U.S. patent application number 09/785087 was filed with the patent office on 2001-09-06 for method and apparatus for drug and gene delivery.
Invention is credited to Feldman, Marc D., Reed, Michael L., Weiss, Lee E., Wu, Clarence C..
Application Number | 20010020151 09/785087 |
Document ID | / |
Family ID | 24990647 |
Filed Date | 2001-09-06 |
United States Patent
Application |
20010020151 |
Kind Code |
A1 |
Reed, Michael L. ; et
al. |
September 6, 2001 |
Method and apparatus for drug and gene delivery
Abstract
An apparatus for treating a patient. The apparatus includes a
deployment mechanism having a surface. The apparatus also includes
at least one probe disposed on the deployment mechanism surface.
The probe extends between 25 microns and 1000 microns from the
surface of the deployment mechanism. The apparatus also includes
material coated on the probe. A method for treating a patient. The
method includes the steps of placing a material with a probe which
extends less than 1000 microns from a surface of a deployment
mechanism. Next, there is the step of inserting the probe into
preferably a blood vessel of a patient. Then, there is the step of
penetrating the interior wall of the vessel from the interior of
the vessel with the probe by activating the deployment mechanism so
the material can contact the vessel.
Inventors: |
Reed, Michael L.;
(Pittsburgh, PA) ; Weiss, Lee E.; (Pittsburgh,
PA) ; Wu, Clarence C.; (Pittsburgh, PA) ;
Feldman, Marc D.; (Pittsburgh, PA) |
Correspondence
Address: |
Ansel M. Schwartz
One Sterling Plaza
201 N. Craig Street, Suite 304
Pittsburgh
PA
15213
US
|
Family ID: |
24990647 |
Appl. No.: |
09/785087 |
Filed: |
February 15, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09785087 |
Feb 15, 2001 |
|
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08743902 |
Nov 6, 1996 |
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6197013 |
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Current U.S.
Class: |
604/103.02 ;
604/508 |
Current CPC
Class: |
A61M 25/10 20130101;
A61F 2/86 20130101; A61F 2250/0067 20130101; A61M 37/0015 20130101;
A61M 2025/105 20130101; A61F 2220/005 20130101; A61M 2037/0023
20130101; A61F 2220/0058 20130101; A61F 2/848 20130101; A61M
2037/0046 20130101 |
Class at
Publication: |
604/103.02 ;
604/508 |
International
Class: |
A61M 029/00; A61M
031/00 |
Claims
What is claimed is:
1. A method for treating a patient comprising the steps of: placing
a material with a probe which extends less than 1000 microns from a
surface of a deployment mechanism; inserting the probe into a
vessel of patient; penetrating the interior wall of the vessel from
the interior of the vessel with the probe by activating the
deployment mechanism so the material can contact the vessel.
2. A method as described in claim 1 wherein the inserting step
includes the step of inserting the probe into a blood vessel of a
patient.
3. A method as described in claim 2 wherein the penetrating step
includes the step of expanding a balloon of the deployment
mechanism on which the probe is disposed until the probe pierces
the interior of the vessel wall.
4. A method as described in claim 3 wherein the placing step
includes the step of coating the material on the surface of the
probe.
5. A method as described in claim 4 wherein the coating step
includes the step of putting DNA on the surface of the probe, where
the surface is made of gold or a material which is both conductive
and to which DNA adheres.
6. A method as described in claim 4 including after the penetrating
step, there is the step of removing the probe from the vessel.
7. A method as described in claim 4 wherein the coating step
includes the step of coating the material with hydrogel or other
biocompatible material which provides a protective coating to drugs
or DNA.
8. A method as described in claim 3 wherein the placing step
includes the step of filling a reservoir on the inside of the probe
with the material.
9. A method as described in claim 1 wherein after the inserting
step there is the step of opening a housing in which the probe is
disposed, said housing protecting the probe and material from body
fluid in the patient.
10. An apparatus for treating a patient comprising: a deployment
mechanism having a surface; at least one probe disposed on the
deployment mechanism surface, said probe extending between 25
microns to 1000 microns from the surface of the deployment
mechanism; and material coated on the probe.
11. An apparatus as described in claim 10 including at least a
second probe disposed on the surface of the deployment mechanism
having material coating on the second probe.
12. An apparatus as described in claim 11 wherein the deployment
mechanism includes a balloon having a surface with the first and
second probes disposed on the surface of the balloon.
13. An apparatus as described in claim 12 wherein each probe is
coated with gold or a material which DNA would adhere, and the
material has DNA.
14. An apparatus as described in claim 13 wherein the material is a
gene encoding for nitric oxide synthase or vascular endothelial
growth factor.
15. An apparatus as described in claim 12 wherein the material is
coated with a hydrogel or other biocompatible material which
provides a protecting coating to drugs or DNA.
16. An apparatus as described in claim 15 wherein the material is
prednisone or low molecular weight heparin or hirudin.
17. An apparatus as described in claim 12 wherein each probe has a
pointed tip.
18. An apparatus as described in claim 17 wherein each probe is
cone shaped.
19. An apparatus as described in claim 12 wherein each probe
extends radially f rom the surface of the balloon.
20. An apparatus as described in claim 19 wherein the deployment
mechanis m includes a removable housing in which the probes are
disposed when the housing is in a closed state, but is separated
from the probes when the balloon is in an inflated state.
21. A method for fabricating probes comprising the steps of:
placing a pattern on a silicon wafer; etching the wafer with the
pattern on the wafer to form a metal lattice with probes; and
rolling the metal lattice into a cylindrical shape.
Description
FIELD OF THE INVENTION
[0001] The present invention is related to the treatment of
patients with therapeutic agents inside arteries. More
specifically, the present invention is related to therapeutic
agents that are delivered to arteries through probes that pierce
the inside of the arteries.
