Shopping cart
0 Items | US$ 0.00
1
Chapter One
INTRODUCTION
1.1 Background of the Study
Coronary artery disease is the most common type of heart diseases and the leading
cause of death worldwide due to heart disease. It occurs when the arteries that supply
blood to the heart become narrowed or blocked by a buildup of cholesterol and other
material called plaque at the inner wall of the artery as shown in Fig.1.1. This buildup is
called atherosclerosis. With time, due to atherosclerosis less blood can flow through the
arteries which results an insufficient supply of blood and oxygen to heart, initiating
chest pain: angina. Limitation of blood flow to the heart causes ischemia (cell starvation
secondary to a lack of oxygen) of the myocardial cells. Myocardial cells may die from
lack of oxygen and this is called a myocardial infarction (commonly called a heart
attack). It leads to heart muscle damage, heart muscle death and later myocardial
scarring without heart muscle re-growth. Chronic high-grade restenosis of the coronary
arteries can induce transient ischemia which leads to the induction of a ventricular
arrhythmia, which may terminate into ventricular fibrillation leading to death.
Myocardial infarction usually results from the sudden occlusion of a coronary artery
when a plaque ruptures; activating the clotting system and atheroma-clot interaction fills
the lumen of the artery to the point of sudden closure. The narrowing of the lumen of
the heart artery before sudden closure is often not severe. The events leading up to
plaque rupture are not understood despite many theories. Myocardial infarction is
almost never caused by temporary spasm of the artery wall occluding the lumen, a
condition also associated with atheromatous plaque and CAD.
Fig. 1.1: Atherosclerosis [1]
2
When blockages in the coronary arteries develop, some symptoms like chest pain or
pressure and/or shortness of breath are found whose causes have been mentioned above.
Treatment for this condition (coronary artery disease) will depend on the type of the
blockage and its extent. Treatment options include medication, surgery known as
coronary artery bypass surgery, or catheter-based procedures. Several types of catheter-
based procedures are available. During balloon angioplasty, a special balloon catheter is
passed into the narrowed segment of the artery and expands the balloon, which thus
opens the artery and compresses the blockage against the wall of the artery. More than
one third of patients who undergo balloon angioplasty may experience restenosis or re-
narrowing of the diseased artery segment within 6 months of the procedure. Stents are
very small metal mesh-tubes that can be inserted via a balloon catheter into the
narrowed segment of the artery as demonstrated in Fig.1.2. When the balloon is inflated,
the stent expands and is embedded into the artery vessel wall, which thus opens the
previously narrowed segment of artery. The balloon is then deflated and removed along
with the catheter, and the stent is left behind to serve as a metal framework for the
artery. Although stented arteries have less chance of re-narrowing than arteries opened
with a balloon alone, in-stent restenosis can still occur in more than 1 in 5 patients after
stent placement because, restenosis within the stented region of a heart artery is caused
by tissue growth as well as inflammation. Thus some stents called drug-eluting stents
have medication on them to inhibit or prevent this tissue growth. Drug-eluting stents are
placed in a fashion similar to other stents; however, their use markedly reduces the rate
of re-narrowing. In fact, about 1 in 10 patients develops re-narrowing in the several
years after drug-eluting stent implantation, a rate about half of that seen for stents
without medication.
As stents expose some foreign material to the blood stream, a small risk exists that a
blood clot may develop in the stent, a process called stent thrombosis. These blood clots
can occur many months and even years after stent implantation and may lead to a heart
attack or death. All stents can potentially be affected by stent thrombosis. For this
reason, most patients with stents are instructed to take anti-clotting medication, usually
a combination of aspirin and clopidogrel or ticlopidine. Each of these medications stops
platelet (particles in the blood that help clots to form) formation with functioning to
their full capacity. The precise duration of anti-clotting medication dose depends on the
type of stent placed.
3
Fig. 1.2: Placing of stent in a diseased artery [2]
1.2 Objective of the study
In case of drug eluting stents a certain amount of anti-flammating drug is loaded in the
coating over the base stent. This drug is released at the wall of diseased artery so that
restenosis cannot take place at the place of artery where stent has been implanted. The
releasing of the drug from the coating depends on the coating type given and drug
loading, drug concentration in the coating and artery tissue properties. Though the drug
given in the coating is only intended to release in the artery wall still some drug may
release to the blood which may complexify the calculation of drug concentration
developed in artery wall. In general, the mass transfer phenomenon occurs in a CAD-
4
DES system is still not fully understood and the studies available in literature is
extremely limited.
Therefore, the main objective of this thesis was to simulate the overall mass transfer
phenomenon occurs in CAD-DES system in the treatment of coronary artery disease.
Where, decay of drug coating thickness and change in drug concentration in the artery
tissue layer with time was evaluated. For this purpose the drug concentration in the
artery tissue layer was described using a second order partial differential equation which
was then solved using finite volume algorithm of computational fluid dynamics.
1.3 Scope of the Study
In this thesis work a drug eluting stent was studied where there was a biodegradable
coating over a bare metal stent in which there was some amount of therapeutic drug.
The degradation of the biodegradable coating layer thickness was determined with
respect to time which was actually representing the remaining drug concentration in the
coating layer. Then using this variable drug concentration as the drug concentration at
initial tissue layer concentration profile of drug in tissue layer with respect to time and
position was determined using finite volume algorithm, where this algorithm was coded
using MATLAB programming language.
1.4 Thesis Organization
This thesis contains six chapters. Those are organized as follows:
Chapter One contains introduction of the thesis. Summary of the background, objective
and scope of the study and thesis organization are included in the chapter.
Chapter Two provides an overview of the CAD and its treatment using DES. Several
existing DES; background of this technology; safety, uses and future of DES are briefly
are discussed here.
Chapter Three describes significance of DES in CAD treatment and specific aim of this
thesis work.
5
Chapter Four details the research methodology of the work where, numerical
background, governing equation, dependence of different parameters of the equation
and elaborated solution technique has been included.
