U.S. patent application number 10/849742 was filed with the patent office on 2010-07-15 for medical devices having multiple layers.
Invention is credited to John Jianhua Chen, Jan Weber.
Application Number | 20100179645 10/849742 |
Document ID | / |
Family ID | 34969489 |
Filed Date | 2010-07-15 |
United States Patent
Application |
20100179645 |
Kind Code |
A1 |
Chen; John Jianhua ; et
al. |
July 15, 2010 |
MEDICAL DEVICES HAVING MULTIPLE LAYERS
Abstract
Described herein are medical devices which are configured for
implantation or insertion into a subject, preferably a mammalian
subject. The medical devices contain one or more multilayer
regions, which contain: (a) one or more (typically a plurality of)
charged nanoparticle layers and (b) one or more (typically a
plurality of) charged polyelectroyte layers. Such multilayers have
a number of desirable attributes, including high strength,
non-compliance, and flexibility. Also described herein are methods
of making such devices.
Inventors: |
Chen; John Jianhua;
(Plymouth, MN) ; Weber; Jan; (Maple Grove,
MN) |
Correspondence
Address: |
VIDAS, ARRETT & STEINKRAUS, P.A.
SUITE 400, 6640 SHADY OAK ROAD
EDEN PRAIRIE
MN
55344
US
|
Family ID: |
34969489 |
Appl. No.: |
10/849742 |
Filed: |
May 20, 2004 |
Current U.S.
Class: |
623/1.42 ;
604/103.02; 604/103.08; 604/265; 623/1.45; 977/734; 977/742 |
Current CPC
Class: |
A61P 23/00 20180101;
A61L 2300/608 20130101; A61L 29/085 20130101; A61L 2300/624
20130101; A61P 3/06 20180101; A61L 29/16 20130101; A61P 7/02
20180101; A61P 29/00 20180101; A61P 35/00 20180101 |
Class at
Publication: |
623/1.42 ;
604/103.08; 623/1.45; 604/103.02; 604/265; 977/734; 977/742 |
International
Class: |
A61L 27/54 20060101
A61L027/54; A61L 29/08 20060101 A61L029/08; A61L 27/28 20060101
A61L027/28; A61L 29/16 20060101 A61L029/16 |
Claims
1. A medical device comprising a multilayer region that comprises:
(a) a charged nanoparticle layer comprising charged nanoparticles;
(b) a plurality of charged polyelectroyte layers comprising charged
polyelectrolyte species, and (c) at least one charged therapeutic
agent, wherein said medical device is configured for implantation
or insertion into a subject.
2. The medical device of claim 1, wherein said medical device is
selected from a balloon catheter, a graft, a stent and a
filter.
3. The medical device of claim 1, wherein said multilayer region
comprises a plurality of charged nanoparticle layers.
4. The medical device of claim 1, said multilayer region comprises
a plurality of charged nanoparticle layers that comprise
nanoparticles selected from carbon nanoparticles, silicate
nanoparticles, and ceramic nanoparticles.
5. The medical device of claim 1, wherein said multilayer region
comprises a plurality of charged nanoparticle layers that comprise
nanoparticles selected from carbon nanotubes, carbon nanofibers,
fullerenes, ceramic nanotubes, ceramic nanofibers, phyllosilicates,
monomeric silicates and dendrimers.
6. The medical device of claim 1, wherein said multilayer region
comprises a plurality of charged nanoparticle layers that comprise
single walled carbon nanotubes.
7. The medical device of claim 1, wherein said multilayer region
comprises a plurality of charged nanoparticle layers that comprise
nanoparticles ranging from 0.5 to 100 nm in smallest dimension.
8. The medical device of claim 1, wherein said multilayer region
comprises a plurality of charged polyelectrolyte layers that
comprise a polycation selected from polyallylamine,
polyethyleneimine, poly(dimethyl diallyl ammonium chloride),
protamine sulfate, chitosan, gelatin, spermidine, and albumin, and
a plurality of charged polyelectrolyte layers that comprise a
polyanion selected from poly(styrene sulfonic acid), poly(aniline
sulfonic acid), polyacrylic acid, sodium alginate, polystyrene
sulfonate, eudragit, gelatin, hyaluronic acid, carrageenan,
chondroitin sulfate, carboxymethylcellulose.
9. The medical device of claim 1, wherein said multilayer region
comprises from 10 to 200 charged polyelectrolyte and nanoparticle
layers.
10. (canceled)
11. The medical device of claim 1, wherein a protective polymer
coating layer is provided over at least a portion of said
multilayer region.
12. The medical device of claim 1, wherein said plurality of
charged polyelectrolyte layers comprises a biodegradable charged
polyelectrolyte layer.
13. The medical device of claim 12, wherein said charged
therapeutic agent is provided beneath or within said biodegradable
polyelectrolyte layer.
14. The medical device of claim 1, wherein said medical device
comprises a plurality of said multilayer regions.
15. The medical device of claim 1, wherein at least a portion of
said multilayer region is freestanding.
16. The medical device of claim 1, wherein at least a portion of
said multilayer region is disposed on an underlying or overlying
structure.
17. The medical device of claim 16, wherein said underlying or
overlying structure is a temporary structure that is not implanted
or inserted with said medical device.
18. The medical device of claim 16, wherein said underlying or
overlying structure is a permanent structure that forms part of
said medical device.
19. The medical device of claim 16, wherein said underlying
structure is a balloon.
20. The medical device of claim 16, wherein said underlying
structure is a catheter.
21. The medical device of claim 16, wherein said underlying
structure is a stent.
22. The medical device of claim 16, wherein said underlying
structure is a graft.
23. The medical device of claim 16, wherein a patterned multilayer
region is provided over said underlying structure.
24. The medical device of claim 16, wherein said underlying
structure is a ceramic,
25. A medical device comprising a multilayer region, the multilayer
region comprising: a) a charged nanoparticle layer comprising
charged nanoparticles; and (b) a plurality of charged
polyelectroyte layers comprising charged polyelectrolyte species,
wherein one or more reinforcement members are provided adjacent to
or within said multilayer region, said device is configured for
implantation or insertion into a subject.
26. The medical device of claim 25, wherein said one or more
reinforcement members are in the form of a fiber mesh, a fiber
braid or a fiber winding.
27. A medical device comprising a multilayer region, the multilayer
region comprising: a) a charged nanoparticle layer comprising
charged nanoparticles; and (b) a plurality of charged
polyelectroyte layers comprising charged polyelectrolyte species,
the medical device further comprising a residue from a removable
substrate adjacent said multilayer region.
28. A medical device comprising a multilayer region, the multilayer
region comprising: a) a charged nanoparticle layer comprising
charged nanoparticles; and (b) a plurality of charged
polyelectroyte layers comprising charged polyelectrolyte species,
wherein charged nanocapsules, which comprise a plurality of charged
polyelectrolyte encapsulation layers, are incorporated into said
multilayer region.
29. The medical device of claim 28, wherein said charged
nanocapsules comprise a therapeutic agent.
30. The medical device of claim 1, wherein said therapeutic agent
is selected from anti-thrombotic agents, anti-proliferative agents,
anti-inflammatory agents, anti-migratory agents, agents affecting
extracellular matrix production and organization, antineoplastic
agents, antimitotic agents, anesthetic agents, anti-coagulants,
vascular cell growth promoters, vascular cell growth inhibitors,
cholesterol-lowering agents, vasodilating agents, and agents that
interfere with endogenous vasoactive mechanisms.
31-52. (canceled)
53. The medical device of claim 1, wherein said medical device
comprises a balloon that is configured for insertion into and
inflation within a body lumen of a subject, said balloon comprising
a multilayer region that further comprises: (a) at least five
charged nanoparticle layers comprising charged carbon nanotubes;
and (b) at least five charged polyelectroyte layers comprising
charged polyelectrolyte species.
54. The medical device of claim 53, wherein said charge
polyelectrolyte layers are selected from polyacrylic acid,
polyethylene imine, or a combination of both.
55. The medical device of claim 53, further comprising an
inflatable balloon underlying said multilayer region.
56. The medical device of claim 53, further comprising a fibrous
reinforcement member.
57. A medical device comprising a multilayer region, the multilayer
region comprising: (a) a charged nanoparticle layer comprising
charged nanoparticles; and (b) a plurality of charged
polyelectroyte layers comprising charged polyelectrolyte species,
wherein at least a portion of said multilayer region is free
standing, and said medical device is configured for implantation or
insertion into a subject.
58. A medical device comprising a multilayer region that comprises:
(a) a charged nanoparticle layer comprising charged nanoparticles;
(b) a plurality of charged polyelectroyte layers comprising charged
polyelectrolyte species, (c) at least one therapeutic agent, and
(d) at least one protective coating is provided over at least a
portion of the multilayer region, wherein said medical device is
configured for implantation or insertion into a subject.
