U.S. patent application number 09/797313 was filed with the patent office on 2001-08-16 for method of manufacturing a medicated porous metal prosthesis.
Invention is credited to Yan, John Y..
Application Number | 20010013166 09/797313 |
Document ID | / |
Family ID | 25275988 |
Filed Date | 2001-08-16 |
United States Patent
Application |
20010013166 |
Kind Code |
A1 |
Yan, John Y. |
August 16, 2001 |
Method of manufacturing a medicated porous metal prosthesis
Abstract
A method of manufacturing a medicated prosthesis such as a
stent. The method includes forming a stent out of porous metal and
loading a therapeutic agent into the pores of the metal. In one
embodiment the stent is formed from a sintered metal wire, sheet,
or tube and can include adding a coating to the stent. When the
stent is implanted into the vasculature of a patient, the
therapeutic agent in the stent dissipates into the tissue of the
vasculature proximate the stent.
Inventors: |
Yan, John Y.; (Los Gatos,
CA) |
Correspondence
Address: |
FULWIDER PATTON LEE & UTECHT, LLP
HOWARD HUGHES CENTER
6060 CENTER DRIVE
TENTH FLOOR
LOS ANGELES
CA
90045
US
|
Family ID: |
25275988 |
Appl. No.: |
09/797313 |
Filed: |
March 1, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09797313 |
Mar 1, 2001 |
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08837993 |
Apr 15, 1997 |
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6240616 |
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Current U.S.
Class: |
29/527.2 |
Current CPC
Class: |
Y10T 428/12153 20150115;
A61L 2300/45 20130101; A61F 2210/0076 20130101; A61F 2/91 20130101;
A61F 2/915 20130101; A61L 31/16 20130101; Y10T 428/12479 20150115;
A61F 2/0077 20130101; A61F 2002/91533 20130101; A61F 2/82 20130101;
A61L 31/146 20130101; A61L 31/148 20130101; A61L 31/022 20130101;
A61F 2250/0067 20130101; A61L 2300/416 20130101; Y10T 29/49982
20150115; A61L 2300/602 20130101; A61F 2/92 20130101 |
Class at
Publication: |
29/527.2 |
International
Class: |
B23P 017/00 |
Claims
What is claimed is:
1. A method of manufacturing a prosthesis, comprising: providing a
porous metal material having a plurality of porous cavities;
forming the material into a prosthesis having a plurality of porous
cavities; and loading a therapeutic agent into the pores of the
prosthesis.
2. The method of claim 1, wherein the forming step comprises
forming the metal into a stent.
3. The method of claim 1, wherein the providing step comprises
providing a sintered metallic material.
4. The method of claim 1, wherein the providing step comprises
weaving metallic fibers and sintering the metallic fibers to form a
sintered metallic material.
5. The method of claim 2, wherein: the providing step includes
providing a sheet of porous metal material; and the forming step
includes chemical etching the sheet into the form of an expandable
stent.
6. The method of claim 5, wherein the providing step includes
sintering metallic particles into said sheet of porous metal
material.
7. The method of claim 5, wherein the providing step includes
weaving metallic fibers into a sheet of porous metal material and
sintering the woven metallic fibers into said sheet.
8. The method of claim 2, wherein: the providing step comprises
providing a sheet of porous metal; and the forming step includes
cutting the sheet with a laser into the form of a stent.
9. The method of claim 8, wherein the providing step comprises
sintering metallic particles into said sheet.
10. The method of claim 8, wherein the providing step comprises
weaving metallic fibers into a sheet of porous metal.
11. The method of claim 10, wherein the providing step further
comprising sintering the woven metallic fibers.
12. The method of claim 2, wherein the providing step further
comprises providing a porous metal wire.
13. The method of claim 12, wherein the providing step further
includes sintering particles to form the wire.
14. The method of claim 12, wherein the providing step comprises
weaving metallic fibers into a sheet of porous metal.
15. The method of claim 14, wherein the providing step further
comprises sintering the metallic fibers.
16. The method of claim 15, wherein the providing step further
comprises: arranging large diameter particles in a first horizontal
plane; arranging small diameter particles on both sides of the
plane; and sintering the large and small diameter particles into a
sheet.
17. The method of claim 2, wherein the providing step further
comprises: arranging large diameter particles along a first axis;
arranging small diameter particles radially outward from and
coaxial to the large diameter particles; and sintering the large
and small diameter particles into a wire.
