Note: Descriptions are shown in the official language in which they were submitted.
CA 02639421 2008-09-23
Docket No. 04-0218PCT
1VIETHODS AND DEVICES
HAVING ELECTRICALLY ACTUATABLE SURFACES
FIELD OF THE INVENTION
[0001] The present invention relates to the field of insertable or implantable
medical
devices, such as balloon catheters, stents and other sitnilar diagnostic or
therapeutic
devices, which may be provided within the body for treatment and diagnosis of
diseases and conditions. In particular, the present invention relates to
devices whose
surfaces are electrically actuatable between a hydrophobic state and a less
hydrophobic state or a hydrophilic state. ~
BACICGROUND OF THE INVENTION
[00021 Numerous medical devices have been developed for the delivery of
therapeutic agents to the body. The desired release profile for the
therapeutic agent is
dependent upon the particular treatment at hand, including the specific
condition
being treated or prevented, the specific site of administration, the specific
therapeutic
agent selected, and so forth.
[0003] In accordance with some typical delivery strategies, a therapeutic
agent is
provided within a polymeric carrier layer and/or beneath a polytneric barrier
layer that
is associated with a medical device. Once the medical device is placed at the
desired
location within a patient, the therapeutic agent is released from the medical
device at a
rate that is dependent upon the nature of the polymeric carrier and/or barrier
layer.
[0004] Implantation of vascular stents is a prime example of a situation where
local
drug therapy is needed, but where it is possible that the drugs will produce
unwanted
systemic side effects. For example, endovascular stents are placed in the
dilated
segment of a vessel lumen to mechanically block the effects of abrupt closure
and
restenosis. Recent developments have led to stents which attempt to provide
anti-
restenotic agents and/or other medications such as anti-thrombosis agents to
regions
of a blood vessel which have been treated by angioplasty or other
interventional
tecllniques.
[0005] However, an ongoing isst.te with the drug release coatings that are
presently
CA 02639421 2008-09-23
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applied to devices such as stents is achieving a therapeutic concentration of
a drug
locally at a target site within the body without potentially producing
unwanted
systemic side effects. For instance, because the stent is placed within a
flowing blood
stream during placement and upon implantation, potential unwanted systemic
effects
may result from the premature release of undesirable quantities of the drug
into the
blood stream. Further, if quantities of therapeutic substance are released
into the
blood stream during positioning of the stent, less substance is available for
actual
local treatment when the stent is expanded, resulting in the potential for
inadequate
local dosing.
[0006] In the prior art are taught various attempts at devices which control
the elution ~
of a drug from a drug-loaded device such as a stent, For example, U.S. Patent
No.
6,419,692 by Yang et al., the contents of which are hereby incorporated by
reference
in their entirety, discloses polymeric layered catheters, wherein a protective
outer
polymer coating prevents elution of a drug-containing layer until expansion of
the
catheter causes fissures in the outer coating that allows exposure of the drug-
containing layer. Also, U.S. Patent No. 5,972,027 by Johnson, the contents of
which
are hereby incorporated by reference in their entirety, discloses a porous
metal stent
wherein pores within the stent are loaded with a drug that is released in the
body.
[0007] Although controlled release of a therapeutic agent has existed in
various forms
for several years, there is nonetheless a continuing need for improved and
more
precise drttg delivery systems that address the need for greater control of
the release
of the therapeutic substance during implantation and following implantation.
There
especially exists a need to provide precise drug delivery systems whose
release
characteristics may be readily modulated in sftat, depending on the required
needs and
conditions.
[00081 There is also a continuing need for medical devices which have
controllable
lubricity such that the devices are able to be moved smoothly within the body
cavity
or vessel during introduction into and removal from the body, while at the
same time
being able to be positioned precisely without shifting or movement when placed
at a
target site. Although various lubricious coatings have been taught for many
years,
there is still a ]ong-standing need for methods and devices wherein the
lubricity can
be adjusted or modulated depending on changing in siiu needs and conditions.
2
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SUMMARY OF THE INVENTION
[0009] These and other challenges of the prior art are addressed by the
present
invention.
[0010] According to an aspect of the invention, an implantable or insertable
medical
device is provided, which comprises a surface region that is electrically
actuatable
between a hydrophobic state and a less hydrophobic state or a hydrophilic
state.
[0011] Such devices are advantageous, for example, in that the surface
lubricity of the
device may be modulated in vivo or ex vivo. Such devices are also
advantageous, for
example, in that drug delivery may be modulated by varying the hydrophobicity/
hydrophilicity of the surface region in vivo.
[0012] These and other embodiments and advantages of the present invention
will
become immediately apparent to those of ordinary skill in the art upon review
of the -
Detailed Description and Claims to follow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. I is a schematic representation of a catheter according to one
embodiment of the present invention having a folded balloon as it is being
inserted
within a body lumen.
[0014] FIG. 2 is a schematic representation in a magnified see-through view of
the
catheter of FIG. I having the balloon in an expanded position at a target
vessel within
the body.
[0015] FIG. 3 is one embodiment of the catheter of FIG. 2 comprising a drug-
eluting
balloon catheter sliowing a close-up of a section A of the wall of the
catheter of FIG 2
that has been positioned within a target vessel in the body. The drug-
containing
catheter is covered with finger-like projections having an overlying
hydrophobic
layer.
[0016] FIG. 4A-4B is a close-up of a longitudinal section A of the catheter of
FIG. 2
according to two embodiments. Electrical energy is applied to the catheter
generating
an electric field through the wall of the balloon catheter causing contact
between the
therapeutic agent of the catheter and the surrounding body fluid.
