U.S. patent application number 14/825526 was filed with the patent office on 2015-12-03 for device for in vivo delivery of bioactive agents and method of manufacture thereof.
The applicant listed for this patent is Advanced Bio Prosthetic Surfaces, Ltd., a wholly owned subsidiary of Palmaz Scientific, Inc.. Invention is credited to Steven R. BAILEY, Christopher E. BANAS, Christoper T. BOYLE, Denes MARTON.
Application Number | 20150342761 14/825526 |
Document ID | / |
Family ID | 36037033 |
Filed Date | 2015-12-03 |
United States Patent
Application |
20150342761 |
Kind Code |
A1 |
MARTON; Denes ; et
al. |
December 3, 2015 |
DEVICE FOR IN VIVO DELIVERY OF BIOACTIVE AGENTS AND METHOD OF
MANUFACTURE THEREOF
Abstract
The drug eluting device consists of an implantable structural
element for in vivo controlled delivery of bioactive active agents
to a situs in a body. The implantable structural element may be
configured as an implantable prosthesis, such as an endoluminal
stent, cardiac valve, osteal implant or the like, which serves a
dual function of being prosthetic and a carrier for a bioactive
agent. Control over elution of the bioactive agents occurs through
a plurality of cantilever-like cover members which prevent drug
elution until an endogenous or exogenous stimulus causes the cover
members to open and permit drug elution.
Inventors: |
MARTON; Denes; (San Antonio,
TX) ; BAILEY; Steven R.; (San Antonio, TX) ;
BANAS; Christopher E.; (Breckenridge, CO) ; BOYLE;
Christoper T.; (Flushing, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Advanced Bio Prosthetic Surfaces, Ltd., a wholly owned subsidiary
of Palmaz Scientific, Inc. |
Dallas |
TX |
US |
|
|
Family ID: |
36037033 |
Appl. No.: |
14/825526 |
Filed: |
August 13, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10936884 |
Sep 9, 2004 |
9107605 |
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14825526 |
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09783633 |
Feb 14, 2001 |
8372139 |
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10936884 |
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09716146 |
Nov 17, 2000 |
8252044 |
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09783633 |
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10258087 |
Aug 19, 2003 |
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09716146 |
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Current U.S.
Class: |
427/2.25 |
Current CPC
Class: |
A61F 2/82 20130101; A61F
2002/91533 20130101; A61F 2/915 20130101; A61L 27/54 20130101; A61L
2300/602 20130101; A61B 5/02055 20130101; A61L 31/16 20130101; A61F
2/07 20130101; A61B 5/6876 20130101; A61B 5/0215 20130101; A61F
2002/91558 20130101; A61F 2250/0067 20130101; A61F 2/86 20130101;
A61B 5/4839 20130101; A61B 5/01 20130101; A61F 2250/0001 20130101;
A61B 5/026 20130101; A61F 2240/001 20130101; A61L 27/04 20130101;
A61B 5/021 20130101; A61F 2002/91541 20130101; A61B 5/076 20130101;
A61B 5/6862 20130101; A61L 31/022 20130101; A61F 2/91 20130101;
A61F 2210/0076 20130101; A61F 2250/0068 20130101 |
International
Class: |
A61F 2/82 20060101
A61F002/82; A61F 2/86 20060101 A61F002/86; A61F 2/91 20060101
A61F002/91 |
Claims
1. A method of making a drug-eluting medical device, comprising the
steps of: a) Vacuum depositing a first layer of a biocompatible
material onto a substrate; b) Vacuum deposing a sacrificial layer
of material onto the first layer of a biocompatible material; c)
Removing portions of the sacrificial layer to form internal chamber
defining regions of the sacrificial layer; d) Vacuum depositing a
second layer of biocompatible material onto the internal chamber
defining regions of the sacrificial layer and the first layer of
biocompatible material; e) Forming at least one of a plurality of
openings passing through the second layer of biocompatible and
communicating with the internal chamber defining regions of the
sacrificial layer; f) Removing the internal chamber defining
regions of the sacrificial layer thereby forming at least one of a
plurality of internal chambers residing entirely between the first
layer of biocompatible material and the second layer of
biocompatible material; and g) Disposing at least one of a
plurality of cover members covering the at least one of a plurality
of openings, the at least one of a plurality of cover members
having a first position which covers at least one of the plurality
of openings and a second position which uncovers at least one of
the plurality of openings.
2. The method according to claim 1, wherein the vacuum depositing
steps further comprise at least one of physical vapor deposition
and chemical vapor deposition.
3. The method according to claim 1, wherein step (g) is conducted
before step (a) and step and further comprises the step of vacuum
depositing the first layer of biocompatible material onto the
plurality of cover members.
4. The method according to claim 1, further comprising the step of
loading at least one bioactive agent into the at least one of a
plurality of internal chambers.
5. The method according to claim 4, further comprising the step of
selecting the at least one bioactive agent from the group of
pharmacologically active antibiotic drugs, antiviral drugs,
neoplastic agents, steroids, fibronectin, anti-clotting drugs,
anti-platelet function drugs, drugs which prevent smooth muscle
cell growth on inner surface wall of vessel, heparin, heparin
fragments, aspirin, coumadin, tissue plasminogen activator,
urokinase, hirudin, streptokinase, antiproliferative agents,
antioxidants, antimetabolites, thromboxane inhibitors,
non-steroidal and steroidal anti-inflammatory drugs,
immunosuppresents, beta and calcium channel blockers, genetic
materials including DNA and RNA fragments, complete expression
genes, antibodies, lymphokines, growth factors, vascular
endothelial growth factor, fibroblast growth factor,
prostaglandins, leukotrienes, laminin, elastin, collagen, nitric
oxide, integrins, paclitaxel, taxol, rapamycin, rapamycin
derivatives and analogues, sirolimus, rapamune, tacrolimus,
dexamethasone, everolimus, ABT-578 and growth factors.
6. The method of claim 1, wherein at least one of the first layer
of biocompatible material, the second layer of biocompatible
material and the at least one of a plurality of cover members
further comprise a thin metallic film.
7. The method of claim 1, wherein the plurality of cover members
are in the first position in their native state and transition to
the second position upon application of a stimulus.
8. The method of claim 1, wherein the drug-eluting device is
selected from the group consisting of stent, covered stents and
vascular grafts.
9. The method of claim 1, wherein the first layer of biocompatible
material, the second layer of biocompatible material and the at
least one of a plurality of cover members further comprise further
comprise a material selected from the group consisting of titanium,
vanadium, aluminum, nickel, tantalum, zirconium, chromium, silver,
gold, silicon, magnesium, niobium, scandium, platinum, cobalt,
palladium, manganese, molybdenum and alloys thereof,
zirconium-titanium-tantalum alloys, nickel titanium alloy,
chromium-cobalt alloy, and stainless steel.
