scholarly journals Assessment of needle tip geometry during infusions into a brain phantom gel

2020 ◽  
Vol 25 (4) ◽  
pp. 616-620
Author(s):  
Gustavo Alejandro Orozco Grajales ◽  
Fernando Casanova García ◽  
Jose Jaime García Álvarez
Keyword(s):  
Convection Enhanced Delivery ◽  
Flow Rates ◽  
Lower Flow ◽  
Therapeutic Drugs ◽  
Limited Efficacy ◽  
Agarose Hydrogel ◽  
Blunt Needle ◽  
Needle Track ◽  
The Brain ◽  
Brain Phantom

Convection-enhanced delivery (CED) is a promising method to deliver therapeutic drugs directly into the brain that has shown limited efficacy, mainly attributed to backflow, in which the infused drug flows back along the needle track rather than forward into tissue. This study evaluates the effect of sharp and blunt needle tips on backflow length under different flow rates via CED. Infusions were performed in a transparent 0.6% (w/v) brain phantom agarose hydrogel. Backflow length was significantly higher using sharp-tip needles for higher flow rates. No significant differences were observed between tip shapes for lower flow rates. In conclusion, sharp-tip needles present limitations for higher flow rates, which are needed to deliver more drug during shortest times.

Revised Scaling Relationship for Backflow Distance Along an Infusion Catheter

2012 ◽  
Author(s):  
José Jaime García ◽  
Joshua H. Smith
Keyword(s):  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Therapeutic Agents ◽  
Convection Enhanced Delivery ◽  
Limited Efficacy ◽  
Scaling Relationship ◽  
Primary Obstacle ◽  
The Central Nervous System ◽  
The Brain

Convection-enhanced delivery (CED) is a means to deliver therapeutic agents directly into brain tissue for the treatment of brain tumors and other disorders of the central nervous system, such as Parkinson’s disease. Recent clinical trials have shown limited efficacy of this procedure, with poor distribution of the infused agent being the primary obstacle [1]. One of the challenges with improving the distribution is the effect of backflow, in which the infused fluid preferentially flows along the outside of the catheter toward the surface of the brain rather than through the tissue toward the desired region for delivery.

Predictions of Drug Distribution During Infusions Into the Brain Using an Axisymmetric Finite Element Biphasic Model That Includes Backflow

2013 ◽  
Author(s):  
Alejandro Orozco ◽  
Joshua H. Smith ◽  
José Jaime García
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Drug Distribution ◽  
Therapeutic Agents ◽  
Positive Pressure ◽  
Convection Enhanced Delivery ◽  
Biphasic Model ◽  
Limited Efficacy ◽  
The Central Nervous System ◽  
The Brain

Convection-enhanced delivery is a technique to infuse therapeutic agents into the brain under positive pressure for the treatment of disorders of the central nervous system. Recent clinical trials [1] have shown limited efficacy of this procedure, attributed to poor distribution of the infused agent that may be due to backflow, in which the infused fluid preferentially flows along the outside of the catheter toward the surface of the brain.

Influence of Compressive Pre-Stress on Backflow During Convection Enhanced Delivery in Hydrogel Tissue Phantoms

2012 ◽  
Author(s):  
Fernando Casanova ◽  
Malisa Sarntinoranont
Keyword(s):  
Neurological Diseases ◽  
Needle Insertion ◽  
Local Drug Delivery ◽  
Convection Enhanced Delivery ◽  
Flow Rates ◽  
Constant Flow Rate ◽  
Specific Targeting ◽  
Tissue Phantoms ◽  
Delivery Technique ◽  
The Brain

Convection enhance delivery (CED) is a local drug delivery technique for the treatment of neurological diseases. With CED, a needle (or cannula) is implanted into tissue and either a constant flow rate or pressure is applied to deliver infusate directly into the extracellular space. Under certain conditions, infusate flows back along the outer cannula wall in the space between the cannula and tissue instead of spreading out into tissue. Higher driving fluid pressures are often needed during CED and this can frequently result in backflow especially at high flow rates or with large needle diameters. Backflow is normally undesirable because specific targeting is not achieved, and drugs can reach regions of the brain where they are not effective, toxic, or result in unintended side effects. Previous models have been developed to predict backflow [1,2] that consider elastic expansion of tissue surrounding the needle due to infusion pressure. However compressive pre-stress between the tissue and the needle wall produced by tissues displaced during needle insertion has not been previously considered.

