Modeling of Drug Release from Drug Eluting Stents employed in Coronary Artery

Sayan Bosea, Amitava Dattab, Ranjan Gangulyb, Moloy Banerjeea (Corresponding author)
a
Department of Mechanical Engineering, Future Institute of Engineering & Management, Sonarpur Station
Road, Kolkata-700150, INDIA
b
Department of Power Engineering, Jadavpur University, Salt Lake Campus, Kolkata-700098, INDIA

Email: moloy_kb@yahoo.com

Abstract:
To examine how administered dose and drug release kinetics control arterial drug uptake,
a model was created using principles of computational fluid dynamics and transient drug
diffusionconvection using the commercial CFD software package ANSYS FLUENT.
Convection due to blood flow had a minimal effect on the diffusion profile. After one
year, the polymer retains 3% of the drug in the polymer, while the remaining diffused
into the intima layer. Sensitivity analysis was also performed to determine which
parameters affect the diffusion profile. Varying the positioning of the stent, and thus, the
contact surface area of the stent to the intima layer, had an effect on the amount of drug
released to the intima. We conclude that computer modeling is an efficient and economic
way to estimate the diffusion of anti-cell proliferation drugs and its effects in preventing
re-constriction of coronary arteries following angioplasty treatment.

Keywords: drug-eluting stent, blood flow, diffusion, coronary artery, restenosis

1. Treatments history of cardiovascular disease:

A drug-eluting stent (DES) is a coronary stent placed into narrowed, diseased coronary
arteries that slowly releases a drug to block cell proliferation. This prevents fibrosis that,
together with clots (thrombus), could otherwise block the stented artery, a process
called restenosis. The stent is usually placed within the coronary artery by an
Interventional cardiologist during an angioplasty procedure. After several clinical trials it
showed that the DES are statistically superior to bare-metal stents (BMS) for the
treatment of native coronary artery narrowings, having lower rates of major adverse
cardiac events (MACE).
The first procedure to treat blocked coronary arteries was coronary artery bypass graft
surgery (CABG), wherein a section of vein or artery from elsewhere in the body is used
to bypass the diseased segment of coronary artery. In 1977, Andreas Grntzig introduced
percutaneous transluminal coronary angioplasty (PTCA), also called balloon angioplasty.
Each year, 800 000 angioplasty procedures are performed to treat plaque-clogged
coronary arteries. This procedure consists of inserting a meshed metal-wire stent
surrounding a balloon catheter into the coronary artery. The balloon is inflated to expand
and insert the stent into the arterial wall. The balloon-catheter is promptly removed while
the expanded stent provides structural support in the artery wall to relieve constriction.
However, in 15-30% of patients who undergo angioplasty, suffers from the restenosis in
which endothelial cell growth proliferates around the device as part of the bodys natural
wound-healing response. To address this problem, many leading biomedical companies,
such as Johnson & Johnson, Boston Scientific, and Medtronic, have developed drug-
eluting stents, which have proven to significantly reduce the rate of restenosis.
The first successful trials were of sirolimus-eluting stents. A clinical trial in 2002 led to
approval of the sirolimus-eluting Cypher stent in Europe in 2002. After a larger pivotal
trial (one designed for the purpose of achieving FDA approval), published in 2003, the
device received FDA approval and was released in the U.S. in 2003.
The Xience V everolimus eluting stent was approved by the FDA in July 2008 and has
been available in Europe and other international markets since late 2006. It is an
investigational device in Japan.

2. Introduction:
Arterial diseases like atherosclerosis are the leading causes of death in the industrialized
world. They may cause a reduction of the blood flow because of the narrowing or
occlusion of the affected arteries. Intravascular stents, which are small tube-like
structures, may be driven and expanded into the stenotic artery to restore blood flow
perfusion to the downstream tissues. Nowadays, stent implantation is a common
procedure with a high rate of success when compared with angioplasty alone [1, 2].
However, some limitations are still present and the major ones are those associated with
the in-stent restenosis process. When it occurs, the treated vessel may become blocked
again. It usually happens within the first 6 months after the initial procedure [3].
Different stages are involved in this process and they can be summarized, as reported by
Edelman and Rogers [4], as thrombosis, inflammation, proliferation and remodeling.
Many factors have been found to influence the degree of restenosis, such as the degree of
damaged endothelial cells and the depth of the injury [5,6], the type of stent expansion
(self or balloon expanding, [7]), the design of the stent [8] and the local fluid dynamics
[9,10]. The stent deployment inside an artery has many implications on the stresses and
deformations in the arterial wall and hence has an impact on the progression of in-stent
restenosis. Computational structural analysis has emerged in recent years to investigate
the mechanical response to angioplasty and stent placement in the arterial wall [11-17].
Recently, the introduction of drug eluting stents in interventional cardiology practice
seemed to bring bare-metal stenting to a rapid decline [18]. In the drug eluting stents a
polymeric matrix is added to the stent struts, loaded with a drug which is released after
the implant. Clinical trials [19, 20] showed a reduction of restenosis when a drug eluting
stent is used. However, research has still to be done to define the variables (i.e. strut
thickness and shape, pore sizes of the stent coating) of stent geometry influencing the
clinical outcome. Indeed, an effective release of the drug from the coating into the wall
depends on many factors, mainly the stent design, the drug and the coating type.
Recently, some computational works considered the convection-diffusion equations to
model the spatial and temporal distribution of drug concentration within the vessel wall
[21,22]. They demonstrated how numerical simulations are viable tools to study these
phenomena. However, to be effective they have to account properly for the expansion of
the struts and their interaction with the vascular wall. Indeed, these aspects influence the
outcome of the stenting procedure.
The present study aims at showing a possible methodology to investigate the drug elution
from a model of a coronary stent. Computational techniques were ideal for this work
because they enable rapid consideration of a range of drug doses and release kinetics
followed by precise monitoring of arterial drug deposition, distribution, and retention.