BACKGROUND OF THE INVENTION
[0002] Heart disease continues to be the leading cause of death in
the United States. The mechanism of this disease is progressive
narrowing of coronary arteries by atherosclerotic plaque which can
lead to acute myocardial infarction and disabling angina. One
commonly used technique to change the natural history of coronary
atherosclerosis is transcatheter therapy, which includes
percutaneous transluminal coronary angioplasty, (or PTCA, commonly
referred to as balloon angioplasty), atherectomy, and coronary
stenting. During these procedures, an expandable balloon, cutting
device, or metal cage mounted on a balloon, respectively, is
threaded over a pre-placed wire to the site of coronary blockage.
In balloon angioplasty, the balloon is inflated, compressing the
atherosclerotic plaque; in atherectomy, the plaque is cut away; and
in stenting, the device is expanded and deployed against the
plaque. In each case, compression of the plaque and expansion of
the coronary artery, or removal of the atherosclerotic plaque,
restores lumen patency.
[0003] Despite the overall initial success of these procedures,
approximately 20% to 50% of all patients undergoing these
therapeutic procedures to clear blocked coronary arteries will
suffer restenosis (re-blockage) within six months of the initial
procedure. One widely accepted paradigm is that restenosis is a
manifestation of the general wound healing response. The injury
induced by coronary intervention causes platelet aggregation,
inflammatory cell infiltration and release of growth factors,
followed by smooth muscle cell proliferation and matrix formation.
In this paradigm, intimal hyperplasia secondary to vascular injury
is believed to be the etiology of restenosis. Numerous
pharmacological agents and genes have been shown to inhibit
restenosis in animal models; however, all have failed in human
trials. One explanation for their failure is that suboptimal doses
of agents were used in order to prevent side effects which will
occur from systemic administration of the higher doses required as
shown by animal studies.
[0004] The concept of localized intravascular delivery of
therapeutics has become an attractive solution to overcome this
limitation. Intravascular local delivery devices were recently
reviewed by Hofling and Huehns [(B. Hofling, T. Y. Huehns,
"Intravascular Local Drug Delivery after Angioplasty," European
Heart Journal 16, 437-440, 1995]. An illustration of these devices
is shown in FIG. 1. The basic principles behind these delivery
devices are: diffusion of drugs or genes through close contact;
assisted diffusion of drugs or genes driven transmurally by
pressure; and transport assisted by physical means. With these
devices, successful delivery of pharmacological agents as well as
genetic materials have been demonstrated in normal arteries. On the
other hand, the atherosclerotic plaque remains a major barrier for
this strategy of localized delivery. Delivery of a reporter gene to
an atherosclerotic artery was attempted by Feldman et. al. [L. J.
Feldman, P G. Steg, L. P. Zheng, "Low-Efficiency of Percutaneous
Adenovirus-Mediated Arterial Gene Transfer in the Atherosclerotic
Rabbit," Journal of Clinical Investigation 95, 2662-2671, 1995]
Compared to normal vessels, the atherosclerotic plaque of the
diseased artery behaved as a barrier and resulted in a 10
fold-reduction in transfer efficiency (0.20% vs. 2.0%,
p=0.0001).
[0005] The only current method which does not rely on passive
diffusion is the needle catheter shown in the right lower corner of
FIG. 1. It consists of 6 needles which cut through the full
thickness of the blood vessel, and deposit a gene or drug in the
adventitia (outer layer) of the vessel wall. The adventitia
contains the source of the blood supply to the vessel wall, which
becomes the means of drug or gene delivery. However, as this
catheter transects the vessel wall in an unpredictable fashion,
there are serious safety concerns. In addition, since the
atherosclerotic plaque will disrupt the blood supply of the
coronary artery, predictable, symmetrical delivery of a drug or
gene is not certain. In contrast, the present invention allows
predictably diffuse delivery of a drug or gene without transection
of the coronary artery. The present invention accomplishes this by
using a probe of a pre-limited length, as opposed to a standard
"long" needle in the needle catheter.
[0006] The present invention uses arrays of micromechanical probes
which penetrate the plaque and allow for efficient transport of
therapeutic agents into the artery media. The probes can be part of
a coronary stent which remains in the artery, or can be part of the
angioplasty balloon, which is removed after the interventional
procedure. Probe height can be varied from less than 25 .mu.m to
over 1000 .mu.m as required by the thickness of the compressed
plaque. This invention differs from conventional methods in that a
direct physical penetration of vascular plaque is accomplished.
Current delivery techniques rely on diffusion of the drug through a
thick layer of plaque; this diffusion is extremely slow, making the
transfer ineffective for clinical purposes. our preferred
embodiment of the invention involves a novel stent design. Stents
are devices used after angioplasty to prevent elastic recoil of the
compressed plaque. One type, the Palmaz-Schatz stent
[Balloon-expandable Palmaz-Schatz coronary stents are manufactured
by Johnson & Johnson], is shown in FIGS. 2a and 2b. FIGS. 2a
and 2b show a Palmaz-Schatz coronary stent before expansion, after
deployment, respectively, in a cardiac artery. The stent consists
of a metal lattice, 1, with interstices, 2. First, a conventional
balloon angioplasty procedure is performed to create a larger lumen
in the occluded vessel. Then, using a second balloon, the stent is
inflated at the site of the occlusion to a diameter slightly larger
than the normal inner diameter of the vessel. The metal members
comprising the stent hold the compressed plaque against the vessel
wall, as shown in FIGS. 3a and 3b. FIG. 3a shows plaque build-up,
3, inside coronary artery. FIG. 3b shows after balloon angioplasty
and stenting. Therapeutic agents coating the stent, 1, can pass
into the vessel wall on the right side, where there is little or no
plaque, but are unable to penetrate the plaque built up on the left
side of the artery. The thickness of residual plaque in patients
with coronary artery disease, following placement of Palmaz-Schatz
stents, is generally 100 to 200 .mu.m. In order to prevent
restenosis, genes or drugs placed on the surface of a stent need a
means to penetrate the maximal 200 .mu.m thick layer of compressed
plaque barrier to gain entry through the internal elastic lamina
into the media where the smooth muscle cells reside. Therapeutic
agents placed on the outside of a conventional stent can diffuse
into the wall of a normal vessel, but cannot penetrate the
plaque.