Description
CROSS REFERENCE TO RELATED INVENTIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/936,884, filed Sep. 9, 2004, now U.S. Pat. No.
9,407,605, which is a continuation-in-part of commonly assigned and
co-pending U.S. patent applications Ser. Nos. 09/783,633, filed
Feb. 14, 2001, now U.S. Pat. No. 8,372,139; Ser. No. 09/716,146,
filed Nov. 17, 2000, now U.S. Pat. No. 8,252,044; and Ser. No.
10/258,087, filing date of Aug. 19, 2003, all of which are herein
incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] The present invention relates generally to an implantable
device for supporting a lumenal passageway and, also, delivering,
in vivo, bioactive compounds. More particularly, the present
invention relates to an implantable device equipped with cantilever
controls for automated delivery of bioactive compounds in response
to a predetermined physiological event.
[0003] Occlusive diseases, disorders or trauma cause patent body
lumens to narrow and restrict the flow or passage of fluid or
materials through the body lumen. One example of occlusive disease
is arteriosclerosis in which portions of blood vessels become
occluded by the gradual build-up of arteriosclerotic plaque, this
process is also known as stenosis. When vascular stenosis results
in the functional occlusion of a blood vessel the vessel must be
returned to its patent condition. Conventional therapies for
treatment of occluded body lumens include dilatation of the body
lumen using bioactive agents, such as tissue plasminogen activator
(TPA) or vascular endothelial growth factor (VEGF) and fibroblast
growth factor (FGF) gene transfers which have improved blood flow
and collateral development in ischemic limb and myocardium (S.
Yla-Herttuala, Cardiovascular gene therapy, Lancet, Jan. 15, 2000),
surgical intervention to remove the blockage, replacement of the
blocked segment with a new segment of endogenous or exogenous graft
tissue, or the use of a catheter-mounted device such as a balloon
catheter to dilate the body lumen or an artherectomy catheter to
remove occlusive material. The dilation of a blood vessel with a
balloon catheter is called percutaneous transluminal angioplasty.
During angioplasty, a balloon catheter in a deflated state is
inserted within an occluded segment of a blood vessel and is
inflated and deflated a number of times to expand the vessel. Due
to the inflation of the balloon catheter, the plaque formed on the
vessel walls cracks and the vessel expands to allow increased blood
flow through the vessel.
[0004] In approximately sixty percent of angioplasty cases, the
blood vessel remains patent. However, the restenosis rate of
approximately forty percent is unacceptably high. Endoluminal
stents of a wide variety of materials, properties and
configurations have been used post-angioplasty in order to prevent
restenosis and loss of patency in the vessel.
[0005] While the use of endoluminal stents has successfully
decreased the rate of restenosis in angioplasty patients, it has
been found that a significant restenosis rate continues to exist
even with the use of endoluminal stents. It is generally believed
that the post-stenting restenosis rate is due, in major part, to a
failure of the endothelial layer to regrow over the stent and the
incidence of smooth muscle cell-related neointimal growth on the
luminal surfaces of the stent. Injury to the endothelium, the
natural nonthrombogenic lining of the arterial lumen, is a
significant factor contributing to restenosis at the situs of a
stent. Endothelial loss exposes thrombogenic arterial wall
proteins, which, along with the generally thrombogenic nature of
many prosthetic materials, such as stainless steel, titanium,
tantalum, Nitinol, etc. customarily used in manufacturing stents,
initiates platelet deposition and activation of the coagulation
cascade, which results in thrombus formation, ranging from partial
covering of the luminal surface of the stent to an occlusive
thrombus. Additionally, endothelial loss at the site of the stent
has been implicated in the development of neointimal hyperplasia at
the stent situs. Accordingly, rapid re-endothelialization of the
arterial wall with concomitant endothelialization of the body fluid
or blood contacting surfaces of the implanted device is considered
critical for maintaining vasculature patency and preventing
low-flow thrombosis. To prevent restenosis and thrombosis in the
area where angioplasty has been performed, anti-thrombosis agents
and other biologically active agents can be employed.
[0006] It has been found desirable to deliver bioactive agents to
the area where a stent is placed concurrently with stent
implantation. Many stents have been designed to delivery bioactive
agents to the anatomical region of stent implantation. Some of
these stents are biodegradable stents which are impregnated with
bioactive agents. Examples of biodegradable impregnated stents are
those found in U.S. Pat. Nos. 5,500,013, 5,429,634, and 5,443,458.
Other known bioactive agent delivery stents include a stent
disclosed in U.S. Pat. No. 5,342,348 in which a bioactive agent is
impregnated into filaments which are woven into or laminated onto a
stent. U.S. Pat. No. 5,234,456 discloses a hydrophilic stent that
may include a bioactive agent adsorbed which can include a
biologically active agent disposed within the hydrophilic material
of the stent. Other bioactive agent delivery stents disclosed in
U.S. Pat. Nos. 5,201,778, 5,282,823, 5,383,927; 5,383,928,
5,423,885, 5,441,515, 5,443,496, 5,449,382, 4,464,450, and European
Patent Application No. 0 528 039. Other devices for endoluminal
delivery of bioactive agents are disclosed in U.S. Pat. Nos.
3,797,485, 4,203,442, 4,309,776, 4,479,796, 5,002,661, 5,062,829,
5,180,366, 5,295,962, 5,304,121, 5,421,826, and International
Application No. WO 94/18906. A directional release bioactive agent
stent is disclosed in U.S. Patent No. 6,071,305 in which a stent is
formed of a helical member that has a groove in the abluminal
surface of the helical member. A bioactive agent is loaded into the
groove prior to endoluminal delivery and the bioactive agent is
therefore in direct apposition to the tissue that the bioactive
agent treats. Finally, International Application No. WO 00/18327
discloses a drug delivery stent in which a tubular conduit is wound
into a helical stent. The tubular conduit has either a single
continuous lumen or dual continuous lumens that extend the entire
length of the conduit. The tubular conduit has regions or segments
thereof that has pores to permit drug "seepage" from the conduit.
One end of the tubular conduit is in fluid flow communication with
a fluid delivery catheter, which introduces a fluid, such as drug
into the continuous lumen and through the pores.
[0007] Where biodegradable or non-biodegradable polymer-based or
polymer-coated stents have been used, the polymers cause an immune
inflammatory response once the drug is eluted out of the polymer.
