U.S. patent application number 11/283032 was filed with the patent office on 2006-06-22 for method and apparatus for treating vulnerable plaque.
Invention is credited to Syed Hossainy, Deborah Kilpatrick, Evgenia Mandrusov, Murthy Simhambhatla.
Application Number | 20060135943 11/283032 |
Document ID | / |
Family ID | 35966178 |
Filed Date | 2006-06-22 |
United States Patent
Application |
20060135943 |
Kind Code |
A1 |
Mandrusov; Evgenia ; et
al. |
June 22, 2006 |
Method and apparatus for treating vulnerable plaque
Abstract
An apparatus and method to treat vulnerable plaque. In one
embodiment, the apparatus has an elongated catheter body adapted
for insertion in a body lumen, with a drug delivery device attached
near a distal portion of the elongated body. The drug delivery
device is configured to deliver a biologically active agent to
stabilize a vulnerable plaque.
Inventors: |
Mandrusov; Evgenia;
(Campbell, CA) ; Kilpatrick; Deborah; (Los Altos,
CA) ; Simhambhatla; Murthy; (San Jose, CA) ;
Hossainy; Syed; (Fremont, CA) |
Correspondence
Address: |
BLAKELY SOKOLOFF TAYLOR & ZAFMAN
12400 WILSHIRE BOULEVARD
SEVENTH FLOOR
LOS ANGELES
CA
90025-1030
US
|
Family ID: |
35966178 |
Appl. No.: |
11/283032 |
Filed: |
November 17, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10262151 |
Sep 30, 2002 |
7008411 |
|
|
11283032 |
Nov 17, 2005 |
|
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Current U.S.
Class: |
604/500 ;
604/523; 604/96.01 |
Current CPC
Class: |
A61M 25/0084 20130101;
A61B 2017/22081 20130101; A61M 2025/0096 20130101; A61M 25/1006
20130101; A61M 25/0026 20130101 |
Class at
Publication: |
604/500 ;
604/523; 604/096.01 |
International
Class: |
A61M 31/00 20060101
A61M031/00 |
Claims
1. An apparatus, comprising: an elongated catheter body adapted for
insertion in a body lumen; and a drug delivery device coupled near
a distal portion of said elongated body, said drug delivery device
configured to deliver a biologically active agent to stabilize a
vulnerable plaque.
2. The apparatus of claim 1, wherein said drug delivery device
comprises: a balloon disposed at a distal end of said drug delivery
device; and at least one needle housed within said drug delivery
device, wherein said at least one needle is moveable from a
retracted position to an extended position, and wherein an angle of
needle penetration relative to said elongated catheter body
corresponds to an inflation of said balloon.
3. The apparatus of claim 2, further comprising a sensor near said
distal portion of said catheter, wherein said sensor determines a
penetration depth of said at least one needle.
4. The apparatus of claim 1, wherein said biologically active agent
comprises lipid lowering agents.
5. The apparatus of claim 1, wherein said biologically active agent
comprises antioxidants.
6. The apparatus of claim 1, wherein said biologically active agent
comprises anti-inflammatory agents.
7. The apparatus of claim 1, wherein said biologically active agent
comprises extracellular matrix synthesis promoters.
8. The apparatus of claim 1, wherein said drug delivery device
delivers up to 600 .mu.g of said biologically active agent.
9. A method for stabilizing a vulnerable plaque in a lumen wall,
comprising: detecting said vulnerable plaque; advancing a needle
catheter near said vulnerable plaque; and delivering a vulnerable
plaque stabilizing agent with said needle catheter near said
vulnerable plaque.
10. The method of claim 9, further comprising determining a
penetration depth of said needle catheter.
11. (canceled)
12. The method of claim 9, wherein delivering said vulnerable
plaque stabilizing drug comprises targeting an intimal layer near
said vulnerable plaque.
13. The method of claim 9, wherein delivering said vulnerable
plaque stabilizing drug comprises targeting an adventitial layer
near said vulnerable plaque.
14. The method of claim 9, wherein delivering said vulnerable
plaque stabilizing drug comprises targeting a media layer near said
vulnerable plaque.
15. The method of claim 9, wherein delivering said vulnerable
plaque stabilizing drug comprises targeting said lipid core of said
vulnerable plaque region.
16. The method of claim 15, wherein targeting said lipid core
comprises delivering a cross-linking agent.
17. A method of claim 15, wherein targeting said lipid core
comprises delivering a matrix-ase inhibitor.
18. The method of claim 13, wherein targeting said adventitial
layer comprises delivering a collagen synthesis promoter.
19. The method of claim 13, wherein targeting said adventitial
layer comprises gene therapy.
20. The method of claim 13, wherein targeting said adventitial
layer comprises inserting said needle into said body lumen wall at
a point proximal to said vulnerable plaque region, and extending
said needle to said adventitial layer.
21. The method of claim 14, wherein targeting said media layer
comprises inserting said needle into said body lumen wall at a
point proximal to said vulnerable plaque region, and extending said
needle to said media layer.
22. (canceled)
23. The method of claim 15, wherein targeting said lipid core
comprises inserting said needle into said body lumen wall at a
point proximal to said lipid core, and extending said needle to
said lipid core.
24. The method of claim 9, wherein said vulnerable plaque
stabilizing agent strengthens said fibrous cap.
25. The method of claim 9, wherein said vulnerable plaque
stabilizing agent reduces a size of a lipid core of said vulnerable
plaque.
26. The method of claim 9, wherein said vulnerable plaque
stabilizing agent thickens said fibrous cap.
27. A method for treating a vulnerable plaque, comprising:
advancing a medical device within a body lumen; and delivering a
biologically active agent from said medical device, wherein said
biologically active agent induces a therapeutic angiogensesis
growth away from said vulnerable plaque to maintain a blood
perfusion in the event of an occlusive thrombosis from a rupturing
of said vulnerable plaque.
28. The method of claim 27, wherein delivering comprises releasing
said biologically active agent upstream from said vulnerable
plaque.
29. A method of claim 28, further comprising providing a drug
delivery catheter to release said biologically active agent.
30. The method claim 27, wherein delivering comprises releasing
said biologically active agent through a bloodstream near said
vulnerable plaque.
31. The method claim 27, wherein delivering comprises releasing
said biologically active agent towards a lumen wall near said
vulnerable plaque.
32. The method claim 27, wherein delivering comprises
sustained-releasing said biologically active agent.
33. The method of claim 32, wherein sustained-releasing said
biologically active agent comprises releasing said biologically
active agent over a period up to about 6 months.
34. The method of claim 29, wherein said drug delivery catheter
comprises dip coating a drug eluting stent with said biologically
active agent.
35. The method of claim 29, wherein said drug delivery catheter
comprises spin coating a drug eluting stent with said biologically
active agent.
36. The method of claim 31, wherein releasing said biologically
active agent towards said lumen wall comprises adhering a plurality
of micro-particles to said lumen wall.
37. The method of claim 27, wherein said biologically active agent
is selected from a group consisting of vascular endothelial growth
factor (VEGF), fibroblast growth factors, monocyte chemoatractant
protein 1 (MCP-1), transforming growth factor alpha (TGF-alpha),
transforming growth factor beta (TGF-beta, DEL-1, insulin like
growth factors (IGF), placental growth factor (PLGF), hepatocyte
growth factor (HGF), prostaglandin E1 (PG-E1), prostaglandin E2
(PG-E2), tumor necrosis factor alpha (TBF-alpha), granulocyte
stimulating growth factor (G-CSF), granulocyte macrophage
colony-stimulating growth factor (GM-CSF), angiogenin, follistatin,
proliferin, pro-angiogenic peptides, and pro-angiogenic small
molecules.
38. The method of claim 27, wherein delivering said biologically
active agent induces a therapeutic angiogenesis growth to a
myocardium.
39. The method of claim 27, wherein delivering said biologically
active agent comprises delivering up to 600 .mu.g of said
biologically active agent.
40. An apparatus for stabilizing a vulnerable plaque in a lumen
wall, comprising: means for detecting said vulnerable plaque; means
for advancing a needle catheter near said vulnerable plaque; and
means for delivering a vulnerable plaque stabilizing agent with
said needle catheter near said vulnerable plaque, wherein said
vulnerable plaque stabilizing agent increases a thickness of a
fibrous cap.
41. An apparatus for treating a vulnerable plaque, comprising:
means for advancing a medical device within a body lumen; and means
for delivering a biologically active agent from said medical
device, wherein said biologically active agent induces a
therapeutic angiogenesis growth away from said vulnerable plaque to
maintain a blood perfusion in the event of an occlusive thrombosis
from a rupturing of said vulnerable plaque.
Description
[0001] This application is a divisional application of co-pending
U.S. patent application Ser. No. 10/262,151, filed Sep. 30,
2002.
FIELD OF THE INVENTION
[0002] The invention, in one embodiment, relates generally to the
treatment of coronary disease, and more particularly, in one
embodiment, to the stabilization of vulnerable plaque.
BACKGROUND OF THE INVENTION
[0003] Coronary heart disease is generally thought to be caused by
the narrowing of coronary arteries by atherosclerosis, the buildup
of fatty deposits in the lining of the arteries. The process that
may lead to atherosclerosis begins with the accumulation of excess
fats and cholesterol in the blood. These substances infiltrate the
lining of arteries, gradually increasing in size to form deposits
commonly referred to as plaque or atherosclerotic occlusions.
