Drug targeting investigation in the critical region of the arterial bypass graft

Highlights

• Challenges of the particle targeting in the bypass graft anastomosis.

• Effect of the flow structure on particles deposition, in the main recirculation region.

• Recirculation region increases the particle near-wall residence time.

• Particles deposition are directly correlated with the flow structure.

• Particle accumulation induces changes of the flow field in the graft.

Abstract

Magnetic targeting is a non-invasive strategy to improve treatment efficacy for graft intimal hyperplasia (the leading cause of the arterial bypass graft failure). The present study aims are to investigate the possibility of MPs retention in the bypass graft anastomosis region where IH are developed after surgical intervention and quantify the particles accumulation function of the position of the external magnetic field. In this study iron (Fe) particles with 10 μm in size were used to model the magnetic carrier mixed in the glycerol-water solutions. The 10 μm diameter iron particle was used only to model the magnetic carrier in experimental investigation (not intended for clinical use), to demonstrate the feasibility of the particle targeting. Magnetic fields are generated by NdFeB external magnet. Positioning permanent magnet near to the diseased area resulted in a deviation of the injected ferromagnetic particles within the blood flux and their capture onto the wall of the bypass graft test section. To increase the accumulation of the particles in the targeted region, it is critical to understand the effect of the flow structure on particle deposition, namely interaction between the instabilities formed in the primary vortex of the anastomosis region. The results presented in this paper, put in evidence the blood constituents migrations to the artery wall for the specific flow pattern (through used iron particles), and demonstrate the feasibility of the magnetic drug targeting as a potential alternative method for effective treatment of the bypass graft intimal hyperplasia.

Introduction

Arterial or vein bypass grafts with single proximal and multiple distal anastomoses are often used in patients undergoing coronary artery bypass graft (CABG) surgery [1].

Bypass graft remodeling is a complex process involving hemodynamic and biological factors. Following CABG surgery, bypass graft failures are classified either as early (cause of graft failure is thrombosis) or late (cause is the neointimal hyperplasia – IH).

Many data from the literature indicate that in the anastomosis configuration, the IH occurs preferentially around the suture line, the toe, and the heel regions. Change of the hemodynamic conditions after surgical intervention induce a change in the flow pattern. This changes in flow pattern have directly correlated with the migration of the wall shear stress value in the pathologic range [2], [3], [4].

For example, one of the main conclusions of the PREVENT IV trial (PREVENT-IV was a phase-3, multicenter, randomized, double-blind, trial to prevent neointimal hyperplasia and vein bypass graft failure). This conclusion refers to the additional studies to better understand the most appropriate conduit of the flow pattern to improve long-term graft patency and clinical outcome of patients undergoing CABG surgery [5].

Magnetic targeting is an attractive non-invasive strategy to improve treatment efficacy for graft intimal hyperplasia. In the current practices, this remains a challenge, until both, techniques and used drugs achieve some desired characteristics like drug durability, drug non-toxicity and drug release in a controlled manner [6], [7], [8].

Our previous work was focused on two distinct directions, namely to the potential application of the magnetic drug targeting for treatment of the intimal hyperplasia in the arterial bypass graft [9], and to investigate and analyze the blood hydrodynamics in the bypass graft anastomosis region for different type of graft geometry (straight and helical geometries) [10], [11].

The post-interventional natural behavior of the bypass graft differs significantly from native vessels inducing higher risk for restenosis. Loss of the graft patency and the risks of repeat surgery are not negligible aspects for the long-term bypass graft evolution. In the current medical practices in the majority of case, percutaneous intervention is the preferred therapeutic modality for treatment of the graft failure (involving stent placement, bare-metal stents – BMS or drug-eluting stents – DES) [12]. Unfortunately, percutaneous intervention is associated with a high rate of the major adverse cardiac event irrespective of the implanted stent type (restenosis and thrombosis) [13].

Traditional local delivery systems of the drug (like drug-eluting stents) have been shown to lack sustained delivery and adverse the event. Therefore, magnetic drug targeting represents a potential alternative for prolonged local delivery of therapeutic agents [12].

For example, Pislaru et al. [14] investigated endothelialization of the synthetic vascular grafts (8 mm diameter Dacron grafts) using superparamagnetic microspheres (SPMs) (0.9 mm diameter, coated iron oxide particle) in the presence of the magnetic force. Authors conclude that endothelial cells loaded with SPMs are rapidly captured and retained on the Dacron graft surface under pulsatile flow conditions.

The present study aims, are to investigate the possibility of the magnetic particles (MPs) retention in the realistic post-surgical bypass graft anastomosis region (30-degree bypass graft angle) and quantify the particles accumulation, function of the position of the external magnetic field.

Because flow velocity in the circulatory system is not a controllable parameter, the dependence of magnetic control efficiency on flow velocity determines the size of blood vessels in which drug targeting is practical. We assume steady flow but use realistic mean velocity values for blood flow in the artery. The analysis is not meant to accurately model magnetic drug targeting in the artery (particles sticking to vessel walls both in proximal and distal sections of the targeted region), but rather to find realistic ranges for a set of parameters that will be used in further simulations and experiments.