Where a polymer is employed as the bioactive agent carrier, it is,
therefore, desirable to isolate the polymer from body tissues in
order to limit the immune inflammatory response after the bioactive
agent has eluted as can be accomplished with the embodiments
disclosed herein.
[0008] There still remains a need for an implantable medical device
that can support a physiological lumen and automatically deliver a
bioactive agent upon need, the need defined by a significant
physiological event. More specifically, there is a need for an
implantable medical device that allows for controlled delivery of a
bioactive agent. Also, there is a further need for an implantable
medical device that can detect a significant physiological event
and can be manually activated to deliver a bioactive agent in a
noninvasive manner.
SUMMARY OF THE INVENTION
[0009] The implantable medical device is deliverable within an
anatomical passageway and is capable of restoring and maintaining
patency of the anatomical passageway and delivering a bioactive
agent within the anatomical passageway. While not limiting the
embodiments disclosed herein, a common use for the implantable
medical device is as a coronary or other vascular stent device
which is percutanteously delivered to a situs within the body's
vascular system using catheter-based approaches and, once implanted
at the desired situs, is capable of releasing a bioactive agent to
facilitate and promote a healing response within damaged or injured
regions of the vasculature.
[0010] More particularly, the implantable medical device is adapted
to deliver the bioactive agent in response to either an endogenous
condition or conditions or an exogenous condition or conditions.
For example, endogenous conditions which may initiate drug delivery
include, without limitation, certain physiological conditions such
as growth of non-endothelial cells on the device, inflammatory
responses, vascular wall pressure or the presence of T-cells or
natural killer cells. Non-limiting examples of exogenous conditions
which may initiation drug delivery include applied RF fields,
magnetic fields, electromagnetic fields, ultrasound, x-ray,
positron emissions, and laser or photon emissions.
[0011] In accordance with one embodiment, there is provided a
structural body, preferably a generally tubular member, having at
least one internal chamber or cavity within the structural body and
a plurality of openings passing through the structural body and
communicating between an external wall surface of the structural
body and the at least one internal chamber. A plurality of
cantilever members are provided on or are formed in a wall surface
of the structural body and are positioned such that each cantilever
member is superimposed over and covering at least one of the
plurality of openings.
[0012] The plurality of cantilever members consist generally of
flap-like members which are preferably fabricated of shape memory
or superelastic material, and have binary functionality, i.e., are
either in an open or a close position. Each of the plurality of
cantilever members may be MEMS (micro-electromechanical systems)
devices responsive to defined stimulus, such as temperature or
pressure, and may be derivitized by attachment of reactive moieties
having binding affinity for specific biochemical markers. As noted,
each of the cantilever members have binary functionality. In a
first or closed position the cantilever members covers and occludes
at least one associated opening that passes through the wall of the
structural body an communicates with the internal chamber or cavity
retaining the bioactive agent within the structural body. In the
second or open position, the cantilever deflects and uncovers the
opening or openings with which it is associated, thereby permitting
the bioactive agent to elute from the opening or openings. The
second or open position of the cantilever occurs as a result of
either the presence or absence of a pre-determined stimulus. For
example, the second position may be responsive to flow pressure,
such as blood flow, such that cessation or diminution of blood flow
resulting from tissue growth or occlusion, activates the second
position. Alternatively, the second position may be responsive to
temperature such that thermal induction, such as that induced by
ultrasound resonance, may activate the second position.
[0013] After the cantilever members assume their open position,
elution of the bioactive agent from the internal chamber or cavity
and out of the uncovered plurality of openings may occur through a
number of mechanisms, including, without limitation, free flow,
pumped or pulsed flow, osmotic-mediated diffusion, capillary
diffusion, displacement flow or the like.
[0014] As used herein the term "bioactive agent" is intended to
include one or more pharmacologically active compounds which may be
in combination with pharmaceutically acceptable carriers and,
optionally, additional ingredients such as antioxidants,
stabilizing agents, permeation enhancers, and the like. The terms
"pharmacologically active agents" and "bioactive agent" as used
herein are used synonymously with "drug(s)". Examples of bioactive
agents which may be used include but are not limited to antiviral
drugs, antibiotic drugs, steroids, fibronectin, anti-clotting
drugs, anti-platelet function drugs, drugs which prevent smooth
muscle cell growth on inner surface wall of vessel, heparin,
heparin fragments, aspirin, coumadin, tissue plasminogen activator
(TPA), urokinase, hirudin, streptokinase, antiproliferative agents
such as methotrexate, cisplatin, fluorouracil, ADRIAMYCIN,
antioxidants such as ascorbic acid, beta carotene, vitamin E,
antimetabolites, thromboxane inhibitors, non-steroidal and
steroidal anti-inflammatory drugs, immunosuppresents, beta and
calcium channel blockers, genetic materials including DNA and RNA
fragments, complete expression genes, antibodies, lymphokines,
growth factors, such as vascular endothelial growth factor (VEGF)
and fibroblast growth factor (FGF), prostaglandins, leukotrienes,
laminin, elastin, collagen, nitric oxide (NO), integrins,
paclitaxel, taxol, rapamycin, rapamycin derivatives, such as those
disclosed in U.S. Patent Application Publication 2003/0170287
published Sep. 11, 2003, sirolimus, rapamune, tacrolimus,
dexamethasone, everolimus, ABT-578 (a rapamycin analogue that
inhibits the mTOR cell cycle regulatory protein), and growth
factors, such as VEG-F.
[0015] A further aspect of the present invention is the provision
of a diametrically changeable structural member. The structural
member may assume a cylindrical, tubular, planar, spherical,
curvilinear or other general shape which is desired and suited for
a particular implant application. For example, in accordance with
the present invention there is provided an endoluminal stent that
is made of a plurality of interconnected members commonly referred
to struts or circumferential rings that define a generally tubular
shape for the endoluminal stent. At least some of the plurality of
interconnected members are fabricated in such a manner as to have
least one internal cavity defined within or on the interconnected
members or their interconnection members and at least one opening
which communicates between the internal cavity and external the
stent. Alternate types of implantable devices contemplated by the
present invention include, without limitation, covered stents,
stent-grafts, grafts, heart valves, venous valves, filters,
occlusion devices, catheters, osteal implants, implantable
contraceptives, implantable anti-tumor pellets or rods, or other
implantable medical devices.
[0016] In one aspect of the present invention, there exists a stent
for delivery of bioactive agents, which consists, in general, of a
plurality of structural elements, at least some of which have
internal cavities that retain the bioactive agents, and openings
that pass between the internal cavities and the surface of the
structural elements to communicate the bioactive agent from the
internal cavity to external the stent. Other than described herein,
the present invention does not depend upon the particular geometry,
material, material properties or configuration of the stent.