Plaques narrow the arterial lumen and impede blood flow. Blood
cells may collect around the plaque, eventually creating a blood
clot that may block the artery completely.
[0004] The phenomenon of "vulnerable plaque" has created new
challenges in recent years for the treatment of heart disease.
Unlike occlusive plaques that impede blood flow, vulnerable plaque
develops within the arterial walls, but it often does so without
the characteristic substantial narrowing of the arterial lumen
which produces symptoms. As such, conventional methods for
detecting heart disease, such as an angiogram, may not detect
vulnerable plaque growth into the arterial wall. After death, an
autopsy can reveal the plaque congested in arterial wall that could
not have been seen otherwise with currently available medical
technology.
[0005] The intrinsic histological features that may characterize a
vulnerable plaque include increased lipid content, increased
macrophage, foam cell and T lymphocyte content, and reduced
collagen and smooth muscle cell (SMC) content. This fibroatheroma
type of vulnerable plaque is often referred to as "soft," having a
large lipid pool of lipoproteins surrounded by a fibrous cap. The
fibrous cap contains mostly collagen, whose reduced concentration
combined with macrophage derived enzyme degradations can cause the
fibrous cap of these lesions to rupture under unpredictable
circumstances. When ruptured, the lipid core contents, thought to
include tissue factor, contact the arterial bloodstream, causing a
blood clot to form that can completely block the artery resulting
in an acute coronary syndrome (ACS) event. This type of
atherosclerosis is coined "vulnerable" because of unpredictable
tendency of the plaque to rupture. It is thought that hemodynamic
and cardiac forces, which yield circumferential stress, shear
stress, and flexion stress, may cause disruption of a fibroatheroma
type of vulnerable plaque. These forces may rise as the result of
simple movements, such as getting out of bed in the morning, in
addition to in vivo forces related to blood flow and the beating of
the heart. It is thought that plaque vulnerability in fibroatheroma
types is determined primarily by factors which include: (1) size
and consistency of the lipid core; (2) thickness of the fibrous cap
covering the lipid core; and (3) inflammation and repair within the
fibrous cap.
[0006] FIG. 1A illustrates a partial cross-section of an artery
having a narrowed arterial lumen caused by the presence of
occlusive atherosclerosis. Plaque accumulates to impede and reduce
blood flow through the arterial lumen and thus often causes
symptoms (e.g., angina pectoris). The arrows indicate the direction
of blood flow through the arterial lumen. FIG. 1B illustrates an
occlusive atherosclerosis within an arterial lumen resulting in
significant reduction in lumen patency. This type of
atherosclerosis can easily be detected through current diagnostic
methods such as an angiogram. FIG. 1B also illustrates, downstream
from the occlusive atherosclerosis, a fibroatheroma type of
vulnerable plaque. The vulnerable plaque, with a lipid core,
develops mostly within the arterial wall with minimal occlusive
effects such that it is not easily detected by current diagnostic
methods. This is partially due to a phenomenon known as "positive
remodeling," which allows the vessel to respond to the presence of
disease. The fibroatheroma vulnerable plaque has grown into the
positively remodeled arterial wall so that vessel occlusion has not
been manifested. A fibrous cap surrounds the vulnerable plaque.
[0007] FIGS. 2A-2C illustrate a cross-sectional view of the
accumulation of vulnerable plaque in the arterial wall. FIG. 2A
illustrates an arterial wall that is not affected by
atherosclerosis. The normal arterial wall consists of an intima
layer, a media layer, and an adventitia layer. The intima is in
direct contact with the blood flow within the arterial lumen. The
intima consists mainly of a monolayer of endothelial cells. The
media consists mostly of smooth muscle cells and extracellular
matrix proteins. The outermost layer of the arterial wall, the
adventitia, is primarily collagenous and contains nerves, blood
vessels, and lymph vessels. FIG. 2B illustrates the large presence
of a fibroatheroma type vulnerable plaque surrounded by a fibrous
cap within the arterial wall. The vulnerable plaque consists mainly
of a large lipid core. The fibrous cap layer shields the lumen of
the artery from the thrombogenic components in the core. FIG. 2C
illustrates an occlusive thrombosis event resulting from the
rupturing of the fibrous cap. Thrombogenic components in the
vulnerable plaque contact luminal blood and cause the thrombotic
event.
[0008] Autopsy studies and other evidence strongly suggest that the
presence of a current acute coronary syndrome (ACS) event and/or
existing thrombus at certain plaque sites may correlate to
predicting a future ACS event in a given patient. The latter
indicates the likelihood of a prior thrombotic event (e.g.,
fibroatheroma rupture) after which the plaque was able to heal
itself, or complete occlusion of the vessel was somehow prevented.
Autopsy studies also indicate that it is reasonable to expect that
at least one vulnerable plaque could exist in the majority of
catheterization laboratory patients being treated for arterial
blockage from visible, occlusive atherosclerosis. Many of the
patients at highest risk, therefore, for future ACS events may
already be receiving interventional treatment, even though current
methods to diagnose occlusive plaques (i.e., non-vulnerable type
plaque) are not effective for enabling therapy for vulnerable
plaque. Furthermore, treating both the occlusive plaques and the
vulnerable plaque in one procedure might be beneficial and
desirable compared to separate treatments. This would provide a
greater convenience to the patient and for the physician.
SUMMARY OF THE INVENTION
[0009] An apparatus and method to treat vulnerable plaque are
described. In one embodiment, the apparatus has a an elongated
catheter body adapted for insertion in a body lumen, with a drug
delivery device attached near a distal portion of the elongated
body. The drug delivery device is configured to deliver a
biologically active agent to stabilize a vulnerable plaque.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] The present invention is illustrated by way of example, and
not limitation, in the figures of the accompanying drawings in
which:
[0011] FIG. 1A illustrates a partial cross-section of an arterial
lumen having occlusive plaque.
[0012] FIG. 1B illustrates a partial cross-section of an arterial
lumen having occlusive plaque and vulnerable plaque.
[0013] FIGS. 2A-2C illustrate the vessel morphology and the
rupturing of a vulnerable plaque.
[0014] FIGS. 3A-3B illustrate the stabilization a vulnerable plaque
by reducing the size of the lipid core and strengthening and
increasing the thickness of the fibrous cap.
[0015] FIG. 4 illustrates one embodiment of using a drug delivery
stent to treat a vulnerable plaque downstream from an occlusive
plaque.
[0016] FIGS. 5A-5C illustrate an alternative embodiment of using a
drug delivery stent to treat a vulnerable plaque downstream from an
occlusive plaque.
[0017] FIG. 6 illustrates one embodiment of microparticles released
towards a vulnerable plaque.
[0018] FIG. 7 illustrates one embodiment of a stent graft used to
treat a vulnerable plaque.
[0019] FIGS. 8A-8B illustrate cross-sectional views of a stent
graft.
[0020] FIGS. 9A-9D illustrate various embodiments of using a needle
catheter to treat a vulnerable plaque.
[0021] FIGS. 10A-10B illustrate one embodiment of a needle
catheter.
[0022] FIGS. 11A-11D illustrate various methods for treating
vulnerable plaque.
[0023] FIG. 12 illustrates one embodiment of inducing therapeutic
angiogenesis growth near a vulnerable plaque.
[0024] FIGS. 13A-13B illustrate cross-sectional views of one
embodiment of a drug eluting stent that can be used to strengthen
and to increase the thickness of the fibrous cap of the vulnerable
plaque in a controlled manner.
DETAILED DESCRIPTION
[0025] In the following description, numerous specific details are
set forth such as examples of specific, components, processes, etc.
in order to provide a thorough understanding of various embodiment
of the present invention. It will be apparent, however, to one
skilled in the art that these specific details need not be employed
to practice various embodiments of the present invention. In other
instances, well known components or methods have not been described
in detail in order to avoid unnecessarily obscuring various
embodiments of the present invention. The term "coupled" as used
herein means connected directly to or indirectly connected through
one or more intervening components, structures or elements. The
terms "drugs," "bioactive agents," and "therapeutic agents" are
used interchangeably to refer to agents (e.g., chemical substances)
to treat, in one embodiment, coronary artery and related diseases
including for example, atherosclerotic occlusions and vulnerable
plaque.
[0026] Apparatuses and their methods of use to treat vulnerable
plaque are described. In one embodiment, the vulnerable plaque or
the region of the artery containing the vulnerable plaque may be
treated alone or in combination with treating occlusive
atherosclerosis. The benefit is that any vulnerable, but not yet
occlusive plaques would be treated without having to place a
therapeutic implant (e.g., a stent) at the vulnerable plaque
region. The only implant placed would be that already being used to
scaffold and treat the existing occlusive plaque. In the following
description, the stabilization of vulnerable plaque is described
with respect to treatment within the artery. The coronary artery is
just one region in the body where vulnerable plaque may form. As
such, it can be appreciated that the stabilization of vulnerable
plaque may be achieved in any vessel of the body where vulnerable
plaque may exist.