[0017] FIGS. 5A-5C are schematic representations of balloon catheters
according to
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Docket No. 04-0218
three embodiments of the present invention sliowing different configurations
for
placement of the coating containing finger-like projections having an
overlying
hydrophobic layer.
[0018] FIG. 6 is a perspective view of a drug-eluting stent in accordance with
an
exemplary embodiment of the present invention.
[0019] FIG. 7A is a magnified, partial perspective view of FIG. 6.
[0020] FIG. 7B is a magnified, cross-sectional view of FIG. 7A across line B-B
illustrating the coating applied to wire inembers of the stent.
[0021] FIGS. 8A and 8B are schematic illustrations of a layer of molecules on
a
positively charged and negatively charged substrate, respectively. The
molecules
have a hydrophobic chain portion (portion with ball tip) and a charged polar
portion.
[00221 Fig. 9A is a schematic, longitudinal, cross-sectional view of the
distal end of a -
balloon catheter as it is advanced over a guidewire, in accordance with an
embodiment of the present invention. Figs. 9B and 9C are schematic, axial,
cross-
sectional views of the balloon catheter of Fig. 9A, taken along planes B-B and
C-C,
respectively.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0023] A more complete understanding of the method and apparatus of the
present
invention is available by reference to the following detailed description of
the
embodiments when talcen in conjunction with the accompanying drawings. The
detailed description of the embodiments which follows is intended to
illustrate but not
limit the invention.
[0024] The present invention relates to implantable or insertable medical
devices,
which contain one or more surface regions that are electrically actuatable
between a
hydrophobic state and a less hydrophobic state or a hydrophilic state.
[0025] Hydrophobic surfaces are defined herein as surfaces having a static
water
contact angle that is greater than 90 , for example ranging from 90 to 100
to 110 to
120 degrees or more. Hydrophilic surfaces are defined herein as surfaces
having a
static water contact angle that is less than or equal to 90 , for example,
ranging from
90 to 75 to 50 to 25 to 10 to 5 or less.
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[0026] In some embodiments of the invention, the surfaces are electrically
actuatable
between a superhydrophobic state and a hydrophilic state. For purposes of the
present
invention, a superhydrophobic surface is one that displays static water
contact angles
above 140' (e.g., ranging from 140 to 150 to 155 to 160 to 165 to 170 to
175 to
180 ).
[0027) Various instruments are available for measuring static contact angles,
for
example, the PG-3 PocketGoniometer contact angle tester from Thwing-Albert
Instrument Company Philadelphia, PA, USA or the Phoenix 450 Contact Angle
Analyzer available from AhTECH LTS Co., Ltd., Korea.
[0028] A typical way of creating hydrophobicity is to employ materials with
low
surface energy, such as fluorocarbon polymers. Low energy materials are
defined
herein as those that display static water contact angles that are greater than
90 .
However, even fluorocarbon materials yield water contact angles that are only
around
120 or so, far short of a superhydrophobic surface as defined herein.
Nevertheless,
surfaces with substantially greater water contact angles do exist in nature,
and they
have been created in the laboratory. In general, in addition to being formed
using low
surface energy (inherently hydrophobic) materials, these surfaces have been
shown to
have microscale and/or nanoscale surface texturing. One superliydrophobic
biological
material commonly referred to in the literature is the lotus leaf, wliich has
been
observed to be textured wit113-10 micron hills and valleys, upon which are
found
nanometer sized regions of hydrophobic material.
[0029] Exemplary hydrophobic polymers which are suitable for use in the
present
invention can be selected from, for example, but not limited, by the following
hydrophobic monomers: vinyl aromatic monomers, including unsubstituted vinyl
aromatics, vinyl substituted aromatics, and ring-substituted vinyl aromatics;
vinyl
esters, vinyl halides, alkyl vinyl ethers, and other vinyl coinpounds such as
vinyl
ferrocene; aromatic monomers otlier than vinyl aromatics, including
acenaphthalene
and indene; acrylic monomers, including alkyl actylates, arylalkyl acrylates,
alkoxyalkyl acrylates, halo-allcyl acrylates, and cyano-alkyl acrylates;
methacrylic
monomers, including methacrylic acid esters (methacrylates) and otlier
methacrylic-
acid derivatives including methacrylonitrile; acrylic monomers, including
acrylic acid
esters and other acrylic-acid derivatives including acrylonitrile, alkyl
methacrylates
CA 02639421 2008-09-23
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and aminoalkyl methacrylates; alkene-based monomers, including ethylene,
isotactic
propylene, 4-methyl pentene, 1-octadecene, and tetrafluoroethylene and other
unsaturated hydrocarbon monomers; cyclic ether monomers; ether monomers other
than acrylates and methacrylates; and other monomers including epsilon-
caprolactone; and (2) hydrophilic monomers including the following: vinyl
amines,
alkyl vinyl ethers, 1-vinyl-2-pyrrolidone and other vinyl compounds;
methacrylic
monomers including methacry[ic acid and methacrylic acid salts; acrylic
monomers
such as acrylic acid, its anhydride and salt forms, and acrylic acid amides;
alkyl vinyl
ether monomers such as methyl vinyl ether; and cyclic ether monomers such as
ethylene oxide.
