In silico investigation to optimize the convection-enhanced diffusion profile with directed extraction

Optimizing drug delivery to brain tumors requires knowledge of momentum transport and molecular diffusion within the interstitial fluid of normal and tumor tissue in the central nervous system (CNS). The delivery method, tissue material properties, individual-specific interstitial fluid flow, and molecular drug properties all impact drug distribution. Convection-enhanced delivery (CED) can deliver drugs to the CNS by helping to bypass the blood-brain barrier (BBB). Improved modeling of CED-mediated drug distribution may help optimize the tumor area covered by the infused drugs. Moreover, rational multi-catheter systems could empower concurrent recovery of pharmacodynamic biomarkers indicative of therapeutic activity within the tumor tissue. Toward this goal, finite element methods (FEM) tools, such as COMSOL Multiphysics, can simulate molecular distribution inside specific predefined shapes and porous material properties. While most CED literature leverages a single catheter to deliver the drug to the tumor, adding extraction catheters could enable biomarkers and spatially-directed fluid convection recovery. We leveraged COMSOL Multiphysics to perform a computational study simulating CED with one or two extraction catheters perturbing the concentration profile over the region of interest. We evaluate volumetric drug distribution across relevant variables by varying the distance between the infusion and extraction catheters, flow rates, and drug diffusivity. We also validated our in silico results with in vitro agarose gel models, a matrix widely used to simulate diffusion within brain tissue. This in silico simulation system can be applied to studies spanning therapeutic local drug delivery and early phase in situ pharmacodynamic drug testing trials within live human and engineered tissues.