Computational methods for predicting drug transport in anisotropic and heterogeneous brain tissue

Linninger, Andreas A.; Somayaji, Mahadevabharath R.; Erickson, Terrianne; Guo, Xiaodong; Penn, Richard D.

doi:10.1016/j.jbiomech.2008.04.025

Cited by 87 publications

(77 citation statements)

References 62 publications

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“…Further, groups have used computational analyses based on diffusion tensor imaging (an MRI technique that measures the restricted diffusion of water in nervous system tissues and measures axonal alignment) that account for preferential fluid flow and diffusion transport directions, which can vary in the extracellular spaces within complex nervous system anatomical structures. 39,40,55,89,101 …”

Section: Biophysical Principles Of Convective Flowmentioning

confidence: 99%

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Convection-enhanced delivery to the central nervous system

Lonser

Sarntinoranont

Morrison

et al. 2015

JNS

187

148

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Based on the rapid progression in understanding the precise pathobiology underlying various neurological diseases, a number of promising new putative therapeutics have been developed for specific disorders that have been ineffectually treated or are not currently treatable. While these agents have been successful in reversing disease-related pathology in vitro and/or in animal models, they have not been successfully translated into clinically effective therapies. One of the largest obstacles to the successful conversion of putative therapeutics into effective treatments is the inability to deliver these agents past the CNS blood-brain barrier (BBB) in a reliable, targeted, and homogeneous way using currently available approaches for drug delivery, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation. 6,15,47,67,80 To surmount the limitations of available CNS drug delivery techniques, targeted direct perfusion of regions of the nervous system using the convection-enhanced delivery (CED) of infusate is increasingly used in research models of neurological disease and in clinical trials to treat neurological disorders. Because infusate is driven by a hydrostatic pressure differential (bulk flow), 7,67 CED can be used to bypass the BBB and distribute putative therapeutics to targeted regions. Further, convective bulk flow properties allow for homogeneous and reproducible perfusion of variably sized regions of the nervous system using compounds with a wide range of molecular weights. The development of co-infused surrogate imaging tracers now permits noninvasive real-time monitoring of convective delivery. We review the biophysical principles of convective flow and the technology, properties, and clinical applications of convective delivery in the CNS. Biophysical Principles of Convective FlowWithin the extracellular space of the CNS, fluids and agents move either by diffusion or by bulk flow. Diffusive flux (J) depends on the concentration gradient (∇C, where ∇ is the gradient operator), as stated by Fick's law, J = -D∇C, where tissue diffusivity (D) is highly dependent on the molecular weight of the molecule. Unfortunately, effective diffusion times are long for macromolecular therapeutic agents, and transport depends on large concentration gradients, often requiring unacceptably high Convection-enhanced delivery (CED) is a bulk flow-driven process. Its properties permit direct, homogeneous, targeted perfusion of CNS regions with putative therapeutics while bypassing the blood-brain barrier. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues. The potential advantages of CED in the CNS over other currently available drug delivery techniques, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation, have led to its application in research studies and clinical trials. The authors review t...

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Section: Biophysical Principles Of Convective Flowmentioning

confidence: 99%

“…The ability to accurately predict optimal cannula placement and the capability to precisely anticipate infusate distribution based on preinfusion CT and MRI planning will be important for clinical trial development. 40,55,56,89,102 references…”

Section: Predictive Modeling For Clinical Applicationmentioning

confidence: 99%

Convection-enhanced delivery to the central nervous system

Lonser

Sarntinoranont

Morrison

et al. 2015

JNS

187

148

View full text Add to dashboard Cite

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“…Therefore, in order to make the models truly patient-specific, local tissue properties would have to be defined and included. Diffusion tensor imaging (DTI) has previously been used for predicting heterogenous and anisotropic drug transport in the brain [15], and could be suitable for patient-specific diffusion simulations. DTI images have low resolution, however, and may not accurately represent local tissue properties within the millimeter range.…”

Section: Model Assumptions and Limitationsmentioning

confidence: 99%

“…The input parameters of this equation have been extensively evaluated for different parts of the brain [10]. Furthermore, the equation has been implemented using the finite element method (FEM) and finite volume discretization methods, in order to simulate and visualize movement of analytes in the brain [14,15].…”

Section: Introductionmentioning

confidence: 99%

A model for simulation and patient-specific visualization of the tissue volume of influence during brain microdialysis

Diczfalusy

Zsigmond

Dizdar

et al. 2011

Med Biol Eng Comput

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“…Fluid transport properties in different places of brain vary regionally with tissue composition. Transport properties, such as hydraulic conductivity and diffusivity, and fluid boundaries, have been found to have significant influence on CED distributions [2,[8][9][10]. Based on our ability to measure transport properties in CNS tissues, tissue regions are usually divided into gray matter (GM), WM, and CSF regions.…”

Section: Introductionmentioning

confidence: 99%

Voxelized Model of Brain Infusion That Accounts for Small Feature Fissures: Comparison With Magnetic Resonance Tracer Studies

Dai

Astary

Kasinadhuni

et al. 2016

Journal of Biomechanical Engineering

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Convection enhanced delivery (CED) is a promising novel technology to treat neural diseases, as it can transport macromolecular therapeutic agents greater distances through tissue by direct infusion. To minimize off-target delivery, our group has developed 3D computational transport models to predict infusion flow fields and tracer distributions based on magnetic resonance (MR) diffusion tensor imaging data sets. To improve the accuracy of our voxelized models, generalized anisotropy (GA), a scalar measure of a higher order diffusion tensor obtained from high angular resolution diffusion imaging (HARDI) was used to improve tissue segmentation within complex tissue regions of the hippocampus by capturing small feature fissures. Simulations were conducted to reveal the effect of these fissures and cerebrospinal fluid (CSF) boundaries on CED tracer diversion and mistargeting. Sensitivity analysis was also conducted to determine the effect of dorsal and ventral hippocampal infusion sites and tissue transport properties on drug delivery. Predicted CED tissue concentrations from this model are then compared with experimentally measured MR concentration profiles. This allowed for more quantitative comparison between model predictions and MR measurement. Simulations were able to capture infusate diversion into fissures and other CSF spaces which is a major source of CED mistargeting. Such knowledge is important for proper surgical planning.

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Computational methods for predicting drug transport in anisotropic and heterogeneous brain tissue

Cited by 87 publications

References 62 publications

Convection-enhanced delivery to the central nervous system

Convection-enhanced delivery to the central nervous system

A model for simulation and patient-specific visualization of the tissue volume of influence during brain microdialysis

Voxelized Model of Brain Infusion That Accounts for Small Feature Fissures: Comparison With Magnetic Resonance Tracer Studies

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