3. Methods:

3.1 Mathematical Model:

Drug transport was modeled using a 2-dimensional axi-symmetric transient model (Fig.
1). The luminal radius (R), 1.5 mm, was 5 times greater than the intima wall thickness. A
layer of adventitia is considered of thickness 0.7 mm on top of the intima layer. The axial
distance along the artery is chosen to be 10 mm, which is based on the fluid mechanic
entry length required to reach fully developed flow [23]. The strut and coating
dimensions were based upon representative dimensions of the CYPHER Sirolimus-
eluting Coronary Stent (Cordis Corporation, a Johnson & Johnson Company). The strut is
assumed to be fully embedded inside the intima layer.

Figure 1: Cross-section of a stent strut fully embedded in the arterial wall, which consists
of the intima and adventitia layer.

The blood flow was assumed steady. This was a necessary simplification, because the
pulsatility of blood at 1 Hz would have required a coupled solution of fluid mechanics
and mass transfer equations, rather than separate handling of these equations. Such a task
would have been computationally prohibitive, because the rapidly changing flow features
combined with the long duration of drug release would have increased the computational
task by 4 orders of magnitude. Thus, for an initial transient analysis, it was concluded that
the steady flow approximation would be sufficient to elucidate any potential role of local
fluid mechanics in transient drug delivery. Similar steady flow assumptions in coronary
arteries have been made in other similar computational studies to facilitate the coupled
study of local fluid mechanics and mass transport [24]. Subsequent studies focusing on
flow pulsatility may employ a modified computational approach to reduce the
computational burden and possibly combine the analysis with parallel experiments.
The blood was assumed Newtonian, because blood viscosity becomes shear-independent
for shear rates above 100 s1 [25] and Reynolds number above 100 [26], both of which
occur in a 3 mm diameter coronary artery with steady 100 cc/min blood flow. The fluid
mechanics were described using continuity and steady state NavierStokes equations as
follows:
.u 0 (1)
2
u.u p u (2)
Where, u is three dimensional velocity vector, is density of the blood, p is pressure,
is viscosity of blood (flow). The inlet profile, applied at entry to the lumen is a parabolic
fully developed velocity profile (Eq. 3).
r 2
u 2u 1 (3)
R
At the outlet of the lumen, zero gauge pressure is applied. All components of blood
velocity were zero at all solidfluid interfaces, which reflects the assumed impermeability
of the vessel to transmural convective flux and the finite blood viscosity that prevents
tangential blood flow at the vessel surfaces. The fluid mechanical blood properties and
volumetric flow rate were obtained from standard reference values [27].
Time-dependent drug transport within the coating, intima and adventitia layer is assumed
to occur solely via transient diffusion of drug (Eq. 46), which was reasonable based on
the sirolimus-eluting stent (CYPHER Sirolimus-eluting Coronary Stent, Cordis
Corporation) coating properties and its application process [28,29].
Cc 2 Cc 2 Cc
Dc 2 2 (4)
t z r
Cin 2Cin 2Cin
Din 2
(5)
t z r 2
Cad 2Cad 2Cad
Dad 2
(6)
t z r 2

The drug release from the stent to the lumen is modeled using a convection diffusion
equation, which can be written as follows:
Cb C C 2C 2C
vz b vr b Db 2b 2b (7)
t z r z r
The diffusivity through the drug polymer Dc , the intima layer Din , the blood Db and
the adventitia Dad were 1x10-7 mm2/s, 2.5x10-10 mm2/s, 1 mm2/s and 1x10-7 mm2/s
respectively.
The luminal inlet drug concentration was assumed zero (Eq. 8), which is valid because in
the convection dominated arterial lumen it is virtually impossible for drug to diffuse 5
mm in the direction opposing blood flow. The outlet of the vessel had an open boundary
condition (Eq. 9), because flowing blood carried solubilized drug downstream. Drug
transport between the tissue and blood was enabled using a continuity of flux condition
(Eq. 10-12) applied to the tissueblood and coat-tissue interface.
Cb 0 inlet (8)
Cb
0 (9)
z outlet

