A multi-scale FE model for convective-diffusive drug transport within tumor and large vascular networks

Abstract Mass transport within an organ occurs through networks of blood vessels and surrounding tissue. This convective–diffusive transport is a very complex process which spans several different scales, from nano- to micro- to macro-scale. The blood vessel network is usually very intricate and irregular with respect to size and geometry, with mass transport being directly coupled to the neighboring tissue. Due to such complexity, development of a comprehensive transport model remains a challenge. The primary focus of this study is on solid tumors which are extremely complex autonomous systems with regard to mass transport. Additionally, tumors develop various biological barriers which hinder effective delivery of drug molecules into cancer tissue. We introduce a multi-scale tumor transport model where larger tumor vessels are modeled by simple 1D finite elements, whereas the capillary bed is replaced by equivalent 3D continuum finite elements. The model couples convective–diffusive transport within capillaries (fluid domain) and tissue (solid domain). These fluid and solid domains are connected by fictitious 1D elements. The proposed tumor model incorporates the imaged inhomogeneous tumor tissue and blood vessel network—from larger vessels to the smallest capillary bed. The tumor model is also applicable to transport within organs, such as the mouse brain, which is presented here as an example.

[1]  Michael Höpfner,et al.  Structural Adaptation and Heterogeneity of Normal and Tumor Microvascular Networks , 2009, PLoS Comput. Biol..

[2]  A. Katchalsky,et al.  Thermodynamic analysis of the permeability of biological membranes to non-electrolytes. , 1958, Biochimica et biophysica acta.

[3]  Robert A. Freitas,et al.  Nanomedicine, Volume I: Basic Capabilities , 1999 .

[4]  A Ziemys,et al.  Interfacial effects on nanoconfined diffusive mass transport regimes. , 2012, Physical review letters.

[5]  Rebecca J. Shipley,et al.  Multiscale Modelling of Fluid and Drug Transport in Vascular Tumours , 2010, Bulletin of mathematical biology.

[6]  Spencer J. Sherwin,et al.  Computational modelling of 1D blood flow with variable mechanical properties and its application to the simulation of wave propagation in the human arterial system , 2003 .

[7]  M. Ferrari,et al.  Transport Phenomena: Computational Models for Convective and Diffusive Transport in Capillaries and Tissue , 2015 .

[8]  Rakesh K. Jain,et al.  Transport of molecules across tumor vasculature , 2004, Cancer and Metastasis Reviews.

[9]  R. Jain,et al.  Measurement of capillary filtration coefficient in a solid tumor. , 1991, Cancer research.

[10]  C. M. Rodkiewicz,et al.  On the application of a constitutive equation for whole human blood. , 1990, Journal of biomechanical engineering.

[11]  A. Pries,et al.  Microvascular blood viscosity in vivo and the endothelial surface layer. , 2005, American journal of physiology. Heart and circulatory physiology.

[12]  George M Yousef,et al.  Microvascular density as an independent predictor of clinical outcome in renal cell carcinoma: an automated image analysis study , 2012, Laboratory Investigation.

[13]  A. Pries,et al.  Blood flow in microvascular networks. Experiments and simulation. , 1990, Circulation research.

[14]  Y. Fung Stochastic flow in capillary blood vessels. , 1973, Microvascular research.

[15]  B. Zweifach,et al.  Network analysis of microcirculation of cat mesentery. , 1974, Microvascular research.

[16]  P. Gullino,et al.  Diffusion and convection in normal and neoplastic tissues. , 1974, Cancer research.

[17]  F. Smith,et al.  Fluid flow through various branching tubes , 2003 .

[18]  Milos Kojic,et al.  Simple concepts in computational mechanics - do they really work? , 2013 .

[19]  A Ziemys,et al.  A multiscale MD-FE model of diffusion in composite media with internal surface interaction based on numerical homogenization procedure. , 2014, Computer methods in applied mechanics and engineering.

[20]  Patrick Nicolas,et al.  Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. , 2004, Cancer research.