59. A medical device comprising a multilayer region that comprises:
(a) a charged nanoparticle layer comprising charged nanoparticles;
(b) a plurality of charged polyelectroyte layers comprising charged
polyelectrolyte species, and (c) one or more reinforcement members
provided adjacent to or within said multilayer region, said
reinforcement members are in the form of a fiber mesh, a fiber
braid or fiber winding, wherein said medical device is configured
for implantation or insertion into a subject.
60. A medical device comprising a multilayer region that comprises:
(a) a charged nanoparticle layer comprising charged nanoparticles;
(b) a plurality of charged polyelectroyte layers comprising charged
polyelectrolyte species, and (c) charged nanocapsules incorporated
into said multilayer region, said charged nanocapsules comprise a
therapeutic agent, wherein said medical device is configured for
implantation or insertion into a subject.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the layer-by-layer assembly
of multilayer regions for implantable and insertable medical
devices, and more particularly, to the formation of multilayer
regions that contain a plurality of nanoparticle layers for such
devices.
BACKGROUND OF THE INVENTION
[0002] Various medical devices are known which are configured for
implantation or insertion into a subject. As such theses devices
have attendant mechanical requirements.
[0003] For example, balloons mounted on the distal ends of
catheters are widely used in medical treatment. A balloon may be
used, for example, to widen a vessel into which the catheter is
inserted or to force open a blocked vessel. The requirements for
the strength and size of the balloon vary widely depending on the
balloon's intended use and the vessel size into which the catheter
is inserted. Perhaps the most demanding applications for such
balloons are in balloon angioplasty (e.g., percutaneous
transluminal coronary angioplasty or "PCTA") in which catheters are
inserted for long distances into extremely small vessels and are
used to open stenoses of blood vessels by balloon inflation. These
applications require extremely thin-walled, high-strength balloons
having predictable inflation properties. Thin walls are necessary,
because the balloon's wall thickness limits the minimum diameter of
the distal end of the catheter and therefore determines the ease of
passage of the catheter through the vascular system and the limits
on treatable vessel size. High strength is necessary because the
balloon is used to push open stenoses, and the thin wall of the
balloon must not burst under the high internal pressures necessary
to accomplish this task (e.g., 10 to 25 atmospheres). The balloon
elasticity should be relatively low (i.e., the balloon should be
substantially non-compliant), so that the diameter is easily
controllable (i.e., small variations in pressure should not cause
wide variations in diameter, once the balloon is inflated).
[0004] As another example, intraluminal stents or stent grafts are
commonly inserted or implanted into body lumens. In one common mode
of implantation, the stent is provided in a compact state over an
inflatable balloon. This assembly is then advanced to the desired
site within a body lumen, whereupon the balloon is inflated and the
stent or stent graft is expanded to support the vessel walls. In
this process, the stent or stent graft is subjected to substantial
forces and therefore must be mechanically robust.
SUMMARY OF THE INVENTION
[0005] The above and other challenges are addressed by the present
invention.
[0006] According to one aspect of the present invention, medical
devices are provided which are configured for implantation or
insertion into a subject. The medical devices contain one or more
multilayer regions, which contain the following: (a) one or more
charged nanoparticle layers and (b) one or more charged
polyelectroyte layers.
[0007] According to another aspect of the present invention,
methods are provided for making such medical devices. These methods
comprise applying a series of charged layers over a substrate. Each
successive layer in the series is opposite in charge relative to
the previously applied layer. Furthermore, the series of charged
layers that are applied over the substrate include the following:
(a) one or more charged nanoparticle layers and (b) one or more
charged polyelectroyte layers
[0008] An advantage of the present invention is that multilayer
medical devices and medical device components can be provided,
which are very thin and flexible, have very high strength, and are
substantially non-compliant.
[0009] These and other aspects, embodiments and advantages of the
present invention will become immediately apparent to those of
ordinary skill in the art upon reading the disclosure to
follow.
BRIEF DESCRIPTION OF THE FIGURES
[0010] FIGS. 1A-1C are schematic illustrations that show a process
for forming a balloon catheter, in accordance with an embodiment of
the present invention.
[0011] FIGS. 2A-2D are schematic illustrations that show a process
for forming a stent draft coating, in accordance with another
embodiment of the present invention.
[0012] FIGS. 3A-3C are schematic illustrations that show a process
for forming a perfusion balloon catheter, in accordance with
another embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0013] According to one aspect of the present invention, medical
devices are provided, which are adapted for implantation or
insertion into a subject and which include one or more multilayer
regions. The multilayer regions contain a plurality of alternating,
oppositely charged layers, including the following: (a) one or more
(typically a plurality of) charged nanoparticle layers, each
containing charged nanoparticles, and (b) one or more (typically a
plurality of) charged polyelectroyte layers, each containing one or
more charged polyelectrolyte species. The nanoparticle layers and
the polyelectrolyte layers have charges that are opposite to the
charges of adjacent layers.
[0014] Examples of medical devices for the practice of the present
invention include implantable or insertable medical devices, for
example, catheters (e.g., renal or vascular catheters such as
balloon catheters), guide wires, balloons, filters (e.g., vena cava
filters), stents (including coronary vascular stents, cerebral,
urethral, ureteral, biliary, tracheal, gastrointestinal and
esophageal stents), stent grafts, cerebral aneurysm filler coils
(including Guglilmi detachable coils and metal coils), vascular
grafts, myocardial plugs, patches, pacemakers and pacemaker leads,
heart valves, vascular valves, biopsy devices, patches for delivery
of therapeutic agent to intact skin and broken skin (including
wounds); tissue engineering scaffolds for cartilage, bone, skin and
other in vivo tissue regeneration, as well as any coated substrate
(which can comprise, for example, glass, metal, polymer, ceramic
and combinations thereof) that is implanted or inserted into the
body.
[0015] The medical devices of the present invention include medical
devices that are used for diagnostics, systemic treatment, or for
the localized treatment of any mammalian tissue or organ. Examples
include tumors; organs including the heart, coronary and peripheral
vascular system (referred to overall as "the vasculature"), lungs,
trachea, esophagus, brain, liver, kidney, bladder, urethra and
ureters, eye, intestines, stomach, pancreas, ovary, and prostate;
skeletal muscle; smooth muscle; breast; dermal tissue; cartilage;
and bone.
[0016] 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 a disease or condition. Typical subjects are
mammalian subjects, more typically human subjects.
[0017] The multilayer regions of the present invention can be
assembled using layer-by-layer techniques. Layer-by-layer
techniques can be used to coat a wide variety of substrates using
charged materials via electrostatic self-assembly. In the
layer-by-layer technique, a first layer having a first surface
charge is typically deposited on an underlying substrate, followed
by a second layer having a second surface charge that is opposite
in sign to the surface charge of the first layer, and so forth. The
charge on the outer layer is reversed upon deposition of each
sequential layer.
[0018] Substrates for the practice of the present invention include
substrates that are incorporated into the finished medical device,
as well as substrates that merely acts as templates for the
layer-by-layer technique, but which are not found in the finished
device (although a residue of the substrate will remain in certain
embodiments). The substrates are commonly formed from ceramic,
metallic, polymeric and other high molecular weight materials,
including stable and disintegrable materials.
[0019] Ceramic substrates may be selected, for example, from
substrates containing one or more of the following: metal oxides,
including aluminum oxides and transition metal oxides (e.g., oxides
of titanium, zirconium, hafnium, tantalum, molybdenum, tungsten,
rhenium, and iridium); silicon-based ceramics, such as those
containing silicon nitrides, silicon carbides and silicon oxides
(sometimes referred to as glass ceramics); calcium phosphate
ceramics (e.g., hydroxyapatite); and carbon-based, ceramic-like
materials such as carbon nitrides.
[0020] Metallic substrates may be selected, for example, from
substrates containing one or more of the following: metal alloys
such as cobalt-chromium alloys, nickel-titanium alloys (e.g.,
nitinol), cobalt-chromium-iron alloys (e.g., elgiloy alloys),
nickel-chromium alloys (e.g., inconel alloys), and iron-chromium
alloys (e.g., stainless steels, which contain at least 50% iron and
at least 11.5% chromium), and noble metals such as silver, gold,
platinum, palladium, iridium, osmium, rhodium, titanium, tungsten,
and ruthenium.