Chapter Five gives through idea of the research finding where all the graphs and data
evaluated from the works has been included.
Chapter Six states the conclusion drawn from the current work and suggests possible
directions for the future work.
6
Chapter Two
LITERATURE REVIEW
At present, coronary artery disease (CAD) is one of the leading causes of death and
disability in the developed world. According to the American Heart Association CAD
was responsible for approximately 445,687 deaths in the United States in 2005,
representing 20% of all deaths that year
[1]
. CAD is caused by the development of
atherosclerotic lesions within one or more of the coronary arteries which deliver oxygen
and vital nutrients to the heart muscle. Several risk factors have been identified that
contribute to the progression of this disease and include smoking, hypertension, diabetes
and increased levels of cholesterol
[1]
. If the lumen becomes sufficiently narrowed,
blood flow to a portion of the heart is restricted, usually resulting in angina pectoris. If
untreated, vulnerable atherosclerotic lesions can become unstable and rupture. This
often results in coronary occlusion and subsequent myocardial infarction.
Over the past two decades, percutaneous trans-luminal coronary angioplasty (PTCA)
with bare-metal stent (BMS) placement has been utilized as a minimally invasive
treatment for obstructive CAD. Typically, a BMS is a small, tubular, wire-mesh device
which is pre-loaded in a collapsed form onto a catheter balloon, threaded to the
narrowed section of the artery and expanded within the vessel. Once expanded, the
BMS acts as a mechanical scaffold, reducing elastic recoil and maintaining vessel
patency post-treatment. For many patients who suffer from CAD, treatment with a BMS
will generally result in extremely favorable initial clinical results. However, at follow-
up (612months), re-narrowing of the treated artery is commonly observed in 2030%
of patients
[2]
. This re-narrowing of the treated artery is due to in-stent restenosis (ISR)
which is defined as diameter stenosis of 50% in the stented area of the vessel
[3]
.
In recent years, DESs have been developed to address the problem of ISR. A DES
typically consists of a BMS platform which has-been coated in a formulation of drugs
and carrier materials. The drugs commonly employed are known to interrupt the key
cellular and molecular processes associated with ISR. To date, clinical evaluation has
overwhelmingly proven the superiority of DESs for the reduction of ISR rates compared
to BMSs, leading to the regulatory approval of a number of DESs by both the European
Union (EU) Conformities' European (CE) and the US Food and Drug Administration
7
(FDA). Despite the success of DESs in the treatment of CAD, concern has arisen over
the long-term safety and efficacy of these devices due to cases of late adverse clinical
events such as stent thrombosis. With this concern in mind, research and development
in DES design is currently centered on increasing their performance and long-term
safety. Though only five distinct DES have received both CE and FDA approval for
commercial sale in theEU and the US, the number of DESs currently undergoing
evaluation is substantial.
In Section
2.1
, a background on current DES technology is provided. In Section
2.2
, the
current CE and FDA approved DESs are discussed in terms of their important design
features and the clinical trials which led to their approval. In Section 2.3, long term
safety of DES is discussed, in section 2.4 some other uses of DES has been given. At
last in section 2.5 some model describing drug releasing behavior has been discussed.
2.1
Background of Current DES Technology
A stent is a medical device to serve as a temporary or permanent internal scaffold to
maintain or increase the lumen of a body conduit. Metallic coronary stents were first
introduced to prevent arterial dissections and to eliminate vessel recoil and intimal
hyperplasia associated with percutaneous trans-luminal coronary angioplasty. It has now
become the established mode of treatment of this type coronary intervention. It has been
shown to reduce late restenosis relative to conventional balloon angioplasty [2] [5] [6].
Today, most stents employed by DESs are manufactured in modular or slotted-tube
configurations and are delivered by balloon-dilation. The stent is crimped to a low-
profile upon a balloon-tipped catheter and introduced to the cardiovascular system via
the femoral or radial arteries. The stent must therefore have a low crimped profile and
must possess a high level of flexibility to enable delivery through the tortuous
cardiovascular system. During expansion the stent should experience minimum
shortening and upon deployment should conform to the vessel geometry without
straightening the vessel unnaturally. The stent should provide optimum vessel coverage
and should possess high radial strength such that it undergoes minimal radial recoil and
achieves a final diameter consistent with that of the host vessel upon unloading
[7]
. As
the stent acts as a conduit for drug-delivery it is also important that its geometrical
configuration facilitates homogeneous distribution of the drug within the vessel
[8]
.
8
The metals used to prepare the stent are selected for strength, electricity and malleability
or shape memory. Stainless steel, tantalum and nitinol alloys are among the most
commonly used materials [9] [10] [11] [12]. Nitinol offers super-elastic and thermal
shape memory properties which allow self-expansion of the stent during deployment
and thermally induced collapse for theoretical removal procedure [13]. In recent years
however, driven by emerging correlations between strut thickness and rates of
ISR,metallic alloys such as cobaltchromium have superseded steel as the material of
choice for stent design
[14]
. These metallic alloys have been developed with increased
levels of strength and X-ray attenuation compared to stainless steel, allowing newer
stents to be designed with significantly thinner struts which do not impair the resulting
strength, corrosion resistance or radiopacity of the device. Further development in stent
design is currently centered on the assessment of stronger metallic alloys, compound
metals andbioabsorbable materials.
The incidence of restenosis remains high despite technical and mechanical
improvements. This restenosis is a result of in-stent neointiaml hyperplasia caused by
proliferation and migration of vascular smooth muscle cells (VSMCs) induced by vessel
wall injury [15]. The pathology of restenosis stems from a complex interaction between
cellular and acellular elements of the vessel wall and the blood [16]. Some
antiproliferative and anti-inflammatory agents have been shown to elute slowly from
polymer coatings and to be associated with reduced neointimal formation in animal
models.