18. The method of claim 2, wherein the step of loading the
therapeutic agent comprises immersing the stent in a liquid
solution containing the therapeutic agent.
19. The method of claim 2, wherein the stent is emersed for a
period of time sufficient to permit a therapeutic agent to be
absorbed into the porous cavities of the stent.
20. The method of claim 2, wherein the therapeutic agent is an
anti-fibrin agent.
21. The method of claim 2, wherein the therapeutic agent is an
antithrombin agent.
22. The method of claim 2, wherein the therapeutic agent is an
anti-proliferative agent.
23. The method of claim 2, wherein the therapeutic agent is an
anti-coagulant.
24. The method of claim 2, wherein the therapeutic agent is a
GPII.sub.6III.sub.a blocker.
25. The method of claim 2, wherein the therapeutic agent is of the
group comprising forskolin, aspirin, dipyridamole, coumadin,
ticlopodine, or heparin.
26. The method of claim 2, wherein the therapeutic agent is a
vaso-active drug.
27. The method of claim 2, wherein the therapeutic agent is an
anti-inflammatory agent.
28. The method of claim 2, wherein the therapeutic agent promotes
endothelialization.
29. The method of claim 2, further comprising coating the stent
with a polymer.
30. The method of claim 29, wherein the coating step occurs after
the loading step.
31. The method of claim 29, wherein the polymer is configured to
release the therapeutic agent at a substantially constant rate.
32. The method of claim 29, wherein the polymer is a
biopolymer.
33. The method of claim 32, wherein the polymer is a poly lactic
acid or fibrin.
34. The method of claim 29, wherein the polymer is a synthetic
polymer.
35. The method of claim 33, wherein the polymer is of the group
comprising polyurethane, polyethylene teraphthalate tetrafluoride,
polyethylene, polyethylene oxide (PEO) or silicone.
36. The method of claim 34, wherein the polymer is a hydrogel.
37. The method of claim 29, wherein the polymer is a heparin
coating.
38. The method of claim 29, wherein the polymer is mixed with the
therapeutic agent.
39. The method of claim 29, wherein the polymer is degradable.
40. A method of manufacturing a stent comprising: sintering the
metalic fibers into a sintered stent material; forming the sintered
stent material into a stent; and loading a therapeutic agent into
porous cavities of the sintered metal stent.
41. A method of manufacturing a sintered metal stent, comprising:
sintering metal particles into a sheet; cutting the sheet into a
porous metal stent; and loading medication into porous cavities of
the metal stent.
42. The method of claim 41, wherein the sintering step includes
weaving the metalic fibers into a sheet of porous metal and
sintering the woven metalic fibers.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention generally relates to a medicated prosthesis
or implant. More particularly, the invention relates to a medicated
intra-vascular prosthesis, such as a stent, that is radially
expandable in the vasculature of a patient and delivers a
therapeutic agent to the site of the implantation.
[0003] 2. Description of Related Art
[0004] Stents are generally cylindrically shaped prosthetic
implants which function to hold open and sometimes expand a segment
of a blood vessel or other anatomical lumen. They are particularly
suitable for supporting and preventing a torn or injured arterial
lining from occluding a fluid passageway. Intravascular stents are
increasingly useful for treatment of coronary artery stenoses, and
for reducing the likelihood of the development of restenosis or
closure after balloon angioplasty.
[0005] The success of a stent can be assessed by evaluating a
number of factors, such as thrombosis; neointimal hyperplasia,
smooth muscle cell migration and proliferation following
implantation of the stent; injury to the artery wall; overall loss
of luminal patency; stent diameter in vivo; thickness of the stent;
and leukocyte adhesion to the luminal lining of stented arteries.
However, the chief areas of concern are early subacute thrombosis,
and eventual restenosis of the blood vessel due to intimal
hyperplasia.
[0006] Therapeutic pharmacological agents have been developed to
improve successful placement of the stent and are delivered to the
site of stent implantation. Stents that are of a common metallic
structure were previously unable to deliver localized therapeutic
pharmacological agents to a blood vessel at the location being
treated with the stent. There are polymeric materials that can be
loaded with and release therapeutic agents including drugs or other
pharmacological treatments which can be used for drug delivery.
However, these polymeric materials may not fulfill the structural
and mechanical requirements of a stent, especially when the
polymeric materials are loaded with a drug, since drug loading of a
polymeric material can significantly reduce the structural and
mechanical properties of the polymeric material.
