Effect of Interstitial Fluid Flow on Drug-Coated Balloon Delivery in a Patient-Specific Arterial Vessel with Heterogeneous Tissue Composition: A Simulation Study

Abstract

Angioplasty with drug-coated balloons (DCBs) using excipients as drug carriers is emerging as a potentially viable strategy demonstrating clinical efficacy and proposing additional compliance for the treatment of obstructive vascular diseases. An attempt is made to develop an improved computational model where attention has been paid to the effect of interstitial flow, that is, plasma convection and internalization of bound drug. The present model is capable of capturing the phenomena of the transport of free drug and its retention, and also the internalization of drug in the process of endocytosis to atherosclerotic vessel of heterogeneous tissue composition comprising of healthy tissue, as well as regions of fibrous cap, fibro-fatty, calcified and necrotic core lesions. Image processing based on an unsupervised clustering technique is used for color-based segmentation of a patient-specific longitudinal image of atherosclerotic vessel obtained from intravascular ultrasound derived virtual histology. As the residence time of drug in a stent-based delivery within the arterial tissue is strongly influenced by convective forces, effect of interstitial fluid flow in case of DCB delivery can not be ruled out, and has been investigated by modeling it through unsteady Navier-Stokes equations. Transport of free drug is modeled by considering unsteady advection-reaction-diffusion process, while the bound drug, assuming completely immobilized in the tissue, by unsteady reaction process. The model also takes into account the internalization of drug through the process of endocytosis which gets degraded by the lysosomes and finally recycled into the extracellular fluid. All the governing equations representing the flow of interstitial fluid, the transport of free drug, the metabolization of free drug into bound phase and the process of internalization along with the physiologically realistic boundary and initial conditions are solved numerically using marker and cell method satisfying necessary stability criteria. Simulated results obtained predict that faster drug transfer promotes rapid saturation of binding sites despite perivascular wash out and the concentrations of all drug forms are modulated by the presence of interstitial flow. Such premier attempt of its kind would certainly be of great help in the optimization of therapeutic efficacy of drug.

Keywords: Bound drug; Drug-coated balloon; Free drug; Image processing; Internalization; Interstitial flow; MAC method; Patient-specific lesion.