100301 Surface regions that are electrically actuatable between a hydrophobic
state
and a hydrophilic state can be constructed in various ways. -
[0031] For example, in certain embodiments of the invention, the surface
region may
comprise a layer of amphiphilic molecules that comprise (i) a hydrophobic
chain
portion that is covalently or non-covalently attached to the surface of a
conductive
region and (ii) a charged polar portion. The charged polar portion is (a)
drawn to the
conductive region when the conductive region has a charge=whose sign is
opposite to
that of the charged polar portion and (b) is repelled from the conductive
region when
the conductive region lias a charge whose sign the same as that of the charged
polar
portion. Typically, the charged polar portion is attached to one end of the
hydrophobic
chain portion, wliereas the other end of the end of the hydrophobic chain
portion is
attached to the conductive region. As defined here, conductive materials
include both
conductive and semi-conductive materials. Examples of conductive materials
include
metals, metal alloys, semiconductors, conductive polymers and so forth.
[0032] Charge may be introduced, for example, by application of a suitable
voltage
between the conductive region and an electrode configured for electrical
contact with
the body, for example, being provided on a surface of said medical device or
being
implantable or insertable in a manner independent of the medical device. The
electrode may be formed form any suitable conductive material and may be
selected,
for example, from those listed elsewhere herein.
[0033] One example of a surface of this type is found, for example, in J.
Lahann et
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Docket No. 04-0218
al., "A Reversibly Switching Surface," Science, vol. 299, 17 January 2003, 371-
374,
which describes a process whereby a monolayer of a molecule containing a chain-
like
hydrophobic portion and a charged end group, specifically an anionic group, is
assembled on a conductive substrate. As shown schematically in Fig. BA, when
the
conductive substrate 800 is supplied with a negative charge, the anionic
groups 820
are repelled from the substrate, presenting a hydrophilic surface to the
surrounding
environment. When the conductive substrate 800 is supplied with a positive
charge
as shown in Fig. 8B, however, the anionic groups 820 are drawn toward the
substrate
surface, causing the molecules to bend over and present the chain-like
hydrophobic
portions 810 to the surrounding environment. As a result, the surface has
controlled
wettability. More specifically, (16-Mercapto) hexadecanoic acid (1VIHA.) was
chosen
because it (i) self-assembles on Au(l 11) into a monolayer and (ii) has a
hydrophobic
chain capped by a negatively charged, hydrophilic carboxylate group. To create
a
monolayer with sufficient spacing between the individual MHA molecules to
allow
the molecules to bend over, they resorted to and self-assembly of a MHA
derivative
with a globular end group. Subsequent cleavage of the end groups resulted in a
monolayer of the MHA, which can then be switched between hydrophilic and
hydrophobic states as discussed above.
[00341 Another type of electrowetting is commonly observed when a droplet of
conductive liquid is placed onto a dielectric coated conductor surface, and a
voltage is
applied across the dielectric coating such that the droplet flattens and
spreads on the
surface. While not wishing to be bound by theory, it is believed that
electrowetting is
a phenomenon that relates changes in surface interfacial energy in the
presence of an
electric field. More particularly, as the electric field is applied across the
dielectric
material, the conductive liquid droplet above the dielectric surface
experiences a
change in surface interfacial energy and thus a change in the droplet's
equilibrium
contact angle. Typically, the presence of the electric field results in a
reduction of
surface interfacial energy and hence the contact angle. The dynamics of the
wetting
behavior of liquids on nanostructured surfaces is discussed in T.N. Krupenkin
et al.,
"From Rolling Ball to Complete Wetting: The Dynamic Tuning of Liquids on
Nanostructured Surfaces," Langinuir, Vol. 20, No. 10, 2004, p. 3824, the
entire
contents of which are hereby incorporated by reference in their entirety.
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[0035] In certain embodiments of the invention, the surface regions of the
medical
devices comprise a conductive region coated with a dielectric layer. (As used
herein a
"layer" of a given material is a region of that material whose thickness is
small
compared to both its length and width. As used herein a layer need not be
planar, for
example, taking on the contours of an underlying substrate. Layers can be
discontinuous, e.g., patterned. Terms such as "film," "layer" and "coating"
may be
used interchangeably herein.) Preferably, such devices are provided with a low-
surface-energy material, which is inherently hydrophobic. Such a surface may
be
provided, for example, by selecting a hydrophobic dielectric coating material.
(Alternatively, a surface of this type may be provided, for example, by
providing a
hydrophobic coating over the dielectric coating.) Examples of dielectrics
include
metal and semiconductor oxides and nitrides, polymers, and so forth. Examples
of
hydrophobic materials include fluorine containing polymers (fluoropolymers),
and
polysiloxanes (e.g., silicones) among others.
[0036] Subsequent application of a suitable voltage across the hydrophobic
dielectric
coating (or across the hydrophobic/dielectric coating combination), for
example by
applying a voltage between the conductive region of the device and an
electrode on
the opposite side of the dielectric coating (or the hydrophobic/dielectric
coating
combination) from conductive region, may then be employed to cause the surface
to
switch from a hydrophobic state to a less hydrophobic state or even a
hydrophilic
state.
[0037) The electrode is therefore configured for electrical contact with the
body, for
example, being provided on a surface of said medical device or being
implantable or
insertable in a manner independent of the medical device. The electrode may be
formed form any suitable conductive material, such as those listed elsewhere
herein.