[21]  Ananth Annapragada,et al.  Evaluation of tumor microenvironment in an animal model using a nanoparticle contrast agent in computed tomography imaging. , 2011, Academic radiology.

[22]  R K Jain,et al.  Extravascular diffusion in normal and neoplastic tissues. , 1984, Cancer research.

[23]  T. Woodcock,et al.  Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. , 2012, British journal of anaesthesia.

[24]  A. Annapragada,et al.  Cerebral Vascular Leak in a Mouse Model of Amyloid Neuropathology , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[25]  Mauro Ferrari,et al.  Hierarchical modeling of diffusive transport through nanochannels by coupling molecular dynamics with finite element method , 2011, J. Comput. Phys..

[26]  R. Jain,et al.  Effect of red blood cell rigidity on tumor blood flow: increase in viscous resistance during hyperglycemia. , 1991, Cancer research.

[27]  Axel R. Pries,et al.  Blood Flow in Microvascular Networks , 2011 .

[28]  Y. Fung Blood flow in the capillary bed. , 1969, Journal of biomechanics.

[29]  A. Katchalsky,et al.  A Physical Interpretation of the Phenomenological Coefficients of Membrane Permeability , 1961, The Journal of general physiology.

[30]  J. Fitz-Gerald Implications of a theory of erythrocyte motion in narrow capillaries. , 1969, Journal of applied physiology.

[31]  F. Yuan,et al.  Nonlinear Dependence of Hydraulic Conductivity on Tissue Deformation During Intratumoral Infusion , 2006, Annals of Biomedical Engineering.

[32]  N. Kojic,et al.  Computer Modeling in Bioengineering: Theoretical Background, Examples and Software , 2008 .

[33]  R. Jain,et al.  Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions. , 1991, Cancer research.

[34]  Masanori Tanaka,et al.  Microvessel Morphology and Vascular Endothelial Growth Factor Expression in Human Colonic Carcinoma With or Without Metastasis , 2002, Laboratory Investigation.

[35]  Mauro Ferrari,et al.  A 1D pipe finite element with rigid and deformable walls , 2014 .

[36]  R. Carr,et al.  Influence of vessel diameter on red cell distribution at microvascular bifurcations. , 1991, Microvascular research.

[37]  R K Jain,et al.  Geometric resistance to blood flow in solid tumors perfused ex vivo: effects of tumor size and perfusion pressure. , 1989, Cancer research.

[38]  C. Song Effect of local hyperthermia on blood flow and microenvironment: a review. , 1984, Cancer research.

[39]  R. Jain,et al.  Microvascular permeability of normal and neoplastic tissues. , 1986, Microvascular research.

[40]  Y. Fung,et al.  Modeling experiments of a single red blood cell moving in a capillary blood vessel. , 1969, Microvascular research.

[41]  Mauro Ferrari,et al.  Capillary-wall collagen as a biophysical marker of nanotherapeutic permeability into the tumor microenvironment. , 2014, Cancer research.

[42]  R. Jain,et al.  Viscous resistance to blood flow in solid tumors: effect of hematocrit on intratumor blood viscosity. , 1989, Cancer research.

[43]  S. Skinner,et al.  Microvascular architecture of experimental colon tumors in the rat. , 1990, Cancer research.

[44]  Kambiz Vafai,et al.  The role of porous media in modeling flow and heat transfer in biological tissues , 2003 .

[45]  Mauro Ferrari,et al.  Polymer Nanoparticles Encased in a Cyclodextrin Complex Shell for Potential Site‐ and Sequence‐Specific Drug Release , 2014 .

[46]  Mauro Ferrari,et al.  Mechanisms of reduced solute diffusivity at nanoconfined solid-liquid interface , 2013 .

[47]  Andrew J. Pullan,et al.  An Anatomically Based Model of Transient Coronary Blood Flow in the Heart , 2002, SIAM J. Appl. Math..

[48]  R K Jain,et al.  Determinants of tumor blood flow: a review. , 1988, Cancer research.

[49]  J. D. Hellums,et al.  Blood flow in capillaries. , 1973, Microvascular research.