scholarly journals Molecular mechanisms of metabotropic GABAB receptor function

2021 ◽  
Vol 7 (22) ◽  
pp. eabg3362
Author(s):  
Hamidreza Shaye ◽  
Benjamin Stauch ◽  
Cornelius Gati ◽  
Vadim Cherezov
Keyword(s):  
G Protein ◽  
Molecular Mechanisms ◽  
Gabab Receptor ◽  
Neurological Diseases ◽  
Activation Mechanism ◽  
Allosteric Modulators ◽  
Inhibitory Neurotransmitter ◽  
Therapeutic Drugs ◽  
G Protein Coupled ◽  
The Brain

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB. Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.

EXTH-31. BRAIN DISTRIBUTION, CLEARANCE AND TOXICITY EVALUATION OF SMALL-MOLECULE INHIBITORS FOLLOWING CONVECTION-ENHANCED DELIVERY TO THE BRAINSTEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi170-vi170
Author(s):  
Erica Power ◽  
Juhee Oh ◽  
Jonghoon Choi ◽  
William Elmquist ◽  
David Daniels
Keyword(s):  
Small Molecule ◽  
Drug Concentration ◽  
Small Molecule Inhibitors ◽  
Efflux Pump ◽  
Sprague Dawley ◽  
Convection Enhanced Delivery ◽  
Efflux Pump Inhibitor ◽  
Delivery Technique ◽  
The Brain

Abstract BACKGROUND Diffuse midline gliomas (DMGs) harboring the H3K27M mutation are highly aggressive, fatal brainstem tumors that primarily occur in children. The blood-brain barrier (BBB) prevents numerous drugs from reaching CNS tumors, like DMG, at cytotoxic concentrations. Convection-enhanced delivery (CED) has emerged as a drug delivery technique that bypasses the BBB through a direct interstitial infusion under a pressure gradient. However, drug distribution and clearance from the brain following CED is poorly understood and has been cited as a potential reason for the lack of efficacy observed in prior clinical trials. OBJECTIVE The objective of this study was to understand how two small molecule inhibitors (alisertib, ponatinib) that inhibit cell growth and proliferation in DMG cells in vitro distribute and clear from the brain following CED to the brainstem. METHODS Sprague-dawley rats underwent a single 60mL CED infusion of drug to the brainstem (200mM alisertib, 10mM ponatinib) and were sacrificed 0.083, 1, 2, 4, 8 and 24 hours following the completion of the infusion. Brains were dissected and drug concentration was determined via HPLC analysis. RESULTS No rats showed any clinical or neurological signs of toxicity post-infusion. Both drugs showed significant differences in drug concentration based on anatomical brain region where higher concentrations were observed in the pons and cerebellum compared to the cortex. Drug half-life in the brain was ~0.5 hours for alisertib and ~1 hour for ponatinib, but this was not significantly increased following co-administration of elacridar, a BBB efflux pump inhibitor. CONCLUSIONS These results suggest that elimination of drugs from the brain in a complex, multifactorial mechanism that warrants further preclinical investigation prior to the initiation of a clinical trial.

Computational Model of Interstitial Transport in the Rat Brain Using Diffusion Tensor Imaging

2007 ◽  
Author(s):  
Jung Hwan Kim ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont
Keyword(s):  
Diffusion Tensor ◽  
Therapeutic Potential ◽  
Treatment Optimization ◽  
Convection Enhanced Delivery ◽  
Tissue Properties ◽  
Large Molecules ◽  
Macromolecular Drugs ◽  
Interstitial Transport ◽  
Blood Spinal Cord Barrier ◽  
The Brain