Equally important as the actual drug or therapeutic agent that is released by
aDESisthemechanismby which the drug is released. To date, the most successful
method of facilitating drug adhesion and delivery from a stent has involved the use of
permanent synthetic polymer coating materials such as polyethylene-co-vinyl acetate
(PEVA), poly-n-butyl methacrylate (PBMA), and the tri-block copolymerpoly (styrene-
b-isobutylene-b-styrene) (SIBS). By carefullymixing anti-restenotic drugs with these
materials, a drug-polymer matrix may be formed and applied to the surface of the stent
platform. Upon deployment, drug-delivery is driven by diffusion from the matrix and
the rate of this diffusion is dictated by the type, composition and number of polymers
used in the drugpolymer matrix.
9
In recent years these permanent polymers have been superseded by advanced
biocompatible permanent polymers such asphosphorylchlorine (PC) and the co-
polymerpoly
(vinylidenefluoride-co-hexafluoropropylene)
(PVDF-HFP).
These
advanced polymers mimic the phospholipids on the outer surfaces of red blood cells
resulting in a stent platform that induces minimal thrombus formation upon deployment
and has minimal adverse clinical effect on late healing of the vessel wall. Further
development in this area is currently centered on the assessment of biocompatible and
bioabsorbable polymer coating materials and on the development of novel mechanisms
of drug release.
During the deployment of a DES, any mechanical injury incurred in the vessel leads to
an immediate healing response in the arterial wall. This healing response is initially
characterized by the activation of platelets within the intima, leading to thrombus
formation and the recruitment of blood-borne monocytes, neutrophils and lymphocytes.
These cells produce mitogenic and chemotactic factors which trigger the activation of
smooth muscle cells (SMCs) which undergo unrestrained proliferation and migration
toward the intimal layer resulting in neointimal growth and ISR
[17]
. As such, the ideal
anti-restenotic agent should exhibit potent antiproliferativeeffects but preserve vascular
healing. To date a vast number of immunosuppressive and anti-proliferative agents have
been investigated for the prevention of ISR, however, only a small number have shown
real effectiveness in clinical evaluation.
Two anti-proliferative agents, paclitaxel [18] [19] and sirolimus [20], have been used in
humans with promising preliminary results. Paclitaxel is a natural or semi-synthetic
diterpane composed of a rigid texane ring and a flexible side chain. It is an anti-
neoplastic agent [21] [22]. However it is potentially cardiotoxic and the dose of
paclitaxel that can be delivered safely has yet to be resolved [23] [24]. Paclitaxel has
been shown to markedly attenuate stent-induced intimal thickening of the lumen [25]
[26]. Paclitaxels'santiproliferative effect is reversible [27]. Its short cellular residence
time: 1 hr, along with the reversible antiproliferative activity, suggests that it should be
formulated in the sustained-release dosage form [28]. Sirolimus is a carbonyl lactone-
lactam macrolide that has been shown to inhibit VSMC growth. This inhibition has been
reported to be concentration dependent, with a threshold limit of 16.7 ng/ml
[29].Sirolimus has been shown to be effective with a remarkable restenosis rate of
almost 0% [30] [31] [32]. However, some criticism has been expressed regarding the
10
absence of data in complex lesions, as well as long-term data [33]. Results of the
RAVEL and SIRIUS trials demonstrated that sirolimus-eluting stents effectively inhibit
restenosis in humans [34] [35]. The TAXUS trials revealed significant inhibition of
coronary restenosis by paclitaxel [36] [37] [38] [39]. Drug eluting polymer coated stents
have thus moved into the lime light as vehicles for the local drug administration [40].
In brief, Sirolimus, zotarolimus and everolimus, potent immunosuppressive agents,
inhibit SMC proliferation in response to cytokine and growth factor stimulation by
binding to the cytosolic FK binding protein 12 (FKBP12). This prevents the activation
of the mammalian target of rapamycin (mTOR) and leads to interruption of the cell-
cycle in the G1-S phase. Paclitaxel, a strong antiproliferative agent, suppresses
neointimal growth by binding with and stabilizing microtubules. The stability of these
microtubules inhibits their disassembly and renders them non-functional, resulting in
cell-cycle arrest in the G0G1 and G2M phases (
Fig. 2.1
)
[17]
. Development in this
area is currently centered on the assessment of further immunosuppressive and anti-
proliferative agents as well as the evaluation of numerous migration-inhibiting,
enhancedhealingand re-endothelialisation agents.
Fig. 2.1: Cell-cycle and mechanism of action of sirolimus, zotarolimus, everolimus and
paclitaxel [4]
11
2.2 Current State of the Art: DES
Since 2002, five distinct DESs have received regulatory approval from the both the EU,
CE and the USFDA: the first-generation Cypher sirolimus-eluting stent (SES) (Cordis,
Johnson & Johnson, NJ, US), the Taxus Express2 paclitaxel-eluting stent (PES) (Boston
Scientific, MS, US) and the TaxusLiberté PES (Boston Scientific), and the second
generation Endeavor zotarolimus-eluting stent (ZES) (Medtronic Vascular, CA, US)
and Xience-V everolimus-eluting stent (EES) (Abbott Vascular, CA, US).
2.2.1 First Generation DES
The Cypher SES consists of a Bx-Velocity BMS (Johnson & Johnson) coated in a
formulation of sirolimus and two permanent polymers, PEVA and PBMA. The Bx-
Velocity BMS is a closed-cell; slotted-tube stent manufactured from 316L stainless steel
and is comprised of a series of sinusoidal strut-segments joined bin-shaped, flexible
link-segments. The drug-polymer coating is applied to the entire stent surface with a
standard concentration of 140µg of sirolimus per cm
2
of stent surface area and is
designed to release approximately 80% of the drug within 30 days of stent
deployment
[41]
. The Cypher SES is currently available in six lengths from 8 to
33mmand four diameters from 2.25 to 3.5mm. The principal safety and efficacy
evidence for the Cypher SES was obtained from five clinical trials: the First In Man
(FIM) trial, the RAVEL trial and the SIRIUS trials (SIRIUS, E-SIRIUS and C-
SIRIUS).The FIM trial was a non-randomized trial involving 45 patients that
demonstrated minimal in-stent neointimal proliferation with both fast- and slow-release
SESs at 4 month follow-up
[42]
. The RAVEL trial was a randomized trial involving 238
patients with relatively low-risk lesions that demonstrated the superiority of theCypher
SES over the Bx-Velocity BMS in terms of in-segment late loss at 6months
[43]
. The
SIRIUS, C-SIRIUS and E-SIRIUS trials were randomized trials involving a total of
1510 patients with more complex lesions than those enrolled in the RAVEL and FIM
trials. The superiority of the Cypher SES over the Bx-Velocity BMSwas
furtherdemonstrated in these trials, with markedly lower rates of target lesion
revascularization and adverse clinical events observed in patients treated with the
Cypher SES
[41][44][45]
. The Cypher SESbecame the first DES to receive both CE and
FDA approval in April2002 and April 2003, respectively.
