U.S. patent application number 12/193523 was filed with the patent office on 2009-01-22 for multi-reservoir medical device having protected interior walls.
This patent application is currently assigned to MICROCHIPS, INC.. Invention is credited to John M. Maloney, John T. Santini, JR., Zouhair Sbiaa, Norman F. Sheppard, JR., Scott A. Uhland.
Application Number | 20090024113 12/193523 |
Document ID | / |
Family ID | 35840525 |
Filed Date | 2009-01-22 |
United States Patent
Application |
20090024113 |
Kind Code |
A1 |
Maloney; John M. ; et
al. |
January 22, 2009 |
MULTI-RESERVOIR MEDICAL DEVICE HAVING PROTECTED INTERIOR WALLS
Abstract
An implantable medical device is provided for controlled
delivery or exposure of reservoir contents. The device may include
a substrate; a plurality of discrete reservoirs in the substrate,
wherein the reservoirs have interior walls and at least one opening
in the substrate; reservoir contents disposed in the reservoirs; a
reservoir cap closing the at least one opening of each of the
reservoirs to seal the reservoir contents in each of the
reservoirs; and control circuitry for selectively disintegrating
the reservoir caps to release or expose the reservoir contents in
vivo, wherein the interior walls of the reservoirs comprise a
material to protect the substrate in vivo. For example, to enhance
the resistance of the substrate to etching in vivo, the interior
sidewalls of the reservoirs may include a protective coating (such
as gold, platinum, carbon, silicon carbide, silicon dioxide, or
platinum silicide), or the sidewalls may include a doped
silicon.
Inventors: |
Maloney; John M.;
(Cambridge, MA) ; Sbiaa; Zouhair; (Everett,
MA) ; Santini, JR.; John T.; (North Chelmsford,
MA) ; Sheppard, JR.; Norman F.; (New Ipswich, NH)
; Uhland; Scott A.; (Medford, MA) |
Correspondence
Address: |
SUTHERLAND ASBILL & BRENNAN LLP
999 PEACHTREE STREET, N.E.
ATLANTA
GA
30309
US
|
Assignee: |
MICROCHIPS, INC.
Bedford
MA
|
Family ID: |
35840525 |
Appl. No.: |
12/193523 |
Filed: |
August 18, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10988667 |
Nov 15, 2004 |
7413846 |
|
|
12193523 |
|
|
|
|
Current U.S.
Class: |
604/890.1 |
Current CPC
Class: |
A61K 9/0024 20130101;
B01L 2300/0819 20130101; B01L 2200/12 20130101; B01L 2400/0677
20130101; A61K 9/0097 20130101; B01L 3/50853 20130101 |
Class at
Publication: |
604/890.1 |
International
Class: |
A61K 9/22 20060101
A61K009/22 |
Claims
1. An implantable medical device for the controlled delivery or
exposure of reservoir contents comprising: a substrate; a plurality
of discrete reservoirs in the substrate, wherein the reservoirs
have interior walls and at least one opening in the substrate;
reservoir contents disposed in the reservoirs; a reservoir cap
closing the at least one opening of each of the reservoirs to seal
the reservoir contents in each of the reservoirs; and control
circuitry for selectively disintegrating the reservoir caps to
release or expose the reservoir contents in vivo, wherein the
interior walls of the reservoirs comprise a material to protect the
substrate in vivo.
2. The device of claim 1, wherein the interior walls have at least
one protective layer of the material coated thereon.
3. The device of claim 2, wherein the protective layer comprises
gold, platinum, diamond-like carbon, silicon carbide, silicon
dioxide, or platinum silicide.
4. The device of claim 1, wherein the interior walls comprise
silicon doped with a dopant to enhance the resistance of the
silicon to etching in vivo.
5. The device of claim 4, wherein the silicon is doped with
boron.
6. The device of claim 1, wherein the substrate comprises a silicon
wafer.
7. The device of claim 1, wherein the substrate comprises a
polymer.
8. The device of claim 1, wherein the reservoirs are
micro-reservoirs.
9. The device of claim 1, wherein the reservoir contents comprise a
drug.
10. The device of claim 1, wherein the reservoir contents comprise
a sensor or sensor component.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional of U.S. application Ser. No.
10/988,667, filed Nov. 15, 2004, now U.S. Pat. No. 7,413,846,
issued Aug. 19, 2008. The application is incorporated herein by
reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] This invention is generally in the field of methods of
fabricating miniaturized reservoir devices for the controlled
release or exposure of reservoir contents, such as drug
formulations and/or sensors.