[0021] Substrates containing polymers and other high molecular
weight materials may be selected, for example, from substrates
containing one or more of the following: polycarboxylic acid
polymers and copolymers including polyacrylic acids; acetal
polymers and copolymers; acrylate and methacrylate polymers and
copolymers (e.g., n-butyl methacrylate); cellulosic polymers and
copolymers, including cellulose acetates, cellulose nitrates,
cellulose propionates, cellulose acetate butyrates, cellophanes,
rayons, rayon triacetates, and cellulose ethers such as
carboxymethyl celluloses and hydroxyalkyl celluloses;
polyoxymethylene polymers and copolymers; polyimide polymers and
copolymers such as polyether block imides, polyamidimides,
polyesterimides, and polyetherimides; polysulfone polymers and
copolymers including polyarylsulfones and polyethersulfones;
polyamide polymers and copolymers including nylon 6,6, nylon 12,
polyether-block co-polyamide polymers (e.g., Pebax.RTM. resins),
polycaprolactams and polyacrylamides; resins including alkyd
resins, phenolic resins, urea resins, melamine resins, epoxy
resins, allyl resins and epoxide resins; polycarbonates;
polyacrylonitriles; polyvinylpyrrolidones (cross-linked and
otherwise); polymers and copolymers of vinyl monomers including
polyvinyl alcohols, polyvinyl halides such as polyvinyl chlorides,
ethylene-vinylacetate copolymers (EVA), polyvinylidene chlorides,
polyvinyl ethers such as polyvinyl methyl ethers, vinyl aromatic
polymers and copolymers such as polystyrenes, styrene-maleic
anhydride copolymers, vinyl aromatic-hydrocarbon copolymers
including styrene-butadiene copolymers, styrene-ethylene-butylene
copolymers (e.g., a polystyrene-polyethylene/butylene-polystyrene
(SEBS) copolymer, available as Kraton.RTM. G series polymers),
styrene-isoprene copolymers (e.g.,
polystyrene-polyisoprene-polystyrene), acrylonitrile-styrene
copolymers, acrylonitrile-butadiene-styrene copolymers,
styrene-butadiene copolymers and styrene-isobutylene copolymers
(e.g., polyisobutylene-polystyrene block copolymers such as SIBS),
polyvinyl ketones, polyvinylcarbazoles, and polyvinyl esters such
as polyvinyl acetates; polybenzimidazoles; ionomers; polyalkyl
oxide polymers and copolymers including polyethylene oxides (PEO);
polyesters including polyethylene terephthalates, polybutylene
terephthalates and aliphatic polyesters such as polymers and
copolymers of lactide (which includes lactic acid as well as d-, l-
and meso lactide), epsilon-caprolactone, glycolide (including
glycolic acid), hydroxybutyrate, hydroxyvalerate, para-dioxanone,
trimethylene carbonate (and its alkyl derivatives),
1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and
6,6-dimethyl-1,4-dioxan-2-one (a copolymer of polylactic acid and
polycaprolactone is one specific example); polyether polymers and
copolymers including polyarylethers such as polyphenylene ethers,
polyether ketones, polyether ether ketones; polyphenylene sulfides;
polyisocyanates; polyolefin polymers and copolymers, including
polyalkylenes such as polypropylenes, polyethylenes (low and high
density, low and high molecular weight), polybutylenes (such as
polybut-1-ene and polyisobutylene), polyolefin elastomers (e.g.,
santoprene), ethylene propylene diene monomer (EPDM) rubbers,
poly-4-methyl-pen-1-enes, ethylene-alpha-olefin copolymers,
ethylene-methyl methacrylate copolymers and ethylene-vinyl acetate
copolymers; fluorinated polymers and copolymers, including
polytetrafluoroethylenes (PTFE),
poly(tetrafluoroethylene-co-hexafluoropropene) (FEP), modified
ethylene-tetrafluoroethylene copolymers (ETFE), and polyvinylidene
fluorides (PVDF); silicone polymers and copolymers; polyurethanes;
p-xylylene polymers; polyiminocarbonates; copoly(ether-esters) such
as polyethylene oxide-polylactic acid copolymers; polyphosphazines;
polyalkylene oxalates; polyoxaamides and polyoxaesters (including
those containing amines and/or amido groups); polyorthoesters;
biopolymers, such as polypeptides, proteins, polysaccharides and
fatty acids (and esters thereof), including fibrin, fibrinogen,
collagen, elastin, chitosan, gelatin, starch, glycosaminoglycans
such as hyaluronic acid, various waxes, including low melting point
waxes used for dental engineering (e.g., for so-called "lost wax"
techniques); as well as blends and further copolymers of the
above.
[0022] Certain substrates are inherently charged and thus readily
lend themselves to layer-by-layer assembly.
[0023] To the extent that the substrate does not have an inherent
net surface charge, a surface charge may nonetheless be provided.
For example, where the substrate to be coated is conductive, a
surface charge can be provided by applying an electrical potential
to the same. Once a first polyelectrolyte layer is established in
this fashion, a second polyelectrolyte layer having a second
surface charge that is opposite in sign to the surface charge of
the first polyelectrolyte layer can readily be applied, and so
forth.
[0024] As another example, the substrate can be provided with a
positive charge by covalently attaching functional groups having
positive charge (e.g., amine, imine or another basic groups) or
functional groups having a negative charge (e.g., carboxylic,
phosphonic, phosphoric, sulfuric, sulfonic, or other acid groups)
using methods well known in the art.
[0025] As another example, a surface charge can be provided on a
substrate by exposing the substrate to a charged amphiphilic
substance. Amphiphilic substances include any substance having
hydrophilic and hydrophobic groups. Where used, the amphiphilic
substance should have at least one electrically charged group to
provide the substrate surface with a net electrical charge.
Therefore, the amphiphilic substances that are used herein can also
be referred to as an ionic amphiphilic substances.
[0026] Amphiphilic polyelectrolytes are used as ionic amphiphilic
substances in some embodiments. For example, a polyelectrolyte
comprising charged groups (which are hydrophilic) as well as
hydrophobic groups, such as polyethylenimine (PEI) or poly(styrene
sulfonate) (PSS), can be employed. Cationic and anionic surfactants
are also used as amphiphilic substances in some embodiments.
Cationic surfactants include quaternary ammonium salts
(R.sub.4N.sup.+X.sup.-), where R is an organic radical and where
X.sup.- is a counter-anion, e.g. a halogenide, for example,
didodecyldimethylammonium bromide (DDDAB), alkyltrimethylammonium
bromides such as hexadecyltrimethylammonium bromide (HDTAB),
dodecyltrimethylammonium bromide (DTMAB), myristyltrimethylammonium
bromide (MTMAB), or palmityl trimethylammonium bromide, or
N-alkylpyridinium salts, or tertiary amines
(R.sub.3NH.sup.+X.sup.-), for example,
cholesteryl-3.beta.-N-(dimethyl-aminoethyl)-carbamate or mixtures
thereof. Anionic surfactants include alkyl or olefin sulfate
(R--OSO.sub.3M), for example, a dodecyl sulfate such as sodium
dodecyl sulfate (SDS), a lauryl sulfate such as sodium lauryl
sulfate (SLS), or an alkyl or olefin sulfonate (R--SO.sub.3M), for
example, sodium-n-dodecyl-benzene sulfonate, or fatty acids
(R--COOM), for example, dodecanoic acid sodium salt, or phosphoric
acids or cholic acids or fluoro-organics, for example,
lithium-3-[2-(perfluoroalkyl)ethylthio]propionate or mixtures
thereof, where R is an organic radical and M is a
counter-cation.
[0027] Hence, in some embodiments, a surface charge is provided on
a substrate by adsorbing cations (e.g., protamine sulfate,
polyallylamine, polydiallyldimethylammonium species,
polyethyleneimine, chitosan, gelatin, spermidine, albumin, among
many others) or by adsorbing anions (e.g., polyacrylic acid, sodium
alginate, polystyrene sulfonate, eudragit, gelatin [gelatin is an
amphiphilic polymer, hence it fits in both categories depending how
it is being prepared], hyaluronic acid, carrageenan, chondroitin
sulfate, carboxymethylcellulose, among many others) to the surface
of the substrate as a first charged layer. Although full coverage
may not be obtained for the first layer, once several layers have
been deposited, a full coverage should ultimately be obtained, and
the influence of the substrate is expected to be negligible. The
feasibility of this process has been demonstrated on glass
substrates using charged polymeric (polyelectrolyte) materials.
See, e.g., "Multilayer on solid planar substrates," Multi-layer
thin films, sequential assembly of nanocomposite materials,
Wiley-VCH ISBN 3-527-30440-1, Chapter 14; and "Surface-chemistry
technology for microfluidics," Hau, Winky L. W. et al. J.
Micromech. Microeng. 13 (2003) 272-278.