12
The Taxus Express PES consists of an Express BMS (Boston Scientific) coated in a
formulation of paclitaxel and a permanent co-polymer, SIBS. The Express BMS is a
closed-cell; slotted-tube stent manufactured from 316L stainless steel and is comprised
of a series of sinusoidal strut-segments joined by straight articulations to short, narrow
strut-segments. The drug-polymer coating is applied to the entire stent surface in single
layer with a standard concentration of 100µg of paclitaxel per cm
2
of stent surface area.
The release of paclitaxel is bi-phasic with an early 48 h burst followed by a low-level
release over the following 10 days
[39]
. TheTaxus Express2 PES is currently available
in six lengths from 8 to 33mmand four diameters from 2.5 to 3.5mm. The principal
safety and efficacy evidence for the Taxus Express2 PES was obtained from three
clinical trials, the TAXUS I, II and IV trials. The TAXUS I trial was a randomized trial
involving 61 patients which demonstrated zero binary in-stent restenosis with PESs at
6months and minimal adverse clinical events compared to BMSs at12 months
[36]
. The
TAXUS II trial was a randomized trial involving536 patients that demonstrated the
superiority of both slow- and fast-release PESs over BMSs in terms of stent volume
obstructed byneointimal proliferation at 6 months
[48]
. The TAXUS IV trial was a
randomized trial involving 1314 patients with more complex lesions than those enrolled
in the TAXUS I and II trials that demonstrated the superiority of the Taxus Express2
PES over the Express BMS in terms of in-stent late loss, binary in-stent restenosisand
target-lesion revascularization at 9 months
[39]
. The TaxusExpress2 PES became the
second DES to receive both CE and FDAapproval in May 2002 and March 2004,
respectively. Following FDA approval of the Taxus Express2 PES, the TAXUSclinical
trial program was succeeded by the TAXUS ATLAS trial, designed to assess the drug-
polymer coating (paclitaxel-SIBS)employed by the Taxus Express2 PES upon a new
BMS platform,the Liberté stent (Boston Scientific). The Liberté stent is a closed-cell,
slotted-tube stent manufactured from 316L stainless steel which has substantially
thinner struts compared to the Express stent (0.097 vs. 0.132mm) allowing for improved
flexibility and deliverability. The Liberté stent platform has also been specifically
designed with a dense strut configuration which ensures homogeneous distribution of
paclitaxel within the vessel. TheTaxusLiberté PES is currently available in seven
lengths from 8 to38mm and five diameters from 2.25 to 4mm. The principal safety and
efficacy evidence for the TaxusLiberté PES was obtained from the TAXUS ATLAS
trial. The TAXUS ATLAS trial was a randomized trial involving 871patients that
compared the safety and efficacy of the TaxusLibertéPES with an historic control arm
13
of patients who were treated with a Taxus Express2 PES in the TAXUS IV and V trials.
Despite a significantly higher incidence of complex lesions in the TAXUSATLAS
patient population the TaxusLiberté PES was found to benon-inferior to the Taxus
Express2 PES with similar rates of adverse clinical events, in-stent late loss and target-
vessel revascularization observed at 9 months
[49]
. The TaxusLiberté PES received CE
andFDA approval in September 2005 and October 2008, respectively.
2.2.2 Second Generation DES
The Endeavor ZES consists of a Driver BMS (Medtronic Vascular) coated in a
formulation of zotarolimus and a biocompatible, permanent PC co-polymer. The Driver
BMS is an open-cell; modular stent manufactured from MP35N cobaltchromium and
is comprised of a series of alternating upper and lower crowns connected by axial struts
in a sinusoidal pattern. The use of MP35N cobaltchromium alloy allows for relatively
thin struts (0.091mm) to be used compared with first-generation DESs. The drug-
polymer coating is applied to the entire stent surface with a standard concentration of
100µg of zotarolimus per cm of stent length and is designed to release approximately
95% of the total dose of zotarolimus within15 days of stent placement
[50]
. The
Endeavor ZES is currently available in eight lengths from 8 to 30mm and three
diameters from2.5 to 3.5mm. The principal safety and efficacy evidence for the
Endeavor ZES was obtained from four clinical trials, the ENDEAVORIIV trials. The
ENDEAVOR I trial was a non-randomized trial involving 100patients that demonstrated
the safety and efficacy of the EndeavorZES with minimal binary in-stent restenosis
observed at four and12 months
[50]
. The ENDEAVOR II trial was a randomizedtrial
involving 1197 patients that demonstrated the superiority of the Endeavor ZES over the
Driver BMS with significantly lower rates of binary in-stent restenosis and target-vessel
revascularization observed at 8 and 9 months, respectively
[51]
. The ENDEAVOR III (n
= 436) and ENDEAVOR IV (n = 1548) trials were randomizedtrials designed to
demonstrate the non-inferiority of the Endeavor ZES with the Cypher SES and Taxus
Express2 PES, respectively. The initial performance of the Endeavor ZES in these trials
was disappointing however, with markedly higher rates of target-lesion
revascularization and significantly higher rates of in-stent late loss observed with the
Endeavor ZES at short-term follow-up in both trials
[52][53]
.Results at longer-term
follow-up have been more reassuring however, with the absolute difference in target-
lesion revascularization reduced to 1.6% at five years in the ENDEAVOR IIItrial and
14
0.5% at three years in the ENDEAVOR IV trial
[54][55]
.The Endeavor ZES received
both CE and FDA approval in July 2005 and February 2008, respectively.