[0007] This problem can be overcome by fabricating the stent such
that it has preferably sharp protrusions along the outer surface,
FIG. 4. FIG. 4 shows probes, 5, covering the surface of the stent,
1. The probes are protrusions consisting of lateral faces, 6, and
sharp tips, 7, which can pierce through the plaque. Therapeutic
agents coating the probes can then diffuse into the media layer of
the vessel to prevent smooth muscle cell growth and subsequent
restenosis. These "probes" can pierce through the plaque, allowing
therapeutic agents to find their way into the media layer of the
vessel where they are needed. FIGS. 5a, b and c show the transfer
of therapeutic agents is greatly enhanced by covering the surface
of the stent, 1, with probes, 5. In FIG. 5a, a conventional stent
compresses the plaque against the vessel wall, consisting of three
layers: the intima, 8, the media, 9, and the adventitia, 10.
Transfer of genes into the media depends on diffusion through the
plaque, a slow and inefficient process. Texturing the surface with
probes, FIG. 5b, allows the gene therapy to penetrate the plaque.
In FIG. 5c, the probes are fabricated with a lumen 11, which is in
communication with a reservoir.
[0008] Recently, Hashmi et. al. [S. Hashmi, P. Ling, G. Hashmi, M.
L. Reed, R. Gaugler, W. Trimmer, "Genetic Transformation of
Nematodes Using Arrays of Micromechanical Piercing Structures,"
BioTechniques 19(5), 766-770, 1995] reported the injection of DNA
into nematode gonads using probes. These probes, as shown in FIG.
6, were fabricated by anisotropic wet etching of silicon in heights
ranging from 10 to over 100 .mu.m. When the nematodes crawled
across these probes, they created a path for therapeutics to enter
their cells. Successful expression of b-galactosidase, a reporter
gene that expresses a blue-green color, was seen in the progeny- of
the nematodes.
[0009] Similar probes have been shown to be able to penetrate both
plant cells [W. Trimmer, P. Ling, C.-K. Chin, P. Orton, R. Gaugler,
S. Hashmi, G. Hashmi, B. Brunett, M. L Reed, "Injection of DNA Into
Plant and Animal Tissues With Micromechanical Piercing Structures,"
Proceedings of the Eighth International Workshop on Micro Electro
Mechanical Systems (MEMS-95), Amsterdam, January 1995, pages
111-115] and blood vessel walls [M. L. Reed, H. Han, L. E. Weiss,
"Silicon Micro-Velcro," Advanced Materials 4(1), 48-51, 1992][H.
Han, L. E. Weiss, M. L. Reed, "Mating and Piercing Micromechanical
Structures for Surface Bonding Applications," Proceedings of the
Fourth IEEE Workshop on Micro Electro Mechanical Systems (MEMS-91),
Nara, Japan, January 1991, pages 253-258][R. Dizon, H. Han, A. G.
Russell, M. L. Reed, "An Ion Milling Pattern Transfer Technique for
Fabrication of Three-Dimensional Micromechanical Structures," IEEE
Journal of Microelectromechanical Systems 2(4), 151-159, 1993] and
can be used for local drug delivery. A coronary stent with a
silicon carbide coating deposited using plasma-enhanced chemical
vapor deposition, a common technology used to fabricate
microelectromechanical systems (MEMS), has also been reported
recently [M. Amon, S. Winkler, A. Dekker, A. Bolz, "Introduction of
a New Coronary Stent with Enhanced Radioopacity and
Hemocompatibility," Proceedings IEEE Engineering in Medicine and
Biology 17, 1995].
SUMMARY OF THE INVENTION
[0010] The present invention pertains to an apparatus for treating
a patient. The apparatus comprises a deployment mechanism having a
surface. The apparatus also comprises at least one probe disposed
on the deployment mechanism surface. The probe extends between 25
microns and 1000 microns from the surface of the deployment
mechanism. The apparatus also comprises material coated on the
probe.
[0011] The present invention pertains to a method for treating a
patient. The method comprises the steps of placing a material with
a probe which extends less than 1000 microns from a surface of a
deployment mechanism. Next, there is the step of inserting the
probe into a vessel which is preferably a blood vessel of a
patient. Then, there is the step of penetrating the interior wall
of the vessel from the interior of the vessel with the probe by
activating the deployment mechanism so the material can contact the
vessel.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] In the accompanying drawings, the preferred embodiment of
the invention and preferred methods of practicing the invention are
illustrated in which:
[0013] FIG. 1 shows various prior art methods of delivering
therapeutic agents to inside coronary arteries.
[0014] FIGS. 2a and 2b show an ordinary stent before expansion and
after deployment, respectively.
[0015] FIGS. 3a and FIG. 3b show plaque build-up inside a coronary
artery, and after balloon angioplasty and stenting,
respectively.
[0016] FIG. 4 is a schematic representation of probes of the
present invention.
[0017] FIGS. 5a, 5b and 5c show a conventional stent against the
vessel wall, a probe of the present invention providing for gene or
drug therapy, and a probe with the lumen in communication with the
reservoir, respectively.
[0018] FIG. 6 shows probes of the prior art.
[0019] FIG. 7 is a schematic representation of a balloon-expandable
probe stent.
[0020] FIG. 8 is a schematic representation of a piercing balloon
for drugs or gene therapy.
[0021] FIG. 9 is a schematic representation of a mask pattern for
producing probes.
[0022] FIGS. 10a, 10b and 10c depict a probe piercing a vessel, a
probe which contains a lumen piercing a vessel, and the probe with
a lumen where the balloon has expanded so that fluid is forced
through the probe, respectively.
[0023] FIG. 11 is a schematic representation of an apparatus of the
present invention.