[0017] Another aspect of the embodiments disclosed herein relates
to sensors that may be incorporated onto the implantable medical
device, or more specifically, onto the cantilever, to monitor or
detect either an endogenous or exogenous stimulus. The endogenous
stimulus will, typically, be a physiological event, such as smooth
muscle cell proliferation, endothelialization, plaque formation,
biochemical changes, cell or cell surface protein binding, or the
like. The sensors are preferably fabricated via thin film vacuum
deposition, either as a monolithic monolayer of material or a
multilayered film, wherein at least portions of the film are
capable of sensing at least one of changes in fluid flow, fluid
flow rate, temperature, pressure, or the presence or absence of
chemical or biochemical species in the body by mechanical,
electrical, chemical, electrochemical or electromechanical
means.
[0018] Specifically, the sensors allow the monitoring of clinically
significant physiological events based upon physical, chemical or
electrical energy differences present in a body passageway. For
example, the sensors of the embodiments disclosed herein may be
employed to sense significant changes to blood flow volume, blood
flow rate, pressure, electrical energy, biochemical interactions,
temperature, or to the degree and type of deposits within the lumen
of an endoluminal implant, such as a stent or other type of
endoluminal conduit. The embodiments disclosed herein also provides
a means to modulate mechanical and/or physical properties of the
endoluminal implant in response to the sensed or monitored
parameter. For example, where the monitored blood flow volume
through an endoluminal device is determined to be below
physiological norms and/or the blood pressure is determined to be
above physiological norms, the implantable medical device, such as
a stent, may be triggered to release a selected bioactive agent,
whether automatically or manually controlled.
[0019] In one aspect of the invention, the sensors allow for
monitoring the environment around the implantable device to detect
stimuli indicative of predetermined events. In a preferred aspect,
the sensors are fabricated onto or in association with the
plurality of cantilever members. Upon detecting the particular
event, a signal can be delivered towards the implantable device
that then triggers the cantilever to undergo transformation from
the closed to open position. Upon transformation, the selected
bioactive agent can is released into the local environment.
[0020] In another aspect of the invention, the sensors also detect
the predetermined stimulus, but instead of simply monitoring, the
sensor signals or transfers energy to the cantilever causing the
cantilever to undergo a physical transformation from the closed to
open position. Preferably, the cantilever is fabricated to act as
the sensor itself so that once the cantilever detects the energy
contributing event, the cantilever responds to the energy
contributing event and undergoes physical transformation from the
closed to open position.
[0021] In accordance with another embodiment of the invention, the
inventive sensor comprises at least one region of the implantable
endoluminal device that is formed of a plurality of cantilever
members having different mechanical properties, such as different
modulus of elasticity, plasticity or stress-strain behaviors. In
accordance with the best mode presently contemplated for the
invention, the cantilever members are preferably fabricated of a
superelastic material. As with the shape-memory cantilever members,
the superelastic cantilever members may be positioned on either a
fluid contacting or tissue contacting surface of the implantable
device, such as the luminal surface of a stent which contacts
blood, or on the abluminal surface of a stent which contacts
neointimal tissue of the blood vessel. Alternatively, the sensors
may be positioned on both the fluid contacting and the
tissue-contacting surface of the implantable device. Unlike the
shape-memory cantilever sensors, the superelastic cantilever
sensors are responsive to changes in force, such as shear forces,
applied to the sensors.
[0022] With both the shape-memory cantilever members sensor and the
superelastic cantilever members sensor, each of the plurality of
cantilever members have first and second positions that are
indicative of either a closed or open position, respectively. The
first or "closed" position of each cantilever members is coplanar
or flush with the surface of the endoluminal device into which the
sensor is positioned. In the second or "open" position, each
activated cantilever members projects outwardly from the surface of
the endoluminal device into which the sensor is positioned. Because
different cantilever members or groups of cantilever members are
fabricated to have either different transition temperatures or
different stress-strain properties, individual cantilever members
or groups of cantilever members which are in the second or "open"
position, are indicative of a given thermal or stress-strain
condition existing within the body into which the endoluminal
device is implanted and allows for the release of bioactive agent
housed in the internal cavities.
[0023] In one particular form of the invention, the inventive
endoluminal device comprises a temperature sensor having a
plurality of cantilever members positioned on at least one of the
proximal, distal or intermediate regions of the endoluminal device
and positioned on at least one of the luminal or abluminal wall
surfaces of the endoluminal device. To facilitate ease of
detection, a plurality of groups of cantilever members are
provided, each group is formed of a plurality of individual
cantilever members, with each individual cantilever members in the
group having identical transition temperatures. The plurality of
groups of cantilever members are arrayed along the longitudinal
axis of the endoluminal device in such a manner as to create a
continuum of groups of cantilever members having different
transition temperatures. Changes in temperature at the site of the
endoluminal device are indicated by the position of the cantilever
members or groups of cantilever members as determined by
radiography, ultrasonography, magnetic resonance imaging or other
means that provides a detectable image of the position of the
cantilever members and groups of cantilever members.
[0024] In another particular form the invention, the sensor
comprises a plurality of cantilever members positioned on at least
one of the proximal, distal or intermediate regions of the
endoluminal device and positioned on at least one of the luminal or
abluminal wall surfaces of the endoluminal device. To facilitate
ease of detection, a plurality of groups of cantilever members are
provided, each group is formed of a plurality of individual
cantilever members, with each individual cantilever members in the
group having identical transition temperatures. The plurality of
groups of cantilever members are arrayed along the longitudinal
axis of the endoluminal device in such a manner as to create a
continuum of groups of cantilever members having different
stress-strain transition pressures. Changes in applied stress or
strain, such as blood pressure or blood flow shear stress, at the
site of the endoluminal device are indicated by the stress and
strain acting on the cantilever members or groups of cantilever
members which provides a corresponding frequency shift in energy
reflected, when compared to a baseline stress-strain for unloaded
cantilever members. The position and frequency shift of the
cantilever members may be determined by radiography,
ultrasonography, magnetic resonance imaging or other means which
provides a detectable image of the position of the individual
cantilever members and groups of cantilever members or is capable
of measuring frequency shifts due to differential stress-strain
loading onto the cantilever members.