[0003] U.S. Pat. No. 5,797,898, U.S. Pat. No. 6,551,838, and U.S.
Pat. No. 6,491,666, all to Santini, et al., describe
microfabricated devices that have a plurality, typically hundreds
to thousands, of tiny reservoirs. In some embodiments, these
reservoirs are provided with a reservoir cap over the contents
(such as a drug formulation) of the reservoir, so that the contents
are released from the device by the controllable disintegration of
the reservoir caps. For example, the reservoir cap can be a metal
film and an electric potential can be applied to cause the metal
film to oxidize and disintegrate. In this embodiment, the microchip
device is connected to an external circuit through wire bond pads
on the microchip (i.e., on the substrate), and an electrical
connection between the reservoir caps and the bond pads is provided
by conductive traces fabricated on the chip. The reservoir caps,
traces, and bond pads can be fabricated, for example, using a
single patterned layer of gold.
[0004] U.S. Patent Application Publication No. 2004/0121486 A1 to
Uhland, et al., also describes devices having an array of
micro-reservoirs each covered by a reservoir cap. The publication
further describes a innovative means for disintegrating the
reservoir cap to expose/release the reservoir contents: An
electrical current is selectively passed through each reservoir
cap, via an input lead and an output lead, in an amount effective
to heat the reservoir cap to cause the reservoir cap to rupture,
thus opening the reservoir. One embodiment includes reservoir caps,
traces, and bond pads fabricated from a conductive material. In one
embodiment, the reservoir caps and traces are fabricated from
different materials and are electrically connected. It would be
desirable to provide devices and fabrication methods in which the
surface of the exterior or interior of the device or the substrate
can be coated or altered to protect the device from the environment
or to obtain a favorable surface chemistry for drug storage. It
would be further desirable to provide methods for fabricating
multi-reservoir devices wherein the circuitry is fabricated in a
robust manner and good physical and electrical contact is
maintained between features of the device that are meant to be
electrically connected.
[0005] U.S. Pat. No. 6,123,861 to Santini, et al., describes
forming reservoirs in a substrate by etching a single crystal
silicon wafer using aqueous potassium hydroxide. Because the
pyramidal reservoirs formed by this process are defined by silicon
crystalline planes, the area density of reservoirs on the wafer is
inversely coupled to the volume of each reservoir.
[0006] It would be advantageous to have micro-reservoir devices
that have a high area density in order to pack more reservoir
contents into as small a total device volume as possible,
particularly for applications where the device is to be implanted
into a patient (such as for controlled drug delivery or
biosensing). It therefore would be desirable to develop improved
devices and new methods of making them in which the reservoir
volume in these devices can be increased without adversely
affecting the area density of reservoirs on/in a substrate.
BRIEF SUMMARY OF THE INVENTION
[0007] In one aspect, a method is provided for making a
multi-reservoir device comprising the steps of (i) patterning one
or more photoresist layers on a substrate; (ii) depositing onto the
substrate at least one metal layer by physical vapor deposition;
(iii) forming a plurality of reservoir caps and conductive traces
from the at least one metal layer by using the one or more
photoresist layers in a liftoff process or wet chemical etching
(iv) removing the one or more photoresist layers using a liftoff
process; (v) forming a plurality of reservoirs in the substrate;
(vi) loading each reservoir with reservoir contents; and (vii)
sealing each reservoir.
[0008] In one embodiment, the reservoir cap comprises a first
conductive metal layer coated with one or more protective noble
metal film layers. For example, the first conductive metal layer
can comprise titanium, and the noble metal film can comprise
platinum. In one embodiment, the thickness of the protective metal
layer is less than about 20% of the thickness of the first
conductive metal layer.
[0009] In another embodiment, the reservoirs comprise interior
sidewalls and the method further includes forming a protective
surface on the sidewalls. For example, a coating layer can be
formed on the sidewalls, such as a material selected from gold,
platinum, diamond-like carbon, silicon carbide, silicon dioxide,
and platinum silicide. In an alternative approach, the reservoirs
comprise interior sidewalls comprising silicon doped with boron or
another impurity to enhance the resistance of the silicon to
etching under in vivo conditions.