[00381 In certain embodiments of the invention, the surface regions may
comprise a
plurality of micro- or nano-protrusions (e.g., columns, pillars, finger-like
projections,
etc.), which further comprise a hydrophobic dielectric coating material (or a
dielectric
coating layer which is provided with a hydrophobic coating). As defined
herein, a
nano-protrusion is a protrusion whose largest lateral dimension (e.g., the
diameter for
a column, the width for a standing plate-like structure, etc.) ranges between
about 0.1
and about 100 nm in length, whereas a micro-protrusion is a protrusion whose
largest
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Docket No. 04-0218
lateral dimension ranges between about 0.1 and about 100 m. Such protrusions
may
be high aspect ratio structures whose height is at least as great as its
largest lateral
dimension, including I to 2 to 5 to 10 to 20 to 50 or more times as great.
Protrusions
can be regular or irregular in cross-section, having for example, a circular
cross-
section (e.g., a cylindrical column, cone, etc.), a square cross-section
(e.g., a square
column, pyramid, etc.), as well as a wide variety of other cross-sections,
including
oval cross-sections, triangular cross-sections, rectangular cross-sections,
trapezoidal
cross-sections, pentagonal cross-sections, and so forth.
[0039] Surfaces of this nature have been reported to be electrically
actuatable
between a superhydrophobic state and a less hydrophobic or hydrophilic state
based
on electrowetting. For example, Krupenkin et al. describe nanostructured
superhydrophobic surfaces, which were constructed by etching a microscopic
array of
cylindrical nanoposts into the surface of a silicon wafer. Each post had a
diameter of
about 350 nm and a height of about 7 m (or an aspect ratio of about 20). The
distance between posts (pitcli) varied from 1 to 4 pm. An oxide layer was
thermally
grown to provide electrical isolation between the substrate and the liquid. A
thin
conformal layer of a low-surface-energy polymer was then deposited to create
the
hydrophobic surface. In the absence of any applied potential, high surface
tension
liquids such as water and molten salt, each resulted in a highly mobile ball
having
high contact angles. Upon the application of a sufficient potential between
the liquid
and the silicon substrate, however, the ball experienced a sharp transition to
an
immobile droplet state. For the rolling ball state, there was little to no
penetration of
liquid in the nanostructured layer. For the immobile droplet, the liquid
penetrated all
the way to the bottom of the nanostructured layer, dramatically increasing the
liquid-
solid interfacial area.
[0040] The ability to transition medical device surface regions between a
hydrophobic
state (including a superhydrophobic state) and a less hydrophobic state or a
hydrophilic state is advantageously utilized in conjunction with drug
delivery.
[0041.] For example, switching medical device surface regions from hydrophobic
to
hydrophilic has been shown to result in more intimate interaction between the
surface
and water. See, e.g., Krupenkin et al., supra. This effect is utilized in
certain
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Docket No. 04-02 3 8
embodiments of the invention to bring a fluid (e.g., a bodily fluid such as
urine, blood,
etc.) into more intimate contact with a therapeutic-agent-containing
reservoir, thereby
permitting or increasing the mass transport of the therapeutic agents (also
referred to
herein as a "drugs").
[0042] Therapeutic agents may be selected, for example, from the following:
adrenergic agents, adrenocortical steroids, adrenocortical suppressants,
alcohol
deterrents, aldosterone antagonists, aniino acids and proteins, ammonia
detoxicants,
anabolic agents, analeptic agents, analgesic agents, androgenic agents,
anesthetic
agents, anorectic compounds, anorexic agents, antagonists, anterior pituitary
activators and suppressants, anthelmintic agents, anti-adrenergic agents, anti-
allergic
agents, anti-amebic agents, anti-androgen agents, anti-anemic agents, anti-
anginal
agents, anti-anxiety agents, anti-arthritic agents, anti-asthmatic agents,
anti-
atherosclerotic agents, antibacterial agents, anticholelithic agents,
anticholelithogenic
agents, anticholinergic agents, anticoagulants, anticoccidal agents,
anticonvulsants,
antidepressants, antidiabetic agents, antidiuretics, antidotes,
antidyskinetics agents,
anti-emetic agents, anti-epileptic agents, anti-estrogen agents,
antifibrinolytic agents,
antifungal agents, antiglaucoma agents, antihemophilic agents, antihemophilic
Factor,
antihemorrhagic agents, antihistaminic agents, antihyperlipidemic agents,
antihyperlipoproteinemic agents, antihypertensives, antihypotensives, anti-
infective
agents, anti-inflammatory agents, antikeratinizing agents, antimicrobial
agents,
antimigraine agents, antimitotic agents, antimycotic agents, antineoplastic
agents,
anti-cancer supplementary potentiating agents, antineutropenic agents,
antiobsessional
agents, antiparasitic agents, antiparkinsonian drugs, antipneumocystic agents,
antiproliferative agents, antiprostatic hypertrophy drugs, antiprotozoal
agents,
antipruritics, antipsoriatic agents, antipsychotics, antirheumatic agents,
antischistosomal agents, antiseborrheic agents, antispasmodic agents,
antithrombotic
agents, antitussive agents, anti-ulcerative agents, anti-urolithic agents,
antiviral
agents, benign prostatic hyperplasia therapy agents, blood glucose regulators,
bone
resorption inhibitors, bronchodilators, carbonic anhydrase inhibitors, cardiac
depressants, cardioprotectants, cardiotonic agents, cardiovascular agents,
choleretic
agents, cholinergic agents, cholinergic agonists, cholinesterase deactivators,
coccidiostat agents, cognition adjuvants and cognition enhancers, depressants,
CA 02639421 2008-09-23
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diagnostic aids, diuretics, dopaminergic agents, ectoparasiticides, emetic
agents,
enzyme inhibitors, estrogens, fibrinolytic agents, free oxygen radical
scavengers,
gastrointestinal motility agents, glucocorticoids, gonad-stimulating
principles,
hemostatic agents, histamine H2 receptor antagonists, hormones,
hypocholesterolemic
agents, hypoglycemic agents, hypolipidemic agents, hypotensive agents, HMGCoA
reductase inhibitors, immunizing agents, immunomodulators, immunoregulators,
imtnunostimulants, immunosuppressants, impotence therapy adjuncts, keratolytic
agents, LHRH agonists, luteolysin agents, mucolytics, mucosal protective
agents,
mydriatic agents, nasal decongestants, neuroleptic agents, neuromuscular
blocking
agents, neuroprotective agents, NMDA antagonists, non-hormonal sterol
derivatives,
oxytocic agents, plasminogen activators, platelet activating factor
antagonists, platelet
aggregation inhibitors, post-stroke and post-head trauma treatments,
progestins,
prostaglandins, prostate growth inhibitors, prothyrotropin agents,
psychotropic agents,
radioactive agents, repartitioning agents, scabicides, sclerosing agents,
sedatives,
sedative-hypnotic agents, selective adenosine Al antagonists, serotonin
antagonists,
serotonin inhibitors, serotonin receptor antagonists, steroids, stimulants,
thyroid
hormones, thyroid inhibitors, thyromimetic agents, tranquilizers, unstable
angina
agents, uricosuric agents, vasoconstrictors, vasoditators, vulnerary agents,
wound
healing agents, xanthine oxidase inhibitors, and the like.