[0027] FIGS. 3A-3B illustrate a cross-sectional view of the
stabilization of vulnerable plaque. FIG. 3A shows a large
vulnerable plaque 310 having lipid core 315 separated from arterial
lumen 330 by thin fibrous cap 320. Thin fibrous caps and reduced
collagen content or degraded collagen in the fibrous caps increase
a plaque's vulnerability to rupture. As illustrated in FIG. 3B,
vulnerable plaque 310 has been stabilized by thickening and/or
strengthening fibrous cap 320 that separates lipid core 315 from
arterial lumen 330. This reduces the likelihood of fibrous cap 320
rupturing. Additionally, lipid core 315 redistribution has occurred
in combination with strengthening fibrous cap 320. Vulnerable
plaque 310 may also be treated by inducing collateral artery or
vessel growth near the vulnerable plaque region such that, in the
event of fibrous cap rupture or occlusive thrombosis, an
alternative blood path exists to bypass the ruptured region (not
shown).
Drug Eluting Stents
[0028] In one embodiment, a drug eluting stent may be implanted at
the region of vessel occlusion that may be upstream from a
vulnerable plaque region. As discussed above, autopsy studies have
shown that vulnerable plaque regions commonly exist in the vicinity
of occlusive plaques. A medical device, such as a drug eluting
stent, may be used to treat the occlusive atherosclerosis (i.e.,
non-vulnerable plaque) while releasing a drug or biologically
active agent to treat a vulnerable plaque region distal or
downstream to the occlusive plaque. The drug may be released slowly
over time, and may include for example, anti-inflammatory or
anti-oxidizing agents. Biologically active agents may also be
released include cells, proteins, peptides, and related
entities.
[0029] The eluting stent may have the vulnerable plaque treating
drug or agent dispersed on the surface of the stent, or
co-dissolved in a matrix solution to be dispersed on the stent.
Other methods to coat the stent with a vulnerable plaque treating
drug include dip coating, spin coating, spray coating, or other
coating methods commonly practiced in the art.
[0030] In one embodiment, therapeutic or biologically active agents
may be released to induce therapeutic angiogenesis, which refers to
the processes of causing or inducing angiogenesis and
arteriogenesis, either downstream, or away from the vulnerable
plaque. Arteriogenesis is the enlargement of pre-existing
collateral vessels. Collateral vessels allow blood to flow from a
well-perfused region of the vessel into an ischemic region (from
above an occlusion to downstream from the occlusion). Angiogenesis
is the promotion or causation of the formation of new blood vessels
downstream from the ischemic region. Having more blood vessels
(e.g., capillaries) below the occlusion may provide for less
pressure drop to perfuse areas with severe narrowing caused by a
thrombus. In the event that an occlusive thrombus occurs in a
vulnerable plaque, the myocardium perfused by the affected artery
is salvaged. Representative therapeutic or biologically active
agents include, but are not limited to, proteins such as vascular
endothelial growth factor (VEGF) in any of its multiple isoforms,
fibroblast growth factors, monocyte chemoatractant protein 1
(MCP-1), transforming growth factor alpha (TGF-alpha), transforming
growth factor beta (TGF-beta) in any of its multiple isoforms,
DEL-1, insulin like growth factors (IGF), placental growth factor
(PLGF), hepatocyte growth factor (HGF), prostaglandin E1 (PG-E1),
prostaglandin E2 (PG-E2), tumor necrosis factor alpha (TBF-alpha),
granulocyte stimulating growth factor (G-CSF), granulocyte
macrophage colony-stimulating growth factor (GM-CSF), angiogenin,
follistatin, and proliferin, genes encoding these proteins, cells
transfected with these genes, pro-angiogenic peptides such as PR39
and PR11, and pro-angiogenic small molecules such as nicotine.
[0031] In another embodiment, therapeutic or biologically active
agents to treat the vulnerable plaque may be delivered through the
bloodstream or vessel wall. These therapeutic or biologically
active agents include, but are not limited to, lipid lowering
agents, antioxidants, extracellular matrix synthesis promoters,
inhibitors of plaque inflammation and extracellular degradation,
estradiol drug classes and its derivatives.
[0032] Prospective studies of high-risk patients in whom complex
plaques were found have indicated that many of the ACS events can
happen within six months to one year after a patient has an
occlusive atherosclerosis lesion treated. In other words, there is
a clinical reason to believe that it would be efficacious to try
and actively treat lesions in those patients for a three to
six-month period of time after treatment of occlusive
atherosclerosis to prevent a recurrent ACS event. Examples of
devices to treat vulnerable plaque regions include drug eluting
stents, and drug loaded bioerodable and bioadhesive
microparticles.
[0033] In one embodiment, the polymer may be coated on a stent
using dip coating, spin coating, spray coating or other coating
methods known in the art. The drug can alternatively be
encapsulated in microparticles or nanoparticles and dispersed in a
stent coating. A diffusion limiting top-coat may optionally be
applied to the above coatings. The active agents may optionally be
loaded on a stent together either by adding them together to the
solution of the matrix polymer before coating, or by coating
different layers, each containing a different agent or combination
of agents. The drug eluting stent can alternatively have an active
agent or a combination of agents dispersed in a bioerodable stent
forming polymer.
[0034] Vulnerable plaque regions may also be treated independent of
treating occlusive lesions near the vulnerable plaque regions. In
another embodiment, a vulnerable plaque treatment drug or
biologically active agent may be injected through or around the
fibrous cap of a vulnerable plaque. Alternatively, in the event of
a thrombotic event, a drug may be injected to prevent complete
occlusion of the vessel. In one embodiment, a needle catheter may
be used to inject the drug. The needle catheter may be modified to
accommodate the following targets around the vulnerable plaque:
fibrous cap, proteoglycan-rich surface layer, subintimal lipid
core, proximal or distal regions of the plaque, media containing
smooth muscle cells around the lipid core, and peri-adventitial
space. In another embodiment, the needle catheter may include a
sensing capability to determine penetration depth of the needle.
Furthermore, the needle catheter may be configured to adopt
balloons of various sizes to control the angle of needle
penetration. Moreover, the use of balloons would enable accurate
penetration of the needle at the desired target.
[0035] In another embodiment, a drug eluting stent may be used to
strengthen or increase the thickness of the fibrous cap of the
vulnerable plaque in a controlled manner. Increasing the thickness
of the fibrous cap may redistribute and lower the stresses in the
fibrous cap. This may stabilize the plaque and prevent it from
rupturing.
[0036] Referring to FIG. 4, a drug delivery stent 450 to treat a
vulnerable plaque region is illustrated. Stent 450 is disposed in
an arterial lumen 430 to treat both occlusive plaque 460 and
vulnerable plaque 410 located downstream from occlusive plaque 460.
As illustrated, stent 450 releases a drug (indicated by arrows 470)
to treat the vulnerable plaque 410. As discussed above, vulnerable
plaque regions commonly exist near occlusive plaque, and treating
both might be advantageous over separate procedures. Occlusive
plaque 460 has grown to cause a narrowing of the arterial lumen
430. Stent 450 is shown in a state before expansion to enlarge the
diameter of the arterial lumen 430. A dilation balloon (not shown)
may be used to expand stent 450, or stent 450 may be made of a
material that self-expands (e.g., Nitinol) so that a dilation
balloon is not needed.
[0037] As illustrated in FIG. 4, vulnerable plaque 410 is located
downstream of the occlusive plaque 460 but does not show any vessel
occlusion. Vulnerable plaque 410 has soft lipid core 415 with
fibrous cap 420 separating vulnerable plaque 410 from arterial
lumen 430. As indicated by arrows 470, stent 450 releases a drug or
biologically active agent through the bloodstream of arterial lumen
430 to treat vulnerable plaque 410. In one embodiment, lipid
lowering agents may be released. Lowering of serum LDL cholesterol
may lead to a reduction in the amount of cholesterol entering
vulnerable plaque 410, and increases high density lipoprotein (HDL)
cholesterol which may contribute to active LDL removal from the
vessel wall 425. Animal studies have shown that removal of lipid
increases the relative collagen content of fibrous cap 420 and
could increase the production of collagen, favoring vulnerable
plaque stabilization. Lipid lowering animal studies suggest this
also treats vulnerable plaque 410 by reducing local inflammation
and the expression and activity of matrix-degrading enzymes,
favoring collagen accumulation in fibrous cap 420, making it more
resistant to rupture. Lipid lowering agents may also change the
composition of lipid core 415 to promote plaque stabilization. It
is thought that the lipid lowering agents may convert the high
concentration of cholesterol esters to insoluble cholesterol
monohydrate crystals, resulting in a more stiff lipid core 415 that
is more resistant to plaque rupture. Lipid lowering agents include,
but are not limited to hydroxy-methylglutaryl coenzyme A (HMG CoA)
reductase inhibitors, niacin, bile acid resins, and fibrates.
[0038] Examples of doses of agents which may be used with
embodiments of the invention, such as a drug delivery stent (i.e.,
the stent having been loaded with a drug which is eluted/released
over time or a needle catheter) are described herein. The
particular effective dose may be modified based on therapeutic
results, and the following exemplary doses are acceptable initial
levels which may be modified based on therapeutic results.
[0039] In an alternative embodiment, antioxidants may be released
from stent 450. The oxidation of LDL cholesterol appears to have
negative impact upon vessel processes during atherogenesis.