[0028] The species for establishing a surface charge can be applied
to the substrate by a variety of techniques. These techniques
include, for example, spraying techniques, dipping techniques, roll
and brush coating techniques, techniques involving coating via
mechanical suspension such as air suspension, ink jet techniques,
spin coating techniques, web coating techniques and combinations of
these processes. The choice of the technique will depend on the
requirements at hand. For example, dipping and spraying techniques
(without masking) can be employed, for instance, where it is
desired to apply the species to an entire substrate. On the other
hand, roll coating, brush coating and ink jet printing can be
employed, for instance, where it is desired to apply the species
only certain portions of the substrate (e.g., in the form of a
pattern).
[0029] Once a sufficient charge is provided on a substrate, it can
be readily coated with a layer of an oppositely charged material.
Multilayer regions are formed by repeated treatment with
alternating, oppositely charged materials, i.e., by alternating
treatment with materials that provide positive and negative surface
charges. The layers self-assemble by means of electrostatic
layer-by-layer deposition, thus forming a multilayered region over
the substrate.
[0030] As noted above, the multilayer regions of the present
invention typically include the following: (a) a plurality of
charged nanoparticle layers, which contain charged nanoparticles,
and (b) a plurality of charged polyelectroyte layers, which contain
one or more charged polyelectrolyte species.
[0031] The nanoparticles for use in the charged nanoparticle layers
of the present invention can vary widely in size, but typically
have at least one dimension (e.g., the thickness for a nanoplates,
the diameter for a nanospheres, nanocylinders and nanotubes, etc.)
that is less than 1000 nm, more typically less than 100 nm. Hence,
for example, nanoplates typically have at least one dimension that
is less than 1000 nm, nanofibers typically have at least two
orthogonal dimensions (e.g., the diameter for cylindrical
nanofibers) that are less than 1000 nm, while other nanoparticles
typically have three orthogonal dimensions that are less than 1000
nm (e.g., the diameter for nanospheres).
[0032] A wide variety of nanoparticles are available for use in the
charged nanoparticle layers of the present invention including, for
example, carbon, ceramic and metallic nanoparticles including
nanoplates, nanotubes, and nanospheres, and other nanoparticles.
Specific examples of nanoplates include synthetic or natural
phyllosilicates including clays and micas (which may optionally be
intercalated and/or exfoliated) such as montmorillonite, hectorite,
hydrotalcite, vermiculite and laponite. Specific examples of
nanotubes and nanofibers include single-wall, so-called "few-wall,"
and multi-wall carbon nanotubes, such as fullerene nanotubes, vapor
grown carbon fibers, alumina nanofibers, titanium oxide nanofibers,
tungsten oxide nanofibers, tantalum oxide nanofibers, zirconium
oxide nanofibers, and silicate nanofibers such as aluminum silicate
nanofibers. Specific examples of further nanoparticles (e.g.,
nanoparticles having three orthogonal dimensions that are less than
1000 nm) include fullerenes (e.g., "Buckey balls"), silica
nanoparticles, aluminum oxide nanoparticles, titanium oxide
nanoparticles, tungsten oxide nanoparticles, tantalum oxide
nanoparticles, zirconium oxide nanoparticles, dendrimers, and
monomeric silicates such as polyhedral oligomeric silsequioxanes
(POSS), including various functionalized POSS and polymerized
POSS.
[0033] One preferred group of nanoparticles for the practice of the
present invention are carbon nanotubes and carbon nanofibers having
a diameter ranging from 0.5 nm to 200 nm.
[0034] In this regard, carbon nanotubes, especially single-wall
carbon nanotubes (SWNT), have remarkable mechanical properties, and
show great promise for enhancing strength in composites, such as
polymer composites. SWNT polymer composites are commonly prepared
by polymer blending or by in situ polymerization techniques.
Unfortunately, even with surface modification of the SWNT, phase
separation is problematic due to the vastly different molecular
mobilities of the components. To overcome phase separation issues
between the SWNT and the polymer, layer-by-layer assembly has been
used in which alternating layers of SWNT and polymeric material
have been deposited. See Arif A. Mamedov et al., "Molecular design
of strong single-wall carbon nanotube/polyelectrolyte multilayer
composites," Nature Material, Vol. 1, No. 3, 2002, pages 191-194,
the entire disclosure of which is incorporated by reference.
[0035] As with the substrate, various techniques are available for
providing charges on nanoparticles that are not inherently charged.
For example, a surface charge can be provided by adsorbing or
otherwise attaching species on the nanoparticles which have a net
positive or negative charge, for example, charged amphiphilic
substance such as amphiphilic polyelectrolytes and cationic and
anionic surfactants (see above). Moreover, where the nanoparticles
are sufficiently stable, surface charges can sometimes be
established by exposure to highly acidic conditions. For example,
it is known that carbon nanoparticles, such as carbon nanotubes,
can be partially oxidized by refluxing in strong acid to form
carboxylic acid groups (which ionize to become negatively charged
carboxyl groups) on the nanoparticles. Establishing a surface
charge on nanoparticles is also advantageous in that a relatively
stable and uniform suspension of the nanoparticles is commonly
achieved, due at least in part to electrostatic stabilization
effects.
[0036] With respect to polyelectrolyte species, a wide variety of
these materials are also available for use in forming charged
polyelectrolyte layers in accordance with the present invention.
Polyelectrolytes are polymers having charged (e.g., ionically
dissociable) groups. Usually, the number of these groups in the
polyelectrolytes is so large that the polymers are soluble in polar
solvents (including water) when in ionically dissociated form (also
called polyions). Depending on the type of dissociable groups,
polyelectrolytes are typically classified as polyacids and
polybases. When dissociated, polyacids form polyanions, with
protons being split off. Polyacids include inorganic, organic and
bio-polymers. Examples of polyacids are polyphosphoric acids,
polyvinylsulfuric acids, polyvinylsulfonic acids,
polyvinylphosphonic acids and polyacrylic acids. Examples of the
corresponding salts, which are also called polysalts, are
polyphosphates, polyvinylsulfates, polyvinylsulfonates,
polyvinylphosphonates and polyacrylates. Polybases contain groups
which are capable of accepting protons, e.g., by reaction with
acids, with a salt being formed. Examples of polybases having
dissociable groups within their backbone and/or side groups are
polyallylamine, polyethylimine, polyvinylamine and
polyvinylpyridine. By accepting protons, polybases form
polycations. Some polyelectrolytes have both anionic and cationic
groups, but nonetheless have a net positive or negative charge.
[0037] Suitable polyelectrolytes for use in accordance with the
invention include those based on biopolymers, for example, alginic
acid, gummi arabicum, nucleic acids, pectins and proteins,
chemically modified biopolymers such as carboxymethyl cellulose and
lignin sulfonates, and synthetic polymers such as polymethacrylic
acid, polyvinylsulfonic acid, polyvinylphosphonic acid and
polyethylenimine. Linear or branched polyelectrolytes can be used
in some embodiments. Using branched polyelectrolytes can lead to
less compact polyelectrolyte multilayers having a higher degree of
wall porosity. Polyelectrolyte molecules can be crosslinked within
or/and between the individual layers in some embodiments, e.g. by
crosslinking amino groups with aldehydes, for example, to increase
stability. Furthermore, amphiphilic polyelectrolytes, e.g.,
amphiphilic block or random copolymers having partial
polyelectrolyte character, can be used in some embodiments to
affect permeability towards polar small molecules.
[0038] Suitable polyelectrolytes include low-molecular weight
polyelectrolytes (e.g., polyelectrolytes having molecular weights
of a few hundred Daltons) up to macromolecular polyelectrolytes
(e.g., polyelectrolytes of synthetic or biological origin, which
commonly have molecular weights of several million Daltons).
[0039] Specific examples of polyelectrolyte cations (polycations)
include protamine sulfate polycations, poly(allylamine) polycations
(e.g., poly(allylamine hydrochloride) (PAH)),
polydiallyldimethylammonium polycations, polyethyleneimine
polycations, chitosan polycations, gelatin polycations, spermidine
polycations and albumin polycations. Specific examples of
polyelectrolyte anions (polyanions) include poly(styrenesulfonate)
polyanions (e.g., poly(sodium styrene sulfonate) (PSS)),
polyacrylic acid polyanions, sodium alginate polyanions, eudragit
polyanions, gelatin polyanions, hyaluronic acid polyanions,
carrageenan polyanions, chondroitin sulfate polyanions, and
carboxymethylcellulose polyanions.
