An evaluation of the relationships between catheter design and tissue mechanics in achieving high-flow convection-enhanced delivery

Convection enhanced delivery is an attractive option for the treatment of several neurodegenerative diseases such as Parkinson, Alzheimer, and brain tumors. However, the occurrence of a backflow is a major problem impeding the widespread use of this technique. In this paper, we analyze experimentally the force impact of high flow microinfusion on the deformable gel matrix. To investigate these fluid structure interactions, two optical methods are reported. First, gel stresses during microinfusion were visualized through a linear polariscope. Second, the displacement field was tracked using 400 nm nanobeads as space markers. The corresponding strain and porosity fields were calculated from the experimental observations. Finally, experimental data were used to validate a computational model for fluid flow and deformation in soft porous media. Our studies demonstrate experimentally, the distribution and magnitude of stress and displacement fields near the catheter tip. The effect of fluid traction on porosity and hydraulic conductivity is analyzed. The increase in fluid content in the catheter vicinity enhances the gel hydraulic conductivity. Our computational model takes into account the changes in porosity and hydraulic conductivity. The simulations agree with experimental findings. The experiments quantified solid matrix deformation, due to fluid infusion. Maximum deformations occur in areas of relatively large fluid velocities leading to volumetric strain of the matrix, causing changes in hydraulic conductivity and porosity close to the catheter tip. The gradual expansion of this region with increased porosity leads to decreased hydraulic resistance that may also create an alternative pathway for fluid flow.

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Designing and Testing of Backflow-Free Catheters

Journal of Biomechanical Engineering ◽

10.1115/1.4004286 ◽

2011 ◽

Vol 133 (6) ◽

Cited By ~ 7

Author(s):

O. Ivanchenko ◽

V. Ivanchenko

Keyword(s):

Porous Media ◽

Hydraulic Conductivity ◽

Flow Direction ◽

Drug Distribution ◽

Fluid Injection ◽

Conductivity Anisotropy ◽

Convection Enhanced Delivery ◽

Delivery Technique ◽

Catheter Design ◽

The Impact

Convection-enhanced delivery (CED) is a drug delivery technique used to target specific regions of the central nervous system (CNS) for the treatment of neurodegenerative diseases and cancer while bypassing the blood–brain barrier (BBB). The application of CED is limited by low volumetric flow rate infusions in order to prevent the possibility of backflow. Consequently, a small convective flow produces poor drug distribution inside the treatment region, which can render CED treatment ineffective. Novel catheter designs and CED protocols are needed in order to improve the drug distribution inside the treatment region and prevent backflow. In order to develop novel backflow-free catheter designs, the impact of the micro-fluid injection into deformable porous media was investigated experimentally as well as numerically. Fluid injection into the porous media has a considerable effect on local transport properties such as porosity and hydraulic conductivity because of the local media deformation. These phenomena not only alter the bulk flow velocity distribution of the micro-fluid flow due to the changing porosity, but significantly modify the flow direction, and even the volumetric flow distribution, due to induced local hydraulic conductivity anisotropy. These findings help us to design backflow-free catheters with safe volumetric flow rates up to 10 μl/min. A first catheter design reduces porous media deformation in order to improve catheter performance and control an agent volumetric distribution. A second design prevents the backflow by reducing the porosity and hydraulic conductivity along a catheter’s shaft. A third synergistic catheter design is a combination of two previous designs. Novel channel-inducing and dual-action catheters, as well as a synergistic catheter, were successfully tested without the occurrence of backflow and are recommended for future animal experiments.

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Controlled Catheter Movement Affects Dye Dispersal Volume in Agarose Gel Brain Phantoms

Pharmaceutics ◽

10.3390/pharmaceutics12080753 ◽

2020 ◽

Vol 12 (8) ◽

pp. 753

Author(s):

Jason N. Mehta ◽

Gabrielle R. McRoberts ◽

Christopher G. Rylander

Keyword(s):

Brain Tissue ◽

Indigo Carmine ◽

Movement Control ◽

Brain Parenchyma ◽

Agarose Gel ◽

Convection Enhanced Delivery ◽

Forward Flow ◽

Needle Tract ◽

Tissue Phantoms ◽

Catheter Design

The standard of care for treatment of glioblastoma results in a mean survival of only 12 to 15 months. Convection-enhanced delivery (CED) is an investigational therapy to treat glioblastoma that utilizes locoregional drug delivery via a small-caliber catheter placed into the brain parenchyma. Clinical trials have failed to reach their endpoints due to an inability of standard catheters to fully saturate the entire brain tumor and its margins. In this study, we examine the effects of controlled catheter movement on dye dispersal volume in agarose gel brain tissue phantoms. Four different catheter movement control protocols (stationary, continuous retraction, continuous insertion, and intermittent insertion) were applied for a single-port stepped catheter capable of intrainfusion movement. Infusions of indigo carmine dye into agarose gel brain tissue phantoms were conducted during the controlled catheter movement. The dispersal volume (Vd), forward dispersal volume (Vdf), infusion radius, backflow distance, and forward flow distance were quantified for each catheter movement protocol using optical images recorded throughout the experiment. Vd and Vdf for the retraction and intermittent insertion groups were significantly higher than the stationary group. The stationary group had a small but significantly larger infusion radius than either the retracting or the intermittent insertion groups. The stationary group had a greater backflow distance and lower forward flow distance than either the retraction or the intermittent insertion groups. Continuous retraction of catheters during CED treatments can result in larger Vd than traditional stationary catheters, which may be useful for improving the outcomes of CED treatment of glioblastoma. However, catheter design will be crucial in preventing backflow of infusate up the needle tract, which could significantly alter both the Vd and shape of the infusion.