The Xience-V EES consists of a Multi-Link Vision BMS (Abbott Vascular) coated in a
formulation of everolimus, PBMA and a permanent biocompatible co-polymer, PVDF-
HFP. The Multi-Link Vision BMS is a closed-cell, slotted-tube stent manufactured from
L605 cobaltchromium alloy and consists of a series of corrugated, zigzag strut-
segments joined by single-turn link-segments. The use of L605 cobaltchromium alloy
allows for relatively thin struts (0.081mm) to be used compared with first-generation
DESs. The drug-polymer coating is applied to the entire stent surface with a standard
concentration of 100µg of everolimus per cm
2
of stent surface area and is designed to
release approximately 80% of the total dose within 30 days of stent placement
[56]
. The
Xience-VEES is currently available in six lengths from 8 to 28mm and five diameters
from 2.5 to 4mm. The principal safety and efficacy evidence for the Xience-V EES was
obtained from four clinical trials: the SPIRIT FIRST trial and the SPIRIT IIIV trials.
The SPIRIT FIRST trial was a randomized trial involving 60patients that demonstrated
the superiority of the Xience-V EESover the Multi-Link BMS in terms of in-stent late
loss and binary in-stent restenosis at 6 months
[56]
. The SPIRIT II trial was a
randomized trial involving 300 patients that demonstrated the superiority of the Xience-
V EES over the Taxus Express2 PES in terms of in-stent late loss at 6 months
[57]
. The
SPIRIT III trial was arandomized trial involving 1002 patients that demonstrated
significantly reduced in-segment late loss and non-inferior rates of target-vessel failure
in patients treated with a Xience-V EES compared to the Taxus Express2 PES at 12
months
[58]
. The SPIRIT Vitriol is a randomized trial involving 3687 patients that has
demonstrated the superiority of the Xience-V EES over the Taxus Express2PES in
terms of target-lesion failure and target-vessel revascularization at 12 months
[59]
.
Interestingly, following three year follow-up of the SPIRIT II and III trials, investigators
observed an increase in the absolute difference in target-vessel failure and adverse
clinical events in favor of the Xience-V EES
[60] [61]
. The Xience-VEES received CE
and FDA approval in January 2006 and July 2008, respectively.
Since obtaining CE and FDA approval, both first- and second generation DESs have
been evaluated in dozens of clinical studies to assess their safety and efficacy when
deployed in a number of patient and lesion sub-groups. These studies include
evaluations of DES delivery in small vessels, long lesions, diabetics, chronic total
15
occlusions (CTOs), bifurcated vessels, sapheneous vein grafts (SVGs), patients
suffering from ISR, ST-elevated myocardial ischemia, multi-vessel disease and by
direct delivery. These DESs have also been subject to a number of physician-driven
registries to assess their relative and real-world performance [62].
2.2.3 Bioresorbable Polymer Stents
Bioresorbablepolymeric stents have attracted much attention as alternative to metallic
stents. There are several reasons for fabricating a stent composed of a biodegradable
polymeric material.Bioresorbable polymeric vascular stents have the potential to remain
in situ for a predicted period of time, keeping the vessel wall patent and degrading to
non-toxic substances. Accumulating evidence indicates that the use of a bioresorbable
coronary stent dramatically decrease the need for a prosthesis after six months [63].
Bioresorbable stents are preferable for treatment of tracheomalacia in newborns and
infants because removal surgeries are not necessary. Furthermore it can be used as
support devices as well as platform for drug protein delivery to the conduit wall in all of
the above mentioned applications.
PLLA, PGA, poly -caprolactone (PCL) and poly-D, L-lactic acid (PDLLA) are the
most frequently used aliphatic poly (-hydroxy-acids) for preparing bioresorbable stents
[64] [65] [66]. The semi-crystalline PLLA and PGA have high initial tensile strength,
permitting a robust mechanical design. The PLLA total degradation time is
approximately 24 months, whereas that of PGA is 6-12 months. PLLA is one of the
most important biodegradable polymers and is used in a wide range of clinical
applications, including devices for orthopedic [67] [68] [69] and cardiovascular surgery
[70], sutures [71] and drug delivering implants [72]. This polymer is very good choice,
especially for the first three above mentioned applications, where high mechanical
strength and toughness are required. PLLA can be formed into fibers, films, tubes and
matrixes using standard processing techniques such as modeling, extrusion, spinning
and solvent casting [71]. PCL is also a semi-crystalline polymer with a relatively high
degree of crystallinity. However, it exhibits lower strength and modulus than PLLA and
PGA owing to its low glass transition temperature. PDLLA is actually a random
copolymer that consists of L-lactic acid and D-lactic acid monomers. It is therefore
amorphous and cannot exhibit crystalline structures. Its strength and modulus are lower
than those of PGA and PLLA. Polydioxanone (PDS) has gained increasing interest in
16
the medical and pharmaceutical fields owing to its excellent biocompatibility [71].
Although it is semi-crystalline polymer it also exhibits lower strength than PLLA and
PGA because it has low glass transition temperature, similar to PCL.