Oxidized LDL binds to cell receptors on macrophages and contributes
to foam cell formation. As such, antioxidants, through their
inhibition of LDL oxidation, may contribute to plaque
stabilization. Antioxidants may also promote plaque stabilization
by reducing matrix degradation within vulnerable plaque 410.
Examples of antioxidants include, but are not limited to vitamin E
.alpha.-tocopherol), vitamin C, and .beta.-carotene supplements.
Additionally, HMG CoA reductase inhibitors may also reduce oxidized
LDL levels by increasing the total antioxidant capacity of
plasma.
[0040] Lipid lowering agents such as statins and antioxidants may
be administered at a level of about 0.5 mg/kg per day; higher doses
(e.g., 5 times higher) appear to inhibit angiogenesis. See Weis et
al., Statins Have Biphasic Effects on Angiogenesis, Circulation,
105(6):739-745 (Feb. 12, 2000). This dosage level may be achieved
by loading a stent with about 10-600 .mu.g of the statin, where the
stent is designed to elute the statin over a period of 8 weeks. In
one embodiment, the stent may have a length of 13 mm and a diameter
of 3 mm. In one embodiment, the stent may have a drug release rate
of 150 .mu.g over 10 hours, or 15 .mu.g per hour. In another
embodiment, the stent may have a lower release rate of about 20
.mu.g over 10 hours, over 2 .mu.g per hour. Additionally, a
compound called "AGI-1067", developed by AtheroGenics, Inc. of
Alpharetta, Ga., may be loaded onto the stent. AGI-1067 has been
shown in studies to have direct anti-atherosclerotic effect on
coronary blood vessels, consistent with reversing the progression
of coronary artery disease.
[0041] In an alternative embodiment, extracellular matrix synthesis
promoters may be released from stent 450. Reduced collagen content
in fibrous cap 420 may result from decreased synthesis of
extracellular matrix by smooth muscle cells (SMC) and/or increased
breakdown by matrix-degrading proteases, thereby leading to
thinning and weakening of fibrous cap 420, predisposing vulnerable
plaque 410 to rupture with hemodynamic or mechanical stresses.
[0042] Vascular SMC synthesize both collagenous and noncollagenous
portions of the extracellular matrix. Lack of sufficient SMC to
secrete and organize the matrix in response to mechanical stress
could render fibrous cap 420 more vulnerable to weakening by
extracellular matrix degradation. Atherosclerosis and arterial
injury lead to increased synthesis of many matrix components. In
contrast, vulnerable plaque, in general, lacks a sufficient
quantity of healthy matrix to provide strength to the fibrous cap
to prevent rupture. Thus, promotion of SMC proliferation may lead
to plaque stabilization. Delivery of cytokines and growth factors
may also achieve SMC proliferation. SMC promoters and proliferative
agents such as lysophosphatidic acid may be loaded onto a stent for
delivery within a vessel. See Adolfsson et al., Lysophosphatidic
Acid Stimulates Proliferation of Cultured Smooth Muscle Cells from
Human BPH Tissue: Sildenafil and Papaverin Generate Inhibition,
Prostate, 51(1):50-8 (Apr. 1, 2002). For example, a SMC promoter
may be administered at a level of about 0.5 mg/kg per day to higher
doses of about 2.5 mg/kg per day. This dosage level may be achieved
by loading a stent with about 10-600 .mu.g of the SMC promoter,
where the stent is designed to elute the drug over a period of 8
weeks. In one embodiment, the stent may have a drug release rate of
150 .mu.g over 10 hours, or 15 .mu.g per hour. In another
embodiment, the stent may have a lower release rate of about 20
.mu.g over 10 hours, over 2 .mu.g per hour.
[0043] In an alternative embodiment, inhibitors of plaque
inflammation and extracellular matrix degradation may be released
from stent 450. Increased matrix degrading activity associated with
enzymes derived from cells such as vascular SMC, macrophages and T
lymphocytes is a common finding in vulnerable plaque. Studies
suggest that matrix metalloproteinases (MMPs) are involved in
matrix degradation. Plaque stabilization could be achieved through
inhibition of extracellular matrix degradation by preventing the
accumulation of macrophages and T lymphocytes in the vulnerable
plaque or by inhibiting the proteolytic enzyme cascade directly.
Possible methods to achieve MMP inhibition include increasing the
levels of natural inhibitors (TIMPS) either by exogenous
administration of recombinant TIMPs or administrating synthetic
inhibitors. Synthetic inhibitors of MMPs, including
tretracycline-derived antibiotics, anthracyclines and synthetic
peptides may also be used. MMP inhibitors may be themselves
antioxidants and statins based on preclinical animal data. Studies
have shown MMP inhibitors, such as cerivastatin to significantly
reduce tissue levels of both total and active MMP-9 in a
concentration-dependent manner. See Nagashima et al., A
3-hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor,
Cerivastatin, Supresses Production of Matrix Metalloproteinase-9 in
Human Abdominal Aortic Aneurysm Wall, J. Vascular Surgery,
36(1);158-63 (July 2002). As with statins as described above, MMP
inhibitors may be administered at a level of about 0.5 mg/kg per
day to higher doses of about 2.5 mg/kg per day. This dosage level
may be achieved by loading a stent with about 10-600 .mu.g of the
SMC promoter, where the stent is designed to elute the drug over a
period of 8 weeks. In one embodiment, the stent may have a drug
release rate of 150 .mu.g over 10 hours, or 15 .mu.g per hour. In
another embodiment, the stent may have a lower release rate of
about 20 .mu.g over 10 hours, over 2 .mu.g per hour. Additionally,
Avasimibe, an ACAT (Acyl-CoA: cholesterol acyltransferase)
inhibitor, in the 10 mg/kg range appears to impact MMPs and plaque
burden, as well as monocyte adhesion. See Rodriguez and Usher,
Anti-atherogenic Effects of the acyl-CoA: Cholesterol
Acyltransferase Inhibitor, Avasimibe (CI-1011), in Cultured Primary
Human Macrophages, Atherosclerosis, 161(1); 45-54 (March 2002).
[0044] Dosages and concentrations described above are exemplary,
and other dosages may be applied such that when delivered over a
biologically relevant time at the appropriate release rate, gives a
biologically relevant concentration. The biologically relevant time
may depend on the biologic target but may range from several hours
to several weeks with the most important times being from 1 day to
42 days. Dosages may also be determined by conducting preliminary
animal studies and generating a dose response curve. Maximum
concentration in the dose response curve could be determined by the
solubility of a particular compound or agent in the solution and
similarly for coating a stent.
[0045] In yet another alternative embodiment, the active agent may
induce collateral artery or vessel growth (i.e., angiogenesis or
arteriogenesis) near the vulnerable plaque region such that, in the
event of a plaque rupture and subsequent occlusive thrombosis,
secondary blood paths may bypass the ruptured region and allow for
continued blood flow throughout the artery. FIG. 12 illustrates one
embodiment of arterial section 1200 with collateral vessels that
have been induced with an active agent. Collateral vessels 1250,
1251, 1252 and 1253 provide paths for blood flow to continue
through arterial section 1200 either temporarily until the
occlusion is treated, or permanently to provide greater blood flow.
The active agent has been delivered through drug delivery stents
1240 and 1242. Primary artery 1230 branches into sections 1231,
1232, and 1233 and arrows 1205 indicate the direction of blood flow
through arterial section 1200. Vulnerable plaque 1210 is disposed
within arterial branch 1232. Stent 1240 induces the growth of
collateral vessels 1250, 1251 and 1252 around vulnerable plaque
1210. Collateral vessel 1251 starts upstream (near stent 1240) from
vulnerable plaque 1210 and ends just downstream from vulnerable
plaque 1210. Collateral vessel 1250 starts upstream from vulnerable
plaque 1210 and ends further downstream of arterial branch 1232.
Collateral vessel 1252 starts upstream from vulnerable plaque 1210
and ends at arterial branch 1233.
[0046] Alternatively, collateral vessel growth may be induced from
an arterial branch that does not contain a vulnerable plaque. Stent
1242 carrying an active agent is disposed within arterial branch
1231 which induces collateral vessel 1253 from arterial branch 1231
to branch 1233. As such, collateral vessel 1253 may provide an
alternate pathway for continued blood flow in the event vulnerable
plaque 1210 ruptures. Although therapeutic or biologically active
agents for angiogenesis and arteriogenesis have been described
above with respect to drug eluting stents, other types of medical
devices may be utilized. In one embodiment, for example, needle
catheters may be used to deliver agents to induce angiogenesis
and/or arteriogenesis. Needle catheters are described in greater
detail below with respect to FIGS. 9-10.
[0047] In one embodiment, therapeutic or biologically active agents
may be released to induce arteriogenesis or angiogenesis either
downstream, or away from the vulnerable plaque to the myocardium.