[0024] FIG. 12 is a schematic representation of a cross-sectional
view of a portion of the apparatus with probes piercing the
vessel.
[0025] FIG. 13 is a schematic representation of a balloon with
strips having a failsafe attachment to a catheter.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0026] Referring now to the drawings wherein like reference
numerals refer to similar or identical parts throughout the several
views, and more specifically to FIG. 11 thereof, there is shown an
apparatus 20 for treating a patient. The apparatus 20 comprises a
deployment mechanism 22 having a surface 24. The apparatus 20 also
comprises at least one probe 5 disposed on the deployment mechanism
22 surface 24. The probe 5 extends between 25 microns and 1000
microns from the surface 24 of the deployment mechanism 22. The
apparatus 20 also comprises material coated on the probe 5.
[0027] Preferably, the apparatus 20 comprises at least a second
probe 5 disposed on the surface 24 of the deployment mechanism 22
having material coating on the second probe 5. The spacing between
probes can be between 5 and 1000 microns. For spacing where the
height of the probe 5 essentially matches the spacing between the
probe 5, the fabrication process discussed below can be used. For
more dense probe 5 relationships, use of anisotropic dry etching
processes accomplishes such increased densities. See H. Jansen, M.
de Boer, M. Elwenspoek, "The black silicon method VI: high aspect
ratio trench etching for MEMS applications," Proceedings of the
Ninth International IEEE Workshop on Micro Electro Mechanical
Systems (MEMS-96), San Diego, February 1996, pages 250-257, 1996,
incorporated by reference herein.
[0028] The deployment mechanism 22 preferably includes a balloon 26
having a surface 24 with the first and second probes disposed on
the surface 24 of the balloon 26. Preferably, the deployment
mechanism 22 includes a removable housing 28 in which the probes
are disposed when the housing is in a closed state, but is
separated from the probes when the balloon 26 is in an inflated
state.
[0029] Preferably, each probe 5 is coated with gold when the
material has DNA. Preferably, when the material has DNA, the
material is a gene encoding for nitric oxide synthase or vascular
endothelial growth factor. Nitric oxide synthase inhibits smooth
muscle cells from growing, and inhibits platelet and white blood
cell adherence to denuded surfaces following coronary intervention.
Vascular endothelial growth factor stimulates reendotheliazation of
an injured vessel.
[0030] Alternatively, instead of the material having DNA, the
material can have a drug, and the material is coated with a
biocompatible material which provides a protective coating to
prevent the drug or gene from being washed away, and allows for the
release of the drug or gene over a period of time. Such coatings
include biodegradable materials, hydrogels, and porous ceramics.
Such materials as hydrogels can be used with drugs having DNA or
not having DNA. The drugs with DNA or without DNA can also be used
without such materials or hydrogels. When the material is a drug
which does not have the DNA, the material is preferably prednisone
or low molecular weight heparin or hirudin. Prednisone inhibits
inflammation. Low molecular weight heparin inhibits muscle cell
proliferation. Hirudin is an anti-thrombin and thus inhibits the
growth of smooth muscle cells or their activation and migration
which causes restenosis.
[0031] Preferably, each probe 5 has a pointed tip 7. Preferably,
each probe 5 is cone shaped. Each probe 5 preferably extends
radially from the surface 24 of the balloon 26.
[0032] The present invention pertains to a method for treating a
patient. The method comprises the steps of placing a material with
a probe 5 which extends less than 1000 microns from a surface 24 of
a deployment mechanism 22. Next there is the step of inserting the
probe 5 into preferably a blood vessel of a patient, although in
most places like vessels such as the digestive tract or organs
where a catheter can reach, the apparatus 20 can be used. Then
there is the step of penetrating the interior wall of the vessel
from the interior of the vessel with the probe 5 by activating the
deployment mechanism 22 so the material can contact the vessel.
[0033] Preferably, the penetrating step includes the step of
expanding a balloon 26 of the deployment mechanism 22 on which the
probe 5 is disposed until the probe 5 pierces the interior of the
vessel wall.
[0034] After the insertion step, there is preferably the step of
opening a housing 28 in which the probe 5 is disposed. Preferably,
the inside of the housing has a hard surface, which the probes 5 do
not abrade or stick in. The housing protects the probe 5 and
material from body fluid in the patient. Additionally, after the
penetrating step, there can be the step of removing the probe 5
from the vessel if it is not necessary or not desired for the probe
5 to remain in place permanently in the vessel wall.
[0035] Preferably, in one embodiment, the placing step includes the
step of coating the material on the surface of the probe 5.
Preferably, the coating step includes the step of putting DNA on
the surface of the probe 5, where the surface is made of gold or a
material which is both conductive and to which DNA adheres. For
instance, after the probe 5 with the DNA pierces the interior of
the vessel wall, the probe 5 can be removed from the vessel.
[0036] Alternatively, the coating step includes the step of coating
the material with hydrogel. Alternatively, the placing step can
include the step of filling a lumen 11 on the inside of the probe 5
with the material.
[0037] In the operation of the preferred embodiment,
micromechanical structures are used to deliver drugs, genes, and
other therapeutic agents into blood vessels. The structures are
preferably pointed probes which can be integrated with a vascular
stent, an angioplasty balloon, or an electrophoretic device. The
probes pierce vascular plaque and deliver agents into the vessel
wall. A primary application is the delivery of therapies which will
prevent restenosis following revascularization procedures such as
balloon angioplasty or stent delivery, but other applications are
possible (i.e., to deliver secretory agents into the vessel wall,
such as therapies to increase the growth of collateral
circulation).
[0038] The following are several types of embodiments that are part
of the apparatus 20:
[0039] 1) One embodiment is to stud a stent such as a
balloon-expandable stent with probes. FIG. 7 shows a
balloon-expandable probe stent, 1, which can be expanded due to the
presence of interstices, 2. The stent is fabricated with integral
micromechanical piercing structures, 5. Coating the stent with the
desired drug or gene will inject the drug into the vessel during
stent deployment. This embodiment is referred to as a probe
stent.