Table 2.1
Characteristics of typical bioresorbablepolymers[46]
Polymer
Melting point (
0
C) Glass transition
Temperature (
0
C)
Modulus (GPa) Degradation time
(months)
PGA
225 230
35 40
70
6 12
PLLA
173 178
60 65
2.7
> 24
PDLLA
Amorphous
55 60
1.9
12 16
PCL
58 63
(-65) (-60)
0.4
> 24
PDS
N/A
(-10) 0
1.5
6 12
85/15 PDLGA
Amorphous
55 55
2.0
5 6
75/25 PDLGA
Amorphous
50 55
2.0
4 5
50/50 PDLGA
Amorphous
45 50
2.0
1 2
Useful combination of the above mentioned materials can be created to alter the
mechanical properties and drug release profiles of bioactive agents from polymeric
structures based on these polymers. For example, 10/90 PDLGA, a random copolymer
that contains 90% glycolic acid and 10% lactic acid has relatively high strength but is
more flexible than PGA and degrades faster. Other PDLGA formulations that contain
relatively high lactic acid contents, such as 85/15 PDLGA, 75/25 PDLGA and 50/50
PDLGA are amorphous therefore they do not exhibit high strength and modulus.
However they can be used for support in case lower strength necessity such as neural
stents.
All above mentioned materials degrade principally by simple hydrolysis of the ester
bond in the polymer backbone. Partial chain scission degrades the polymer to 10 - 40µm
particles. These particles can be phagocytized and metabolized to carbon dioxide and
water, which are of course fully resorbed. The polymers degradation time is a function
of its chemical structure and molecular weight. Crystallinity contributes to a higher
degradation time because crystalline domains are denser than amorphous domains and
water molecule cannot penetrate them easily. Table 2.1 demonstrates that a relatively
17
small number of polymers provide a large variety of degradation times for various
medical support applications.
2.3 Long-term DES Safety
Following the strong performance of the first-generation DESs in clinical evaluation,
these devices were widely adopted by interventional cardiologists with up to 90% of
stent procedures carried out in the US involving DES placement by late 2005
[74]
. Over
the following two years, however, major concerns arose over the long-term safety of
DESs when a number of clinical and observational studies reported significantly
increased risk of mortality in patients treated with DESs compared to BMSs beyond 12
months
[75] [76] [77] [78]
. Prompted by these results, a number of large-scale, meta-
analyses were undertaken to assess both the short- and long-term safety of DESs
relative to BMSs
[79] [80] [81]
. Reassuringly, no increased risk of mortality was
observed between patients treated with DES and BMS with similar rates of death and
myocardial infarction reported for DESs in each of these studies. Furthermore, in a
resentment-analysis of long-term follow-up (14 years) from over 22 randomized
clinical trials and 34 observational studies, patients treated with DESs were associated
with lower rates of death and myocardial infarction and repeat revascularizations
compared to patients treated with BMSs
[82]
.
Today, the primary concern with long-term DES safety is stent thrombosis, a potentially
fatal adverse event that often leads to myocardial infarction and/or death. In the debate
that followed the initial concerns over the long-term safety of DESs it emerged that
restrictive and non-uniform definitions of stent thrombosis had been utilized during the
initial clinical evaluation of the firstgenerationDESs. The Academic Research
Consortium subsequently recommendedstandardized definitions of stent thrombosis and
in2007 these definitions were adopted in a pooled analysis of the long-term follow-up
from eight clinical trials involving both the Cypher SES and the Taxus Express2 PES.
Though similar rates of early (less than 1 month) and late (112 months) stent
thrombosis were observed between DESs and BMSs in this analysis, higher rates of
very-late (greater than 12 months) stent thrombosis were reported with DESs
[83]
.
Evaluation of the long-term follow-up of clinical trials and registries has since
supported this observation
[84] [85] [86]
.
18
Although the exact cause of stent thrombosis is not yet fully understood a number of
patient, lesion, and procedural factors have been associated with an increased risk of
stent thrombosis. These include, increasing age, diabetes mellitus, renal failure,
increasing stent and/or lesion length, decreasing stent and/or vessel diameter, treatment
of bifurcation, treatment of CTO, treatment of ISR,stent under-expansion and premature
discontinuation of dual anti-platelet therapy
[87] [88]
. Of note, recent studies have
identified delayed healing and incomplete endothelial strut coverage as a primary risk
factor for stent thrombosis
[89] [90] [91] [92]
. It has been shown that the non-erodible
polymer coatings employed by DESs (particularly the first-generation Cypher SES and
Taxus Express2 PES)impair stent strut endothelialisation and may induce late
hypersensitivity reactions and subsequent stent thrombosis
[93]
.As a result of these
findings, research in this area is currently centered on the development and evaluation
of improved DESs which maintain the impressive clinical benefits observed with
currently approved devices while eradicating long-term safety concerns such as stent
thrombosis.
2.4 Other uses of Stents
The range of stent application has expanded as more experience has been gained and
following encouraging results in the treatment of vascular diseases. Stents have been
used for treating urethral obstruction caused by benign prostatic hyperplasia and for
treating benign or malignant tracheobronchial obstructions. They have also been use for
supporting the neonatal trachea in tracheal malacia for treating benign and malignant
esophageal, gastrointestinal and bile duct strictures and for treating arterial dissections,
aneurysms and various neurovascular diseases.
2.4.1 Stents in Urology
Stents have been used to prevent urine retention following thermal treatment of benign
prostatic hyperplasia (BPH) by various means, including trans-urethral microwave
therapy and direct vision laser ablation of the prostate. Several stent designs were shown
to prevent obstruction of the prostatic urethra and restructure of the anterior urethra.
These stents include the Barnes, Finnish biodegradable self-reinforced polyglycolic acid
(SR-PGA) spiral; the Nissenkorn; and the Trestle stents [94] [95] [96]. In clinical
studies, researchers have used biodegradable stents to treat benign prostatic hyperplasia.
The results obtained yield more positive outcomes compared with those using
19
suprapublic catheters [97]. Self-reinforced poly (L-lactic acid) PLLA bioresorbable
spiral stents are also undergoing evaluation for use in the anterior and posterior urethra
and upper urinary tract for preventing urinary retention and for repairing local urethral
trauma or defects [98] [99].