[0025] In yet another form of the invention, the inventive sensor
is a biosensor that is microfabricated from a material capable of
undergoing elastic, plastic, shape-memory or superelastic
deformation, and has a plurality of cantilever members formed
therein, as described above. Each of the plurality of cantilever
members has at least one binding domain selective for at least one
indicator of endothelialization selected from the group of
endothelial cell surface proteins, antigens, antibodies, cytokines,
growth factors, co-factors, or other biological or biochemical
marker of endothelial cells or endothelial cell precursors. Binding
of the at least one indicator to at least one of the plurality of
cantilever members causes a change in strain applied to the
cantilever members, thereby causing the relevant cantilever members
or groups of cantilever members to undergo superelastic
transformation from the first or "closed" position to the second or
"open" position. As with the above-described embodiments of the
invention, the position of the sensor cantilever members in the
second or "open" position relative to the endoluminal device is
indicative of the progress of endothelialization and allows for
release of bioactive agents housed in the internal cavities.
[0026] Similarly, the fact of or the progress of atherosclerotic
plaque formation may be sensed and treated with the appropriate
bioactive agent by using a plurality of elastic or superelastic
cantilever members. In accordance with a first embodiment, the
plurality of superelastic cantilever members undergo martensitic
transformation as a result of the strain applied to the cantilever
members resulting from growth of atherosclerotic plaque onto the
cantilever members. In accordance with a second embodiment, the
plurality of superelastic cantilever members has at least one
binding domain selective for at least one indicator of
atherosclerotic plaque or its precursors. Binding of the
atherosclerotic plaque or precursors of atherosclerotic plaque to
the binding domain on the cantilever members, adds a quantum of
strain to the cantilever members sufficient to cause the cantilever
members to undergo superelastic transformation from the first or
"closed" position to the second or "open" position. As with the
above-described embodiments of the invention, the position of the
sensor cantilever members in the second or "open" position relative
to the endoluminal device is indicative of the progress of
arteriosclerosis and results in the release of the appropriate
bioactive agent housed in the internal cavities.
[0027] Because of their use as a structural scaffold and the
requirement that stents be delivered using transcatheter
approaches, stents necessarily are delivered in a reduced diametric
state and are expanded or allowed to expand in vivo to an enlarged
diametric state. Thus, all stents have certain structural regions
that are subject to higher stress and strain conditions than other
structural regions of the stent. Thus, it may be advantageous to
position the internal cavities that retain the bioactive agents in
structural regions of the stent that are subjected to relatively
lower stress and strain during endoluminal delivery and deployment.
Alternatively, where delivery of a bolus of a bioactive agent is
desired, internal cavities may be positioned in regions that
undergo large deformation during delivery and deployment thereby
forcing the bioactive agent out of the internal cavity under the
positive pressure exerted by the deformation.
[0028] Diffusion forces, then, elute remaining bioactive agent
present in either the region of large deformation or the regions of
lower stress and strain.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1 is a perspective view of an implantable member having
a plurality of cantilever members in accordance with the
embodiments disclosed herein.
[0030] FIG. 2 is a fragmentary plan view taken from area 2 of FIG.
1.
[0031] FIG. 3 is a cross-sectional view taken along line 3-3 of
FIG. 2 illustrating the a plurality of cantilever members in a
first or closed position.
[0032] FIG. 4 is the same cross-sectional view as in FIG. 3,
illustrating the plurality of cantilever members in a second or
open position.
[0033] FIG. 5 is a cross-sectional view taken along line 5-5 of
FIG. 1.
[0034] FIG. 6 is a cross-sectional view of an alternate embodiment
of embodiments disclosed herein.
[0035] FIG. 7 is a fragmentary plan view of a drug-eluting stent in
accordance with a preferred embodiment of the embodiments disclosed
herein.
[0036] FIG. 8 is a photomicrograph of a transverse section of a
drug-eluting stent in accordance with a preferred embodiment of the
embodiments disclosed herein.
[0037] FIGS. 9A-9G are sequential cross-sectional views
illustrating the method of fabricating the inventive drug eluting
implantable medical device in accordance with the embodiments
disclosed herein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0038] With particular reference to FIGS. 1 and 2, the drug-eluting
device 10 of the embodiments disclosed herein consists generally of
a body element 12, which for purposes of illustration only, is
depicted in a generally tubular conformation having a first wall
surface 14 and a second wall surface 16, a first end surface 13 and
an opposing second end surface 15. A plurality of openings 20 pass
through either or both of the first wall surface 14 and the second
wall surface 16 and communicate between at least one chamber 21,
shown in phantom, which resides entirely within the z-axis
thickness of the drug-eluting device 10 and is defined between the
first wall surface 14 and the second wall surface 16 with only at
least one of the plurality of openings 20 communicating between the
internal chamber 21 and either the first 14 or second 16 wall
surface of the drug-eluting device 10. A plurality of cover members
18 are provided in or in association with either or both of the
first wall surface 14 and the second wall surface 16, and are
positioned such that at least one of the plurality of openings 20
are covered by one of the plurality of cover members 18. The
plurality of openings 29 and the associated plurality of cover
members 18 may, optionally, be arrayed in a pattern of groupings
23a-23e of openings 20 and cover members 18. Each of the plurality
of cover members 18 have generally binary functionality in that
they have a first or closed position where the associated at least
one opening 20 is covered and occluded by the cover member 18, and
a second or open position where the associated at least one opening
20 is uncovered by the cover member 18. Transition between the
first position and the second position preferably occurs by either
shape memory or superelastic phase transitions in the material used
to fabricate the plurality of openings 20. The binary transition of
the plurality of cover members 18 may be synchronous or
asynchronous. That is, that all of the plurality of cover members
18 may transition between the first to the second position under
common conditions and, therefore, act synchronously; alternatively,
either individual cover members 18 or groups of cover members, but
not all cover members 18, may transition under common conditions,
while other cover members 18 do not undergo a binary transition,
therefore, acting asynchronously.
[0039] While the drug-eluting device 10 of the embodiments
disclosed herein is illustrated and will be described with
reference to a generally tubular embodiment, those of ordinary
skill in the art will understand and appreciate that alternate
geometric conformations are contemplated and feasible, including,
without limitation, spherical, ovoid, planar, curvilinear or
cylindrical conformations.
[0040] In accordance with a preferred embodiment of the embodiments
disclosed herein, the plurality of cover members 18 comprise
cantilever-like members fabricated of shape memory or superelastic
metal or pseudometal material. The cantilever-like cover members 18
may be formed as integral components in the first wall surface 14,
the second wall surface 16, or both, may be formed as a layer upon
the first wall surface 14, the second wall surface 16 or both, or,
alternatively, may be discrete members which may be coupled to the
first wall surface 14, the second wall surface 16, or both.
