Research articlesDrug targeting investigation in the critical region of the arterial bypass graft
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.
Section snippets
Experimental setup
Experimental setup used for particle trapping is shown in Fig. 1 (this setup described in detail in our previous work [9]).
Magnetic particles were injected into the main flow upstream of the bypass graft inlet section. The syringe pump was used to push the carrier fluid into the main flow. Injecting the particles (suspension) at a distance of 2D (D – graft diameter) before the graft inlet section, facilitated dispersion of them in the fluid flow stream at the entrance of the graft.
The
Magnetic targeting
The magnetic drug targeting (MDT) involves exposure of the area of interest (targeted region) to an externally applied magnetic field, followed by the administration of magnetic particles. After administration (injection during a specific time), particles were delivered to the area of interest by the fluid flow.
The significant limitations of the MDT consist in low retention of the MNP’s due to the reduced value of the magnetic force comparatively with the hydrodynamic force acting in the
Flow hydrodynamics
Real human arteries are tortuous and induce secondary flows, defined as velocity components that are not parallel to the local tube axis. From the arterial flow point of view, it is essential to determine whether secondary flows change the shear-dependent viscosity variation.
During the flow through the bypass graft, the generated inertial and circumferential forces imposed a change in fluid flow direction. As can see in Fig. 8A, downstream to the stagnation point, a strong double helicoidal
Clinical perspective
In the real case of blood flow in the arteries, flowing blood components (red blood cells, leukocytes, platelets) migrate inward from the wall at a rate that increases with cell size and cell deformability [34]. Practically, it has been demonstrated that the tendency of the constituents of the blood to migrate toward the center of a perfused vessel, in decreasing order, is as follows: red cell aggregates, leukocytes, single red blood cells, and platelets (in decreasing order of the cell size)
Conclusions
Based on experimental results, the following general features of the flow field can be identified:
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from the graft tube, a core fluid enters in the anastomosis junction and travels towards on the bed of the host tube;
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presence of the stagnation point, split flow structure into forwarding and retrograde components. Both structures induce a large near-wall velocity fluctuation in the anastomosis region;
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strong recirculation region is developed between main flow jet and occluded part of the proximal
Acknowledgments
For S.I. Bernad this work was partially supported by the CFATR/LHC 2016–2020 research programme, and partially by a mobility grant of the Romanian Ministry of Research and Innovation, CNCS-UEDISCDI, project number PN-III-P1-1.1-MC-2018-0234. For E.S. Bernad and L. Vekas this work was supported by the grant of the Romanian National Authority for Scientific Research and Innovation, CNCS/CCCDI – UEFISCDI, project number PN-III-P2-2.1-PED-2016-0293.
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