In spite of the high therapeutic potential of macromolecular drugs, it has proven difficult to apply them to recovery after injury and treatment of cancer, Parkinson’s disease, and other neurodegenerative diseases. One barrier to systemic administration is low capillary permeability, i.e., the blood-brain and blood-spinal cord barrier. To overcome this barrier, convection-enhanced delivery (CED) infuses agents directly into tissue to supplement diffusion and increase the distribution of large molecules in the brain [1,2]. Predictive models of distribution during CED would be useful in treatment optimization and planning. To account for large infusion volumes, such models should incorporate tissue boundaries and anisotropic tissue properties.

scholarly journals Powder flow down a vertical pipe: the effect of air flow

2002 ◽  
Vol 459 ◽  
pp. 317-345 ◽  
Author(s):  
Y. BERTHO ◽  
F. GIORGIUTTI-DAUPHINÉ ◽  
T. RAAFAT ◽  
E. J. HINCH ◽  
H. J. HERRMANN ◽  
...  
Keyword(s):  
Small Diameter ◽  
Stationary Flow ◽  
Momentum Conservation ◽  
Wall Friction ◽  
Particle Fraction ◽  
Friction Forces ◽  
Flow Rates ◽  
Lower Flow ◽  
Grain Flow ◽  
Grain Distribution

The dynamics of dry granular flows down a vertical glass pipe of small diameter have been studied experimentally. Simultaneous measurements of pressure profiles, air and grain flow rates and volume fractions of particles have been realized together with spatio-temporal diagrams of the grain distribution down the tube. At large grain flow rates, one observes a stationary flow characterized by high particle velocities, low particle fractions and a downflow of air resulting in an underpressure in the upper part of the pipe. A simple model assuming a free fall of the particles slowed down by air friction and taking into account finite particle fraction effects through Richardson–Zaki's law has been developed: it reproduces pressure and particle fraction variations with distance and estimates friction forces with the wall. At lower flow rates, sequences of high-density plugs separated by low-density bubbles moving down at a constant velocity are observed. The pressure is larger than outside the tube and its gradient reflects closely the weight of the grains. Writing mass and momentum conservation equations for the air and for the grains allows one to estimate the wall friction, which is less than 10% of the weight for grains with a clean smooth surface but up to 30% for grains with a rougher surface. At lower flow rates, oscillating-wave regimes resulting in large pressure fluctuations are observed and their frequency is predicted.

scholarly journals Design and Validation of a Multi-Point Injection Technology for MR-Guided Convection Enhanced Delivery in the Brain

2021 ◽  
Vol 3 ◽  
Author(s):  
Kayla Prezelski ◽  
Megan Keiser ◽  
Joel M. Stein ◽  
Timothy H. Lucas ◽  
Beverly Davidson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Low Flow ◽  
Limiting Factor ◽  
Volume Distribution ◽  
Convection Enhanced Delivery ◽  
Flow Rates ◽  
Point Injection ◽  
Subcortical Regions ◽  
Injection Technology

Convection enhanced delivery (CED) allows direct intracranial administration of neuro-therapeutics. Success of CED relies on specific targeting and broad volume distributions (VD). However, to prevent off-target delivery and tissue damage, CED is typically conducted with small cannulas and at low flow rates, which critically limit the maximum achievable VD. Furthermore, in applications such as gene therapy requiring injections of large fluid volumes into broad subcortical regions, low flow rates translate into long infusion times and multiple surgical trajectories. The cannula design is a major limiting factor in achieving broad VD, while minimizing infusion time and backflow. Here we present and validate a novel multi-point cannula specifically designed to optimize distribution and delivery time in MR-guided intracranial CED of gene-based therapeutics. First, we evaluated the compatibility of our cannula with MRI and common viral vectors for gene therapy. Then, we conducted CED tests in agarose brain phantoms and benchmarked the results against single-needle delivery. 3T MRI in brain phantoms revealed minimal susceptibility-induced artifacts, comparable to the device dimensions. Benchtop CED of adeno-associated virus demonstrated no viral loss or inactivation. CED in agarose brain phantoms at 3, 6, and 9 μL/min showed >3x increase in volume distribution and 60% time reduction compared to single-needle delivery. This study confirms the validity of a multi-point delivery approach for improving infusate distribution at clinically-compatible timescales and supports the feasibility of our novel cannula design for advancing safety and efficacy of MR-guided CED to the central nervous system.

Sign in / Sign up

Export Citation Format

Share Document