[00431 Specific examples of therapeutic agents include paclitaxel, sirolimus,
everolimus, tacrolimus, Epo D, dexainethasone, estradiol, haloftiginone,
cilostazole,
geldanamycin, ABT-578 (Abbott Laboratories), trapidil, liprostin, Actinomcin
D,
Resten-NG, Ap-17, abciximab, clopidogrel, Ridogrel, beta-blockers, bARKct
inhibitors, phospholamban inhibitors, and Serca 2 gene/protein among others,
many
of which are anti-restenotic agents. Numerous additional therapeutic agents
useful for
the practice of the present invention are also disclosed in U.S. Patent
Application
2004/0175406, the entire disclosure of which is incorporated by reference.
[0044] A wide range of therapeutic agent loadings can be used in connection
with the
medical devices of the present invention, with the therapeutically effective
amount
being readily determined by those of ordinary skill in the art and ultimately
depending, for example, upon the condition to be treated, the age, sex and
condition
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Docket No. 04-02 18
of the patient, the nature of the therapeutic agent, the nature of the
composite
region(s), the nature of the medical device, and so forth.
[00451 Now referring to the drawings, wherein like reference numerals refer to
like
elements throughout several views, FIGS. 1 and 2 depict the incorporation of
surface
regions in accordance with the present invention into a balloon catheter
design.
Referring to FIG. 1, an illustrated embodiment of a balloon catheter 10 of the
present
invention is shown to include an elongated tubular member 12 having disposed
on a
distal portion thereof an inflatable balloon 14. The balloon 14 is shown
within a
vessel 16 within the vascular system with a lumen 18 that is defined by luinen
walls
20. As shown, the lumen 18 is partially blocked by a stenosis or thrombosis
22. The
balloon catheter 10 of FIG. 1 is depicted in a folded or uninflated profile
which is
suitable for inserting into the lumen 18 of the blood vessel 16. Referring now
to FIG.
2, the balloon catheter 10 of FIG. 1 is shown in an expanded state located
across the
stenotic area 22.
[0046] As shown in FIG. 2, the balloon 14 having an inner luinen 23 includes a
conductive layer 24, such as a metallic layer, metallic wire or circuit
traces, attached
to the wall 26 of the balloon 14 which is capable of transmitting energy, e.g.
electrical
energy, to the balloon 14. In certain embodiments, the conductive layer 24
comprises
a plurality of elements attached to the wall 26 of the balloon 14 which are
capable of
transmitting electrical energy. As also shown in FIG. 2, the balloon in
certain
embodiments also includes a reservoir such as a drug-containing layer 28 which
includes a drug or therapeutic substance 29. Overlying the drug-containing
layer 28 is
a surface-modulating region 30 (e.g., an electrically actuatable surface
region).
[0047] FIG. 3 is a close-up of a longitudinal section A of the wall of the
catheter of
FIG. 2 that has been positioned within a target vessel in the body wherein the
surface-
modulating region 30 is adjacent body fluid or blood 50 contained within the
vessel,
and a boundary layer 44 is observed between the body fluid or blood 50 and the
surface-modulating region 30. As shown in FIG. 3, in one embodiment, the
surface-
lnodulating region 30 comprises two components: a plurality of electrically
conductive protrusions such as columns 32, each having a base 33 and a tip 34
and
hydrophobic dielectric coating such as a hydrophobic polymeric coating 35
(e.g., a
fluorinated or silicone polymer) overlying at least a portion of the surface
of
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Docket No. 04-0218
conductive columns 32. Such columns 32 may be formed from a variety of
conductive materials including metals, metal alloys and semiconductors such as
silicon. As shown in FIG. 3, the columns 32 are in electrical communication
with the
conductive layer 24 ttirough a drug-containing layer 28 containing drug 29,
and the
conducting layer 24 in also directly adjacent to the balloon wall 26.
[0048] In certain embodiments, a layer of dielectric material (not shown) may
be
further provided between the conductive columns 32 and a hydrophobic polymer
coating 35 as noted above. As a specific example, the protrusions may comprise
conductive columns that comprise silicon, the dielectric material layer may
comprise
a silicon compound, e.g., Si02, and the hydrophobic polymeric may comprises a
fluorinated polymer such as, but not including but not limited to
polytetrafluoroethylenes (PTFE) or a silicone such as poly(dimethylsiloxane)
(PDMS). Like fluoropolymers, PDMS is intrinsically extremely hydrophobic.
