A Nonlinear Biphasic Model for Mass Transport During Constant Flow-Rate Infusion Into Brain Tissue

2010 ◽  
Author(s):  
Joshua H. Smith ◽  
José Jaime García
Keyword(s):  
Mass Transport ◽  
Brain Tissue ◽  
Solid Phase ◽  
Phase 1 ◽  
Convection Enhanced Delivery ◽  
Biphasic Model ◽  
Constant Flow Rate ◽  
Nonlinear Stress ◽  
Tension And Compression ◽  
Rate Infusion

Convection-enhanced delivery is a means to deliver therapeutic agents directly into brain tissue. Biphasic models have been used to study the concomitant fluid and mass transport that occurs during infusion, however previous studies have been limited by the assumption of linear elasticity of the solid phase [1]. In contrast, nonlinear stress-strain curves have been documented for brain tissue under finite deformation in tension and compression [2, 3].

A Nonlinear Biphasic Model for Fluid Transport and Tissue Deformation During Constant Flow Rate Infusion Into Brain Tissue

2009 ◽  
Author(s):  
Joshua H. Smith ◽  
Jose Jaime García
Keyword(s):  
Brain Tissue ◽  
Fluid Transport ◽  
Solid Phase ◽  
Phase 1 ◽  
Therapeutic Agents ◽  
Tissue Deformation ◽  
Convection Enhanced Delivery ◽  
Adequate Treatment ◽  
Biphasic Model ◽  
Constant Flow Rate

The delivery of therapeutic agents into the brain is impeded by the blood-brain barrier, preventing adequate treatment of diseases of the central nervous system. Convection enhanced delivery was developed as a means to deliver therapeutic agents directly into brain tissue and to transport the drugs in the extracellular space using convective flow. Poroelastic or biphasic models have been used to study the concomitant fluid transport and tissue deformation that occurs during infusion, however previous studies have been limited by the assumption of linear elasticity of the solid phase [1].

Effect of Transvascular Fluid Exchange for Nonlinear, Biphasic Analyses of Flow-Controlled Infusion in Brain

2011 ◽  
Author(s):  
Joshua H. Smith ◽  
Kathleen A. Starkweather ◽  
José Jaime García
Keyword(s):  
Interstitial Fluid ◽  
Fluid Pressure ◽  
Therapeutic Agents ◽  
Constant Flow ◽  
Convection Enhanced Delivery ◽  
Fluid Exchange ◽  
Nonlinear Variation ◽  
Biphasic Model ◽  
Constant Flow Rate ◽  
Nonlinear Stress

Convection-enhanced delivery (CED) is a means to deliver therapeutic agents directly into brain tissue. Since CED often results in a rather significant interstitial fluid pressure, it is possible that infusions could result in a loss of fluid to the vasculature. While previous studies have included the effects of transvascular fluid exchange, they did so under the assumption of rigidity of the tissue [1, 2] or without considering its effect on the transport of the infused agent [3]. Recently, we proposed a spherical, biphasic model for constant flow-rate infusions that considers nonlinear stress-strain curves under finite deformation and nonlinear variation of hydraulic conductivity with deformation [4]. We have incorporated the effect of transvascular fluid exchange into this model and have studied the implications of variations in the vascular permeability, which may be of interest for improving drug delivery by CED.

A Biphasic Hyperelastic Model for Analysis of Fluid Transport in Brain Tissue

2008 ◽  
Author(s):  
Joshua H. Smith ◽  
Jose Jaime García
Keyword(s):  
Hydraulic Conductivity ◽  
Brain Tissue ◽  
Fluid Transport ◽  
Solid Phase ◽  
Finite Deformations ◽  
Positive Pressure ◽  
Convection Enhanced Delivery ◽  
Nonlinear Variation ◽  
Nonlinear Stress ◽  
Hyperelastic Model

Poroelastic or biphasic models have been used to study hydrocephalus [1] and the fluid transport that occurs during positive pressure infusion, also called convection enhanced delivery [2,3]. Each of the studies is limited by the assumption of linear elasticity of the solid phase. Nonlinear stress-strain curves under finite deformations have been documented for brain tissue under tension [4] and compression [5]. The nonlinear variation of hydraulic conductivity with strain has also recently been taken into account [1,3] and this effect has been deemed to play an important role in both the mechanics of the tissue and the associated fluid transport.