[0007] It has been known in the art to coat a metallic stent with a
polymeric material and load the polymeric material with a drug.
Alternatively stents of polymeric materials have been reinforced
with metal structure. These stent designs have the strength
necessary to hold open the lumen of the vessel because of the
reinforced strength of the metal. Stents made of both polymeric
material and metal have a larger radial profile because the volume
occupied by the metal portion of the stent cannot absorb and retain
drugs. Reducing the profile of a stent is preferable because it
increases the in vivo diameter of the lumen created by the stent.
Thus it is desirable to configure a metallic stent to deliver drugs
to the blood vessel walls without substantially increasing the
profile of the stent. The present invention meets these needs.
SUMMARY OF THE INVENTION
[0008] Briefly and in general terms, the present invention is a
method of manufacturing a medicated prosthesis. The method
comprises providing a porous metal material having a plurality of
porous cavities, forming the material into a prosthesis having a
plurality of porous cavities, and loading therapeutic agents into
the pores of the prosthesis. In one embodiment, the prosthesis is a
stent for implantation into a blood vessel, biliary duct, esophagus
or other body lumen. In one embodiment, the method comprises
sintering metal particles including spherical particles, filaments
or fibers into a wire, a sheet or tube. Then, the wire, sheet, or
tube is further manufactured by forming the stent from the same.
Sheets or tubes can be formed into stents by chemical etching or
laser cutting the same according to a stent pattern. In another
embodiment, the sheet is formed by weaving metallic fibers and
sintering the metallic fibers in a metal wire or a sheet.
[0009] In yet another embodiment, a sheet of stent material is
formed in a plurality of layers. A layer of large diameter
particles are arranged in a first horizontal plane. Two layers of
small diameter particles are arranged on both sides of the plane.
The particles are sintered into a sheet of particles that has a
large core formed of large diameter particles sandwiched between
two layers of small diameter particles. Similarly, a sintered stent
wire can be formed by arranging large diameter particles along a
first axis and then arranging small diameter particles radially
outward from and coaxial to the large diameter particles. Then, the
particles are sintered to form a stent wire that has a
substantially porous central cavity and an outer layer that has
smaller pore diameter.
[0010] In yet another embodiment, the method of forming a stent
comprises arranging a sheet of solid metal between two layers of
particles. The particles are then sintered to both sides of the
sheet. Similarly, the particles can be sintered to one side of the
metal sheet. Alternatively, particles can be oriented radially
outward from a solid metal wire and sintered into a partially
porous wire. The partially porous wire and the stent with a sheet
metal core are believed to improve the strength of the overall
stent.
[0011] According to one embodiment of the present invention, a
therapeutic agent can be loaded into the pores of the stent by
immersing the stent in a liquid solution containing the therapeutic
agent. The stent is emersed for a period of time sufficient to
permit therapeutic agent to be absorbed into the porous cavities of
the stent. The therapeutic agent may be any number of drugs or
chemical agents that treat arterial diseases and stent implantation
side effects.
[0012] In yet another embodiment of the invention the method
includes coating the stent with a polymer. The polymer may itself
be loaded with one or more therapeutic agents or may be applied to
delay the release of medicine or otherwise control the rate that
the therapeutic agent diffuses into the body.
[0013] These and other features of the present invention will
become apparent from the following more detailed description, when
taken in conjunction with the accompanying drawings which
illustrate, by way of example, the principles of the present
invention.
DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a longitudinal sectional view of a blood vessel
with stent manufactured according to one embodiment of the present
invention.
[0015] FIG. 2 is a porous stent wire or strut in a partially
magnified, partially cut away perspective manufactured according to
one embodiment of the present invention.
[0016] FIG. 3 is a magnified, cross-sectional view of unsintered
packed particle.
[0017] FIG. 4 is a porous stent wire or strut in partially
magnified, partially cut away perspective manufactured according to
one embodiment of the present invention.
[0018] FIG. 5 is a porous stent wire or strut in partially
magnified, partially cut away perspective manufactured according to
one embodiment of the present invention.
[0019] FIG. 6 is a cross-sectional view of a stent wire or strut
manufactured according to one embodiment of the present
invention.
[0020] FIG. 7 is a cross-sectional view of a stent wire or strut
manufactured according to one embodiment of the present
invention.
[0021] FIG. 8 is a sheet of sintered stent manufactured according
to one embodiment of the present invention.