[0049] In some embodiments, the electrically conductive columns 32 may
comprise a
plurality of cotuinns or other finger-like projections that are aligned to
form an array.
In one exemplary embodiment, the conductive columns 32 are patterned and
coated
with a thin hydrophobic dielectric layer. The conductive columns 32 have a
typical
height ranging form about I to about 10 m, more typically about 7 m and a
column
diameter (for a circular column) of about 100 to 500 nm, more typically about
350
nm. The distance between columns 32 (pitch) may vary, for example, from about
1 to
5}un, among other ranges. As shown in FIG. 4A, by supplying electrical energy
42,
e.g., voltage of suitable magnitude and polarity between the body fluid 50 and
the
columns 32, the surface temporarily behaves as if it were a hydrophilic
surface,
drawing the body fluid 50 into the channel regions 40 between the columns 32,
where
it comes into contact with the drug-containing layer 28, promoting transport
of the
drug 29 therefrom. A typical voltage suitable for causing the desired
electrowetting
effects is about 10-25 V.
100501 In the field of microelectronics and microfluidics, researchers have
been
utilizing electric fields to control dynamically the wetting properties of a
surface to
transport fluids in micrometer-sized channels. Certain embodiments of the
invention
also use the principle of electrowetting using electric fields for driving or
puinping
liquid segments on a surface or through a channel. With reference to Fig. 4A,
as
13
CA 02639421 2008-09-23
Docket No. 04-0218
electrical energy 42 is applied to the conductive layer 24, an electrical
field is
generated between the conducting column 32 and the blood or body fluid.
Aqueous
liquid such as blood or body fluid 50 nonnally will not penetrate or "wet" the
channels 40 defined by the hydrophobic polymer coated conducting columns 32,
wherein "channels" refers to the spaces between the coluinns. In contrast,
without
application of such electrical energy 42, as shown in FIG. 3, a boundary layer
44 is
observed across the surface-modulating region 30. Upon applying an electric
potential
between the blood 50 and the conducting column 32, the surface-modulating
layer
region 30 becomes hydrophilic, causing the blood to advance through the
channels 40
and wet the entire region of the conducting columns 32 and the drug-containing
layer
28 above the electrically activated conducting layer 24.
[0051] In certain other embodiments, as shown in FIG. 4B, the conductive layer
24
and the conductive columns 32 are in electrical communication with one
another. The
conductive columns 32 extend through the drug-containing layer 28 such that
the base
33 of the columns is directly adjacent the conductive layer 24. As indicated
previously, release of a therapeutic substance may be enhanced by contact with
water
or.other liquids present in the blood or other body lumen. When the surface-
modulating region 30 is "wetted," the blood or body fluid 50 comes into
contact with
the drug-containing layer 28, which may cause the drug 29 to be released by
diffusion, dispersion, disintegration or dissolution. The therapeutic agent or
drug 29
may be, for example, solid or liquid, in the forin of, for example, powders
such as
nanoparticles or dry or wet coatings (e.g., gels) and may be in a discrete
form or
integrated into the structure of the drug-containing layer 28 in a carrier
matrix.
[0052] In certain aspects and embodiments of the invention, the selected
therapeutic
agents are charged therapeutic agents. By "charged therapeutic agent" is
ineant a
therapeutic agent that has an associated charge. For example, a therapeutic
agent may
have an associated charge (a) because it is inherently charged (e.g., because
it is an
acid, base, or salt), (b) because it has been modified to carry a cliarge by
covalently
linking a charged species to it, (c) becatise it is non-covalently linked to a
charged
species (e.g., based on hydrogen bonding with the charged species, or because
it
forms complexes and/or coordinative bonds with charged species), or (d)
because it is
attached to or encapstilated within a charged particle, such as a charged
nanoparticle
14
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LJOCKet No. 04-0218
(i.e., a charged particle of 100 nm or less in diameter), including
nanocapsules and
charged micelles, among others. Taking paclitaxel as one specific example,
various
cationic and anionic forms of paclitaxel are known. See for example, U.S.
Patent No.
6,730,699, which is incorporated by reference in its entirety.
[00531 In certain embodiments, the entire surface of the balloon wall 26 is
coated
with a drug-containing layer 28 (which may, for example, consist of the drug
in pure
form or admixed with another substance, and whicli may, for example, be in the
fonn
of a collection of particles or in the form of drug-containing layer). In
other
embodiments, only certain portions of the wal126 of the balloon 14 are coated
with a
drug-containing layer 28.
[00541 FIGS. 5A, 513, and 5C are perspective views of balloon catheters 10
wherein
discrete portions of the surface 26 of the balloon 14 are covered with surface-
modulating regions 30, which may be associated with drug-containing layers 28
as
described above.
[00551 As would be appreciated by one of skill in the art, a wire (not shown)
for
providing power to the conductive layer(s) 24 on the balloon 14 may, for
example,
extend as a trace along the wal126 of the balloon 14 or may be encapsulated or
otherwise disposed within the body of the catheter 10. The wire connects to an
electrical cable 38 that extends from the proximal end 40 of the balloon 14.
FIG. 5B
shows that the cable 38 ends with a plug 39 that connects with an energy
source and
appropriate conventional catheter control equipment (not shown).