A Biphasic Viscoelastic Constitutive Model for Brain Tissue

2019 ◽  
Author(s):  
Mohammad Hosseini Farid ◽  
Mohammadreza Ramzanpour ◽  
Mariusz Ziejewski ◽  
Ghodrat Karami
Keyword(s):  
Constitutive Model ◽  
Brain Tissue ◽  
Mechanical Response ◽  
Solid Phase ◽  
Saturated Porous Medium ◽  
Bovine Brain ◽  
Coefficient Of Determination ◽  
Solid Matrix ◽  
Biphasic Model ◽  
Viscoelastic Constitutive Model

Abstract In this study, a rate-dependent biphasic model will be introduced to account for phenomenological behavior of brain tissue. For this purpose, a poro-hyper viscoelastic constitutive model is developed. The tissue is treated as a fluid-saturated porous medium, modeled as biphasic matter constituting of a solid matrix and interstitial liquids fill the porous spaces. The interactions between the two phases are assumed to be governed by Darcy’s law. This suggested model is calibrated with the experimental results of the bovine brain tissue, tested under high deformation rates (10, 100, 1000 mm/sec). The model will successfully take care of the detailed mechanical responses for solid and fluid phases, and their contributions to morphological behavior of this biological tissue. The material parameters of the model have been examined to agree well (R2 ≥ 0.96, where R is the coefficient of determination) with various deformation rates. In addition to representing the complete mechanical response and deformation of the solid phase, this biphasic model demonstrates the flow and diffusion of the liquid through the tissue networks.

scholarly journals DDRE-21. PNOC015: PHASE 1 STUDY OF MTX110 DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PREVIOUSLY TREATED WITH RADIATION THERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii66-ii66
Author(s):  
Sabine Mueller ◽  
Cassie Kline ◽  
Javier Villanueva-Meyer ◽  
Carly Hoffman ◽  
Shannon Raber ◽  
...  
Keyword(s):  
Phase 1 ◽  
Volume Ratio ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Convection Enhanced Delivery ◽  
Catheter Position ◽  
Pharmacodynamic Effects ◽  
Distribution Volume Ratio ◽  
Previously Treated ◽  
Grade 3

Abstract OBJECTIVE To determine safety and distribution of MTX110 delivered by CED in newly diagnosed DIPG patients. METHODS DIPG patients (3–21 years) were enrolled after radiation. CED of MTX110 combined with gadoteridol was completed based on dose levels (DL) (30–90 µM with volumes ranging from 3 cc (single dose) to 2 consecutive doses of 6 cc; total number of DL=7). Catheter position was chosen to maximize tumor coverage. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4–8 weeks if tolerated. Quality of life (QOL) assessments using PedsQL Generic Core and Brain Tumor modules were obtained at baseline (n=5), 3-months (n=3), and end of therapy (n=2). Single-cell RNA sequencing and analysis of histone modifications was performed to assess pharmacodynamic effects on DIPG cells. RESULTS Between May 2018-Dec 2019, 6 patients were enrolled (median age 8 years, range 5–21). Dose limiting toxicities included: grade 3 gait disturbance (DL7; cycle 1); grade 3 muscle weakness/vagus nerve disorder (DL5; cycle 4) and grade 2 intolerable dysphagia (DL7; cycle 4). Twelve CED procedures were completed at DL7 and repeated cycles ranged from 2 to 7. Infusion to distribution volume ratio was approximately 1:3.5. There were no significant changes in self-reported QOL. Parent ratings of patients’ worry (p = 0.04) and overall QOL (p = 0.03) significantly decreased at 3-months. CONCLUSION Repeat CED of MTX110 at the highest dose is tolerable. Tissue concentrations are likely to be substantially higher compared to oral dosing. Pharmacodynamic effects will be presented.

Sensitivity of Thermal Transport and Phase-Change in Thin Porous Layers to the Distribution of the Solid Matrix

2013 ◽  
Author(s):  
Vinaykumar Konduru ◽  
Ezequiel Medici ◽  
Jeffrey S. Allen
Keyword(s):  
Fuel Cell ◽  
Mass Transport ◽  
Polymer Electrolyte ◽  
Solid Phase ◽  
Polymer Electrolyte Membrane ◽  
Operating Conditions ◽  
Transport Layer ◽  
Solid Matrix ◽  
High Water Content ◽  
Electrolyte Membrane

Understanding the water transport in the Porous Transport Layer (PTL) is important to improve the operational performance of polymer electrolyte membrane fuel cells (PEMFC). High water content in the PTL and flow channel decreases the transport of the gas reactants to the polymer electrolyte membrane. Dry operating conditions result in increased ohmic resistance of the polymer electrolyte membrane. Both cases result in decreased fuel cell performance. Multi-phase flow in the PTL of the fuel cell is simulated as a network of pores surrounded by the solid material. The pore-phase and the solid-phase of the PTL are generated by varying the parameters of the Weibull distribution function. In the network model, the mass transfer takes place in the pore-phase and the bulk heat transfer takes place in the both the solid-phase and liquid phase of the PTL. Previous studies have looked at the thermal and mass transport in the porous media considering the pore size distribution. In the present study, the sensitivity of the thermal and mass transport to the different arrangements of the solid-phase is carried out and the effect of different solid-phase distributions on the thermal and liquid transport in PTL of PEM fuel cell are discussed.