[0022] FIG. 9 is a stent formed from a sheet of sintered metal
according to one embodiment of the present invention.
[0023] FIG. 10 is a cross-sectional, partially cut away view of a
sheet of sintered metal manufactured according to the principles of
one embodiment of the present invention.
[0024] FIG. 11 is a cross-sectional view of a stent wire or strut
manufactured according to the principles of one embodiment of the
present invention.
[0025] FIG. 12 is a cross-sectional view, partially cut away of a
sheet of sintered metal manufactured according to the principles of
one embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0026] Referring now to FIG. 1, the prosthesis of one embodiment is
a porous stent 12 that is radially expandable against the walls 14
of a vessel 16. The stent is loaded with a therapeutic agent in the
pores (18 of FIG. 2) of the stent. When placed in the vasculature,
the therapeutic agent is delivered to the tissue that comes into
contact with the stent. The stent of one preferred embodiment is
formed of a stent wire that is porous. An example of a porous stent
wire is a sintered metal wire. FIG. 2 illustrates a partial
microscopic view of a sintered wire that is suitable for use in one
embodiment of the present invention. The wire is porous and has
several porous cavities 18. The size of the cavities preferably
range between 0.01 and 20 microns in size.
[0027] Porous metal is made, according to one preferred embodiment,
by the process of sintering metal. Sintering is a process of
fabrication where particles are bonded together without entirely
melting the particles. Particles are pressed together or molded
into a desired shape. A considerable amount of pressure is first
applied to press the particles together. Then, the metal is heated
to temperatures slightly below the melting point of the metal.
Without entirely melting, the particles bond to each other at their
respective surfaces. Space remains between the lattice of the
particles which define the porous cavities 18.
[0028] The formation of sintered metal is illustrated with
reference to FIG. 3 and continued reference to FIG. 2. FIG. 3 is a
microscopic view of a packed lattice 22 of metallic particles 24.
Gaps 26 exist between each particle despite the fact that the
particles are pressurized and are in contact with adjacent
particles. Particles are preferably sized between 0.02 microns and
20 microns in diameter. Prior to heating, there are no chemical
bonds formed between the individual particles. When the metal is
heated to slightly below the melting point of the metal, the
particles bond with neighboring particles. The gaps in the packed
lattice form pores 18 when the particles are sintered. Thus in FIG.
2, the metal stent wire formed by the process of sintering has
porous cavities 18 extending throughout the entire wire, thereby
interconnecting the cavities. The cavities then can be filled with
a therapeutic agent as hereinafter described. The appropriate
pressure and temperature of sintering a particular metal is
specific to that particular metal. One skilled in the art of metal
fabrication would understand how to sinter any given metal or
alloy.
[0029] For each of the embodiments, the metal stent material member
can be a suitable metal such as stainless steel, tantalum,
nickel-titanium alloy, platinum-iridium alloy, molybdenum-rhenium
alloy, gold, magnesium, combinations thereof, although other
similar materials also may be suitable. The metal can be modified
to exhibit different hardnesses, and thus varying stiffnesses, by
well known annealing and manufacturing processes.
[0030] One of the most important factors to be considered when
making a stent according to one embodiment of the present invention
is the porosity of the metal. Porosity is the total volume of pores
in the sintered metal divided by the total volume of the metal.
Porosity determines the amount of a therapeutic agent that can be
loaded into a stent of predetermined dimensions. High porosity
means that a stent can deliver more therapeutic agents or have a
narrower profile because it is less dense. High porosity, according
to some embodiments of the present invention, adversely affects the
strength and elasticity of a metal. Consequently, there is an
ongoing tradeoff between stent strength, on the one hand, and stent
profile and stent load capacity on the other hand.
[0031] Pore size is a function of particle size and dimension. In
one embodiment of the present invention illustrated in FIG. 3, the
particles 24 are generally spherical. Size of the pore 18,
particularly with generally spherical particles, is proportional to
particle size. When the particles 24 have inconsistent size,
smaller particles tend to fill the gaps between the larger
particles. Thus, the porosity of such particles are less
predictable. Consistent pore size is also important to ensure that
drugs are evenly distributed throughout the stent. Consistent
distribution on the other hand ensures that the tissue in contact
with the stent will receive an even distribution of a therapeutic
agent.
[0032] There are several types of drugs that are currently
administered at the site that a stent is placed in the vessel.