In the event that an occlusive thrombus occurs from a vulnerable
plaque, the myocardium perfused by the affected artery may be
salvaged. Representative therapeutic or biologically active agents
include, but are not limited to, proteins such as vascular
endothelial growth factor (VEGF) in any of its multiple isoforms,
fibroblast growth factors, monocyte chemoatractant protein 1
(MCP-1), transforming growth factor alpha (TGF-alpha), transforming
growth factor beta (TGF-beta) in any of its multiple isoforms,
DEL-1, insulin like growth factors (IGF), placental growth factor
(PLGF), hepatocyte growth factor (HGF), prostaglandin E1 (PG-E1),
prostaglandin E2 (PG-E2), tumor necrosis factor alpha (TBF-alpha),
granulocyte stimulating growth factor (G-CSF), granulocyte
macrophage colony-stimulating growth factor (GM-CSF), angiogenin,
follistatin, and proliferin, genes encoding these proteins, cells
transfected with these genes, pro-angiogenic peptides such as PR39
and PR11, and pro-angiogenic small molecules such as nicotine. In
one embodiment, 10-600 .mu.g of one or a mixture of these agents
may be loaded onto a stent for delivery within a vessel. These
agents may have a release rate for up to eight weeks. In another
embodiment, a stent may be loaded with 300 micrograms of an
angiogenic agent with a release rate of eight weeks. Alternatively,
a dose may be determined by those skilled in the art by conducting
preliminary animal studies and generating a dose response curve.
Maximum concentration in the dose response curve would be
determined by the solubility of the compound in the solution.
[0048] In using drug eluting stents and related technology to
deliver the vulnerable plaque treatment agent (e.g., stent 450 of
FIG. 4), the active agent may be dispersed or co-dissolved directly
in a solution of a matrix such as ethylene vinyl alcohol, ethylene
vinyl acetate, poly(hydroxyvalerate), poly (L-lactic acid),
poly(D,L-lactic acid), poly(glycolic acid),
poly(lactide-co-glycolide) polycaprolactone, polyanhydride,
polydiaxanone, polyorthoester, polyamino acids, poly(trimethylene
carbobnate), or other suitable synthetic polymers. The polymer may
be coated on a stent using dip coating, spin coating, spray coating
or other coating methods known in the art.
[0049] FIGS. 5A-5C illustrate the placement of drug delivery stent
550 to treat both occlusive plaque 560 and vulnerable plaque 510
localized downstream from occlusive plaque 560. In this example,
vulnerable plaque 510 is located near a branched region of arterial
lumen 530. In one embodiment, stent 550 is a self-expanding stent,
and is disposed near distal end 542 of catheter 540. Catheter 540
is advanced through arterial lumen 530 and positioned near
occlusive plaque 560. Retractable sheath 545 maintains stent 550 in
a crimped and collapsed position so that stent 550 may be fit
within arterial lumen 530. As illustrated in FIG. 5A, as sheath 545
retracts, stent 550 expands and applies physical pressure to
occlusive plaque 560. In effect, stent 550 widens arterial lumen
530 that has been narrowed because of occlusive plaque 560. FIG. 5B
illustrates stent 550 in a fully expanded position, allowing normal
blood flow through arterial lumen 530.
[0050] Stent 550 may be coated with a drug or biologically active
agent that releases from the surface of stent 550 when sheath 545
retracts and stent 550 becomes exposed to the blood in arterial
lumen 530. The flow of the blood through arterial lumen 530
migrates the agent (as indicated by the arrows 570) towards
vulnerable plaque 510. The agent targets vulnerable plaque 510. In
one embodiment, the agent thickens and/or strengthens fibrous cap
520. In doing so, the likelihood of fibrous cap 520 rupturing is
reduced. In another embodiment, the distribution, size or
consistency of lipid core 515 is altered. A combination of agents
may be utilized both to thicken fibrous cap 520 and alter the size
or consistency of lipid core 515 of vulnerable plaque 510 to
strengthen fibrous cap 520. FIG. 5C illustrates the treatment
effects of deploying stent 550. Occlusive plaque 560 has been
treated physically by compressing it against the arterial wall.
Vulnerable plaque 510 has been treated through strengthening and/or
thickening fibrous cap 520 and the favorable alteration of the size
or distribution of the lipid core 515.
[0051] A vulnerable plaque treatment agent may be delivered
independent of treating occlusive atherosclerosis. FIG. 6
illustrates a vulnerable plaque treatment agent delivered in the
form of a microcapsule or microparticle 670. The use of
microparticle 670 allows for delivery of a treatment agent in a
controlled manner to ensure treatment over a desired period of
time. Some microparticles 670 possess the characteristic of being
degradable at a designated rate.
[0052] Microparticles 670 may also be designed to adhere to vessel
wall 635 by blending in or coating microparticles 670 with
materials that promote adhesion to vessel wall 635. Microparticles
670 may be rendered bioadhesive by modifying them with bioadhesive
materials such as gelatin, hydroxypropyl methylcellulose,
polymethacrylate derivatives, sodium carboxymethycellulose,
monomeric cyanoacrylate, polyacrylic acid, chitosan, hyaluronic
acid, anhydride oligomers, polyycarbophils, water-insoluble metal
oxides and hydroxides, including oxides of calcium, iron, copper
and zinc. Microparticles 670 may be modified by adsorbing the
bioadhesive material on microparticles 670 through ionic
interactions, coating the bioadhesive material on the
microparticles by dip or spray coating, conjugating the bioadhesive
material to the polymer constituting microparticle 670, or blending
in the bioadhesive material into the polymer constituting the
microparticles 670, before the microparticles 670 are formed.
[0053] The particle size of microcapsules 670 may be less than
about 10 microns to prevent possible entrapment in the distal
capillary bed. Microparticles 670 may be delivered intra-arterially
near the site of vulnerable plaque 610, and also prophylactically
at locations that are proximal and distal to vulnerable plaque 610
(not shown). Upon delivery with infusion catheter 640,
microparticles 670 travel a short distance distally before adhering
to vessel wall 630 near vulnerable plaque 610. The active agent of
microparticles 670 is then released over time to thicken and/or
strengthen fibrous cap 620, alter the size or distribution of lipid
core 615, or both. Microparticles 670 may be delivered with
infusion catheter 640 or any other delivery device known in the
art. In one embodiment, infusion catheter may be a needle catheter
having one or more injection ports to release microparticles
670.
[0054] Suitable polymers for the controlled-release microparticles
670 include, but are not limited to, poly (L-lactide), poly
(D,L-lactide, poly(glycolide), poly lactide-co-glycolide),
polycaprolactone, polyanhydride, polydiaxanone, polyorthoesters,
polyamino acids, poly (trimethylene carbonate), and combinations
thereof. Several methods exist for forming microparticles 670,
including, but not limited to solvent evaporation, coacervation,
spray drying, and cryogenic processing.
[0055] In solvent evaporation, the polymer is dissolved in a
volatile organic solvent such as methylene chloride. The treatment
agent is then added to the polymer solution either as an aqueous
solution containing an emulsifying agent such as PVA, or as a solid
dispersion, and stirred, homogenized or sonicated to create a
primary emulsion of treatment agent in the polymer phase. This
emulsion is stirred with an aqueous solution that contains a
polymer in the aqueous phase. This emulsion is stirred in excess
water, optionally under vacuum to remove the organic solvent and
harden the microparticles. The hardened microparticles are
collected by filtration or centrifugation and lyophilized.
[0056] The microparticles may also be formed by coacervation. In
this method, a primary emulsion of treatment agent in an aqueous
phase is formed as in the solvent evaporation method. This emulsion
is then stirred with a non-solvent for the polymer, such as
silicone oil to extract the organic solvent and form embryonic
microparticles of polymer with trapped treatment agent. The
non-solvent is then removed by the addition of a volatile second
non-solvent such as a heptane, and the microparticles harden. The
hardened microparticles are collected by filtration or
centrifugation and lyophilized.
[0057] In spray drying, the treatment agent, formulated as
lyophilized powder is suspended in a polymer phase consisting of
polymer dissolved in a volatile organic solvent such as methylene
chloride. The suspension then spray dried to produce polymer
microparticles with entrapped treatment agent.
[0058] Microparticles may also be formed by cryogenic processing.
In this method, the treatment agent, formulated as lyophilized
powder is suspended in a polymer phase consisting of polymer
dissolved in a volatile organic solvent such as methylene chloride.
The suspension is sprayed into a container containing frozen
ethanol overlaid with liquid nitrogen. The system is then warmed to
-70.degree. C. to liquefy the ethanol and extract the organic
solvent from the microparticles. The hardened microparticles are
collected by filtration or centrifugation and lyophilized.
[0059] FIGS. 13A-13B illustrate cross-sectional views of one
embodiment of a drug eluting stent that may be used to increase the
thickness or strengthen, in a controlled manner, the fibrous cap
near a vulnerable plaque. Strengthening of and increasing the
thickness of the fibrous cap may redistribute and lower the
stresses in the fibrous cap, effectively stabilizing the plaque and
preventing its rupture.
[0060] Cross-sectional views 1300 include lumen 1330 (e.g., an
arterial lumen) with lipid core 1315 of a vulnerable plaque and
fibrous cap 1320. Stent 1340 having stent struts, for example
struts 1342, 1344, is placed within lumen 1330 near lipid core 1315
and fibrous cap 1320. In one embodiment of using a drug eluting
stent, stent 1340 serves as a vehicle for delivering an appropriate
therapeutic or biologically active agent to the site of the
vulnerable plaque. After stent 1340 has been deployed at a desired
location, it may cause platelet deposition, fibrosis and neointimal
formation in the stented region. This fibromuscular response may
cause the original fibrous cap 1320 thickness to increase, thereby
lowering the stresses in fibrous cap 1320 (as illustrated in FIG.