[0040] In some embodiments, biodisintegrable polyelectrolytes are
utilized. For example, by using polyelectrolytes that are
biodisintegrable near the outer surface of the multilayer region, a
therapeutic agent can be released into the subject at a rate that
is dependent upon the rate of disintegration of the polyelectrolyte
layers. As used herein, a "biodisintegrable material" is a material
which undergoes dissolution, degradation, resorption and/or other
disintegration processes over the period that the device is
designed to reside in a patient. Conversely, in some embodiments,
biostable polyelectrolytes are utilized. As used herein, a
"biostable material" is a material which does not undergo
substantial dissolution, degradation, resorption and/or other
disintegration processes over the period that the device is
designed to reside in a patient.
[0041] Examples of biodisintegrable and biostable polyelectrolytes
include polyglycolic acid (PGA), polylactic acid (PLA), polyamides,
poly-2-hydroxy-butyrate (PHB), polycaprolactone (PCL),
poly(lactic-co-glycolic)acid (PLGA), protamine sulfate,
polyallylamine, polydiallyldimethylammonium species,
polyethyleneimine, chitosan, eudragit, gelatin, spermidine,
albumin, polyacrylic acid, sodium alginate, polystyrene sulfonate,
hyaluronic acid, carrageenan, chondroitin sulfate,
carboxymethylcellulose, heparin, other polypeptides and proteins,
and DNA, among others.
[0042] In some embodiments of the invention, at least one
therapeutic agent is disposed on or within the polyelectrolyte
multilayer region of the medical devices of the present invention.
Several techniques are available for establishing the therapeutic
agent within the multilayer region.
[0043] In some embodiments, the therapeutic agent is charged, for
example, because it is itself a charged molecule or because it is
intimately associated with a charged molecule. Examples of charged
therapeutic agents include small molecule and polymeric therapeutic
agents containing ionically dissociable groups, for example,
therapeutic agents containing carboxylic, phosphonic, phosphoric,
sulfuric, sulfonic, or other acid groups, or therapeutic agents
containing amine, imine or another basic groups. As noted above,
acidic groups generally become anionic groups in aqueous solution
by donating protons, while basic groups generally become cations by
accepting protons. In some cases, the therapeutic agent will
contain both acidic and basic groups, yet will have a net (overall)
charge. Examples of charged therapeutic agents include
polynucleotides (e.g., DNA and RNA), polypeptides (e.g., proteins,
whose overall net charge will vary with pH, based on their
respective isoelectric points), and various small molecule drugs,
among others. For example, insulin is a negatively charged molecule
at neutral pH, while protamine is positively charged. Other
examples include heparin, hyaluronan, immunogloubulins and so
forth.
[0044] Even where the therapeutic agent does not possess one or
more charged groups, it can nevertheless be provided with a charge,
for example, through non-covalent association with a charged
species. Examples of non-covalent associations include hydrogen
bonding, hydrophilic/lipophilic interactions, and so forth. For
instance, the therapeutic agent can be associated with an ionic
amphiphilic substance, such as one of those set forth above.
[0045] In certain embodiments where a charged therapeutic agent is
employed, one or more layers of the charged therapeutic agent
is/are deposited during the course of assembling the multilayer
region. For example, in some instances, the therapeutic agent is
itself a polyelectrolyte (e.g., where the therapeutic agent is a
polypeptide or a polynucleotide) and it is used, as such, to create
one or more polyelectrolyte layers within the multilayer region. In
other instances, the charged therapeutic agent is not a
polyelectrolyte (e.g., it may be a charged small molecule drug).
Nevertheless, one or more layers of the charged therapeutic agent
can be substituted for one or more layers of the same charge (i.e.,
positive or negative) during the multilayer assembly process. In
each of the above cases, the therapeutic agent is disposed on
and/or within the multilayer region.
[0046] In still other embodiments, the therapeutic agent is
provided within charged nanocapsules, which are formed, for
example, using layer-by-layer techniques such as those described
herein and in commonly assigned U.S. Ser. No. 10/768,388, entitled
"Localized Drug Delivery Using Drug-Loaded Nanocapsules," the
entire disclosure of which is incorporated by reference. In these
embodiments, one or more layers of the charged nanocapsules can be
deposited during the course of assembling the multilayer
region.
[0047] In still other embodiments, the multilayer region is loaded
with therapeutic agent subsequent to its formation. In this regard,
various techniques have been reported for incorporating therapeutic
agents into pre-formed microscopic polyelectrolyte multilayer
capsules, and these techniques are equally applicable to the
multilayer-coated structures of the present invention.
[0048] For example, techniques are known in the polyelectrolyte
multilayer art for increasing the porosity, and thus the
permeability, of polyelectrolyte multilayer structures. For
instance, techniques have been reported for introducing different
materials into polyelectrolyte multilayer capsules by varying the
pH. In particular, polyelectrolyte multilayer structures are known
(e.g. PSS-PAH multilayer structures) which are effectively closed
at higher pH's. However, at more acidic pH's (e.g., pH 6 and
below), the multilayer structures open up, allowing macromolecules
(e.g., FITC-labeled dextran, MW.about.75,000 and MW.about.2,000,000
as well as FITC-labeled albumin have been demonstrated) to freely
permeate the capsule. See, e.g., Antipov, A. A. et al.,
"Polyelectrolyte multilayer capsule permeability control," Colloids
and Surfaces A: Physicochemical and Engineering Aspects, 198-200
(2002) pp. 535-541.
[0049] In the present invention, layer-by-layer assembly is
preferably conducted by exposing a selected charged substrate to
solutions or suspensions that contain species of alternating net
charge, including solutions or suspensions that contain charged
nanoparticles, charged polyelectrolytes, and, optionally, charged
therapeutic agents. The concentration of the charged entities
within these solutions and suspensions can vary widely, but will
commonly be in the range of from 0.01 to 10 mg/ml, and more
commonly from 0.1 to 1 mg/ml. Moreover the pH of these suspensions
and solutions are such that the nanoparticles, polyelectrolytes,
and optional therapeutic agents maintain their desired charge.
Buffer systems may be employed for this purpose, if needed,
although the charged entities chosen are commonly ionized at
neutral pH (e.g., at pH 6-8) or at the pH of the body location
where the device is to be inserted or implanted.
[0050] The solutions and suspensions containing the charged species
(e.g., solutions/suspensions of polyelectrolytes, charged
nanoparticles, or other optional charged species such as charged
therapeutic agents) can be applied to the charged substrate surface
using a variety of techniques including, for example, spraying
techniques, dipping techniques, roll and brush coating techniques,
techniques involving coating via mechanical suspension such as air
suspension, ink jet techniques, spin coating techniques, web
coating techniques and combinations of these processes. As a
specific example, layers can be applied over an underlying
substrate by immersing the entire substrate into a solution or
suspension containing the charged species, or by immersing half of
the substrate into the solution or suspension, flipping the same,
and immersing the other half of the substrate into the solution or
suspension to complete the coating. In some embodiments, the
substrate is rinsed after application of each charged species
layer, for example, using a washing solution that has a pH that
will ensure that the charge of the outer layer is maintained.
[0051] Using these and other techniques, multiple layers of
alternating charge are applied over the underlying substrate,
including the application of one or more (typically a plurality of)
charged nanoparticle layers and the application of one or more
(typically a plurality of) charged polyelectroyte layers. For
example, in some embodiments, between 10 and 200, more typically
between 30 and 100 layers are applied over the substrate. The total
thickness of the multilayer region that is assembled will typically
range, for example, from 10 nanometers to 40 micrometers (microns),
more typically between 100 nanometers and 10 microns.
[0052] In many beneficial embodiments, the multilayer region
comprises an alternating series of negatively charged nanoparticle
layers and positively charged polyelectroyte layers. In other
beneficial embodiments, the multilayer region comprises an
alternating series of positively charged nanoparticle layers and
negatively charged polyelectroyte layers. In still other beneficial
embodiments, the multilayer region comprises an alternating series
of positively and negatively charged nanoparticle layers. One class
of nanoparticles that come both in positively and negatively
charged forms are dendrimers.
[0053] One preferred material for use in forming charged
polyelectroyte layers in accordance with the present invention is
polyethyleneimine (PEI), which, as noted above, is an amphiphilic
polyelectrolyte and thus is useful for establishing an initial
charged layer on a substrate and can be used to provide subsequent
polyelectrolyte layers as well. Being positively charged, PEI is
useful in combination with adjacent layers that contain negatively
charged species, for example, carboxyl functionalized carbon
nanotubes. PEI having a molecular weight of about 70,000 is readily
available from Sigma Aldrich. For example, to form a multilayer
stack, the substrate can be dipped in a solution of PEI, followed
by dipping in a suspension of carbon nanotubes, and so forth, with
the number of alternating layers established ultimately depending,
for example, upon the desired thickness and strength of the final
multilayer region.