Examples of therapeutic drugs, or agents that can be combined with
the polymeric layers include antiplatelets, antifibrin,
antithrombin and antiproliferatives. Examples of anticoagulants,
antiplatelets antifibrins and antithrombins include but are not
limited to sodium heparin, low molecular weight heparin, hirudin,
argatroban, forskolin, vapiprost, prostacyclin and prostacyclin
analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic
antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet
membrane receptor antibody, recombinant hirudin, thrombin inhibitor
(available from Biogen), and 7E-3B.RTM. (an antiplatelet drug from
Centocore). Examples of cytostatic or antiproliferative agents
include angiopeptin (a somatostatin analogue from Ibsen),
angiotensin converting enzyme inhibitors such as Captopril.RTM.
(available from Squibb), Cilazapril.RTM. (available from
Hoffman-LaRoche), or Lisinopril.RTM. (available from Merck);
calcium channel blockers (such as Nifedipine), colchicine,
fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty
acid), histamine antagonists, Lovastatin.RTM. (an inhibitor of
HMG-CoA reductase, a cholesterol lowering drug from Merck),
methotrexate, monoclonal antibodies (such as to PDGF receptors),
nitroprusside, phosphodiesterase inhibitors, prostaglandin
inhibitor (available from Glazo), Seramin (a PDGF antagonist),
serotonin blockers, steroids, thioprotease inhibitors,
triazolopyrimidine (a PDGF antagonist), and nitric oxide. Other
therapeutic drugs or agents which may be appropriate include
alpha-interferon and genetically engineered epithelial cells, for
example.
[0033] While the foregoing therapeutic agents have been used to
prevent or treat restenosis, they are provided by way of example
and are not meant to be limiting, since other therapeutic drugs may
be developed which are equally applicable for use with the present
invention. The treatment of diseases using the above therapeutic
agent are known in the art. Furthermore, the calculation of
dosages, dosage rates and appropriate duration of treatment are
previously known in the art.
[0034] The therapeutic agent of one embodiment is preferably in
liquid form and is loaded into a stent by immersing the stent in a
medicated solution. The therapeutic agent may be dissolved in a
solvent or suspended in a liquid mixture. If a suspension of drugs
are used, it is important that the pore size of the stent is
considerably larger than the therapeutic agent. An average pore
size that is more than ten (10) times the particle size of a
suspended therapeutic agent is suitable. After the stent is emersed
in the medicated solution, the therapeutic agent absorbs into the
pores of the stent. At which time, the loaded stent can be removed
from the solution and implanted into the vasculature of a patient.
Additionally, a therapeutic agent can be loaded into the stent by
applying pressure to the fluid to aid the passage of medicated
fluid into the porous cavities of the stent. This can be done
similar to how fluid can be pressurized through the pores of a
filter.
[0035] Once loaded, the therapeutic agent remains in place by the
surface tension between the walls 28 of the several porous cavities
18 and the therapeutic agent. As shown in FIG. 1, the loaded or
medicated stent 12 is then deployed to the site of arterial closure
13 and is expanded. The expanded stent engages the walls 14 of the
vessel 16 to maintain the patency of the vessel. Once in the
vessel, the therapeutic agent disseminates from the porous cavities
18, as depicted in FIG. 2, of the stent and is absorbed into the
tissue of the walls of the vessel that are in contact with the
stent.
[0036] The advantage of the stent of the present invention over
prior art medicated stents is one of profile and strength. Metal,
including sintered metal, is stronger than synthetic materials that
are capable of being loaded with a therapeutic agent. Thus, in
order for a medicated stent to deliver an appropriate amount of a
therapeutic agent and structurally maintain vessel patency, the
profile of the stent must be substantially larger than metal
stents. This is true whether a metal stent is coated with a
therapeutic agent, or if the stent is entirely made of a plastic
material.
[0037] Sintered metal has strength and elasticity that is
comparable to regular metal. Sintered metal furthermore has the
added feature that it is porous. Consequently, a sintered stent can
be made having a profile that is substantially comparable to a
conventional metal stent. Yet, a therapeutic agent can be loaded
into the pores and delivered to the site of stent implantation
without the aid of medicated coatings.
[0038] Additionally, many synthetic materials, including materials
that are bioabsorbable, cause inflammation of the tissue. A
medicated stent that has a therapeutic agent loaded directly into
the pores of the stent can avoid synthetic coatings that have been
known to cause irritation at the site of stent implantation.