Alternatively, the
devices of the present invention may be battery-powered or remotely powered
using
standard wireless or passive sensor technology known to one of skill in the
art. For
exaniple, several types of wireless or passive sensors that harvest RF energy
have
been developed for various in vivo applications such as measuring intraocular,
intracranial and arterial pressure. See LaVan et al., Sinall-scale systems for
in vivo
drug delivery, Nature Biotechnology 21(10):1184-1191 (October 2003), the
contents
of which are hereby incorporated by reference in their entirety.
[00561 With respect to the conductive material 24 for use in this embodiment
of the
present invention, they may be formed from any conductive material suitable
for
supporting the drug delivery technique employed by the medical device,
including
those typically employed for drug delivery by other electrical methods
including
CA 02639421 2008-09-23
Docket No. 04-0218
iontophoresis and/or electroporation. Examples of conductive materials include
suitable members of the following, among many others: metals and metal alloys
(e.g.,
stainless steel or gold or platinum, due to their high conductivity, oxidation
resistance,
and radioopacity, which facilitates visibility of the device during
fluoroscopy or the
like, or magnesium, which can be left in the tissue where it will eventually
oxidize in
vivo), conductive polymers, seiniconductors (e.g., silicon) including doped
semiconductors, and conductive carbon. The conducting layer 24 may take on
innumerable shapes, in addition to the preferred layer, including rods, wires,
tubes,
blades, and grids, among many others. The conducting layer 24 is configured
such
that, when the medical device is properly deployed in a subject and a suitable
constant
or variable voltage is applied between the conducting layer 24 and the body
fluid 50,
an electric field is generated such that the body fluid 50 is driven down into
the
channels 40 to contact the drug-containing layer 28. In certain embodiments,
the
therapeutic agent 29 is also electrically charged so that it is driven outward
from the
device and into the body fluid 50 under the influence of the electric field.
[00571 FIGS. 6 and 7 depict the incorporation of the present invention into a
stent
design. Now refen=itig to FIG. 6, a stent 100 is shown in a perspective view,
in a non-
expanded form, in accordance with one embodiment of the present invention. The
skeletal frame of the stent 100 preferably includes a structural network 102
that
includes distinct, repetitive serpentine elements 108. Each serpentine element
108
consists of multiple U-shaped curves 104 and has no recognizable beginning or
end.
These U-shaped curves 104 form interstitial spaces 106. Due to its serpentine
nature,
each serpentine element 108 is radially expandable. Serpentine elements 108
are
arranged along the longitudinal axis of the stent 100 so that the U-shaped
curves 104
of abutting serpentine elements 108 may be joined via interconnecting elements
120,
forming the stent 100.
[00581 As would be appreciated by one of ordinary skill in the art, the
structural
frame of the stent 100 can be of a variety of configtirations and be made of
any
number of stent materials including metals, metal alloys, and polymeric
materials, that
perform the desired applications of radially expanding and maintaining the
patency of
various lumen passages within the human body, and all such variations are
within the
16
CA 02639421 2008-09-23
Docket No. 04-0218
scope of the present invention, such as those manufactured by Boston
Scientific
Corporation, Natick, Massachusetts.
[0059] Referring now to FIG. 7A and FIG. 7B, a portion of the stent in FIG. 6
is
depicted (in magnified cross-sectional view in FIG. 7B) with the surface-
modulating
region 132 disposed over at least a portion of the exterior surface of
structural
members 102. As described above for the catheter embodiments of the present
invention, this surface-modulating region 132 is selectively applied to at
least a
portion of the exterior surface of the structural network 102 and may
comprise, for
example, a plurality of conductive columns coated with a hydrophobic
dielectric
layer. The stent 100, in certain embodiments, also includes a drug-containing
layer
128 which includes a drug or therapeutic substance 129. Where the structural
networlc 102 is formed of a conductive material, a separate conductor may not
be -
required. The drug-containing layer 128 is associated with the surface-
modulating
region 132 as described above. As described above, once the stent is deployed
within
the body, an electrical potential may be applied, for example, between the
structural
network 102 and the surrounding bodily fluid (not shown). As a result, an
electric
field is generated, which results in contact between the drug-containing layer
128 and
body fluid (not shown) when.
[0060] In those embodiments wherein the structural network 102 of the stent100
is
not made of a conductive material, such as a metal or ainetal alloy, the
structure of
the stent 100 may include a conductive layer (not shown), which is capable of
producing an electrical potential between the conductive layer and the
surrounding
bodily fluid, generating an electrical field through the surface-modulating
region.
[00611 In certain preferred embodiments, the therapeutic substance is
comprised, at
least in part, of an anti-restenotic, anti-proliferative, andlor anti-
angiogenic drug. For
example, such a therapeutic agent can be dispersed and contained in a
polymeric
carrier matrix. As noted above, release of the therapeutic substance may be
enhanced
by contact with bodily fluids that are present in the blood or other body
lumen.
[0062] In some embodiments, the present invention is directed to implantable
or
insertable devices comprising neurostimulators, electrostimulators, and
implantable
electrodes. The present invention is also directed to implantable or
insertable medical
devices, such as the catheters and stents described above, but which do not
have a
17
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Uocket No. 04-0218
drug-containing layer. For example, resistance to movement between a medical
device and an adjacent solid may be reduced in either wet or dry conditions by
providing the medical device with a low energy surface. Low energy surfaces
are
defined herein as surfaces that have hydrophobic static water contact angles
(i.e.,
contact angles greater than 90 , preferably 110 to 120 to 130 to 140 to
150 to
160 to 170 to 180 ). FIGS. 8A and 8B show the behavior of a prior art low
energy
surface made of a layer of moleeules on a positively charged and negatively
charged
substrate, respectively. The molecules have a hydrophobic chain poi-tion and a
charged polar portion.
