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

Flow Rates ◽

Constant Flow Rate ◽

Specific Targeting ◽

Tissue Phantoms ◽

Delivery Technique ◽

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.

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

Neuro-Oncology ◽

10.1093/neuonc/noab196.670 ◽

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 ◽

Efflux Pump Inhibitor ◽

Delivery Technique ◽

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.

PDTM-30. UNDERSTANDING THE EFFECTS OF MOLECULAR SIZE ON VOLUME OF DISTRIBUTION IN CONVECTION-ENHANCED DELIVERY

Neuro-Oncology ◽

10.1093/neuonc/noz175.806 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi193-vi194

Author(s):

Erica Power ◽

Julian Rechberger ◽

Liang Zhang ◽

David Daniels

Keyword(s):

Molecular Weight ◽

Single Injection ◽

Fluorescent Microscopy ◽

Molecular Size ◽

Volume Of Distribution ◽

Sprague Dawley ◽

Microscopy Imaging ◽

Delivery Technique ◽

Abstract BACKGROUND Diffuse midline gliomas harboring the H3K27M mutation, previously known as diffuse intrinsic pontine gliomas (DIPG), are rare and aggressive pediatric brain tumors. Over 100 clinical trials with different chemotherapeutics have failed to show any therapeutic benefit. One reason for failure is likely due to poor delivery of these agents to the brainstem. Convection-enhanced delivery (CED) is an emerging delivery technique used to directly inject the agent of interest into the brainstem under pressure. While there is evidence that this may be an effective delivery method, little work has been done to understand the optimal physical properties of these drugs. We sought characterize volume of distribution in the brain based on molecular size of the agent delivered via CED. METHODS Sprague- Dawley rats underwent a single injection of FITC-dextran (3,000 Da, 10,000 Da, 20,000 Da, 70,000 Da, 150,000 Da) via CED into the pons. Post-injection, animals were sacrificed and their brains harvested. Fluorescent microscopy imaging was used to calculate the volume of distribution of the FITC-dextran throughout the brain. RESULTS The volume of distribution (Vd) decreased exponentially according to a two-phase delay (r2= 0.94) as the molecular size of the FITC-dextran increased. The highest mean Vd (107.87mm3) was at a molecular weight of 3,000 Da, and lowest mean Vd (26.48 mm3) was at a molecular weight of 150,000 Da. ANOVA analysis was statistically significant (p= 0.0017). CONCLUSIONS As the molecular size of the FITC-dextran increased, the volume of distribution within the brain following a single injection via CED into the pons decreased. A better understanding of how drugs distribute by convection will allow us to optimize treatment regimens for DIPG tumors.

Influence of Needle Insertion Speed on Backflow for Convection-Enhanced Delivery

Journal of Biomechanical Engineering ◽

10.1115/1.4006404 ◽

2012 ◽

Vol 134 (4) ◽

Cited By ~ 19

Author(s):

Fernando Casanova ◽

Paul R. Carney ◽

Malisa Sarntinoranont

Keyword(s):

Analytical Model ◽

Tissue Damage ◽

Needle Insertion ◽

Similar Rate ◽

Local Damage ◽

Flow Rates ◽

Local Tissue ◽

Tissue Phantom ◽

Brain Tissues

Fluid flow back along the outer surface of a needle (backflow) can be a significant problem during the direct infusion of drugs into brain tissues for procedures such as convection-enhanced delivery (CED). This study evaluates the effects of needle insertion speed (0.2 and 1.8 mm/s) as well as needle diameter and flow rate on the extent of backflow and local damage to surrounding tissues. Infusion experiments were conducted on a transparent tissue phantom, 0.6% (w/v) agarose hydrogel, to visualize backflow. Needle insertion experiments were also performed to evaluate local damage at the needle tip and to back out the prestress in the surrounding media for speed conditions where localized damage was not excessive. Prestress values were then used in an analytical model of backflow. At the higher insertion speed (1.8 mm/s), local insertion damage was found to be reduced and backflow was decreased. The compressive prestress at the needle-tissue interface was estimated to be approximately constant (0.812 kPa), and backflow distances were similar regardless of needle gauge (22, 26, and 32 gauge). The analytical model underestimated backflow distances at low infusion flow rates and overestimated backflow at higher flow rates. At the lower insertion speed (0.2 mm/s), significant backflow was measured. This corresponded to an observed accumulation of material at the needle tip which produced a gap between the needle and the surrounding media. Local tissue damage was also evaluated in excised rat brain tissues, and insertion tests show similar rate-dependent accumulation of tissue at the needle tip at the lower insertion speed. These results indicate that local tissue damage and backflow may be avoided by using an appropriate insertion speed.

Convection-Enhanced Delivery in silico study for personalized brain cancer treatment

10.21203/rs.3.rs-998895/v1 ◽

2021 ◽

Author(s):

Chryso Lambride ◽

Vasileios Vavourakis ◽

Triantafyllos Stylianopoulos

Keyword(s):

Brain Cancer ◽

In Silico ◽

Drug Transport ◽

Drug Distribution ◽

Local Drug Delivery ◽

Patient Specific ◽

Formidable Challenge ◽

The Impact ◽

Abstract Brain cancer therapy remains a formidable challenge in oncology. Convection-enhanced delivery (CED) is an innovative and promising local drug delivery method for the treatment of brain cancer, overcoming the challenges of the systemic delivery of drugs to the brain. To improve our understanding about CED efficacy and drug transport, we present an in silico methodology for brain cancer CED treatment simulation. To achieve this, a three-dimensional finite element biomechanics formulation is utilized which employs patient-specific brain model representation and is used to predict the drug deposition in CED regimes. The model encompasses nonlinear biomechanics and the transport of drugs in the brain parenchyma. Drug distribution was studied under various patho-physiological conditions of the tumor, in terms of tumor vessel wall pore size and tumor tissue hydraulic conductivity as well as for drugs of various sizes, spanning from small molecules to nanoparticles. Our contribution reports for the first time the impact of the size of the vascular wall pores and that of the therapeutic agent on drug distribution during and after CED. The in silico findings provide useful insights of the spatio-temporal distribution and average drug concentration in the tumor towards an effective treatment of brain cancer.