[0039] FIG. 4 illustrates an alternative embodiment of a stent wire
30 constructed according to the present invention. The stent is
formed of elongated particles 32, i.e., filaments and fibers.
Sintered particles (24 of FIG. 2) that are generally spherical in
shape are capable of forming sintered metal having a porosity in
the range of 0.30 to 0.05. However, when filaments or fibers 32 are
sintered, the porosity can be increased above 0.30. The technique
of fabricating a stent with elongated filaments or fibers are
similar to the method described above for spherical particles or
powders. The filaments or fibers are molded and pressurized. Then
the fibers are heated to a temperature just below the melting point
of the metal.
[0040] Greater porosity of a stent made of metal filaments or
fibers 32 rather than spherical particles (24 of FIG. 2) is
obtained because of the irregular shape of the particles. The
particles cannot be packed as tightly as regular generally
spherical particles. Furthermore, the particles can be packed less
densely and still maintain contact between the particles to allow
sintering. Thus, the void space or pores 34 in the sintered metal
are larger.
[0041] The strength of a stent wire 30 using filaments in FIG. 4 is
improved because the individual strands have larger surface area to
volume and contact a greater number of neighboring strands. Thus,
each filament or fiber will have a larger bonding surface and may
bond with a greater number of neighboring fibers. A matrix of
overlapping filaments or fibers is thus formed with greater
porosity and stronger inter-particle bonding.
[0042] In yet another embodiment, wire fibers 36 are woven or
twined into a structure 38 as illustrated in FIG. 5. The individual
strands cooperate in a synergistic manner to reinforce the strength
of the wire. Additionally, the wire fibers can be woven into the
form of a sintered metal sheet having improved and reinforced
strength or a sintered metal tube. Other combinations of particle
size and shape can be employed to form a stent wire having
different characteristics.
[0043] In another embodiment illustrated in FIG. 6, the stent wire
42 is formed of an inner core 44 and an outer layer 41 of sintered
particles. The outer layer is formed from particles having a
different diameter than the diameter of the particles that form the
inner core. For example, the core of the metal is formed of
particles that have a diameter in the range of 10-20 microns at the
core of the wire. Surrounding the core are particles that have a
diameter in the range of 2-4 microns on the outer surface. The
larger particles create a core having larger pores 52. This results
in higher porosity and thus a higher load capacity. The smaller
particles on the outer layer form smaller pores 54 which reduce the
rate of diffusion of drugs into the tissue of the vessel.
[0044] When a therapeutic agent is loaded into a stent formed of
the stent wire 42 illustrated in FIG. 6 a larger volume can be
stored in the larger pores 52 at the core 44 of the stent wire.
Once the stent is placed into the vessel, the therapeutic agent in
the stent wire is delivered at a rate determined by the smaller
pores 54 in the outer layer 46 of the stent wire. Such a structure
is expected to have a benefit of being able to store a large amount
of therapeutic agent at the core and deliver the therapeutic agent
at a slower rate. Consequently, this design is desirable for
low-dose, long-term drug therapy.
[0045] Alternatively, according to another embodiment of the
present invention shown in FIG. 7, a stent wire 56 is formed from
sintered particles 58. The pores 62 formed between the sintered
metal particle surrounding the solid core retain the therapeutic
agent. The total porosity of a stent having a solid core and porous
outer layer is much lower than a stent wire of similar proportion
that is entirely made of sintered particles. However, the solid
core reinforces the tensile strength and elasticity of the metal
stent and is considerably stronger. Thus, it is desirable to use a
sintered stent with a solid core for applications where maximum
tensile strength and elasticity is desirable and only a relatively
small amount of therapeutic agent is needed.
[0046] The sintered metal stent of yet another embodiment of the
present invention can be made of material formed in different
shapes than sintered metal. For example, the stent can be formed of
a sheet of sintered metal as shown in FIG. 8 or a sintered metal
tube. By way of example, metal particles 66 are arranged and
pressurized into a sheet. The sheet is heated to a temperature
below the melting point of the particles as described previously.
The sheet of sintered metal is porous and has a plurality of pores
68.
[0047] The same principles that apply to porosity and pore size of
a wire apply equally to a sintered stent that is formed into a
sheet or tube. The advantage of forming the stent from a sheet of
metal is that the stent is radially expandable without placing a
great deal of strain on the metal lattice when it is expanded. A
sheet or tube of sintered metal can be cut in the desired shape to
form the metal structural member with a laser, such as a continuous
CO.sub.2 laser, a pulsed YAG laser, or an excimer laser, for
example, or alternatively, by chemical etching or stamping. When
cut from a flat sheet, the stent is then rolled into a cylindrical
configuration and laser welded along the longitudinal edges.