[0010] In one embodiment, the method further comprises bonding an
additional substrate portion with through-substrate holes aligned
with the reservoirs. For example, the additional substrate portion
can comprise a silicon wafer or a glass wafer. In one embodiment,
the additional substrate portion and the substrate are bonded
together with an intermediate film, such as a borosilicate glass.
In one embodiment, the substrate and/or the additional substrate
portion comprises silicon and the reservoirs and/or through holes
are further treated with an isotropic silicon etchant to widen the
hole or to smooth the surface of the hole. In various embodiments,
the additional substrate portion and the substrate are bonded by a
process comprising anodic bonding, thermocompression bonding, or
eutectic bonding.
[0011] In still another embodiment, the method includes a bilayer
liftoff process. For instance, a bilayer photoresist which
comprises an upper layer and a lower layer, can be deposited where
the lower layer is disposed on the substrate and the upper layer is
disposed on the lower layer. Preferably, the method provides a
metal layer with no tags created by the sputtering and liftoff
processes. For example, the lower layer can be laterally etched
before the sputtering step, to create an overhang of the upper
layer so that substantially no sputtered material is deposited on
the sidewall of the lower layer. In an alternative embodiment, the
process includes the formation of tags connected to the metal layer
and the tags are then removed. In one example, the tags are removed
by a process comprising: (i) depositing a mask layer is deposited
over the metal traces and/or reservoir caps, wherein the mask
layer:metal layer thickness ratio is from about 1:5 to about
1:1000; and (ii) etching away the tags to yield metal traces and/or
reservoir caps. In another example, the tags are removed by a
sonication process.
[0012] In one particular embodiment, a method is provided for
making a multi-reservoir device comprising the steps of (i)
depositing a layer of a nitride material on a silicon substrate;
(ii) patterning the nitride layer with photoresist; (iii) etching
the silicon substrate using an RIE process; (iii) stripping off the
photoresist; (iv) anistropically etching the silicon substrate; (v)
forming metal traces by depositing and patterning a first metal
layer using a liftoff technique; (vi) forming reservoir caps by
depositing and patterning a second metal layer using a liftoff
technique to form a structure; (vii) applying a passivation layer
onto the structure; and (viii) etching the dielectric layer and the
metal layer from under the reservoir cap. In a further embodiment,
the method further includes anodically bonding a patterned glass
wafer to the substrate.
[0013] In another aspect, a microfabrication method is provided
comprising the steps of (i) patterning a bilayer of photoresist on
a substrate, wherein the bilayer photoresist comprises an upper
layer and a lower layer, the lower layer being disposed on top of
the substrate and the upper layer being disposed on top of the
lower layer; (ii) etching the lower layer away in select areas to
form one or more bridges comprising areas of the upper layer over
and spaced apart from the substrate; (iii) depositing onto the
substrate at least one metal layer by physical vapor deposition,
wherein the one or more bridges provide a shielding effect to
produce a metal film or patterned metal feature with a thickness
variation within a single metal layer, without etching the metal
layer. In one embodiment, the method further comprises (iv) forming
a plurality of reservoir caps and conductive traces from the at
least one metal layer by using the one or more photoresist layers
in a liftoff process or wet chemical etching; (v) removing the
bilayer photoresist layers using a liftoff process; (vi) forming a
plurality of reservoirs in the substrate; (vii) loading each
reservoir with reservoir contents; and (viii) sealing each
reservoir, wherein the thickness of the metal layer is varied due
to a shielding effect caused by the bridges. In various
embodiments, the method of depositing the metal layer is selected
from evaporation, sputtering, and ion beam deposition.
[0014] In preferred embodiments of these methods, the reservoirs
are micro-reservoirs, the reservoir contents comprises one or more
drugs, the reservoir contents comprises one or more sensors or
sensor components, and/or the reservoir contents are hermetically
sealed within the reservoirs.
[0015] In another aspect, an implantable medical device is provided
for the controlled delivery or exposure of reservoir contents. The
device comprises (i) a substrate; (ii) a plurality of discrete
reservoirs in the substrate, wherein the reservoirs have interior
walls and at least one opening in the substrate; (iii) reservoir
contents disposed in the reservoirs; (iv) reservoir caps closing
the at least one opening to seal the reservoir contents in the
reservoirs; and (v) control circuitry for selectively
disintegrating the reservoir caps to release or expose the
reservoir contents in vivo, wherein the interior walls of the
reservoirs comprise a material to protect the substrate in vivo. In
one embodiment, the interior sidewalls have at least one protective
layer of the material coated thereon. For example, the protective
layer can comprise gold, platinum, diamond-like carbon, silicon
carbide, silicon dioxide, or platinum silicide. In another
embodiment, the interior sidewalls comprise silicon doped with
boron or another impurity to enhance the resistance of the silicon
to etching in vivo.