[0054] The PEI layer can also be followed by a layer of a
negatively charged polyelectrolyte such as polyacrylic acid (PAA).
The negatively charged polyelectrolyte is useful, for instance, in
combination with adjacent layers that contain positively charged
species, such as positively charged nanoparticles, for example
dendrimers and functionalized gold nanoparticles, or additional PEI
layers (e.g., where it is desired to establish multiple
polyelectrolyte layers beneath, between or above the nanoparticle
layers).
[0055] With respect to functionalized gold nanoparticles, it is
noted that these particles could help to create a radio-opaque
layer. Gold nanoparticles can be made positively charged by
applying a outer layer of lysine to the same. See, for example,
"DNA-mediated electrostatic assembly of gold nanoparticles into
linear arrays by a simple drop-coating procedure," Murali Sastrya
and Ashavani Kumar, Applied Physics Letters, Vol. 78, No. 19, 7 May
2001.
[0056] The bonding between a substrate and PEI can be enhanced, for
example, by providing as substrate with negatively charged groups.
For example, a Pebax.RTM. balloon surface can be modified to have a
negative charge by providing the balloon with negatively charged
functional groups such as carboxylate groups.
[0057] As noted above, in some embodiments, a multilayer region is
formed upon an underlying substrate that becomes incorporated into
the finished medical device. As one specific example, a multilayer
region with reinforcement properties in accordance with the present
invention can be built upon a preexisting balloon, such as a
Pebax.RTM. balloon.
[0058] In some embodiments, on the other hand, the underlying
substrate merely acts as a template (e.g., as a mold) for
application of the layer-by-layer technique, and the multilayer
region is freed from the substrate after forming the multilayer
region. The multilayer region is applied in some instance to the
inside of the removable substrate, and is applied in other
instances to the outside of the removable substrate.
[0059] In some cases, the removable substrate is releasably engaged
with the multilayer region, for example, by forming a weak
(dissolvable) first electrostatic layer on top the substrate. As
another example, hollow capsules have been formed by forming a
series of polyelectrolyte multilayers around cores of melamine
formaldehyde or manganese carbonate, followed by removal of the
core material by dissolution. See Sukhorukov et al., "Comparative
Analysis of Hollow and Filled Polyelectrolyte Microcapsules
Templated on Melamine Formaldehyde and Carbonate Cores," Macromol.
Chem. Phys., 205, 2004, pp. 530-535. Using analogous procedures, a
layer of melamine formaldehyde or manganese carbonate is formed on
a removable substrate. After forming the desired polyelectrolyte
layers on the substrate, the layer of melamine formaldehyde or
manganese carbonate is dissolved, releasing the substrate. The
substrate can be in the form, for instance, of a reusable one-piece
or multi-piece (e.g. two-piece) mold, as is known in the art.
[0060] In other cases, the substrate is removed by destroying it,
for example, by melting, sublimation, combustion, dissolution or
other process, in order to free the multilayer region. For
instance, in some embodiments, a so-called "lost core" mold is
used. These molds can be made, for example, from materials that
melt at moderately elevated temperatures (e.g., 60.degree. C.), for
instance, dental waxes such as those available from MDL Dental
Products, Inc., Seattle, Wash., USA. Other examples of materials
that can be used for the formation of destroyable molds are
materials that are essentially insoluble in cold water, but are
soluble in hot water. Polyvinyl alcohol (PVOH) is one example of
such a material.
[0061] Where the multilayer region is provided over a substrate, it
can extend over all or only a portion of the substrate. For
example, multilayer regions can be provided over multiple surface
portions of an underlying substrate and may be provided in any
shape or pattern (e.g., in the form of a series of rectangles,
stripes, or any other continuous or non-continuous pattern).
Techniques by which patterned multilayer regions may be provided
are described above and include ink jet techniques, roll coating
techniques, etc. For example, in some embodiments, a patterned
multilayer region is created, to provide differences in strength or
functionality across the medical device.
[0062] In some embodiments, one or more reinforcement members are
provided adjacent to or within the multilayer regions of the
present invention. For example, in some cases, one or more
reinforcement members are applied to an underlying substrate,
followed by a series of polyelectrolyte and nanoparticle layers. As
another example, in some cases, a first series of polyelectrolyte
layers or a first series of both polyelectrolyte and nanoparticle
layers are provided, followed by the application of one or more
reinforcement members, followed by a second series of
polyelectrolyte layers or a second series of both polyelectrolyte
and nanoparticle layers.
[0063] Examples of reinforcement members include fibrous
reinforcement members such as metal fiber meshes, metal fiber
braids, metal fiber windings, intermingled fibers (e.g., metal
fiber, carbon fibers, high density polyethylene fibers, liquid
polymer crystals) and so forth. Metals that can be used for this
purpose include, for example, various metals listed above for use
in forming metallic substrates. For example, very fine steel wire
is available from Bekaert (Belgium) for use as a reinforcement
member. If desired, the reinforcement members can be provided with
a surface charge to enhance incorporation of the reinforcement
members onto or into the multilayer regions. For example,
layer-by-layer techniques such as those described herein can be
used to encapsulate the reinforcement members, thereby providing
them with a charged outer layer and enhancing interaction of the
reinforcement members with an adjacent layer (e.g., a
polyelectrolyte or nanoparticle layer) of opposite charge.
[0064] A variety of outer top layers can be provided for the
multilayer regions of the present invention. For instance, in some
embodiments, the outer top layer is a charged nanoparticle layer, a
charged polyelectrolyte layer, charged therapeutic agent layer, and
so forth. As a specific example, the outer top layer can be a
carbon nanoparticle layer (e.g., a layer of charged carbon
nanotubes, C60 "Buckey balls", etc.).
[0065] In other embodiments, an outer polymer layer is provided
over the multilayer region (e.g., using conventional thermoplastic
or solvent processing techniques) to protect the outer surface of
the multilayer region and to contain any debris in the unlikely
event that the multilayer region becomes damaged (e.g., in the
unlikely event of a balloon burst). Such polymer layers can be
selected from the various polymeric materials described above for
use in connection with substrates.
[0066] As indicated above, in some embodiments of the invention,
one or more therapeutic agents are incorporated onto or into the
multilayer region, giving the medical device, for example, a drug
releasing function upon implantation.
[0067] Therapeutic agents may be used singly or in combination in
the medical devices of the present invention. "Drugs," "therapeutic
agents," "pharmaceutically active agents," "pharmaceutically active
materials," and other related terms may be used interchangeably
herein. These terms include genetic therapeutic agents, non-genetic
therapeutic agents and cells.
[0068] Exemplary non-genetic therapeutic agents for use in
connection with the present invention include: (a) anti-thrombotic
agents such as heparin, heparin derivatives, urokinase, and PPack
(dextrophenylalanine proline arginine chloromethylketone); (b)
anti-inflammatory agents such as dexamethasone, prednisolone,
corticosterone, budesonide, estrogen, sulfasalazine and mesalamine;
(c) antineoplastic/antiproliferative/anti-miotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin, angiopeptin, monoclonal
antibodies capable of blocking smooth muscle cell proliferation,
and thymidine kinase inhibitors; (d) anesthetic agents such as
lidocaine, bupivacaine and ropivacaine; (e) anti-coagulants such as
D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing
compound, heparin, hirudin, antithrombin compounds, platelet
receptor antagonists, anti-thrombin antibodies, anti-platelet
receptor antibodies, aspirin, prostaglandin inhibitors, platelet
inhibitors and tick antiplatelet peptides; (f) vascular cell growth
promoters such as growth factors, transcriptional activators, and
translational promotors; (g) vascular cell growth inhibitors such
as growth factor inhibitors, growth factor receptor antagonists,
transcriptional repressors, translational repressors, replication
inhibitors, inhibitory antibodies, antibodies directed against
growth factors, antibodies recognizing receptors on endothelial
progenitor cells, proteins of the tetraspanin family, such as CD9
Beta-1 and Beta-3 integrins, CD63, CD81, FcgammaRII, bifunctional
molecules consisting of a growth factor and a cytotoxin,
bifunctional molecules consisting of an antibody and a cytotoxin;
(h) protein kinase and tyrosine kinase inhibitors (e.g.,
tyrphostins, genistein, quinoxalines); (i) prostacyclin analogs;
(j) cholesterol-lowering agents; (k) angiopoietins; (l)
antimicrobial agents such as triclosan, cephalosporins,
aminoglycosides and nitrofurantoin; (m) cytotoxic agents,
cytostatic agents and cell proliferation affectors; (n)
vasodilating agents; (o) agents that interfere with endogenous
vasoactive mechanisms; (p) inhibitors of leukocyte recruitment,
such as monoclonal antibodies; (q) cytokines; and (r) hormones.