13B). This additional hyperplasia, combined with original fibrous
cap 1320 produced by stent 1340 can be thought of as a "neo-cap."
Neo-cap 1360, as illustrated in FIG. 13B, has developed near the
inner diameter of stent 1340. The controlled release of a drug or
biologically active agent from stent 1340 may allow an increase in
fibrous cap 1320 thickness because of the injury sufficient to
stabilize lipid core 1315, but may minimize or prevent excessive
restenosis. The type of biologically active agent, the dosage,
release rate and the duration of release may influence the growth
of neo-cap 1360. Therefore, by controlling these factors the growth
of neo-cap 1360 may be controlled. After the thickness of fibrous
cap 1320 has been increased and lipid core 1315 has been
stabilized, the size of lumen 1330 may be increased by balloon
angioplasty if necessary.
[0061] The biologically active agent used for controlling fibrous
cap 1320 growth may be delivered using a metal stent platform
(e.g., stent 1340). The drug may be released through a polymer
membrane-matrix system that is deposited on the surface of the
stent. Polymers such as EVAL can be used for the membrane-matrix
system. Several choices of metals are available for making the
stent, including but not limited to, stainless steel,
cobalt-chromium alloy and shape-memory alloys such as Nitinol.
Depending on the design of the stent and delivery system, it may be
possible to direct the biologically active agent to act in specific
locations of interest in the vulnerable plaque. For example,
biologically active agents which are anti-inflammatory in nature
may be optimally delivered into or around the plaque shoulder
regions, a site of inflammatory cell accumulation where the lipid
core edges meet the normal wall opposite the vulnerable plaque.
Conversely, it may be possible to direct the biologically active
agent away from specific locations of interest in the vulnerable
plaque. For example, biologically active agents which are
anti-restenotic, such as Actinomyocin-D, may be directed to act
away from the expected regions of high stress in fibrous cap 1320,
which cover lipid core 1315 in general. These regions would be the
shoulder regions or the portion of fibrous cap 1320 centered
circumferentially along lipid core 1315 edge nearest lumen 1330.
And finally, it may also be possible to design stent 1340 or other
types of delivery systems that selectively diffuse a biologically
active agent appropriately, by leveraging through stent 1340 design
the stress-assisted diffusion properties at the stent-plaque
interface in these select regions.
[0062] The biologically active agent may also be delivered using a
biodegradable polymeric stent. In this case, after the biologically
active agent has eluted from the stent, the stent degrades within a
certain period of time leaving behind a stabilized plaque. The
polymers available for making the stent include poly-L-lactide,
polyglycolic/poly-L-lactic acid (PGLA), Poly-L-latic acid (PLLA),
poly-L-lactide, polycaprolactone (PCL),
poly-(hydroxybutyrate/hydroxyvalerate) copolymer (PHBV) or shape
memory polymers such as a compound of oligo(e-caprolactone)
dimethacrylate and n-butylacrylate.
[0063] Examples of therapeutic or biologically active agents
include but are not limited to rapamycin, actinomycin D (ActD) and
their derivatives, antiproliferative substances, antineoplatic,
antinflammatory, antiplatelet, anticoagulant, antifebrin,
antithrombin, antimitotic, antibiotic and antioxidant substances.
Examples of antineoplastics include taxol (paclitaxel and
docetaxel). Examples of antiplatelets, anticoagulants, antifibrins
and antithrombins include sodium heparin, low molecular weight
heparin, hirudin, IIb/IIIa platelet membrane receptor antagonist
and recombinant hirudin. Examples of antimitotic agents include
methotrexate, azathioprine, vincristine, vinblastine, fluororacil,
adriamycin and mutamycin. Examples of cytostatic or
antiproliferative agents include angiopeptin, calcium channel
blockers (such as Nifedipine), Lovastatin (an inhibitor of HMG-CoA
reductase, a cholestrol lowering drug from Merck). Other
therapeutic or biologically active agents which may be utilized
include alpha-interferon, genetically engineered epithelial cells
and dexamethasone. Dosages comparable to that described above with
respect to drug eluting stents may be used.
Stent Grafts
[0064] In one embodiment, a stent graft may be used for the
treatment of vulnerable plaque. The stent graft may have a thin,
expandable polytetrafluoroethylene (ePTFE) cylindrical tube affixed
to an inner surface of a self-expandable stent. The inner surface
of the ePTFE tube may have a layer of endothelial cells. The
endothelial cells, when dispersed near the vulnerable plaque
region, may promote cell migration to form a fully lined monolayer
on the lumen surface. The stent graft may also shield existing
vulnerable plaque from the possibility of an acute, thrombotic
event. If the plaque ruptures, a cascade of blood-vessel wall
interactions occurs, resulting in thrombosis and ultimately partial
or total arterial occlusion. Therefore, shielding vulnerable plaque
from the vessel lumen would eliminate the possibility of plaque
contents being exposed to blood flow in case of rupture. In
addition, the stent graft may provide reinforcement to the fibrous
cap and reduce any physical stress placed on it due to the size of
the lipid core.
[0065] FIG. 7 illustrates another embodiment for treating
vulnerable plaque in which stent graft 750 is deployed near
vulnerable plaque 710. Stent graft 750 has a thin expandable
polytetrafluoroethylene (ePTFE) cylindrical tube 754 affixed to
inner surface 751 of self-expandable stent 752. Inner surface 755
of ePTFE tube 754 has a layer of endothelial cells 756. The layer
of endothelial cells 756 promotes cell migration that eventually
forms a complete monolayer on the surface of arterial lumen 730. As
such, stent graft 750 shields existing vulnerable plaque 710 from
an occlusive thrombosis event. Moreover, stent graft 750 may
provide reinforcement to fibrous cap 720 and reduce any increased
physical stress placed on it in vivo due to lipid core 715 presence
or other hemodynamic forces.
[0066] ePTFE tube 754 serves as a physical barrier between
vulnerable plaque 710 and arterial lumen 730. Because ePTFE lumen
surface 755 acts as an arterial equivalent, ePTFE tube 754 should
remain free from occlusion. In one embodiment, the ePTFE tube 754
is made anti-thrombotic by surface treatment. The surface of ePTFE
tube 754 may be made anti-thrombotic for use as a vascular graft by
seeding surface 755 with endothelial cells 756. Endothelial cells
756 seeded within vascular grafts have been shown to promote cell
migration that eventually form a fully lined monolayer on a lumen
surface.
[0067] Several approaches exist to seed stent graft 750 with
endothelial cells 756. In one embodiment, a pressurized sodding
technique may be used in which ePTFE tube 754 is expanded to 5 psi
using media that contain endothelial cells. Endothelial cells 756
are isolated from the canine falciform ligament fat. Endothelial
cells may also be isolated from human liposuction fat micro-vessel,
umbilical veins, and other comparable sources.
[0068] Stent graft 750 may be disposed near a target vulnerable
plaque 710 in a manner similar to that of a drug eluting stent 450,
550 at an occlusive site discussed above (e.g., with respect to
FIGS. 4 and 5A-5C). Stent graft 750 is disposed near a distal end
of a catheter (not shown). The catheter is passed through arterial
lumen 730 so that stent graft 750 is positioned near vulnerable
plaque 710. A retractable sheath (not shown) maintains the stent
graft in a crimped position so that the stent graft may be advanced
within arterial lumen 730. As illustrated in FIG. 7, stent graft
750 expands and applies physical pressure to fibrous cap 720
surrounding vulnerable plaque 710. FIG. 7 illustrates stent graft
750 in a fully expanded position, allowing normal blood flow
through arterial lumen 730.
[0069] FIGS. 8A-8B illustrate cross-sectional views of stent graft
850 having inner tube 854 lined with endothelial cells 856 for
treating vulnerable plaque. A self-expandable stent 852 is used as
structural support to keep stent graft 850 secured in place within
arterial lumen 730. A self-expandable stent may be advantageous
over a balloon expandable stent. A self-expandable stent does not
require an internal lumen pressure to expand, and so any seeded
cells 856 are kept intact. In contrast, a balloon expandable stent
could damage cells 856 of stent graft 850 when expanded. The
self-expanding stent 852 may be made from a shape memory alloy such
as NiTi (e.g., Nitinol). In order to provide additional flexibility
to stent 852, stent links (e.g., 860, 861) may be eliminated from
stent 852. In an alternative embodiment, stent 852 may have a
series of shape memory metallic rings (not shown) bonded to the
outer surface of ePTFE tubing 854.
[0070] Various techniques are available to bond ePTFE tube 854 to
stent 852. For example, to bond the ePTFE tube to the metal, a
primer is first applied to the metallic portions (e.g., 860, 861)
of stent 852. These rings are then inserted over ePTFE tube 854.
Silicon adhesive is used to bond metallic rings 860, 861 to ePTFE
tubing 854. The stent graft is cured at about 150.degree. C. for
approximately 15 minutes. The silicon adhesive seeps through the
ePTFE tube matrix and after curing acts as a medium that
mechanically fastens the ePTFE tube to the metal. The inner surface
of the polymeric tube is then seeded with endothelial cells.