[0048] The stent can be formed into a particular pattern known in
the art for stents formed from metal sheets. One such pattern is a
rolled locking design and is illustrated in FIG. 9. The sheet is
etched into a stent configuration that has a head portion 72 that
includes one or more slots 74 for receipt of a like number of tail
portions 76. The tail portions are received into the slots so as to
form a cylindrical loop. The tail end includes a plurality of teeth
78 adapted to cooperatively engage the slot of the head portion.
When the teeth engage the slot, the tail is retained in place in an
expanded state. Additionally, holes 80 are formed throughout the
stent to reduce the metal to air ratio of the stent. The less metal
in contact with the wall 14 of the vessel 16, the better the blood
compatibility of the stent.
[0049] Prior to deployment, the tail end is coiled into a retracted
position. The tail is threaded through the slot and wound. It is
expanded by a balloon according to principles that are well known
in the art for delivering and implanting a stent. As the stent is
expanded by a balloon during deployment it unwinds and the teeth
lock into the slots at a desired radial diameter to prevent the
stent from returning to its original retracted state.
[0050] A benefit of the coiled stent shown in FIG. 9 is that the
stent 70 can be etched to have a minimal surface area that comes in
contact with the walls of the vessel. This may be an important
feature when it is desired to cover an entire portion of the walls
of a blood vessel with a therapeutic agent because the coiled sheet
metal stent can be configured to maintain maximum surface area
contact with the wall of the blood vessel in contrast to wire
stents.
[0051] With reference to FIG. 10, another embodiment of the present
invention is a sheet formed of sintered particles that are sintered
to both sides 84 and 86 of a metal sheet 82. The stent of FIG. 10
is similar in structure to the stent wire of FIG. 7 that has a
solid core and has porous particles sintered to the core forming a
porous outer layer. The solid core reinforces the strength of the
metal. The metal sheet also provides a barrier through which a
therapeutic agent cannot pass. Thus, a therapeutic agent loaded
into the pores 92 on the top side of 84 the sheet permeates in a
first direction 88 outward from the solid core. A therapeutic agent
loaded into the pores 94 on the bottom side 86 of the solid wire
permeates only in a second direction 90 opposite to the direction
of the therapeutic agent loaded into the pores on the top side.
[0052] When a stent as shown in FIG. 10 is looped into a
cylindrical formation and placed into a vessel, only the top side
84, which is directed radially outward, engages the walls of the
vessel. The bottom side 94 faces radially inward and does not come
in contact with the walls of the vessel. Thus, if it is desired, a
first therapeutic agent can be loaded into the top side to treat
the tissue in the wall of the vessel. A second therapeutic agent
can be loaded into the bottom side to prevent coagulation of the
blood flowing in the vessel. Additionally, the stent can be formed
so that particles are sintered only to one side of the stent. A
therapeutic agent is loaded into the sintered metal on the porous
side of the stent. When a stent is formed from a one-sided porous
stent, it can be oriented radially outward to deliver a therapeutic
agent to the tissue in the wall of the stent.
[0053] FIG. 11 illustrates a cross-sectional view of a stent wire
of strut according to one embodiment of the invention. The sheet
has a plurality of porous cavities or pores 98. A therapeutic agent
is loaded into the pores of the sintered metal. Then, a coating 100
is applied to the sintered metal. The coating may be used for
several purposes as illustrated hereinafter.
[0054] With reference to FIG. 12, another embodiment of the
invention is shown wherein the stent is formed of a sintered sheet
104 of metal having core 106 formed of large diameter particles 108
that form large pores. The core layer 106 is sandwiched between two
layers 110 and 112 formed of smaller diameter particles 114 or
particles that form smaller diameter pores. Such a sheet is formed
by orienting a middle or core layer 106 of large diameter particles
along a plane. A top layer of smaller diameter particles is
arranged in a plane parallel to and above the middle layer. A
bottom layer of particles are arranged in a plane parallel to and
below the middle layer. The three layers are pressed together and
sintered into a single sheet. The sheet can then be cut or etched
into a stent configuration.