[0040] 2) Instead of a stent, a balloon is used to expand an
apparatus which injects the drug or gene, but does not remain in
the vessel like a stent. For example, longitudinal strips of probes
on a flexible backing attached to a balloon. FIG. 8 shows a
piercing balloon for intravascular delivery of drug or gene
therapy. Strips of material (metal, polyimide, or other materials)
with probes are fastened longitudinally along a balloon. When
inflated, the balloon forces the probes through the plaque and into
the arterial wall, transferring drugs or DNA into the artery media.
When deflated, the probes retract and are removed along with the
balloon. This arrangement is called a piercing balloon.
[0041] 3) The probes themselves can have lumens, which will allow
drugs or genes to be injected from a reservoir. This is an
improvement on the class of pressure-driven apparatuses shown in
the center column of FIG. 1, where the reservoir is the inflation
balloon.
[0042] 4) The probes can be constructed from a porous material
which will create many microminiature reservoirs, which will hold
increased amounts of the drug by surface tension. Porous surfaces
can be created by anodization of the metal probes, a process which
produces a metal oxide with well-ordered arrays of small holes.
[0043] 5) Another embodiment uses an electric potential to drive
the drug from a reservoir into the vessel wall. This iontophoretic
technique would especially benefit from the sharp probe tips since
electric field is enhanced near an asperity.
[0044] 6) The apparatuses can be made of metal, or other
materials.
[0045] For example, polymer compounds which dissolve in the body,
similar to dissolving sutures commonly used in surgery.
[0046] The fabrication techniques for the various embodiments are
now described. These methods have in common the fabrication of a
template from a crystalline silicon substrate. First, the
fabrication of this template wafer is described. Then, it is shown
how this wafer is used to build the various types of intravascular
delivery apparatuses: a stent covered with probes and the piercing
balloon embodiment where the probes are removed after use. In both
of these embodiments, the probes can have lumens, and have porous
surfaces; methods for creating each of these are described.
[0047] Conventional stents are manufactured using electric
discharge machining (EDM) of a metal tube. This method is
ill-suited to the mass fabrication of probes. A better method is to
use silicon micromachining techniques to produce a template from
which metal apparatuses with integrated probes are constructed.
Such methods are familiar to technologists in the area of
microelectromechanical systems and are common for building
apparatuses such as pressure sensors and accelerometers. They are
detailed in many widely available textbooks, such as "VLSI
Fabrication Principles" [S. K. Ghandhi, "VLSI Fabrication
Principles," John Wiley and Sons, 1981] and "Semiconductor Sensors"
[S. M. Sze "Semiconductor Sensors," John Wiley and Sons, 1994],
both of which are incorporated by reference herein. However,
because these techniques are not commonly employed in the
application described here, a complete description of the process
used is given to create the apparatuses for intravascular drug and
gene delivery.
[0048] The starting material is a crystalline silicon wafer cut
from a boule such that the surfaces are (100) oriented planes. This
is the standard crystal orientation used for building integrated
circuits and as such is widely available. The wafer thickness
depends on the height desired for the probes, and should be at
least 200 .mu.m thicker than the probe height. For example, if 200
.mu.m high probes are desired, the starting wafer should be at
least 400 .mu.m thick. The reason for this is that the final
silicon structure must be rigid enough to withstand handling.
[0049] The wafer is oxidized in a thermal oxidation furnace
(approximately 1000.degree. C.), using a mixture of oxygen and
water vapor, so that a film of thermal silicon dioxide (SiO.sub.2)
is grown on the surface. [S. K. Ghandhi, "VLSI Fabrication
Principles," John Wiley and Sons, 1981], incorporated by reference
herein. The film must be thick enough to withstand the etching
action of a step performed later in potassium hydroxide; a
thickness of 1 .mu.m to 2 .mu.m is generally sufficient.
[0050] The next set of steps are designed to transfer a pattern
into the SiO.sub.2 layer. A standard photolithographic patterning
process is used, which begins with a singe step. The wafer is
heated, in air, to a temperature of at least 200.degree. C., in
order to drive off loosely bonded water on the SiO.sub.2 surface
which would otherwise prevent good adhesion of photoresist. Next,
the wafer is treated with an adhesion promoter, such as
hexamethyldisilizane (HMDS), to help the photoresist layer adhere
to the wafer. The adhesion promoter is applied with a spin
technique (described below).
[0051] Photoresist is applied to the wafer surface by spin coating,
or spinning. In this operation, the substrate is placed on a vacuum
chuck which holds the wafer in place. Next, a quantity of resist is
dispensed from a nozzle while the chuck is rotated at a slow speed.
Finally, the speed is ramped up to several thousand rpm which
causes all but a thin layer of resist (about 1 to 2 .mu.m thick) to
be thrown off. After a uniform layer of photoresist is deposited,
most of the solvents in the photoresist are driven out in the
softbake step. This can done either in a convection oven (typically
90.degree. C. for 30 minutes), in an infrared oven (.sup.-3-4
minutes), on a hotplate (.sup.-1 minute), or with a microwave
source, which takes only a few seconds. The softbake also improves
the adhesion of the photoresist to the substrate.
[0052] At this point the wafers are exposed using a mask and
exposure tool. The mask consists of a transparent glass plate
covered with a regular array of the dark shapes shown in FIG. 9.