Assessment of an Exponential Scaling Relationship for Backflow Length in Brain Tissue

2013 ◽  
Author(s):  
Alejandro Orozco ◽  
Joshua H. Smith ◽  
José J. García
Keyword(s):  
Large Deformations ◽  
Solid Phase ◽  
Axial Flow ◽  
External Boundary ◽  
Fluid Viscosity ◽  
Convection Enhanced Delivery ◽  
Annular Gap ◽  
Scaling Relationship ◽  
Infinitesimal Deformations ◽  
The Brain

Convection enhanced delivery is a protocol to deliver large volumes of drugs over localized zones of the brain for the treatment of diseases and tumors. Brain infusion experiments at higher flow rates showed backflow, in which an annular zone is formed outside the catheter and the infused drug preferentially flows toward the surface of the brain rather than through the tissue in the direction of the area targeted for delivery. The foundational model of Morrison et al. [1] considered the deformation of the tissue around the external boundary of the catheter, the axial flow in the annular gap formed around the cannula, and the radial flow from this annular region into the porous tissue in the development of an exponential correlation for backflow length L: (1)L∝Q0.6R0.8rc0.8G-0.6μ-0.2, where Q is the infusion flow rate, R is a tissue hydraulic resistance, rc is the catheter radius, G is the tissue shear modulus, and μ is the fluid viscosity. However, this formula was derived under some limiting assumptions, such as considering the solid phase of the infused tissue as a linearly elastic material under infinitesimal deformations, whereas mechanical testing has shown large deformations under physiological loadings [2, 3].

scholarly journals ATIM-06. TREATMENT OF RECURRENT/REFRACTORY (R/R) ANAPLASTIC ASTROCYTOMA (AA, WHO GRADE 3) PATIENTS WITH ANTI-TGFß2 RNA THERAPEUTIC OT-101 VERSUS TEMOZOLOMIDE IS ASSOCIATED WITH IMPROVED OVERALL SURVIVAL

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi2-vi2
Author(s):  
Fatih Uckun ◽  
Sanjive Qazi ◽  
David Nam ◽  
Larn Hwang ◽  
Vuong Trieu
Keyword(s):  
Overall Survival ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Clinical Results ◽  
P Value ◽  
Convection Enhanced Delivery ◽  
Chi Square ◽  
Who Grade ◽  
Exact Test

Abstract BACKGROUND OT-101 is a first-in-class RNA therapeutic designed to disrupt the immunosuppressive action of TGFß2. During Phase 1 clinical trials, OT-101 induced partial responses in R/R AA patients. We now report our clinical results from a randomized Phase IIB study (NCT00431561) that further evaluated its single agent activity in R/R AA patients in side-by-side comparison with the standard chemotherapy drug temozolomide (TMZ). METHODS OT-101 was administered via high-flow microperfusion with an intratumoral catheter using a convection enhanced delivery (CED) system. 26 AA patients (12: 2.5 mg/cycle; 14: 19.8 mg/cycle) received 7-day cycles of OT-101 every other week via continuous infusion for 4–11 cycles. Response determinations were based on central review of MRI scans by an independent review committee according to standard as well as modified McDonald criteria. 11 patients in the active control arm were treated with TMZ (150–200 mg/m2, 5 days/28-day cycles x up to 6 treatment cycles). Standard statistical methods were applied for the analysis of data. RESULTS 14 of 26 patients (53.8%) treated with 4–11 cycles of OT-101 had either a CR (N=2) or PR (N=12) as their best overall response. The average time until 99% reduction of their tumor volumes ranged from 9.9 to 115.4 (median: 23.7) months. In contrast, only 1 of 10 evaluable patients (10%) treated with TMZ achieved an objective response which was a PR (Fisher’s exact test, 2-tailed, P-value = 0.0002). The median overall survival (OS) was 1154 days (95% CI: 811 - >1743) for the OT-101 group and 590 days (95% CI: 287 - >1137) days for the TMZ group (Log Rank Chi Square = 7.55, P-value = 0.006). CONCLUSION Our results confirm and extend previous studies and provide early evidence that the anti-TGFß2 RNA therapeutic OT-101 is at least as active as TMZ in salvage therapy of R/R AA patients.

Sign in / Sign up

Export Citation Format

Share Document