[0063] Referring now to Figs. 9A-9C in which the distal end of a guidewire-
balloon
catheter system is illustrated, this system includes a guidewire 950, which
passes
through a lumen formed by an inner tubular member 910. Also shown is an outer
tubular member 920, which, along with inner tubular member 910, forms an
annular
inflation lumen 915 that provides for the flow of inflation fluid into balloon
930.
Figs. 9B and 9C are schematic, axial, cross-sectional views of the balloon
catheter of
Fig. 9A, taken along planes B-B and C-C, respectively.
[0064] In such a system, it may be desirable to vary the surface friction at
various
times, including the friction that exists (a) between the inside surface of
the member
that forms the guidewire lumen of the catheter (e.g., inner tubular member
910) and
the outside surface of the guidewire 950 over which it is passed, (b) between
the
between the outside surface of the balloon 930 and the vasculature, and/or (c)
between
the outside surface of the outer tubular member 920 and the vasculature. For
this
purpose, such surfaces may be rendered electrically actuatable between a
hydrophobic
state and a hydrophilic state in accordance with the present invention, for
example, by
providing a surface-modifying region such as those described elsewhere herein.
[00651 For example, to reduce friction during balloon 930 advancement and
withdrawal along the guidewire 950, it may be desirable to provide the outside
surface
of the guidewire 950, the inside surface inner tubular member 910, the outside
surface
of the balloon 930, and the outside surface of the outer tubular member 920
with a
hydrophobic surface, and preferably a superhydrophobic surface. During balloon
inflation, on the other hand, it may be desirable to render one or more of
these
surfaces (e.g., the surface of the balloon 930, etc.) inoderately hydrophilic
(and
18
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Docket No. 04-0218
preferably not so hydrophilic so as to create a slippery surface, for example,
having a
contact angle of 90 to 80 to 70 to 60 ) so as to increase axial movement of
the
device within the body. This may be done by electrowetting the hydrophobic
surface(s), as described elsewhere herein.
[0066] Similarly where a stent is deployed by a catheter such as balloon
catheter 900,
it may be desirable to electrowet the inside surface of the stent and/or the
outside
surface of the balloon by application of an electrical potential during stent
advancement and expansion and, after stent expansion, to remove the potential
and
return the inside surface of the stent and/or the outside surface of the
balloon to a
hydrophobic or superhydrophobic state, allowing the balloon to be more readily
withdrawn.
[0067] Although the above description has been applied to stents and
catheters, it will
be understood by one of ordinary skill in the art that the invention may be
applicable
to other insertable or implantable devices for use within the body,
particularly those
that come into contact with blood or body fluids.
[0068] For example, medical devices for use in conjunction with the present
invention
include a wide variety of implantable or insertable medical devices, which are
implanted or inserted either for procedural uses or as implants. Examples
include
balloons, catheters (e.g., renal or vascular catheters sucli as balloon
catheters), guide
wires, filters (e.g., vena cava filters), stents (including coronary artery
stents,
peripheral vascular stents such as cerebral stents, urethral stents, ureteral
stents,
biliary stents, tracheal stents, gastrointestinal stents and esophageal
stents), stent
grafts, vascular grafts, vascular access ports, embolization devices including
cerebral
aneurysm filler coils (including Guglilmi detachable coils and metal coils),
myocardial plugs, pacemaker leads, left ventricular assist hearts and puinps,
total
artificial hearts, heart valves, vascular valves, tissue bulking devices,
anastomosis
clips and rings, tissue staples and ligating clips at surgical sites,
cannulae, metal wire
ligatures, orthopedic prosthesis, joint prostheses, as well as various other
medical
devices that are adapted for implantation or insertion into tiie body.
[00691 The medical devices of the present invention include implantable and
insertable medical devices that are used for diagnosis, for systemic
treatment, or for
the localized treatment of any tissue or organ. Non-limiting examples are
tumors;
19
CA 02639421 2008-09-23
1JocKet No. U4-011 8
organs including the heart, coronary and peripheral vascular system (referred
to
overall as "the vascuiature"), the urogenital system, including kidneys,
bladder,
urethra, ureters, prostate, vagina, uterus and ovaries, eyes, lungs, trachea,
esophagus,
intestines, stomach, brain, liver and pancreas, skeletal muscle, smooth
muscle, breast,
dermal tissue, cartilage, tooth and bone. As used herein, "treatment" refers
to the
prevention of a disease or condition, the reduction or elimination of symptoms
associated with a disease or condition, or the substantial or complete
elimination of a
disease or condition. Typical subjects (also referred to as "patients") are
vertebrate
subjects, more typically mammalian subjects and even more typically human
subjects.
[00701 Although various embodiments are specifically illustrated and described
herein, it will be appreciated that modifications and variations of the
invention are
covered by the above teachings and are within the purview of the appended
claims
without departing from the spirit and intended scope of the invention. For
example,
radiofrequency transmitters for the medical devices are depicted herein, yet
other
means for energizing the device to modulate the electrowetting and other
properties of
the device are possible without departing from the scope of the present
invention.
Substitute means for energizing the device and which function similarly to
radiofrequency transmitters will be obvious to one of ordinary skill in the
art. Further,
the above examples should not be interpreted to limit the modifications and
variations
of the invention covered by the claims but are merely illustrative of possible
variations.
