Prediction of convection-enhanced drug delivery to the human brain

Linninger, Andreas A.; Somayaji, Mahadevabharath R.; Mekarski, Megan; Zhang, Libin

doi:10.1016/j.jtbi.2007.09.009

Cited by 129 publications

(103 citation statements)

References 30 publications

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“…For IV and intratumour drug delivery, several distributed models have been described based on patient datasets [60][61][62][63]. To date, no such patient-specific models have been described in the context of IP chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Modelling drug transport during intraperitoneal chemotherapy

Steuperaert

Debbaut

Segers

et al. 2017

Pleura and Peritoneum

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Despite a strong rationale for intraperitoneal (IP) chemotherapy, the actual use of the procedure is limited by the poor penetration depth of the drug into the tissue. Drug penetration into solid tumours is a complex mass transport process that involves multiple parameters not only related to the used cytotoxic agent but also to the tumour tissue properties and even the therapeutic setup. Mathematical modelling can provide unique insights into the different transport barriers that occur during IP chemotherapy as well as offer the possibility to test different protocols or drugs without the need for in vivo experiments. In this work, a distinction is made between three different types of model: the lumped parameter model, the distributed model and the cell-based model. For each model, we discuss which steps of the transport process are included and where assumptions are made. Finally, we focus on the advantages and main limitations of each category and discuss some future perspectives for the modelling of IP chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Modelling drug transport during intraperitoneal chemotherapy

Steuperaert

Debbaut

Segers

et al. 2017

Pleura and Peritoneum

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“…2b). Concluding, the values obtained here are transferred into quantities which are used in the modelling approach, as it is shown in [3]. This leads to the full information of the inhomogeneous and anisotropic properties of the initial permeability K SI,n 0S , the initial diffusivity D D,n 0 and the fibre direction a S,n 0 (corresponding eigenvector of the largest eigenvalue) at each voxel.…”

Section: Inhomogeneous and Anisotropic Brain-tissue Characteristicsmentioning

confidence: 93%

Multiphasic modelling of human brain tissue for intracranial drug‐infusion studies

Wagner

Ehlers

2012

Proc Appl Math and Mech

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A direct intracranial infusion of a therapeutic solution into the extra-vascular space of human brain tissue is a promising medical application for the effective treatment of malignant brain tumours [1]. The advantage of this method, compared to an intra-vascular medication, is the targeted delivery with the circumvention of the blood-brain barrier (BBB), which prohibits the passing of therapeutic macro-molecules across the vascular walls into the brain parenchyma.The prediction of the resulting therapeutical distribution by a numerical simulation is challenging, since the spreading is affected by the complex nature of living brain tissue. For this purpose, a macroscopic continuum-mechanical model is established within the Theory of Porous Media (TPM), proceeding from a homogenisation of the underlying micro-structure [5]. The ternary four-component model consists of an elastically deformable solid skeleton (composed of tissue cells and vascular walls), which is perfused by two mobile but separated liquid phases, the blood and the overall interstitial fluid (treated as a real two-component mixture of the liquid solvent and the dissolved therapeutic solute). The strongly coupled solid-liquidtransport problem is simultaneously approximated in all primary unknowns using mixed finite elements (uppc-formulation) and consequently solved in a monolithic manner with an implicit time-integration scheme.This numerical investigation allows the computational study of several circumstances influencing the irregular distribution of infused drugs, as observed in clinical studies. Therefore, the microstructural perfusion characteristics in the extra-cellular space of the white-matter tracts are considered by a spatial diversification of the anisotropic permeability tensors, provided by Diffusion Tensor Imaging (DTI). Furthermore, Magnetic Resonance Angiography (MRA) enables the in vivo location of blood vessels within the brain tissue. Finally, the selection of appropriate material parameters has a crucial influence on the drug distribution profile and further occurring effects beyond. Motivation and introductionThe conventional treatment of brain tumour diseases makes use of radiotherapy, chemotherapy or the complete removal of a malignant tumour. However, these highly invasive therapies are often not successful and the life-expectancy after a medical finding remains poor. A promising modern treatment method, the so-called convection-enhanced drug delivery (CED), proceeds from a direct infusion of therapeutic agents into the extra-vascular space of the brain tissue in order to facilitate a targeted delivery and to bypass the restricting blood-brain barrier [1]. The aim of this work is to provide a simulation environment which allows relevant numerical studies on the complex drug-infusion process and, therefore, helps to enable the physicians in crucial decisions concerning several surgical issues.2 Extended multiphasic and multicomponent modelling approach for brain tissue The multicomponent structure of living human brain ti...

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“…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

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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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Prediction of convection-enhanced drug delivery to the human brain

Cited by 129 publications

References 30 publications

Modelling drug transport during intraperitoneal chemotherapy

Modelling drug transport during intraperitoneal chemotherapy

Multiphasic modelling of human brain tissue for intracranial drug‐infusion studies

Convection-enhanced delivery to the central nervous system

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