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DIPG-42. TOWARD MULTIMODALITY THERAPY FOR DIPG/DMG: DEVELOPMENT AND INVESTIGATION OF CRANIOSPINAL IRRADIATION AND CONVECTION-ENHANCED DELIVERY PDX MODELS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.089 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii295-iii295

Author(s):

Aaron J Knox ◽

Ahmed Gilani ◽

Benjamin van Court ◽

Ayman Oweida ◽

Patrick Flannery ◽

...

Keyword(s):

Metastatic Tumor ◽

Craniospinal Irradiation ◽

Tumor Control ◽

Systemic Delivery ◽

Convection Enhanced Delivery ◽

Term Survival ◽

Pdx Model ◽

Tumor Dissemination ◽

Catheter Design ◽

Pdx Models

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) are metastatic diseases, as demonstrated by early convection-enhanced delivery (CED) clinical trials in which prolonged local tumor control can sometimes be achieved, but fatal disseminated disease then develops. We hypothesize that improvements in treatment of both focal disease and the entire neuraxis are necessary for long-term survival, and patient-derived xenograft (PDX) models can help advance these efforts. METHODS We used a BT245 murine orthotopic DIPG PDX model for this work. We developed a protocol and specialized platform to deliver craniospinal irradiation (CSI) with a pontine boost. We separately compared intratumoral drug concentration by CED and intraperitoneal delivery. In our CED model, mice receive gemcitabine 60 ug x1 in 15 ul at 0.5 ul/minute through a stepped catheter design with silica tubing extending 2mm beyond a 27G needle. RESULTS Mice receiving CSI (4 Gy x2d) plus boost (4 Gy x2d) showed minimal spinal and brain leptomeningeal metastatic disease by bioluminescence, MRI, and pathology compared to mice receiving radiation to the pons only (4 Gy x4d) or no radiation. CED achieved an intratumoral gemcitabine concentration 50-fold greater than intraperitoneal dosing when controlled for dose. CONCLUSIONS In a DIPG PDX model, CSI+boost minimizes tumor dissemination compared to focal radiation, and CED achieves clinically significant improvements in intratumoral chemotherapy concentration compared to systemic delivery. Adding these modalities to current treatment could improve both focal and metastatic tumor control, leading to meaningful improvements in survival.

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Anisotropic Membranes as Substrates for Sem

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100092189 ◽

1976 ◽

Vol 34 ◽

pp. 444-445

Author(s):

Thomas P. Turnbull ◽

W. F. Bowers

Keyword(s):

Electron Microscopy ◽

Scanning Electron Microscopy ◽

Transmission Electron Microscopy ◽

High Flow ◽

Polymer Chemistry ◽

Surface Porosity ◽

Transmission Electron ◽

Pore Texture ◽

Spongy Layer ◽

Scanning Electron

Until recently the prime purposes of filters have been to produce clear filtrates or to collect particles from solution and then remove the filter medium and examine the particles by transmission electron microscopy. These filters have not had the best characteristics for scanning electron microscopy due to the size of the pores or the surface topography. Advances in polymer chemistry and membrane technology resulted in membranes whose characteristics make them versatile substrates for many scanning electron microscope applications. These polysulphone type membranes are anisotropic, consisting of a very thin (0.1 to 1.5 μm) dense skin of extremely fine, controlled pore texture upon a much thicker (50 to 250μm), spongy layer of the same polymer. Apparent pore diameters can be controlled in the range of 10 to 40 A. The high flow ultrafilters which we are describing have a surface porosity in the range of 15 to 25 angstrom units (0.0015-0.0025μm).

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High Flow Oxygen Therapy and the Pressure to Feed Infants With Acute Respiratory Illness

Perspectives of the ASHA Special Interest Groups ◽

10.1044/2020_persp-19-00158 ◽

2020 ◽

Vol 5 (4) ◽

pp. 1006-1010

Author(s):

Jennifer Raminick ◽

Hema Desai

Keyword(s):

Clinical Practice ◽

Clinical Practice Guidelines ◽

Practice Guidelines ◽

Oxygen Therapy ◽

Respiratory Illness ◽

High Flow ◽

Oral Feeding ◽

Respiratory Support ◽

Acute Respiratory Illness ◽

High Flow Oxygen

Purpose Infants hospitalized for an acute respiratory illness often require the use of noninvasive respiratory support during the initial stage to improve their breathing. High flow oxygen therapy (HFOT) is becoming a more popular means of noninvasive respiratory support, often used to treat respiratory syncytial virus/bronchiolitis. These infants present with tachypnea and coughing, resulting in difficulties in coordinating sucking and swallowing. However, they are often allowed to feed orally despite having high respiratory rate, increased work of breathing and on HFOT, placing them at risk for aspiration. Feeding therapists who work with these infants have raised concerns that HFOT creates an additional risk factor for swallowing dysfunction, especially with infants who have compromised airways or other comorbidities. There is emerging literature concluding changes in pharyngeal pressures with HFOT, as well as aspiration in preterm neonates who are on nasal continuous positive airway pressure. However, there is no existing research exploring the effect of HFOT on swallowing in infants with acute respiratory illness. This discussion will present findings from literature on HFOT, oral feeding in the acutely ill infant population, and present clinical practice guidelines for safe feeding during critical care admission for acute respiratory illness. Conclusion Guidelines for safety of oral feeds for infants with acute respiratory illness on HFOT do not exist. However, providers and parents continue to want to provide oral feeds despite clinical signs of respiratory distress and coughing. To address this challenge, we initiated a process change to use clinical bedside evaluation and a “cross-systems approach” to provide recommendations for safer oral feeds while on HFOT as the infant is recovering from illness. Use of standardized feeding evaluation and protocol have improved consistency of practice within our department. However, further research is still necessary to develop clinical practice guidelines for safe oral feeding for infants on HFOT.

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