[0071] In addition to the shape memory alloys, stent rings 860, 861
may also be made from shape memory polymers. Various shape memory
polymers with great potential for biomedical applications are
currently in the research phase. For example oligo(e-caprolactone)
dimethacrylate and n-butyl acrylate are two monomeric compounds
that, when combined, generate a family of polymers that exhibit
excellent shape memory characteristics. The oligo(e-caprolactone)
dimethacrylate furnishes the crystallizable "switching" segment
(characteristic of shape memory materials) that determines both the
temporary and permanent shape of the polymer. By varying the amount
of the comonomer, n-butyl acrylate, in the polymer network, the
cross-link density can be adjusted. This allows the mechanical
strength and transition temperature of the polymers to be tailored
over a wide range. Therefore, the stent incorporating these
polymers can be deployed using their shape memory characteristics.
Furthermore, other polymers such as polyurethane and ultra high
molecular weight polyethylene (UHMWPE) can also be used for tubing
used in the stent graft.
[0072] In an alternative embodiment, stent graft 850 may also be
used as an apparatus for local drug delivery. Stent graft 850 may
be loaded with anti-restenotic, anti-thrombotic, or other
vulnerable plaque treatment agents (e.g., as discussed above with
respect to FIGS. 4 and 5A-5C). Furthermore, in yet another
alternative embodiment, stent graft 850 may be radioactively
enhanced or incorporated with a material that generates a magnetic
susceptibility artifact of stent graft 850.
Needle Catheter
[0073] In another embodiment, a vulnerable plaque treatment drug or
biologically active agent may be injected through or around a
vulnerable plaque region. In one embodiment, a needle catheter may
be used to inject the biologically active agent. The needle
catheter may be adjusted to penetrate various targets around the
vulnerable plaque including, but not limited to: fibrous cap,
proteoglycan-rich surface layer, subintimal lipid core, proximal or
distal regions of the vulnerable plaque, media containing smooth
muscle cells around the lipid core, and the periadventitial
space.
[0074] In an alternative embodiment, the needle catheter may
include sensing capabilities to determine the depth of penetration
of the needle, as well as dial-in needle extension. Furthermore,
different angle balloons may be added in order to use case-specific
ramp angle to penetrate into the vulnerable plaque region while
positioning the needle catheter below the actual occlusion. The
needle catheter may be placed proximal or distal to the vulnerable
plaque region because studies have shown cell localization,
activity, and apoptosis have preferential occurrence in the
upstream or downstream parts of vulnerable plaque regions.
[0075] FIG. 9A illustrates a cross-sectional view of one embodiment
of needle catheter 950 that may be used to inject a vulnerable
plaque treatment agent into arterial wall 980 near vulnerable
plaque 910. Vulnerable plaque 910 has developed within arterial
wall 980, separated from arterial lumen 930 by fibrous cap 920.
Distal end 941 of catheter 940 has inflatable balloon 948 with at
least one needle lumen 945 extending from distal end 941 of
catheter 940 along proximal end 947 of balloon 948. Retractable
needle 945 extends from needle lumen 942 and penetrates arterial
wall 980. Inflated balloon 948 secures needle catheter 950 at a
target location. Moreover, because needle sheath 942 is coupled
along proximal end 947 of balloon 948, inflated balloon 948
provides a penetration angle for needle 945. Needle catheter 950,
as illustrated, has two needles 945, 946 extending from distal end
941 of catheter 950. Any number of needles may be utilized with
needle catheter 950. For example, in an alternative embodiment, the
needle catheter may have only one needle for injecting a vulnerable
plaque treatment agent.
[0076] As illustrated, needle catheter 950 targets lipid core 915
of vulnerable plaque 910 directly. In one embodiment, a lipid
lowering agent may be injected into vulnerable plaque 910, or
agents which could change lipid core properties could be injected.
PEG with an aldehyde/gluteraldehyde mix may be injected into lipid
core 915 potentially cross-linking vulnerable plaque 910 components
to inhibit erosion, rupture, or other forms of destabilization.
Other vulnerable plaque treatment agents may be used, including
antioxidants, and extracellular matrix synthesis promoters (e.g.,
as discussed with respect to FIGS. 4 and 5A-5C).
[0077] Needle catheter 950 may also be configured to include a
feedback sensor (not shown) for mapping the penetration depth of
needles 945, 946. The use of a feedback sensor provides the
advantage of accurately targeting the injection location. Depending
on the type of treatment agent used and treatment desired, the
target location for delivering the treatment agent may vary. For
example, it may be desirable to inject a drug near fibrous cap 920
or media 984 of arterial wall 980. Alternatively, it may be
desirable to inject a drug into lipid core 915, or adventitia
986.
[0078] In use, distal end 941 of needle catheter 950 is inserted
into the lumen of a patient and guided to a vulnerable plaque
region. As illustrated in FIG. 9A, distal end 941 of needle
catheter 950 is positioned near a proximal end 912 of vulnerable
plaque 910. Alternatively, needle catheter 950 may be positioned
near a distal end 914 of vulnerable plaque 910. Vulnerable plaque
910 may be detected using the sensor (not shown) disposed on needle
catheter 950. By utilizing a sensor, the injection site for
treating vulnerable plaque 910 may be precisely identified.
[0079] FIGS. 10A and 10B illustrate cross sectional views of one
embodiment of a needle catheter for injecting a vulnerable plaque
treatment drug or biological agent. FIG. 10 illustrates needle
catheter 1001 with sensing capabilities having elongated catheter
body 1010 that surrounds needle lumen 1012 and inner lumen 1014.
Housed within inner lumen 1014 are fluid lumen 1016 and inner
member 1018 that also contains guide wire 1020, guide wire lumen
1022, and ultrasonic element lumen 1024. Inflatable balloon 1026 is
coupled to inner lumen 1014 and the inner member 1018. Proximal end
1028 of balloon 1026 is coupled to distal end 1030 of inner lumen
1014 and distal end 1032 of balloon 1026 is coupled to distal end
1036 of inner member 1018.
[0080] In an alternative embodiment, both guide wire 1022 and
retractable ultrasonic element 1034 may be housed within inner
member 1014. Elongate body 1010 surrounds inner member 1014 and
needle lumen 1012. Housed within inner lumen 1014 are inner member
1018 and fluid lumen 1016. Inner member 1018 surrounds guide wire
1022 and retractable ultrasonic element 1034. Inflatable balloon
1026 is coupled to inner lumen 1014 and inner member 1018. Proximal
end 1028 of balloon 1026 is coupled to distal end 1030 of inner
lumen 1014 and distal end 1032 of balloon 1026 is coupled to distal
end 1036 of inner member 1018.
[0081] The ultrasonic element lumen 1024 of inner member 1018
houses retractable ultrasonic element 1034. The distal end of the
ultrasonic element has an ultrasound transducer or transducer array
and the proximal end contains the associated co-axial cable that
connects to an imaging display system (not shown). Ultrasonic waves
generated by the ultrasonic element impinge on the surface of a
vulnerable plaque or vulnerable plaque region. The timing/intensity
of the ultrasonic waves reflected back to the transducer
differentiates between the various anatomic boundaries or
structures of the vulnerable plaque region, for example, the
various layers of an arterial wall. The waves detected by the
transducer are converted to electric signals that travel along the
coaxial cable to the imaging system. The electrical signals are
processed and eventually arranged as vectors based on the digitized
data. In one embodiment, the ultrasound transducer has
piezoelectric crystal configured for optimal acoustic output
efficiency and energy conversion. In alternative embodiments, the
crystal is made of PZT or lead-ceramic materials such as
PbTiO.sub.3 (lead titanate) or PbZrO.sub.3 (lead zirconate).
[0082] As further illustrated in FIGS. 10A-10B, retractable needle
1013 is housed in needle lumen 1012 and freely movable therein. The
hollow, tubular shaped needle 1013, having an inner diameter within
a range of approximately 0.002 inch to 0.010 inch
(5.1.times.10.sup.-3 cm to 25.4.times.10.sup.-3 cm) and an outer
diameter within the range of approximately 0.004 inch to 0.012 inch
(10.2.times.10.sup.-3 cm to 30.5.times.10.sup.-3 cm), provides a
fluid channel that extends from proximal end 1040 to distal end
1042 of needle 1013. Distal end 1042 of needle 1013 has a curved
tip. In one embodiment, needle 1013 has an angle of curvature of
about 30 degrees to 90 degrees. The curvature of needle 1013
facilitates placement of the needle tip near or within a desired
target of a vulnerable plaque region. Needle 1013 may be formed
from a variety of metals including, but not limited to stainless
steel, NiTi (nickel titanium) (e.g., Nitinol) or other comparable
semi-rigid materials.
[0083] Proximal end 1040 of needle 1013 is coupled to adapter 1050
that couples needle 1013 to needle lock 1052 and needle adjustment
knob 1054. Needle lock 1052 is used to secure needle 1013 in place
and prevent further movement of needle 1013 within an arterial
lumen once needle 1013 is placed in the target position. Needle
adjustment knob 1054 controls accurate needle extension out of the
distal end of the catheter and depth of penetration into the
vulnerable plaque region. As such, movement of needle adjustment
knob 1054 moves needle 1013 in and out of needle lumen 1012. Once
needle 1013 has penetrated a target to a desired depth, needle lock
1052 enables needle 1013 to be secured in place thereby preventing
any movement of needle 1013 within needle lumen 1012.