FIG. 9 shows a mask pattern for producing silicon probes. The
silicon under the main square area, 12, is protected from the
etchant until convex corner undercutting produces an apex. The
corner compensation structures, 13, increase the vertical height
achievable with the anisotropic etching process. The shapes consist
of a square area, 12, and four rectangular corner compensation
structures, 13. The corner compensation structures delay the
undercutting of the main square area which occurs during the
anisotropic etching process. Inclusion of these structures
increases the height of probes attainable using this process. The
dimensions of the pattern will vary depending on the desired height
of the probes, but are typically 200 .mu.m across. The wafers are
then placed in the exposure tool and aligned so that one long edge
of the patterns is parallel to the wafer flat, which in
commercially available wafers is always perpendicular to a (011)
plane. The photoresist is exposed and developed using standard
procedures [S. K. Ghandhi, "VLSI Fabrication Principles," John
Wiley and Sons, 1981] [S. M. Sze "Semiconductor Sensors," John
Wiley and Sons, 1994], both of which are incorporated by reference
herein. The exposure process increases the solubility of the resist
in the developer by a large factor, compared to the unexposed
areas. Therefore, when the resist is developed, unexposed areas are
largely untouched while the exposed portions are quickly washed
away. Because the solubility of unexposed resist is finite, careful
control of the development process (i.e., developer concentration;
development temperature and time) is essential in controlling the
pattern dimensions.
[0053] After development, the wafer is rinsed, dried, and inspected
under a microscope. (Up to this point, the lithographic steps must
be performed in a "yellow room" with special illumination to
prevent undesired resist exposure. Once the resist is developed,
there is no problem with direct white light illumination such as
that found in a microscope.) The purpose of this "develop inspect"
step is to check for lithography defects such as incomplete
development, resist lifting, underexposure or overexposure, and the
like. If all is well at this point, then processing proceeds to the
next step. If, however, there are problems such as incorrect
exposure or development, resist scumming, lifting, or particles,
then the resist is reworked. This is accomplished by stripping the
resist and returning to the first step. Because the
photolithographic processes (up to the etch step) are all low
temperature and do not affect the underlying layers, multiple
reworks are possible without harm. Photolithography is very
sensitive to environmental conditions such as relative humidity,
and can even be affected by the level of air pollution. Thus
day-to-day variations in exposure and development time, along with
a certain percentage of rework, are a normal, expected part of the
lithography process.
[0054] The wafer now undergoes a hardbake; typical conditions are
150 to 180.degree. C. for 1 hour in a convection oven. The purpose
of the hardbake is to remove any remaining solvents and rinse water
from the photoresist, and to provide even more adhesion of the
photoresist patterns to the substrate. The back surface of the
wafer must be protected with a layer of photoresist or other
material during this step to prevent the backside oxide from being
stripped during the etching process to be performed next. This is
accomplished by spinning a layer of photoresist on the back surface
and hardbaking.
[0055] The pattern, which has now been transferred from the mask to
the photoresist, is now transferred to the SiO.sub.2 film. The
wafer is immersed in a solution of HF and water, hydrof luoric
acid, which selectively attacks the SiO.sub.2 film but does not
harm the photoresist pattern or the underlying silicon. This step
transfers the patterns of FIG. 9 to the oxide layer. Standard
practice is to use commercially available buffered HF solutions at
room temperature. The wafer is inspected again under a microscope
to gauge whether or not the etch process has progressed enough. If
insufficient etching has taken place, the wafers can be returned to
the etch bath for further processing. Etching is complete when all
SiO.sub.2 between the patterns has been removed.
[0056] The photoresist layers are removed using a convenient
method. Standard methods include ashing in an oxygen plasma, or
immersion in hot solvents, (i.e. , a sequence of trichloroethane,
acetone, and alcohol), or a 4:1 mixture of sulfuric acid and
hydrogen peroxide. The last lithographic step is a final inspection
under a microscope to verify that all of the photoresist has been
removed.
[0057] The silicon probes are formed by etching the patterned
wafers in a mixture of potassium hydroxide (KOH) and water at
85.degree. C. A typical etchant concentration is a 1:1 volumetric
combination of 49% (by weight) KOH solution (a standard
commercially available concentration) and water. The etchant
temperature must be carefully maintained, using a circulating bath,
to produce consistent results. Etching continues until the mask
patterns lift off, resulting in a silicon surface studded with an
array of pyramidal structures. The time required for etching
depends on the probe height, but will be on the order of one hour
for 100 .mu.m high probes using the etch conditions outlined
here.
[0058] The silicon wafer thus processed forms a template for
building various embodiments of the intravascular delivery
apparatus.
[0059] To build a stent with probes, the silicon surface is then
coated (on the side with the probes) with a sacrificial layer such
as SiO.sub.2. This layer can be deposited using RF-magnetron
sputtering or chemical vapor deposition (CVD). Using CVD, wafer is
introduced into a furnace at approximately 450.degree. C. and
exposed to a low pressure atmosphere of silane and an oxidant,
whereupon a layer of SiO.sub.2 is deposited. [S. K. Ghandhi, "VLSI
Fabrication Principles," John Wiley and Sons, 1981, incorporated by
reference herein.] This is followed by a thick layer of metal
(approximately 100 .mu.m) which can be deposited using a
combination of evaporation, sputtering and electroplating, and
electroless deposition methods. [S. K. Ghandhi, "VLSI Fabrication
Principles," John Wiley and Sons, 1981, incorporated by reference
herein][S. M. Sze "Semiconductor Sensors," John Wiley and Sons,
1994, incorporated by reference herein.].
[0060] The metal is now patterned using the conventional
photolithographic technique described above. The appropriate
pattern for a Palmaz-Schatz type stent is a dark-field pattern of
long offset rectangles (i.e., the planer version of the cylindrical
pattern of FIG. 2). Methods for reproducing a pattern into the
metal layer from a lithographic mask are well-known [S. K. Ghandhi,
"VLSI Fabrication Principles," John Wiley and Sons, 1981,
incorporated by reference herein].
[0061] Next, the sandwich of silicon (with probes), sacrificial
layer, and patterned metal layer is inserted into an etch bath
containing an etchant which will preferentially attack the
sacrificial layer. (A sacrificial layer of SiO.sub.2 is etched in
hydrofluoric acid.) Etching is continued until the patterned metal
layer lifts off from the underlying substrate as the sacrificial
layer is dissolved. The result is a thin film of metal, with
pyramidal protrusions arising from the silicon probes, and long
rectangular holes etched during the second lithographic step. The
silicon wafer can be recoated with a sacrificial layer and the
metal layers and used repeatedly as a template for additional
apparatuses.