Further, the cantilever-like cover members may be provided in
regular or irregular pattern arrays. The cantilever 15 can cover
any or all openings 14 in any desired pattern. Additionally, some
of the plurality of openings 20 may have no associated
cantilever-like cover member 18, or all of the plurality of
openings 20 may have associated cantilever-like cover members 18.
The plurality of openings 20 have dimensions sufficient to permit
the bioactive agent to elute by diffusion, osmotic pressure or
under the influence of a positive pressure applied by cellular
in-growth into the at least one interior chamber 21.
[0041] FIGS. 3 and 4 illustrate the binary functioning of the
plurality of cantilever-like cover members 18. In the embodiments
illustrated in FIGS. 3 and 4, the plurality of cantilever-like
cover members 18 are formed integrally in wall surface 14, and each
of the plurality of cantilever-like cover members 18 subtend an
associated opening 20 which underlies the cover member 18. Those
skilled in the art will appreciate that openings 20 and cover
members 18 could also be formed in and associated with opposing
wall surface 16. The interior chamber 21 is defined entirely within
the Z-axis thickness of the device 10 and intermediate the first
wall surface 14 and the second wall surface 16. An elutable
bioactive agent 24 is retained with the interior chamber 21. FIG. 3
illustrates the plurality of cantilever-like cover members 18 in
their first or closed position where each of the plurality of
cantilever-like cover members 18 are in co-planar relationship with
one another along wall surface 14. FIG. 4 illustrates the plurality
of cantilever cover members 18 in their second or open position
where each of the plurality of cantilever-like cover members are
deformed to uncover each associated opening 20, and permit elution
of the bioactive agent 24 from the interior chamber 21 and through
the openings 20. As noted above, while FIGS. 3 and 4 depict
synchronous function of the plurality of cantilever-like cover
members 18, the plurality of cantilever-like cover members 18 may
function asynchronously.
[0042] FIG. 5 is a transverse cross-sectional view taken along line
5-5 of FIG. 1 and illustrates the drug-eluting implantable device
30 in an embodiment consisting of a generally tubular member 32,
which may be a cylindrical stent, or may be an individual strut of
a stent. The tubular member 32 has at least one of a plurality of
internal chambers 34 formed entirely between a first wall surface
14 and a second wall surface 16 of the tubular member 32 which act
as a reservoir for a bioactive agent 36. A central lumen 31
provides a fluid flow channel for bodily fluids to traverse the
device 30. Alternatively, where the tubular member 32 may be an
individual strut of a stent, the central lumen 32 may serve as the
internal chambers 34 for retaining the bioactive agent 36 to be
eluted from the device 30, in which case, the plurality of internal
chambers 24 may, optionally, be eliminated. The plurality of
openings 38 communicate between the at least one of a plurality of
internal chambers 34, the central lumen 31 and external the device
30. The plurality of cantilever-like cover members 42 are formed in
an outer circumferential layer 40 which forms the first wall
surface 14 of device 30.
[0043] FIG. 6 is a transverse cross-section view of an alternate
embodiment of the invention depicted in FIG. 5. The alternative
embodiment of the drug-eluting device 45 depicted in FIG. 6 is
substantially similar to that in FIG. 5, with the exception that
the plurality of openings 47 communicate between the plurality of
interior chambers 43 and central lumen 31 of the device 45.
Additionally, the plurality of cantilever-like members 48 are
formed in a lumenal layer of material 46 and cover the plurality of
openings 47 to control elution of the bioactive agent 36 from the
interior chambers 43. Thus, in FIG. 5, when at least some of the
plurality of cantilever-like cover members 42 transition from their
first, closed position to their second, open position, the
bioactive agent 36 is eluted abluminally from the device 30, while
in FIG. 6, the bioactive agent 36 is eluted luminally from the
device 45.
[0044] The position of each of the plurality of openings 20 may
vary dependent upon the particular indication or application for
which the drug-eluting implantable device 10 is intended. The
plurality of openings 20 may open to either a luminal wall surface
16 of the device 10, or to an abluminal wall surface 14 of the
device 10, or both the luminal wall surface 16 and the abluminal
wall surface 14 of the device 10. As an alternative to having a
uniform distribution of openings 20 about the circumferential and
longitudinal axes of the device 10, there may be provided a higher
density of openings 20 toward a proximal or distal end of the
device 10. Alternatively, a higher density of openings 20 may be
provided along an intermediate region o the device 10. It will be
understood that where there is provided a higher density of
openings 20, a larger dosage of the bioactive agent 36 may be
released at any one time due to the higher density of openings
20.
[0045] In addition to the foregoing positioning of the plurality of
openings 21, the plurality of internal chambers 34, 41, may be
either continuous or discontinuous within the z-axis thickness of
the device 10 and may be present in different circumferential or
longitudinal regions of the device 10. Where discontinuous internal
chambers 34, 41 are provided, plural bioactive agents may be loaded
into the device 10 for either synchronous or asynchronous
elution.
[0046] By employing asynchronous functioning plurality of
cantilever-like cover members 18, differential drug delivery may be
accomplished based upon occurrence of different physiological
conditions.
[0047] The body element 12 is preferably fabricated of a
biocompatible metal such as titanium, vanadium, aluminum, nickel,
tantalum, zirconium, chromium, silver, gold, silicon, magnesium,
niobium, scandium, platinum, cobalt, palladium, manganese,
molybdenum and alloys thereof, such as zirconium-titanium-tantalum
alloys, nickel-titanium alloy, chromium-cobalt alloy or stainless
steel. The plurality of cantilever-like cover members 18 are
preferably fabricated of a shape memory or superelastic material,
such as nickel-titanium or chromium cobalt alloy.
[0048] Each of the plurality of cantilevers 18 may be fabricated of
a material capable of undergoing elastic, plastic, shape memory
and/or a superelastic deformation. Materials such as stainless
steel, titanium, nickel, tantalum, gold, vanadium, nickel-titanium,
or alloys thereof may be employed to fabricate the plurality of
cantilever members. Different electrical, thermal or mechanical
properties may be imparted to the cantilevers 18 by altering the
alloy ratios of the material. It is preferable to vacuum deposit
both the body element 12 and cantilevers 18 to permit tight control
over the material composition, electrical, mechanical and thermal
properties of the material, as well as provide for tight control
over the tissue and fluid contacting surfaces and the bulk material
of the device. For example with nickel-titanium alloys, the
titanium content of the target, in a nickel-titanium binary target,
may be changed a known amount to precisely alter the transition
temperature of a cantilever members 18.