2.4.2 Stents for Managements of Tracheobronchial Obstruction
Techeobronchial obstruction owing to either benign or malignant disease causes
significant morbidity and mortality. Metal stents which are originally developed for
vascular system have been adapted for lesions involving the tracheobronchial tree and
include the Gainturco-Z, Palmaz, Strecker, Ultraflex and Wallstent stents [100]. These
stents were used successfully for treating patients with bronchogenic cancer, inoperable
esophageal tumors, primary tracheal tumors and meta-static malignancies.
Bioresorbable external tracheal stents have been investigated for treating pediatric
tracheal malacia, for solving the problem of limited tracheal growth in children with
rigid external fixation and for avoiding the necessity of a second procedure for
removing the synthetic material [100] [101] [102]. Metal stents are nonexpendable
tubular stable (non-degradable) where polymeric stents were tried as internal stents with
tracheomalacia [103] [104]. The results from these studies suggest that stenting is a
promising method for treating tracheal obstruction.
2.4.3 Stents in the Esophagus and Gastrointestinal Tract
Many malignant and benign esophageal and gastrointestinal strictures can be treated by
minimally invasive alternatives to surgery, including the use of stents. The most
commonly used stents in the esophagus and in gastrointestinal tract are the Esophacoil,
Flamingo, Gianturco-Z, Ultraflex and Wallstent stents. These stents are generally
effective in relieving esophageal dysphasia [105] [106] [107], a success that has led to
the employment of stents to manage lesions of the gastrointestinal tract, including the
stomach, pylorus, duodenum, upper small intestine and colon [106] [107]. Use of
bioresorbable materials for the esophageal stent is currently being explored.
2.5 Theoretical Models to Describe Drug Releasing Behavior
Biodegradable polymeric coatings on cardiovascular stents can be used for local
delivery of therapeutic agents to diseased coronary arteries after stenting procedures. A
valid mathematical model can be a very important tool in the design and development of
20
such coating for drug delivery. The model should incorporate the important
physicochemical processes responsible for the polymer degradation and drug release.
Such a model can be used to study the effect of different coating parameters and
configurations on the degradation and the release of the drug from the coating. A
simultaneous transport-reaction model predicting the degradation and release of the
drug Everolimus from a poly lactic acid (PLA) based stent coating has been modeled
which describe transportation of water into polymeric matrix, transport of degraded
PLA monomers, oligomers, lactic acid and drug using second order partial differential
equation with respect to time and radial position [108].These differential equations were
then solved using numerical methods. The previously mentioned model was further
modified using by assuming two different phase of drug distribution: highly percolated
phase and polymer encapsulated phase [109]. Another theoretical model is found which
characterize drug release behavior of drug-eluting stents with durable polymer matrix
coating [110]. In this model, in vitro and in vivo drug release and tissue
pharmacokinetics was described by a second order partial differential equation of drug
concentration which was then solved by analytical procedure using Bessel function.
2.6 Conclusion
From the review it is found that Coronary artery disease is the most common type of
heart diseases and the leading cause of death worldwide due to heart disease. The drug-
eluting stents is generally considered as the best catheter-based therapy for coronary
artery disease. However, the mass transfer of the drug from DES to the tissue is not
fully understood till date.
21
Chapter Three
OBJECTTIVE WITH SPECIFIC AIMS AND RESEARCH
SIGNIFICANCE
3.1 Objectives of Study with Specific Aims
Coronary artery disease is the most common type of heart diseases and the leading
cause of death worldwide due to heart disease. The drug-eluting stents is generally
considered as the best catheter-based therapy for coronary artery disease. However, the
mass transfer of the drug from DES to the tissue is not fully understood till date. Hence,
the main objective of this thesis is to simulate the overall mass transfer phenomenon
occurs in CAD-DES in the treatment of coronary artery disease. When a biodegradable
coating (containing drug at the porous place of the coating) is given on the main
structure of the stent, then this coating is degraded with time and drug releasing
property from the stent also become changed. With degraded coating, the diffusion
resistance of the drug is changed. At the same time the characteristic diffusion length
and drug concentration also become changed. Thus, the thesis work focus on the change
in coating resistance as well as the equilibrium drug concentration with respect to time
and drug concentration changing due to changed equilibrium drug concentration with
respect to time and position (radial) in the artery wall. These changes are observed by
solving two partial differential equations for concentration and coating thickness where
initial and boundary conditions are assumed. The simulated model is intended for the
following specific aims:
To show the decay of drug coating thickness (including the change in concentration
of therapeutic drug in the coating) with time.
To show the change in drug concentration in the artery tissue layer with time both in
radial and longitudinal directions (i.e., a two-dimensional concentration profile).
The model will finally be generalized incorporating an extra-component of drug
mass transfer from the drug coating through the bare stent into the external blood
flow in artery channel.
22
3.2 Research Significance
The main target of this research work was to develop a model which will be able to
predict drug mass transfer in CAD-DES. The significance or importance of this model
has been briefly indicated below:
The time taken by drug coating to decay completely can reasonably be determined
using the simulated model. This will help to determine the safe working period of a
drug eluting stent (DES). The model can be employed to study the effect of the
properties of DES on their safe working period.
The distribution of therapeutic drug molecules in the artery tissue along axial and
radial directions after the release from stent can be studied using the simulated
model. This will greatly help to evaluate the therapeutic performances of the various
DES.
The time taken by therapeutic drug molecules to cover the entire artery tissue can
also reasonably be determined from the simulated model. This will help to evaluate
the activity fastness of a DES.
The simulated model can also be used to optimize several parameters related to DES
and drug concentration profile.
Overall, the design, operation and performance of DES-based angioplasty would be
benefited immensely from the present study.