[0084] A drug injection port 1060 is disposed near proximal end
1062 of needle catheter 1001. Drug injection port 1060 couples
needle catheter 1001 with various dispensing devices such as a
syringe or fluid pump. Fluids injected into drug injection port
1060 travel through needle 1013 and are dispensed from the distal
tip of needle 1013.
[0085] FIGS. 9B-9D illustrate embodiments of needle catheter 950
targeting various regions near a vulnerable plaque for injection of
a vulnerable plaque treatment agent. As discussed above, needle
catheter 950 may have a feedback sensor (e.g., ultrasonic element
1034 of FIG. 10B) to determine and control a penetration depth for
needles 945, 946. The sensor provides the advantage of accurately
targeting a desired injection site. As such, needle catheter 950
may inject a vulnerable plaque stabilizing drug or biologically
active agent into fibrous cap 920 as illustrated in FIG. 9B,
regions within the subintimal space 982 of arterial wall 980 as
illustrated in FIG. 9C, or regions distal to vulnerable plaque 910
as illustrated in FIG. 9D.
[0086] For example, with respect to FIG. 9B antioxidants such as
reactive oxygen scavengers (ROS), vitamin C and E may be injected
into fibrous cap 920. The oxidant acts as a matrix-ase inhibitor to
prevent significant collagen degradation within fibrous cap
920.
[0087] In another embodiment, needle catheter 950 may also be used
as part of a biological or gene therapy method to treat vulnerable
plaque 910. For example, upregulators of tissue inhibitors of
metalloproteinases (TIMPS) may be injected into adventitia 986.
TIMPS are expressed by surrounding smooth muscle cells to
downregulate MMP production. Alternatively, recombinant TF pathway
inhibitors (TFPI) may one day be injected into lipid core 915 to
inhibit thrombosis due to erosion, rupture or other forms of plaque
destabilization.
[0088] In yet another embodiment, needle catheter 950 may be used
to deliver an agent to induce angiogenesis and/or arteriogenesis as
described above with respect to FIG. 12. The therapeutic
angiogenesis agents and drugs discussed above may be injected near
a treatment site as an alternative to delivery by a drug eluting
stent.
[0089] FIGS. 11A-11D illustrate flowcharts describing methods for
stabilizing vulnerable plaque. The methods described with respect
to FIGS. 11A-11D include detecting vulnerable plaque. Various
techniques may be utilized to detect the presence and location of
vulnerable plaque. For example, an ultrasound probe (IVUS) or an
optical coherence tomography probe (OCT) may be guided through the
arteries to scan for vulnerable plaque. Alternatively, magnetic
resonance imaging (MRI) devices may be able to detect vulnerable
plaque. Near Infrared spectroscopy is another technique for
detecting vulnerable plaque. For example, certain wavelengths of
light penetrate the arterial wall and produce a specific chemical
signature that could correlate to vulnerable plaque composition.
Additionally, thermography may also be used to detect vulnerable
plaque. Plaques that rupture tend to be inflamed, and data
indicates this correlates to a higher temperature compared to
non-vulnerable type plaques that do not rupture. As such, a
temperature sensitive probe that measures the temperature of
arteries could indicate the presence of vulnerable plaque.
Alternatively, liquid crystal thermography methods may also be
used. For example, a balloon material made of a thermochromic
liquid crystal material may be able to optically detect property
changes when exposed to increases in temperature. When the balloon
contacts a vulnerable plaque, the higher temperature of the
vulnerable plaque may be detected by analyzing a beam of light
directed towards the suspected vulnerable plaque region and the
balloon material in contact therewith. The light may undergo a
color change in the balloon material as a result of the higher
temperature.
[0090] FIG. 11A describes a method to treat vulnerable plaque
downstream from an occlusive plaque. The occlusive plaque may be
treated with a stent or balloon catheter. The vulnerable plaque may
be treated by altering the lipid core and/or strengthening or
thickening the fibrous cap surrounding the vulnerable plaque. The
vulnerable plaque is first detected by any one of the techniques
described above, including but not limited to IVUS, OCT, MRI, near
infrared spectroscopy, thermography, and liquid crystal
thermography. The vulnerable plaque may be downstream from an
occlusive plaque that has been detected, for example, with an
angiogram. A drug delivery catheter is provided having a vulnerable
plaque stabilizing agent. In one embodiment, the drug delivery
catheter may deploy a drug eluting stent. The drug eluting stent is
positioned at the occlusive plaque to widen the arterial lumen
whose blood flow has been impeded by the plaque. The vulnerable
plaque stabilizing agent is released towards a vulnerable plaque
region located downstream from the release site. Alternatively, the
agents may be in the form of microparticles to control the release
of the agents over time. The agents released from the drug delivery
catheter may include lipid lowering agents, antioxidants,
extracellular matrix synthesis promoters, or inhibitors of plaque
inflammation and extracellular degradation.
[0091] FIG. 1B describes a method to treat vulnerable plaque by
inducing collateral artery or vessel growth to the myocardium
downstream from or adjacent to an occlusive plaque. The occlusive
plaque may be treated with a stent or balloon catheter. By inducing
therapeutic angiogenesis (e.g., collateral artery or vessel
growth), blood flow is maintained in case a vulnerable plaque
ruptures leading to an occlusive thrombosis. The vulnerable plaque
is first detected by any one of the techniques described above,
including but not limited to IVUS, OCT, MRI, near infrared
spectroscopy, thermography, and liquid crystal thermography. The
vulnerable plaque may be downstream from an occlusive plaque that
has been detected, for example, with an angiogram.
[0092] A drug delivery catheter or stent is provided having an
agent that induces collateral artery or vessel growth. In one
embodiment, the drug delivery catheter may deploy a drug eluting
stent. The drug eluting stent is positioned at the occlusive plaque
to widen the arterial lumen whose blood flow has been impeded by
the plaque. The agent to induce collateral artery or vessel growth
is released towards a vulnerable plaque region located downstream
from the drug release site. Representative therapeutic or
biologically active agents include, but are not limited to,
proteins such as vascular endothelial growth factor (VEGF) in any
of its multiple isoforms, fibroblast growth factors, monocyte
chemoatractant protein 1 (MCP-1), transforming growth factor alpha
(TGF-alpha), transforming growth factor beta (TGF-beta) in any of
its multiple isoforms, DEL-1, insulin like growth factors (IGF),
placental growth factor (PLGF), hepatocyte growth factor (HGF),
prostaglandin E1 (PG-E1), prostaglandin E2 (PG-E2), tumor necrosis
factor alpha (TBF-alpha), granulocyte stimulating growth factor
(G-CSF), granulocyte macrophage colony-stimulating growth factor
(GM-CSF), angiogenin, follistatin, and proliferin, genes encoding
these proteins, cells transfected with these genes, pro-angiogenic
peptides such as PR39 and PR11, and pro-angiogenic small molecules
such as nicotine.
[0093] FIG. 11C describes a method to treat vulnerable plaque by
implanting a stent graft on the arterial wall near a vulnerable
plaque. This method of vulnerable plaque stabilization may be
performed independent of treating an occlusive plaque. The
vulnerable plaque is first detected by any one of the techniques
described above, including but not limited to IVUS, OCT, MRI, near
infrared spectroscopy, thermography, and liquid crystal
thermography. The stent graft is disposed near a distal end of a
catheter and advanced within the arterial lumen and positioned near
a vulnerable plaque. Retracting a sheath covering the stent graft
deploys the stent graft. In one embodiment, the stent graft has a
thin ePTFE cylindrical tube affixed to the inner surface of a
self-expandable stent. The inner surface of the stent has a layer
of endothelial cells. The layer of endothelial cells promote cell
migration that forms a fully lined monolayer on the arterial lumen
surface. As such, the stent graft shields existing vulnerable
plaque from an occlusive thrombotic event. Moreover, the stent
graft provides reinforcement to the fibrous cap and reduces any
physical stress placed on it due to the presence of the lipid core
and hemodynamic forces.
[0094] FIG. 11D describes another method to treat vulnerable
plaque. The vulnerable plaque may be treated by injecting a
stabilizing drug or biologically active agent at various locations
within and around the vulnerable plaque. The vulnerable plaque is
first detected by any one of the techniques described above,
including but not limited to IVUS, OCT, MRI, near infrared
spectroscopy, thermography, and liquid crystal thermography. A
needle catheter is advanced through an arterial lumen and
positioned near a proximal end of the vulnerable plaque.
Alternatively, the needle catheter may be positioned at or near a
distal end of the vulnerable plaque. A sensor disposed on the
needle catheter determines a penetration depth for the needle
catheter. The needle catheter may be adjusted to penetrate various
targets around the vulnerable plaque including, but not limited to:
fibrous cap, proteoglycan-rich surface layer, subintimal lipid
core, proximal or distal regions of the vulnerable plaque, media
containing smooth muscle cells above the lipid core and the
adventitial space. The agents released from the drug delivery
catheter may include lipid lowering agents, antioxidants,
extracellular matrix synthesis promoters, inhibitors of plaque
inflammation and extracellular degradation.
[0095] In the foregoing specification, the invention has been
described with reference to specific exemplary embodiments thereof.
It will, however, be evident that various modifications and changes
may be made thereto without departing from the broader spirit and
scope of the invention as set forth in the appended claims. The
specification and drawings are, accordingly, to be regarded in an
illustrative rather than a restrictive sense.
* * * * *