[0049] In accordance with one embodiment either or both of the body
member 12 and the plurality of cantilevers 18 are fabricated of
thin metallic films. As used herein, the term "thin metallic film"
or "metal thin film" are used synonymously to refer to
biocompatible materials made of metallic or pseudometallic
materials. The inventive thin metallic films may be fabricated by
conventional wrought metal processing techniques, or may be made by
nanofabrication techniques such as physical vapor deposition or
chemical vapor deposition.
[0050] Such thin metallic films as are used with the embodiments
disclosed herein may be comprised of single or plural layer films
fabricated of biocompatible metals or biocompatible pseudometals
having thicknesses greater than 0 .mu.m and less than about 125
.mu.m.
[0051] Each of the plurality of cantilevers 18 preferably have
binary functionality to provide a first "closed" position
indicative of an austenite phase of the cantilevers 18 and a second
"open" position indicative of a martensite phase of the cantilevers
18. The closed position is configured such that it is in a lowered
position that is substantially co-planar with the surface. On the
other hand, the open position is configured such that it is in the
raised position or projecting outwardly relative to the
surface.
[0052] It will be understood, therefore, that as the implanted
temperature sensor encounters different in vivo temperatures,
different sets of cantilever members will be exposed to their
transition temperature and change from the "closed" position to the
"open" position. Once in the open position, the cantilevers do not
impede elution of bioactive agents through the openings from the
internal cavities.
[0053] The plurality of cantilever-like cover members 18 function
as sensors in that they may be fabricated to sense and respond to
changes in a physiological state, such as pressure, temperature,
cell or protein binding, the presence or absence of a given
biochemical marker, or the like. Alternatively, the plurality of
cantilever-like cover members 18 may be fabricated to respond only
to a specific externally applied stimulus. In this manner, an
exogenous stimulus, such as a magnetic field, RF energy,
ultrasound, heat or the like may be applied to actuate at least
some of the plurality of cantilever-like cover members 18 and
permit elution o the bioactive agent.
[0054] As illustrated in FIG. 1, ordered arrays, generally denoted
as element 23, of cantilever like cover members 18 may form sensor
groups, such that, for example, a cantilever-like cover members 18
forming a first array 23a may be fabricated to have a martensitic
stress/strain transition coefficient a, while cantilever-like cover
members 18 forming second array 23b are fabricated to have a
transition coefficient .sigma.+1, cantilever-like cover members 18
forming a third array 23c are fabricated to have a transition
coefficient of .sigma.+2, etc. such that different cover members 18
or groups of cover members 18 change their position based upon a
given quantum of stress or strain applied to the cantilever-like
cover members 18 in vivo.
[0055] Alternatively rather than having merely binary
functionality, each of the plurality of cover members 18 may have a
response curve which is dependent upon the modulus of the material
and the moment of inertia of each cantilever member. This response
curve allows for varying degrees of impedance of the openings as
the cover members 18 gradually shift from a closed to opening
position, thereby, resulting in varying elution profiles through
the openings.
[0056] Each of the cover members 18 may be configured to have a
variation in Z-axis thickness along an X-Y axis of the cover
members 18. By configuring the cover members 18 with variable
Z-axis thicknesses, different cover members 18 or different
groupings of cover members 18 will exhibit different stress-strain
responses due to the different material modulus and different
moment of inertia attendant to the altered geometry of the cover
members 18. With this alternate construct of the cover members 18,
for a given quantum of stress-strain applied to the cover members
18, the cover members 18 will deflect and shift a returned
resonance frequency applied from an external energy source. The
degree of deflection will then correlate to the stress and strain
forces acting upon the cover members 18. It will be understood, of
course, that this alternate construct of the cover members 18 still
provides binary "closed" and "open" functionality with the "closed"
and "open" positions merely being indicative of the outlying
positions of the cover members 18.
[0057] It will be understood, therefore, that as the implanted
sensor encounters different stress and strain associated with, for
example, changes in physiological blood pressure, fluid shear
stress, endothelialization, arterioschlerotic plaque development,
different sets of cantilever members will be exposed to their
transition conditions and change from the "closed" position to the
"open" position.
[0058] Each of the above-described preferred embodiments may be
fabricated by a number of methods. In accordance with embodiments
disclosed herein, it is contemplated that either forming wrought
metal parts, such as capillary tubing, into the implantable device
or forming the implantable devices by vacuum deposition techniques
are the preferred method of making the implantable structural
elements of the embodiments disclosed herein. Where an implantable
device is to be fabricated of a plurality of individual tubular
elements, pre-existing microtubular members having an outer
diameter, for example, between 60 and 400 .mu.m and a wall
thickness of between 10 and 350 .mu.m, may be employed to fabricate
extremely small dimensioned devices suitable for intracranial or
coronary artery applications. The microtubular members may be
formed into a cylindrical endoluminal device, such as by braiding
or bending and joining microtubular members together by spot
welding. Where ends of the microtubular members are formed to be
self-cannulating, the self-cannulating ends may be exposed on the
abluminal surface of an endoluminal device at any point along the
longitudinal axis thereof. The plurality of openings passing
through the wall of each of the individual tubular elements may be
formed by microdrilling the openings through the wall and into the
internal cavity or lumen of the individual tubular members. The
plurality of openings may be laser cut, etched or formed by EDM
methods, and may be formed either pre- or post-formation of the
tubular elements into the three-dimensional conformation of the
implantable device.
[0059] Where an implantable device is to be formed from
non-preexisting structural elements, vacuum deposition techniques
may be employed to form the implantable structural body, such as
sputtering, reactive ion etching, chemical vapor deposition, plasma
vapor deposition, or the like, as are known in the microelectronics
fabrication arts and are more fully described in commonly assigned
U.S. Pat. No. 6,379,383, issued Apr. 30, 2002 and commonly assigned
U.S. patent application Ser. No. 10/211,489, published as U.S.
Published
[0060] Patent Application No. 20030059640 published Mar. 27, 2003,
both of which are hereby incorporated by reference as teaching
methods of fabrication of implantable materials using physical
vapor deposition processes.
[0061] The internal chambers, the plurality of openings and the
cover members may each be formed during deposition. In order to
form these elements by vacuum deposition, the vacuum deposition
process may be modified requisite patterns of sacrificial material
to form the regions of the internal chambers and openings, over a
base layer of structural material, then depositing a second layer
of structural material over the sacrificial material and the base
layer. The sacrificial material may then be removed, such as by
etching, to leave the internal cavities and plurality of openings
formed within the deposited bulk material. The plurality of cover
members may be formed by depositing a layer of cover material, then
defining the cover members in the layer of cover material, such as
by laser etching to define the cantilever-like cover members in the
cover material.
