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.

3D modelling of drug-coated balloons for the treatment of calcified superficial femoral arteries

“…From the findings on the impact of different tissue composition on drug transport, and in accordance with previous literature on DCB computational modelling [ 15 , 16 , 18 ], marked differences in terms of free and bound concentrations were found between the regions Ω HEAL and Ω CALC . These results reflected the difference in terms of effective drug diffusivity, which was 4 orders of magnitude lower in the diseased region than in the healthy one, and the lower maximum binding sites density [ 21 ].…”

“…The model developed here is characterized by a wide versatility that, for example, could also allow replacement of the idealized geometry with a patient-specific geometrical model (e.g. reconstructed from clinical images as previously performed on 2D sections [ 16 ]), with the final aim of exploring personalized DCB applications. Furthermore, this 3D setting also enables the integration of structural simulations of DCB application, which may provide realistic values of the pressure gradient across the vessel wall to facilitate the realistic incorporation of interstitial flow.…”

Understudied factors in drug‐coated balloon design and evaluation: A biophysical perspective

“…Several studies have investigated the role of the heterogeneous atherosclerotic lesion on the eventual efficacy of the therapy. 66 , 67 , 68 In a 2013 study, computational modeling was performed to explore the pharmacokinetics of zotarolimus as a therapeutic agent instead of paclitaxel, the drug used in almost every other study. 21 Additionally, Kolandaivelu et al presented a supervised machine learning framework, using drug coated balloons as an exemplary scenario (Figure 6 ), to process data generated from coarse meshes to predict results derived from highly‐refined meshes – thereby drastically increasing the efficiency in the computational modeling workflow.…”

Theoretical modeling of endovascular drug delivery into a multilayer arterial wall from a drug-coated balloon

“…Numerical studies are typically computationally expensive and make a number of (different) assumptions to enable solutions to be obtained in a reasonable time frame. Drug delivery from the DCB is typically modeled as either a constant concentration for a finite time [11] or a timedependent flux [6][7][8][9][10]. All of the aforementioned numerical models assume that drug is transported through the arterial wall due to diffusion: only two models [8,9] account for advective transport due to the known pressure gradient across the arterial wall.…”

“…Drug delivery from the DCB is typically modeled as either a constant concentration for a finite time [11] or a timedependent flux [6][7][8][9][10]. All of the aforementioned numerical models assume that drug is transported through the arterial wall due to diffusion: only two models [8,9] account for advective transport due to the known pressure gradient across the arterial wall. Drug binding is dependent on the physio-chemical properties of the particular drug and is handled in different ways in these models, ranging from linear reversible binding kinetics through to multiple phases of nonlinear reversible binding [12].…”