[0062] Finally, the metal lattice is rolled into a cylindrical
shape and welded to form the cylindrical stent. One method is to
form the lattice around a cylindrical copper mandrel, clamp each
end around the mandrel, and use an electron beam welder to join the
apparatus along the seam. The metal film can be cut into the
appropriate size before rolling, or can be cut after the seam
welding process. The process of rolling the metal lattice around
the mandrel is essentially that of winding up a roll of metal foil,
but for only one turn. Once the film has wrapped around the
mandrel, a long blade brought down perpendicular to the mandrel
near the point where the two edges meet will provide a guide for
the welding process.
[0063] Apparatus dimensions depend on the size of the blood vessel
where it will be deployed. Typical dimensions are 1-4 cm in length,
and 1-6 mm in diameter. The end result is the structure shown in
FIG. 7.
[0064] To fabricate the piercing balloon embodiment, the silicon
template wafer is started with and the procedure is followed for
making the probe stent up to the deposition of the thick metal
layer. However, the second photolithographic step, which in the
case of stents forms a regular array of long holes in the metal, is
modified. Instead of making many holes to form a lattice, only a
few holes in the metal are produced to allow the etchant to reach
the sacrificial layer. The result is a metal film with integral
probes (with a few holes). This film is cut into thin strips,
approximately 1 cm long and less than approximately 1 mm wide,
which are fastened, preferably longitudinally, along a balloon. The
strips may be fastened with adhesive along their entire length
although no adhesive could be placed on each strip near the distal
end so the balloon can more easily expand. See FIG. 8. In the case
of adhesive failure, a failsafe attachment can also be made by
extending the proximal end of each strip 32 to the distal end of
the catheter 34 and attaching the strip to the distal end, as shown
in FIG. 13. The distal end can contain a metal band 36 to which the
strip is adhered or spot welded. When inflated, the balloon forces
the probes through the plaque and into the arterial wall,
transferring drugs or DNA into the artery media. When deflated, the
probes retract and are removed along with the balloon.
[0065] Another method for making this apparatus is to follow the
procedure for making the stent, except that the width of the metal
struts between the interstices is made smaller. This apparatus is
again fastened to the balloon with adhesive. Unlike the stent,
which retains its larger diameter when expanded due to plastic
deformation of the metal, this apparatus collapses along with the
balloon.
[0066] Another method to fabricate these apparatuses is to first
fabricate a cylindrical mandrel with the probes on the surface.
This could be accomplished by employing micro-EDM techniques on a
metal tube or rod. The mandrel is then coated (by electroplating,
electroless deposition, evaporation, or other techniques) by a
conformal layer of metal. Holes for the lattice pattern, 2, can be
made with EDM, or a selective deposition technique could be used
which results in metal deposition only where it is wanted. After
dissolving or otherwise removing the mandrel, the apparatus is
released and ready for use.
[0067] In both the probe stent and piercing balloon embodiments, it
is possible to make the individual probes with lumens. Lumens
through the probes provide a channel for drugs, genes, or other
therapeutic material to flow from a reservoir such as inside a
porous balloon. This increases the amount of material which can be
transferred into the blood vessel during a single interventional
procedure, compared to simply coating the outside of the probes
with the therapy.
[0068] To produce probes with lumens, the above procedure is
modified. Before patterning the metal layer (i.e., the second
lithographic step), the tips of the probes are abraded using a
mechanical polishing wheel. This removes the metal at the very tips
of the probes, yet leaves a sharp structure capable of penetrating
the plaque.
[0069] To increase the amount of drugs or genes held by the
apparatus, the structural material could be made porous. A
straightforward way of accomplishing this goal is to anodize the
metal forming the apparatus. Anodization produces a high density of
small, vertically oriented pores, of which the size and
configuration can be controlled by varying the anodization current,
temperature, and solution concentration.
[0070] The probes themselves are coated with a thin (<1 .mu.m)
layer of gold which is well known to have desirable properties for
attracting and holding DNA. The gold coating can be applied at
different stages of manufacture, using various standard processes.
For example, the silicon template wafer, after the sacrificial
layer is applied, can be coated with gold using a standard
evaporation or sputtering process. Subsequent structural layers of
metal can then be plated using the gold as a seed layer.
Alternatively, the gold can be physically deposited at a later
stage, such as after stent formation and welding.
[0071] The fabrication processes described here illustrate
intravascular delivery apparatuses made from metal. Commercially
available stents are made from metals chosen for their mechanical
properties and biocompatibility. These same considerations apply to
the apparatuses described here. Suitable modifications to the
preceding processes can be employed to fabricate apparatuses made
from other materials. For example, polyimides are commonly used in
MEMS technology and can be easily employed for this application as
well. Dissolvable polymers which are used in surgery are another
possibility. Biodegradable polymers such as polylactide,
polyglycolide, and polyorthoster can be used to carry drugs, thus
stents wholly or partially made from these materials will release
therapy over an extended period.
[0072] An important feature of this invention is the probes which
pierce through the atherosclerotic plaque and deliver drug or gene
therapy to the artery media. These probes can either be part of a
stent, or attached to the balloon. Gene or drug therapy can be
applied either to the surface of the probe or delivered through a
hollow probe. The drug or gene can either be applied acutely during
several minutes of balloon inflation, or left in place permanently
by normal deployment of the stent.