[0055] While one of the benefits of the present invention is to
provide a stent that does not require a coating for the purpose of
delivering a therapeutic agent to the blood vessel, the application
of a coating after a therapeutic agent is loaded into the pores of
the sintered metal does not defeat the utility of the present
invention. For example, when a therapeutic agent is loaded into the
pores of the stent and into a polymeric coating, the profile of the
polymeric coating can be reduced. Alternatively, a larger dosage of
a therapeutic agent can be delivered to the site of stent
implantation. Additional benefits are observed by loading a stent
with a therapeutic agent in the pores of the metal and then further
applying a coating to the stent. Furthermore, even if a coating is
applied to the stent, the principles of reducing profile and
reinforcing the stent are still apparent because a greater volume
of therapeutic agent can be delivered by a coated sintered stent
than a coated, solid stent have comparable dimensions.
[0056] The polymeric material that coats a sintered metal stent of
the invention preferably comprises a biodegradable, bioabsorbable
polymeric film that is capable of being loaded with and capable of
releasing therapeutic drugs. The polymeric coatings preferably
include, but are not limited to, polycaprolactone (PCL),
poly-DL-lactic acid (DL-PLA) and poly-L-lactic acid (L-PLA) or
lactide. Other biodegradable, bioabsorbable polymers such as
polyorthoesters, polyiminocarbonates, aliphatic polycarbonates, and
polyphosphazenes may also be suitable, and other non-degradable
polymers capable of carrying and delivering therapeutic drugs may
also be suitable. Examples of non-degradable synthetic polymers are
polyurethane, polyethylene, polyethylene teraphthalate, ethylene
vinyl acetate, silicone and polyethylene oxide (PEO). The polymeric
layers, according to one embodiment is to be loaded with a
pharmacologic agent for use in localized drug therapy. As used in
this description, the terms biodegradable, bioabsorbable,
reabsorbable, degradable, and absorbable are meant to encompass
materials that are broken down and gradually absorbed or eliminated
by the body, whether these processes are due to hydrolysis,
metabolic processes, bulk or surface erosion. In each of the
foregoing embodiments, one polymeric layer is preferably about
0.0001 to 0.002 inches thick.
[0057] The thin polymeric films used to coat the stent are
preferably first intermixed with the drug or drugs to be delivered,
and then are typically laminated or solvent cast to the surface of
the metal structural member. Lamination processing methods and
temperatures can vary widely depending on the polymers used and the
temperature sensitivity of the loaded drugs. Alternatively, the
metal structure of the stent can be encapsulated in the layers of
polymeric material by solvent casting, melt processing, insert
molding, and dip coating.
[0058] In one embodiment of the present invention, the membrane is
bioabsorbable, but no therapeutic agent is loaded into the polymer.
The coating 100 dissolves after implantation and this delays the
time that a therapeutic agent is released into the vasculature of a
patient. The thickness of the coating as well as the rate at which
the coating is bioabsorbed determines the length of time that the
stent is mounted into the vascular before a therapeutic agent is
delivered from the pores of the stent. Additionally, a therapeutic
agent can be loaded into the bioabsorbable coating. Thus a
therapeutic agent will be delivered to the stent at a rate
determined by the bioabsorbability of the coating. Once the
bioabsorbable material has completely dissolved, the therapeutic
agent in the pores can be delivered at a rate determined by the
pore size and porosity.
[0059] In another embodiment, it is preferred that the coating 100
is permeable and non-absorbable. In such circumstances, the rate at
which the drugs permeate into the tissue is controlled by the
physical properties of the particular coating selected.
Additionally, the coating may be selected to reduce restenosis,
thrombosis or other tissue inflammation. For example, a heparin
coating is known in the art to reduce blood clotting. Heparin, when
coated on a stent reduces clotting of blood on the surface of the
stent. The heparin coating is affixed to the surface of the stent
through ionic bonding, end point attaching, or photo-linking the
heparin.
[0060] In yet another embodiment, a first therapeutic agent is
loaded into the coating and a second therapeutic agent is loaded
into the pores of the stent. This may be the case when a series of
drug dosages or concentrations are needed. When such a stent is
placed into the vasculature, the first therapeutic agent is
absorbed first by the stent and a second therapeutic agent is
absorbed later by the vasculature. This variation adds a further
dimension to drug treatment allowing for sequential drug therapy at
the site of placement of a stent.
[0061] It will be apparent from the foregoing that while particular
forms of the invention have been illustrated and described, various
modifications can be made without departing from the spirit and
scope of the invention. Accordingly, it is not intended that the
invention be limited, except as by the appended claims.
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