[0062] FIGS. 7 and 8 illustrate an exemplary drug-delivery stent 50
in accordance with the embodiments disclosed herein, which is
depicted without the covering members 18 for purposes of clarity.
Those of ordinary skill in the art will understand and recognize
that alternative device designs and geometries are also
contemplated by the embodiments disclosed herein. Stent 50 is
comprised generally of a plurality of structural elements 52
interconnected at a plurality of hinge regions 54 and defining a
plurality of interstices 56 bounded by the plurality of structural
elements and the plurality of hinge regions 54. As described above,
the material used to fabricate the inventive device has a Z-axis
wall thickness in the device material. The inventive device 50
incorporates at least one of a plurality of internal cavities 56
within the wall thickness of the material used to form the
implantable device or endoluminal stent 50. The plurality of
internal cavities 56 are preferably positioned in the plurality of
structural elements 52 and are preferably not present in the hinge
regions 54.
[0063] A plurality of micropores 58 are provided and communicate
between a external surface of the device 50 and one of the
plurality of internal cavities 56. As noted above, the plurality of
micropores 58 are dimensioned to permit the bioactive agent to
elute from the at least one of a plurality of internal cavities 56
and through the associated plurality of micropores 58 by diffusion,
osmotic pressure or under the influence of a positive pressure
applied by cellular in-growth into the plurality of internal
cavities 56 or under positive pressure applied by stress and/or
strain exerted on the plurality of internal cavities 56 due to
deformation of the individual structural elements 52. The plurality
of micropores 58 may furthermore be provided to communicate between
an internal cavity 56 and either a luminal or abluminal surface of
the inventive endoluminal stent, such as to expose the bioactive
agent retained within the plurality of internal cavities 56 either
to the blood stream, in the case of luminal micropores 58, and/or
to adjacent tissue, in the case of abluminal micropores 58.
[0064] The at least one of a plurality of internal cavities 56 may
be continuous or discontinuous throughout the inventive device 50.
Specifically, in accordance with one preferred embodiment of the
invention, the plurality of internal cavities 56 is discontinuous
and each of the plurality of discontinuous internal cavities 56
reside within regions of the device 50 that are substantially
non-load bearing regions of the device. In the particular
embodiment illustrated in FIG. 7, the plurality of hinge regions 54
are devoid of internal cavities 56 because they are load bearing
regions of the stent. It is contemplated, however, that regions of
the inventive device 50 that are deformed or that are load bearing
may include either continuous internal cavities 56 or discontinuous
internal cavities within their wall thickness and provide for
elution of a bioactive agent retained within the internal cavity
positioned at the load bearing region under the influence of a
positive motivating pressure exerted on the bioactive agent by
deformation or load stress transferred by the device geometry to
the internal cavity and to the bioactive agent. By providing
regions of continuous and discontinuous internal cavities 56, a
plurality of bioactive agents may be loaded into different internal
cavities 56 for achieving different elution rates and
pharmacological effects. FIG. 8 is a photomicrograph illustrating a
transverse cross-sectional view through an individual structural
element 52 illustrating the internal cavity 56 and the construction
of the structural element 53 in which there is a base layer of
material and a cap-layer of material overlaying and enclosing the
base layer to form the internal cavity 56.
[0065] An exemplary method 60 for making the inventive drug-eluting
medical device of the embodiments disclosed herein is illustrated,
sequentially, in FIGS. 9A through 9G. As depicted in FIG. 9A, a
substrate 62 is provided; a first layer of biocompatible material
64 is deposited onto the substrate 62, followed by a sacrificial
material layer 66. In FIG. 9B, the following step entails
patterning the sacrificial material layer 66 to leave patterned
sections 68 of the sacrificial layer 66. The pattern sections 68
will, as described hereinafter, form the internal chambers 21 of
the inventive device. A second layer of biocompatible material 70
is then deposited onto the patterned sections 68 and the first
layer of biocompatible material 64 as illustrated in FIG. 9C. As
illustrated in FIG. 9D, a plurality of openings 72 are formed in
the second layer of biocompatible material 70 and communicate with
the patterned sections 68 of the sacrificial material layer 66.
Then, as illustrated in FIG. 9E, the sacrificial material remaining
in the patterned sections 68 is removed through the openings 72 to
leave interior chambers 72 bounded entirely by the second layer of
biocompatible material 70 and the first layer of biocompatible
material 64. A third layer of biocompatible material 76 is then
provided to cover the second layer of biocompatible material 70 and
the plurality of openings 72 therein, as illustrated in FIG. 9F.
This third layer of biocompatible material 76 may have been
preformed with a plurality of cantilever members 78 having
separation gaps 80 between adjacent cantilever members 78 and
adhesion regions 82 formed between the gap 80 and the opening 72
which the cantilever member 78 covers, as illustrated in FIG. 9G.
Those skilled in the art will appreciate that the third layer of
biocompatible material may be provided as a discrete layer of
material or may consist of a plurality of individual cantilever
members 78 each coupled to the second layer of biocompatible
material 70 at adhesion regions 82. The third biocompatible
material 76 may be deposited directly onto the second layer of
biocompatible material 70, then the plurality of individual
cantilever members 78 formed, such as by laser cutting or selective
etching. However, it will be important to interpose a sacrificial
interlayer mask which covers the second biocompatible layer 70 and
the plurality of openings 72, but exposes only the adhesion regions
82 so that, after removal of the sacrificial interlayer mask, the
plurality of cantilever members 78 are free to deflect from and
open the plurality of openings 72.
[0066] Regardless of which fabrication method is employed, the
bioactive agent must be loaded into the internal cavities of the
implantable device. Loading of the bioactive agent may be
accomplished by flowing a liquid or semi-liquid state of the
bioactive agent through the plurality of openings and into the
internal cavities, either throughout the entire device or in
regions of the implantable device. Flow loading may be facilitated
by applying positive pressure, temperature change or both, such as
is used in hot isostatic pressing (HIP). In HIP the pressurizing
medium is typically a gas, and the process is carried out at
elevated temperatures for specific time periods. While HIP is
typically utilized to densify materials, to heal casting defects
and voids, or to bond similar or dissimilar materials it may be
used to drive a fluid or semi-fluid from external the implantable
device into the internal cavities of the implantable device.
Alternative, diffusion-mediated loading, osmotic loading or vacuum
loading may be employed to load the bioactive agent into the
internal cavities.
[0067] While the present invention has been described with
reference to its preferred embodiments, those of ordinary skill in
the art will understand and appreciate that variations in
structural materials, bioactive agents, fabrication methods, device
configuration or device indication and use may be made without
departing from the invention, which is limited in scope only by the
claims appended hereto.
* * * * *