Cc C C C
Dc Din in and Dc c Din in (10)
z z r r
Cin Cb Cin Cb
Din Db and Din Db (11)
z z r r
C Cad C Cad
Din in Dad and Din in Dad (12)
z z r r

3.2 Numerical Model:

Commercially available geometry/mesh generation and computational fluid dynamics

software (Ansys Fluent) is used to apply the mathematical model. The geometry was
discretized into approximately 200,000 triangular mapped mesh elements (Fig. 2). The
mesh density is greater near the region just outside the drug polymer, where the greatest
change in drug concentration will occur. To ensure that the discretized geometry had
sufficient resolution to detect changes induced by model parameters, a mesh sensitivity
study was performed. Results show that doubling local mesh density resulted in less than
2% change in local and average arterial and coating drug concentrations. The discretized
geometry was imported into Fluent, a finite volume based software. Second order
discretization schemes were used for all velocities and concentration variables. The
momentum and continuity equations were solved iteratively using SIMPLEC algorithm
[30] for pressurevelocity coupling; the diffusionconvection equations were handled
with upwind differencing.

0.00015

0.0001
Y

5E-05

0.0048 0.00485 0.0049 0.00495 0.005 0.00505 0.0051 0.00515 0.0052

X

Figure 2: Discretized geometry.

4. Results and Discussions:
In this model we use a stent strut that was fully-embedded into the intimal tissue and
included two layers in the artery wall, namely the intima and adventitia, with different
diffusivities. Additionally, convection from the blood was modeled by solving the
convection-diffusion transport equation inside the lumen. Initial drug concentration at the
polymer media is assumed to be 1.
After almost 8 months, the polymer contains a maximum concentration of approximately
4.3% of the original concentration, and after almost 1 year the stent contains a maximum
concentration of approximately 3.2% of the original concentration. At almost one year,
the diffusion profile near the surface of the stent strut is no longer circular because it has
reached the end of the intima layer. The faster diffusivity of the adventitia (1x10 -7
mm2/s) than the intima (2.5x10-10 mm2/s) coupled with the low concentration at the
intima-adventitia interface results in a flat green concentration at 347.22 days. The 400
times greater diffusivity value of the adventitia results in a much faster diffusion through
it, resulting in an extremely low (negligible) concentration of the drug.

Time = 1.2 day Time = 5 months

Time = 8 months
Time = 1 year

Figure 3: Drug concentration contour at various time

Qualitative results can be seen in Figure 3 below. After 1 day, the drug polymer of the
stent contains a maximum concentration of approximately 63% of the original
concentration. The amount of drug concentration decreases exponentially, and after
almost 4 months the stent contained a maximum concentration of approximately 6.9% of
the original concentration. It can be deduced from this that any drug no longer contained
within the polymer layer has effectively diffused out of the polymer and into the tissue.
This would suggest that by 4 months following initial drug release, over 93% of the drug
has diffused into the intimal tissue and is binding within this region to act to prevent cell
proliferation and restenosis. The contour lines become perpendicular to the bottom of the
intima, showing a region of no flux. We assume that none of the drug will diffuse back
into the lumen (bloodstream), but the only source of drug loss will be due to the
convective flow of blood.
The concentration (Fig. 4) exponentially decreases from the maximum concentration of 1
g/mm2 for the point taken inside the drug polymer layer at the top of the stent strut. The
majority (over 80%) of the drug is diffused out of the polymer layer and into the arterial
tissue by day 25. The highest diffusion rate occurs from day 0 to day 30, and a drug
concentration of 0.14 g/mm2 is shown to be within the polymer and stent on day 30 and
decreases to 3% after about half the year.

0.8

0.7

0.6

0.5
Concentration
Drug

0.4

0.3

0.2

0.1

0
100 200 300

Time (day)

Figure 4: Variation of concentration at a particular location within the coat with time

Conclusion
In this paper a numerical investigation has been done to model the drug transport from
the stent which is fully embedded inside the tissue. The result shows that within one
month, over 80% of the drug is lost from the polymer and diffused and bound to proteins
within the intima. This is a good indication that the diffusion is effective. The analysis
here suggests that effect of the drug eluted out of the polymer can be expected to take
effect within one month of the initial drug release. Further, it can also be concluded that
drug concentration with the appropriate conditions is maintained at a concentration of
around 3% over the course of over one year for the prevention of restenosis within the
intima, it will prove to be effective therapy superior to regular stent placed by
angioplasty.

Acknowledgements
The author gratefully acknowledges the financial support from the DST under the SERC
FAST TRACK project (Ref no.SERC/ET-0173/2011)
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