23
Chapter Four
RESEARCH METHODOLOGY
Mass transport refers to the movement of mass, i.e. the species of interest which is drugs
in the case of a DES, within a defined system. This transport of species may be
provoked by concentration gradients between two points, but quite often in systems,
especially in the vasculature, overpowering complex flow dynamics will ultimately be
responsible for the mass transport outcome. In the absence of a free flowing system the
presence of these concentration gradients induces diffusion, e.g. between the DES and
the artery wall. Mass transport can be broken up into two types within the human
vasculature. Firstly blood side mass transport (BSMT) refers to species transport within
the vessel lumen and is subject to the hemodynamic therein. Often evanescent due to
hemodynamic washout, BSMT can only be effective in transporting anti-proliferative
agents to the wall in regions of high recirculation. The second, and most important,
mode of mass transport is in relation to transport within the wall of the artery, referred
to as wall side mass transport (WSMT). Along with the properties of the species being
transported within the artery wall, WSMT depends on the structural condition of the
wall itself, whereby a damaged intimal layer could facilitate accelerated mass transport
through to the medial layer. WSMT can be governed by two transport forces, a pressure
driven convective force and a diffusive force. The Peclet number (Pe) is a dimensionless
parameter that can be used to determine the relative influences of these two forces. A
small Pe (Pe<1) is representative of transport which is dominated by diffusion, while a
higher Pe (Pe>1) indicates convection dominated mass transport.
4.1 Governing Equation of the Problem
In the present thesis work, the main objective was to consider WSMT where drug
concentration was evaluated with respect to time and position in artery wall. In this
purpose, two drug mass transfer model was developed. In 1D model drug concentration
has been evaluated with respect to time and radial position (r) in the artery wall. In 2D
model a drug concentration profile was developed with respect to time and radial (r) and
longitudinal position (z) in the artery wall.
24
The assumptions applied when modeling fluid flow problems of DES are as follows:
The flow is incompressible and isothermal
The fluid is Newtonian and possesses constant physical properties
Flow is considered to be laminar
Drug coating over the DES was a continuous film
Species transport via diffusion is a process driven by concentration gradients between
two locations. Fick's first law can be used to describe the diffusion flux (Jx, mol/m
2
s) of
such species, shown in 1D in equation 4.1, where D (m
2
/s) is diffusivity and c is
concentration (mol/m
3
):
. = -
(4.1)
The negative term in equation 4.1 indicates that the flux is positive in the presence of a
negative concentration gradient. Biological mass transport often requires the application
of a time-dependent mass transport process that can predict variations in concentration
overtime. Fick's second law (equation 4.2) can provide such a relationship and is
defined here in one dimension:
.
=
(4.2)
The addition of a convective term, equal to the product of the fluid velocity and the
local concentration, to equation 4.2 demonstrates the 3D transport of species in a
flowing solution. This is known as the convection-diffusion equation.
.
+
+
+
=
+
+
(4.3)
For a cylindrical coordinate system, the equation 4.3 becomes,
.
+
+
+
=
1
+
1
+
(4.4)
Here, u, v and w are the velocity at the r, and z direction respectively.
In reality the classification of problems of this nature are inherently patient specific and
as such no one representation of the problem is correct. However, there are innate
25
similarities between patients. Blood flow within the vasculature is a highly complex 3D
process to model given the pulsatile nature of arterial haemo-dynamics. Coupled with
this pulsatile process, the coronary arteries are situated on the surface of the heart and as
such are subject to cyclic motion due to the beating of the organ. Therefore the
modeling of drug transport from a DES in these arteries is multifaceted in nature,
comprising of both luminal and artery wall mass transport, the latter of which may also
be subject to a reaction giving that some drug may bind to the arterial tissue. The
introduction of a multi-layered artery wall to the model increases the complexity of the
domain even further. If it is considered that, DES has been placed in multilayer diseased
artery, then in absence of a lumen and subsequent blood stream mass transport, the wall
side mass transport is approximately diffusive with a little convection flux arisen due to
high concentration difference. Thus the diffusion of drug from DES occurs at the radial
direction with a small amount convection of drug at the r direction with a velocity u. In
equation 4.4, setting velocity v and w to zero and concentration gradient at and z
direction to zero, it is found that,
+
=
1
=
+
-
. 0
;
=
-
(4.5)
Now by putting,
=
; =
= equation 4.5 can be converted into
dimensionless format where,
,
are dimensionless time, radius and concentration
respectively.
( )
=
( )
( )
-
( )
( )
=
-
Dividing both side by,
, the equation become
26
=
-
.
=
-
(4.6)
Equation 4.6 is the governing equation of the drug concentration in artery wall at
dimensionless form, where unsteady drug concentration is considered in radial direction
only.
A common assumption for DES mass transport studies is that the intimal layers of the
artery are denuded and that the stent is in direct contact with the medial layer of the
artery wall. This negates the need to model the endothelial, intima and internal elastic
lamina layers. Regardless of the inclusion or exclusion of these layers the continuity
equation should be the default setting for all interior boundaries. This condition states
that in the absence of sources or sinks, the flux in the normal direction is continuous
across the boundary, i.e. the concentration is equal on both sides of the boundary
At the vascular wall and at the up- and down-stream wall boundaries there should be a
sufficient distance away from the stent. It specifies where the domain is well insulated
or it can reduce the size of a model by taking advantage of symmetry. Intuitively this
condition states that the gradient across the boundary must be zero, therefore it is
impermeable to mass transport.
Again if, diffusion of drug from DES occurs at the radial direction with a small amount
diffusion of drug at the z direction due to high concentration gradient, then from
equation 4.4 it is found that,
.
+
=
1
+
(4.7)
Equation 4.7 is the governing equation of the drug concentration in artery wall at radial
and axial direction with respect to time.
The implementation of an arterial pulse and a beating heart are neglected by most
researchers. Often the artery is modeled as rigid in space in order to analyze mass
transport post DES deployment. This is an effective assumption but one must consider
the deformation of the artery wall due to the dynamic expansion of the stent, as this can
have an impact on the mass transport outcome due to the porous nature of the wall and
Excerpt out of 131 pages
- scroll top
Details
- Quote paper
- , 2017, Simulation of Mass Transfer Phenomenon in a CAD Drug Eluting Stent System, Hamburg, Bedey Media GmbH, https://www.anchor-publishing.com/document/368612
Comments