[0073] After manufacture, the apparatuses are sterilized and stored
until ready for use. When needed, the apparatuses would first be
coated with the desired drug or gene therapy material. This can be
accomplished by dipping, spraying, spinning, or rolling the
apparatuses with a liquid or gel containing the therapeutic
material. To prevent the therapeutic material from washing off in
the bloodstream, one or more means can be employed: (1) a
protective sheath, preferably with a hard interior surface, covers
the entire apparatus, which is retracted when the apparatus is
about to be deployed at the site in the artery; (2) a coating of a
biocompatible material which provides a protective coating to
prevent the drug or gene from being washed away, and allows for the
release of the drug or gene over a period of time, such as hydrogel
applied to the probes on top of the therapeutic material to cover
and hold the drug or genes in place. The hydrogel will dissolve in
the circulatory system over an extended period, slowly allowing the
drug or gene to be deployed.
[0074] Application of the probe stent will be performed via
standard catheterization techniques. These methods are well known
to cardiac physicians and are described in detail in many standard
references [D. S. Baim, W. Grossman (editors), "Cardiac
Catheterization, Angiography and Intervention," 5th edition,
William & Wilkins, 1996, incorporated by reference herein] [S.
G. Ellis, D. R. Holmes, Jr., "Strategic Approaches in Coronary
Intervention," William & Wilkins, 1996, incorporated by
reference herein]. In brief, percutaneous access of the femoral or
brachial arteries is obtained with standard needles, guide wires,
sheaths, and catheters. After engagement of the coronary arteries
with a hollow guiding catheter, a wire is passed across the
coronary stenosis where the probe stent or piercing balloon is to
be deployed. The apparatus is then passed over this wire, using
standard coronary interventional techniques, to the site of
atherosclerotic coronary plaque where drug or gene therapy is to be
delivered.
[0075] Immediately prior to balloon inflation, a protective sheath
is retracted to expose the probes to the diseased vessel wall.
(This protective sheath is a standard component of current stents,
such as the Palmaz-Schatz stent manufactured by Johnson &
Johnson, and recently approved for clinical use by the FDA. ) The
balloon is then inflated to force the probes through the
atherosclerotic plaque, so the probe tips reach the media portion
of the vessel wall, as shown in FIG. 12. FIG. 12 shows a
cross-sectional view of drug or gene delivery apparatus expanded
inside a blood vessel. Probes, 5, pierce through the layer of
compressed plaque, 3, and into the vessel media, 9. This allows for
efficient transfer of material into the blood vessel. Balloon
inflation is performed using standard interventional techniques.
The therapeutic material which coats the probe tips now enters the
artery media, where it performs its desired biological
function.
[0076] The apparatus has now performed its task, delivery of drug
or gene therapy through atherosclerotic plaque into the vessel
wall. In the case of the probe stent, the stent is deployed
permanently, and the deploying balloon and wire are removed. Probes
mounted directly on a balloon are removed when the balloon is
deflated with negative pressure.
[0077] Probes with lumens are employed using the same procedure,
except that a reservoir of drug or gene therapy is provided so that
a larger supply of material can be delivered more acutely to the
vessel. Apparatuses with lumens through the probes can use a porous
balloon containing the drug or gene therapy which would be pumped
through the lumens during the procedure. A reservoir is created by
coating the underside of the apparatus (i.e., the side away from
the probe tips) with a viscous liquid or gel containing the drug or
gene therapy; the lumens through the probes provide a pathway for
material from the reservoir into the vessel wall. The various means
by which drug or gene therapy is delivered to the vessel, in
apparatuses with and without lumens, is illustrated in FIGS. 10a, b
and c. FIGS. 10a, b and c show three mechanisms for transferring
drug or gene therapy, 14, into the vessel media, 9, using a probe,
5. FIG. 10a shows a probe, 5 (without a lumen) pierces the vessel,
when balloon, 15, expands to the left. This provides a pathway for
the drug or gene therapy, coating the probe, to enter the vessel.
In FIG. 10b, there is shown a probe which contains a lumen 11,
which holds the drug or gene therapy 14, by surface tension. The
lumen can have a diameter between 5 microns and 100 microns through
the probe. Additional therapy is in reserve in a liquid or gel
reservoir between the probe and expansion balloon. When the
balloon, 15, is expanded, this forces therapy from the reservoir
through the lumen. In the embodiment shown in FIG. 10c, the
reservoir is inside the expansion balloon, 15. The probe lumen
extends through the balloon so that fluid forces used to expand the
balloon also force additional therapy through the lumen. In
general, the technology existing regarding angioplasty and the
sizes typically used of balloons, stents, etc. are applicable to
the apparatus here.
[0078] A probe carrying apparatus can have an electrical connection
with a power mechanism, carried down the guiding catheter, which
would place the apparatus at an electrical potential with respect
to a counterelectrode placed elsewhere in or on the patient. FIG.
11 shows a cutaway diagram of a delivery apparatus inside a blood
vessel, 4. Current supplied through a wire, 16, connected to the
conducting drug or gene delivery apparatus causes enhanced
iontophoretic transfer of the therapy through the probe points.
Note, the wire need not be connected to the probes. If the probes
are in place (i.e. the stent) another catheter with an electrode
can be inserted which carries the current. A small current through
the resulting circuit will drive charged drugs or genes, through
iontophoresis, into the vessel wall. Typical current densities for
this method are in the range of 2-8 mA/cm.sup.2 and would remain on
long enough (possibly up to 6 hours) for the drug or genes to
effectively transfer from the probe 5 to the vessel. A large
increase in drug or gene uptake occurs using this technique since
much larger driving forces (i.e., electric fields) are produced
near the sharp tips of the probes, compared to a conventional
iontophoretic balloon. While the apparatus 20 works without any
electrical connection or electrical potential, such electrical
means is an additional feature which facilitates greater control
over the movement of the drugs, whether the drugs are with or
without genes or DNA or RNA or nucleic acid in general.
[0079] Although the invention has been described in detail in the
foregoing embodiments for the purpose of illustration, it is to be
understood that such detail is solely for that purpose and that
variations can be made therein by those skilled in the art without
departing from the spirit and scope of the invention except as it
may be described by the following claims.
* * * * *