[0069] Preferred non-genetic therapeutic agents include paclitaxel,
sirolimus, everolimus, tacrolimus, dexamethasone, estradiol,
ABT-578 (Abbott Laboratories), trapidil, liprostin, Actinomcin D,
Resten-NG, Ap-17, abciximab, clopidogrel and Ridogrel.
[0070] Exemplary genetic therapeutic agents for use in connection
with the present invention include anti-sense DNA and RNA as well
as DNA coding for the various proteins (as well as the proteins
themselves): (a) anti-sense RNA, (b) tRNA or rRNA to replace
defective or deficient endogenous molecules, (c) angiogenic and
other factors including growth factors such as acidic and basic
fibroblast growth factors, vascular endothelial growth factor,
endothelial mitogenic growth factors, epidermal growth factor,
transforming growth factor .alpha. and .beta., platelet-derived
endothelial growth factor, platelet-derived growth factor, tumor
necrosis factor .alpha., hepatocyte growth factor and insulin-like
growth factor, (d) cell cycle inhibitors including CD inhibitors,
and (e) thymidine kinase ("TK") and other agents useful for
interfering with cell proliferation. Also of interest is DNA
encoding for the family of bone morphogenic proteins ("BMP's"),
including BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1),
BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and
BMP-16. Currently preferred BMP's are any of BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided as
homodimers, heterodimers, or combinations thereof, alone or
together with other molecules. Alternatively, or in addition,
molecules capable of inducing an upstream or downstream effect of a
BMP can be provided. Such molecules include any of the "hedgehog"
proteins, or the DNA's encoding them.
[0071] Vectors for delivery of genetic therapeutic agents include
viral vectors such as adenoviruses, gutted adenoviruses,
adeno-associated virus, retroviruses, alpha virus (Semliki Forest,
Sindbis, etc.), lentiviruses, herpes simplex virus, replication
competent viruses (e.g., ONYX-015) and hybrid vectors; and
non-viral vectors such as artificial chromosomes and
mini-chromosomes, plasmid DNA vectors (e.g., pCOR), cationic
polymers (e.g., polyethyleneimine, polyethyleneimine (PEI)), graft
copolymers (e.g., polyether-PEI and polyethylene oxide-PEI),
neutral polymers PVP, SP1017 (SUPRATEK), lipids such as cationic
lipids, liposomes, lipoplexes, nanoparticles, or microparticles,
with and without targeting sequences such as the protein
transduction domain (PTD).
[0072] Cells for use in connection with the present invention
include cells of human origin (autologous or allogeneic), including
whole bone marrow, bone marrow derived mono-nuclear cells,
progenitor cells (e.g., endothelial progenitor cells), stem cells
(e.g., mesenchymal, hematopoietic, neuronal), pluripotent stem
cells, fibroblasts, myoblasts, satellite cells, pericytes,
cardiomyocytes, skeletal myocytes or macrophage, or from an animal,
bacterial or fungal source (xenogeneic), which can be genetically
engineered, if desired, to deliver proteins of interest.
[0073] Numerous therapeutic agents, not necessarily exclusive of
those listed above, have been identified as candidates for vascular
treatment regimens, for example, as agents targeting restenosis.
Such agents are useful for the practice of the present invention
and include one or more of the following: (a) Ca-channel blockers
including benzothiazapines such as diltiazem and clentiazem,
dihydropyridines such as nifedipine, amlodipine and nicardapine,
and phenylalkylamines such as verapamil, (b) serotonin pathway
modulators including: 5-HT antagonists such as ketanserin and
naftidrofuryl, as well as 5-HT uptake inhibitors such as
fluoxetine, (c) cyclic nucleotide pathway agents including
phosphodiesterase inhibitors such as cilostazole and dipyridamole,
adenylate/Guanylate cyclase stimulants such as forskolin, as well
as adenosine analogs, (d) catecholamine modulators including
.alpha.-antagonists such as prazosin and bunazosine,
.beta.-antagonists such as propranolol and
.alpha./.beta.-antagonists such as labetalol and carvedilol, (e)
endothelin receptor antagonists, (f) nitric oxide donors/releasing
molecules including organic nitrates/nitrites such as
nitroglycerin, isosorbide dinitrate and amyl nitrite, inorganic
nitroso compounds such as sodium nitroprusside, sydnonimines such
as molsidomine and linsidomine, nonoates such as diazenium diolates
and NO adducts of alkanediamines, S-nitroso compounds including low
molecular weight compounds (e.g., S-nitroso derivatives of
captopril, glutathione and N-acetyl penicillamine) and high
molecular weight compounds (e.g., S-nitroso derivatives of
proteins, peptides, oligosaccharides, polysaccharides, synthetic
polymers/oligomers and natural polymers/oligomers), as well as
C-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds and
L-arginine, (g) ACE inhibitors such as cilazapril, fosinopril and
enalapril, (h) ATII-receptor antagonists such as saralasin and
losartin, (i) platelet adhesion inhibitors such as albumin and
polyethylene oxide, (j) platelet aggregation inhibitors including
aspirin and thienopyridine (ticlopidine, clopidogrel) and GP
IIb/IIIa inhibitors such as abciximab, epitifibatide and tirofiban,
(k) coagulation pathway modulators including heparinoids such as
heparin, low molecular weight heparin, dextran sulfate and
.beta.-cyclodextrin tetradecasulfate, thrombin inhibitors such as
hirudin, hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylketone)
and argatroban, FXa inhibitors such as antistatin and TAP (tick
anticoagulant peptide), Vitamin K inhibitors such as warfarin, as
well as activated protein C, (l) cyclooxygenase pathway inhibitors
such as aspirin, ibuprofen, flurbiprofen, indomethacin and
sulfinpyrazone, (m) natural and synthetic corticosteroids such as
dexamethasone, prednisolone, methprednisolone and hydrocortisone,
(n) lipoxygenase pathway inhibitors such as nordihydroguairetic
acid and caffeic acid, (o) leukotriene receptor antagonists, (p)
antagonists of E- and P-selectins, (q) inhibitors of VCAM-1 and
ICAM-1 interactions, (r) prostaglandins and analogs thereof
including prostaglandins such as PGE1 and PGI2 and prostacyclin
analogs such as ciprostene, epoprostenol, carbacyclin, iloprost and
beraprost, (s) macrophage activation preventers including
bisphosphonates, (t) HMG-CoA reductase inhibitors such as
lovastatin, pravastatin, fluvastatin, simvastatin and cerivastatin,
(u) fish oils and omega-3-fatty acids, (v) free-radical
scavengers/antioxidants such as probucol, vitamins C and E,
ebselen, trans-retinoic acid and SOD mimics, (w) agents affecting
various growth factors including FGF pathway agents such as bFGF
antibodies and chimeric fusion proteins, PDGF receptor antagonists
such as trapidil, IGF pathway agents including somatostatin analogs
such as angiopeptin and ocreotide, TGF-.beta. pathway agents such
as polyanionic agents (heparin, fucoidin), decorin, and TGF-.beta.
antibodies, EGF pathway agents such as EGF antibodies, receptor
antagonists and chimeric fusion proteins, TNF-.alpha. pathway
agents such as thalidomide and analogs thereof, Thromboxane A2
(TXA2) pathway modulators such as sulotroban, vapiprost, dazoxiben
and ridogrel, as well as protein tyrosine kinase inhibitors such as
tyrphostin, genistein and quinoxaline derivatives, (x) MMP pathway
inhibitors such as marimastat, ilomastat and metastat, (y) cell
motility inhibitors such as cytochalasin B, (z)
antiproliferative/antineoplastic agents including antimetabolites
such as purine analogs (e.g., 6-mercaptopurine or cladribine, which
is a chlorinated purine nucleoside analog), pyrimidine analogs
(e.g., cytarabine and 5-fluorouracil) and methotrexate, nitrogen
mustards, alkyl sulfonates, ethylenimines, antibiotics (e.g.,
daunorubicin, doxorubicin), nitrosoureas, cisplatin, agents
affecting microtubule dynamics (e.g., vinblastine, vincristine,
colchicine, paclitaxel and epothilone), caspase activators,
proteasome inhibitors, angiogenesis inhibitors (e.g., endostatin,
angiostatin and squalamine), rapamycin, cerivastatin, flavopiridol
and suramin, (aa) matrix deposition/organization pathway inhibitors
such as halofuginone or other quinazolinone derivatives and
tranilast, (bb) endothelialization facilitators such as VEGF and
RGD peptide, and (cc) blood rheology modulators such as
pentoxifylline.
[0074] Numerous additional therapeutic agents useful for the
practice of the present invention are also disclosed in U.S. Pat.
