Injury Research

“…The data are presented as mean ± SEM. show promise for targeted delivery of therapies into the brain [25][26][27][28], can be developed and refined for improving the effectiveness of therapies administered into the spinal cord [25,29].…”

Resveratrol targeting of AKT and p53 in glioblastoma and glioblastoma stem-like cells to suppress growth and infiltration

“…For intracranial delivery, local brain molar concentrations were approximated from whole brain total drug mass using CED parameters reported in the literature. A volume distribution (V d ) to volume injected (V i ) ratio of 5.23±1.67 32 was used to calculate the molar concentration of resveratrol at infusion site. This V d /V i ratio is an experimentally-derived value for CED using a 1 μl/min flow rate into non-human primate brain 32 .…”

Three-dimensional nonlinear finite element model to estimate backflow during flow-controlled infusions into the brain

“…Currently, the pressure that occurs during clinical or experimental CED is measured in the infusion line rather than in the brain tissue or agarose gel at the tip of the catheter. [70][71][72][73] In comparison to the infusion-line Figure 7. Fluid velocity distributions for a cannula distance of 36 mm for each flow rate (1 and 4 mL/min) and two relative ventricle pressures (0 and 100 Pa).…”