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

Scientia et technica ◽

10.22517/23447214.21511 ◽

2020 ◽

Vol 25 (4) ◽

pp. 616-620

Author(s):

Gustavo Alejandro Orozco Grajales ◽

Fernando Casanova García ◽

Jose Jaime García Álvarez

Keyword(s):

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.

A Computational Model of Direct Infusion Into the Rat Brain: Corpus Callosum and Hippocampus

ASME 2009 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2009-205945 ◽

2009 ◽

Author(s):

Jung Hwan Kim ◽

Garrett W. Astary ◽

Thomas H. Mareci ◽

Malisa Sarntinoranont

Keyword(s):

Therapeutic Potential ◽

Experimental Studies ◽

Extracellular Fluid ◽

Treatment Optimization ◽

Macromolecular Drugs ◽

Delivery Technique ◽

The Central Nervous System ◽

Brain And Spinal Cord ◽

Despite the high therapeutic potential of many macromolecular drugs, it has proven difficult to apply them to treatment of cancer and other degenerative diseases of the central nervous system (CNS) due to low capillary permeability and low diffusivity. To overcome these barriers, recent experimental studies have shown local infusion, i.e., convection-enhanced delivery (CED), to be a promising delivery technique in the brain and spinal cord [1–3]. Predictive models of extracellular fluid flow and transport during CED would be useful for treatment optimization and planning.

Molecular mechanisms of metabotropic GABAB receptor function

Science Advances ◽

10.1126/sciadv.abg3362 ◽

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 ◽

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.

Human Monocytes Plasticity in Neurodegeneration

Biomedicines ◽

10.3390/biomedicines9070717 ◽

2021 ◽

Vol 9 (7) ◽

pp. 717

Author(s):

Ilenia Savinetti ◽

Angela Papagna ◽

Maria Foti

Keyword(s):

Neurodegenerative Disorders ◽

Current Knowledge ◽

Neurological Diseases ◽

Surface Marker ◽

First Line ◽

Surface Marker Expression ◽

Physiological Properties ◽

Attractive Therapeutic Target ◽

The Brain ◽

Lateral Sclerosis

Monocytes play a crucial role in immunity and tissue homeostasis. They constitute the first line of defense during the inflammatory process, playing a role in the pathogenesis and progression of diseases, making them an attractive therapeutic target. They are heterogeneous in morphology and surface marker expression, which suggest different molecular and physiological properties. Recent evidences have demonstrated their ability to enter the brain, and, as a consequence, their hypothetical role in different neurodegenerative diseases. In this review, we will discuss the current knowledge about the correlation between monocyte dysregulation in the brain and/or in the periphery and neurological diseases in humans. Here we will focus on the most common neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis.

Molecular mechanisms of cell death in neurological diseases

Cell Death and Differentiation ◽

10.1038/s41418-021-00814-y ◽

2021 ◽

Author(s):

Diane Moujalled ◽

Andreas Strasser ◽

Jeffrey R. Liddell

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Molecular Mechanisms ◽

Neuronal Development ◽

Neurological Diseases ◽

Treatment Strategies ◽

Current Treatment ◽

Response To Therapy ◽

Signalling Cascades ◽

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

A Destruction Model of the Vascular and Lymphatic Systems in the Emergence of Psychiatric Symptoms

Biology ◽

10.3390/biology10010034 ◽

2021 ◽

Vol 10 (1) ◽

pp. 34

Author(s):

Kohei Segawa ◽

Yukari Blumenthal ◽

Yuki Yamawaki ◽

Gen Ohtsuki

Keyword(s):

Neurodegenerative Diseases ◽

Lymphatic System ◽

Psychiatric Symptoms ◽

Neurological Diseases ◽

Immune Surveillance ◽

Brain Network ◽

Cellular Mechanisms ◽

Postmortem Brains ◽

New Interpretation ◽

The lymphatic system is important for antigen presentation and immune surveillance. The lymphatic system in the brain was originally introduced by Giovanni Mascagni in 1787, while the rediscovery of it by Jonathan Kipnis and Kari Kustaa Alitalo now opens the door for a new interpretation of neurological diseases and therapeutic applications. The glymphatic system for the exchanges of cerebrospinal fluid (CSF) and interstitial fluid (ISF) is associated with the blood-brain barrier (BBB), which is involved in the maintenance of immune privilege and homeostasis in the brain. Recent notions from studies of postmortem brains and clinical studies of neurodegenerative diseases, infection, and cerebral hemorrhage, implied that the breakdown of those barrier systems and infiltration of activated immune cells disrupt the function of both neurons and glia in the parenchyma (e.g., modulation of neurophysiological properties and maturation of myelination), which causes the abnormality in the functional connectivity of the entire brain network. Due to the vulnerability, such dysfunction may occur in developing brains as well as in senile or neurodegenerative diseases and may raise the risk of emergence of psychosis symptoms. Here, we introduce this hypothesis with a series of studies and cellular mechanisms.