No. 5,733,925 assigned to NeoRx Corporation, the entire disclosure
of which is incorporated by reference.
[0075] 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 of the patient, the nature of the therapeutic agent, the
nature of the medical device including the nature of its multilayer
region(s), and so forth.
[0076] Further specific embodiments of the invention will now be
described with reference to the Figures.
[0077] Referring now to FIGS. 1A-1C, one embodiment of the
construction of a balloon catheter will now be described. Because
polyelectrolyte multilayers containing SWNT have been measured to
have an ultimate strength of 220 Mpa (similar to PET film), the
embodiment of the invention described in these figures utilizes a
destroyable mold for the formation of the multilayer region. In
other embodiments, of course, the balloon can be made using a
substrate that is not ultimately destroyed, such as a two-piece,
releasable mold or such as a pre-existing balloon that is
incorporated into the device.
[0078] Turning now to FIG. 1A, an assembly is illustrated which
includes a "lost core" mold 140, an inner guidewire lumen 110 and
an outer inflation lumen 120, although it will immediately become
clear on one of ordinary skill in the art that the balloon can
built independently of the guidewire and inflation lumens.
Guidewire and inflation lumens are well known in the art and are
commonly formed from materials such as nylons including nylon 12,
thermoplastic polyester elastomers (e.g., Hytrel.RTM.),
polyether-block co-polyamide polymers (e.g., Pebax.RTM.), high
density polyethylene, and polyurethane. Guidewire lumens are
commonly provided with lubricious materials on their inner
surfaces, for example, polytetrafluoroethylene or high density
polyethylene.
[0079] In the next step, a multilayer coating 130, containing
multiple alternating layers of polyelectrolyte (e.g., PEI) and
nanoparticles (e.g., SWNT), is applied over the mold 140 as
illustrated in FIG. 1B. Note that, in this embodiment, the
multilayer coating 130 extends beyond the proximal end (left end)
of the mold 140, where it engages the outer inflation lumen 120,
and extends beyond the distal (right) end of the mold 140, where it
engages the inner guidewire lumen 110.
[0080] Finally, the mold 140 is removed, thereby providing a
finished balloon catheter having an inner guidewire lumen 110, an
outer inflation lumen 120, and a multilayer balloon 130 as
illustrated in FIG. 1C.
[0081] Of course innumerable variations on the above themes are
possible.
[0082] For example, in the above steps, the multilayer coating 130
is formed not only on the wax mold 140, but also over a portion of
the guidewire lumen 110 and the outer inflation lumen 120. As a
result a separate step is avoided for sealing the balloon 130 to
the lumens 110, 120. In other embodiments, on the other hand, the
balloon is independently formed and subsequently attached to the
lumens 110, 120.
[0083] As another example, a braiding, winding or fiber meshwork,
preferably having a charged surface to ensure optimal adherence to
subsequently assembled layers, can be provided on top of the wax
mold. The braiding, winding or fiber meshwork can also be provided
after several polyelectrolyte and/or nanoparticle layers have been
deposited, if desired.
[0084] As another example, the mold of FIG. 1A can be extended to
the proximal side of the assembly (not shown), thereby allowing
part of the outer lumen to be constructed using the layer-by-layer
technology. In fact, an entire outer lumen can be constructed in
this fashion. Similarly, it is also possible to build the tip of
the inner lumen in the same fashion.
[0085] With reference now to FIGS. 3A-3C, in other embodiments, the
finished balloon 330 can be provided with longitudinal perfusion
channels, for example, by longitudinally placing tubes 350 inside
the wax mold 340, as illustrated in the assembly of FIG. 3A. As can
be seen from FIG. 3A, the tubes 350 protrude out of both sides of
the wax mold 340.
[0086] A multilayer coating 330 containing multiple alternating
polyelectrolyte and nanoparticle layers is then applied over the
assembly as shown in FIG. 3B.
[0087] Finally, the wax mold 340 is removed, thereby providing a
finished balloon catheter having an inner guidewire lumen 310, an
outer inflation lumen 320, and a multilayer balloon 330, as
illustrated in FIG. 3C. Note that the tubes 350 are incorporated
into the balloon structure, forming perfusion channels. The
protruding ends of the tubes 350 are subsequently be trimmed as
desired. Note than such tubes 350 can also be used as guidewire
lumens, if desired, rendering the inner tube 310 in the structure
superfluous.
[0088] Balloons made by procedures such as those discussed herein
are designed to be flexible, strong, non-compliant and durable
(e.g., having good puncture and abrasion resistance). Of course,
the present invention has applicability to a wide range of medical
devices other than balloon catheters.
[0089] Referring now to FIGS. 2A-2D, the encapsulation of a stent
(i.e., the formation of a stent graft) will now be described. As in
FIGS. 1A-1C and 3A-3C above, the mold illustrated in FIG. 2A is a
removable mold 240 made, for example, from a material such as
dental wax. The mold 240 in this embodiment is in the form of an
annulus and is positioned inside the stent 220. The outer surfaces
of the struts of the stent 220 remain uncovered by the mold 240 as
shown.
[0090] As illustrated in FIG. 2B, a first multilayer coating 230a,
which contains multiple alternating polyelectrolyte and
nanoparticle layers, is then applied over the mold 240 and stent
220, using, for example, techniques such as those described
above.
[0091] The wax mold 240 is then removed, yielding the structure
illustrated in FIG. 2C. Of course, a multilayer coating could be
provided on the inside of the stent by placing a mold, or some
other removable substrate such as a polymeric wrap, on the outside
of the stent structure.
[0092] In some embodiments, it is desirable to apply multilayer
coatings on both the outside and the inside of the stent structure.
For example, a second multilayer coating 230b, which, like coating
230a, contains multiple alternating polyelectrolyte and
nanoparticle layers, can be applied to the inside of the structure
of FIG. 2C, using the stent 220 and multilayer coating 230a as a
substrate for the layer assembly. This yields the encapsulated
stent structure of FIG. 2D. Note that the multilayer coating 230a,b
extends beyond both ends of the stent 220 in the embodiment
shown.
[0093] As with the balloons above, innumerable variations on the
above themes are possible. For example, instead of using a lost-wax
method to build the graft, it is also possible to add additional
layers to an existing graft using the techniques described
herein.
[0094] Stent grafts formed in accordance with the present invention
can be delivered to a subject by a variety of known stent delivery
systems, including various balloon catheters for stent delivery. In
some embodiments, stent grafts can be delivered using a catheter
that contains a multilayer balloon, also formed in accordance with
the present invention.
Example 1
[0095] A mold 3 mm in diameter of polyvinyl alcohol (PVOH) series
C-5 (purchased from Adept Polymers Limited, London) is insert
molded at 190.degree. C. A metal core pin is embedded through the
center of the mold.
[0096] The following solutions/suspensions are prepared: (1)
Polyurethane Pellethane 70D (Dow Chemical, Midland, Mich.) in
Tetrahydrofuran (THF) at a concentration of 5%; (2)
polyethylenimine (PEI) (Aldrich) in water at a concentration of 1%;
(3) polyacrylic acid (PAA) (Aldrich) in water at a concentration of
1%; and (4) carbon nanotubes (CNT) (Carbolex, Inc., Lexington, Ky.,
USA) in water at a concentration of 0.6%. The CNT are
functionalized by refluxing them in nitric acid.
[0097] A first layer of the polyurethane is deposited (by dipping)
on the PVOH core. Then, a layer of PEI is deposited on top of the
polyurethane layer. After this, 204 layers are deposited by
repeating the following sequence seventeen times:
PAA-PEI-CNT-PEI-CNT-PEI-CNT-PEI-CNT-PEI-CNT-PEI. The PAA layers are
introduced to reinforce the electrostatic attraction.
[0098] After deposition of the layers, the metal core pin is pulled
out of the mold and water at a temperature of 60.degree. C. is
flushed for 2 hours through the opening left by the core pin, thus
dissolving the PVOH core.
Example 2
[0099] The procedures of Example 1 are followed, with the following
changes: Instead of the core and the first polyurethane layer, an
existing PEBAX 7233 single wall balloon (Boston Scientific Corp.)
is used as a non-removable substrate. First, a layer of PEI
deposited on the balloon. After this, 96 layers are deposited by
following the following sequence eight times:
PAA-PEI-CNT-PEI-CNT-PEI-CNT-PEI-CNT-PEI-CNT-PEI. As above, the PAA
layers reinforce the electrostatic attraction between the
layers.
[0100] Although various embodiments of the invention are
specifically illustrated and described herein, it will be
appreciated that modifications and variations of the present
invention are covered by the above teachings without departing from
the spirit and intended scope of the invention.
* * * * *