[0016] In another aspect, an implantable medical device is provided
for the controlled delivery or exposure of reservoir contents. The
device comprises (i) a substrate; (ii) a plurality of reservoirs in
the substrate, wherein the reservoirs have interior walls and at
least one opening in the substrate; (iii) reservoir contents
disposed in the reservoirs; (iv) reservoir caps closing the at
least one opening to seal the reservoir contents in the reservoirs;
and (v) control circuitry for selectively disintegrating the
reservoir caps to release or expose the reservoir contents in vivo,
wherein the reservoir caps comprises a first conductive metal layer
coated with one or more protective layers comprising a noble metal
film. For example, the first conductive metal layer can comprise
titanium, and the noble metal film can comprise platinum. In
preferred embodiments, the thickness of the protective metal layer
is less than about 20% of the thickness of the first conductive
metal layer.
[0017] In one embodiment, the control circuitry includes traces in
electrical connection to the reservoir caps, wherein the traces
comprise two or more layers of conductive materials. In one
specific embodiment, the traces comprise a titanium/gold/titanium
structure. In another specific embodiment, the reservoir cap
comprises a titanium/platinum/titanium/platinum/titanium structure.
In a further embodiment, the device includes a passivating layer
covering the device except for at least a portion of the reservoir
caps. In one embodiment, the substrate comprises a silicon wafer
bonded to a glass wafer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIGS. 1A-B are cross-sectional views of a substrate with a
reservoir therein, illustrating the area density limitations of
pyramidal reservoirs in a single layer substrate (FIG. 1A) and a
modification of this substrate with increased reservoir volume by
using a multilayer substrate without increasing the exterior
surface area occupied by the reservoirs (FIG. 1B).
[0019] FIG. 2 illustrates the steps involved in one method of
creating through-holes in a silicon substrate by an anisotropic
etch and then smoothing the sidewalls of the hole (reservoir) by an
isotropic etch.
[0020] FIGS. 3A-B are cross-sectional views of a substrate and
single reservoir covered by a single-layer reservoir cap (FIG. 3A)
or by a multi-layer reservoir cap with protective layers (FIG. 3B).
FIG. 3C details the structure of the multi-layer reservoir cap in
FIG. 3B.
[0021] FIG. 4 illustrates the steps involved in one process method,
showing remaining material left after combining the liftoff process
with sputter deposition.
[0022] FIGS. 5A-C are cross-sectional views of feature sidewalls
with three different angles, which show unfavorable and favorable
sidewall angles and typical results after film deposition.
[0023] FIGS. 6A-B are cross-sectional views showing the sidewalls
resulting from using an increased photoresist overhang (FIG. 6A) or
by reducing the pressure during sputtering or using a collimator
(FIG. 6B).
[0024] FIG. 7 illustrates the steps involved in one process for
removing unwanted tags from deposited features masking with
additional layers in a one-step deposition process.
[0025] FIGS. 8A-B are cross-sectional views showing the fabrication
steps (FIG. 8A) in one embodiment of the processes described
herein, and a close-up of the resulting structure (FIG. 8B) made
thereby.
[0026] FIGS. 9A-B are cross-sectional views showing the fabrication
steps in another embodiment of the processes described herein.
[0027] FIG. 10 is a process flow diagram and cross-sectional view
of an intermediate structure in a fabrication process comprising a
liftoff process, where unwanted tags are formed and removed before
completion of the reservoir (forming) etching process. The figure
shows the nitride layer reinforced by part of the silicon substrate
that has not yet been etched away.
[0028] FIG. 11 is a cross-sectional view of another intermediate
structure in a fabrication process comprising a liftoff process,
where unwanted tags are formed and removed and a temporary,
polymeric material fills the reservoir to support the nitride layer
during tag removal.
[0029] FIGS. 12A-B show a plan view (FIG. 12A) and a
cross-sectional view (FIG. 12B) of an intermediate structure in
which a bilayer photoresist is used to create bridges over the
substrate which can be used in a subsequent metal deposition
process to vary the thickness of the deposited metal layer.
[0030] FIG. 13 is a perspective/cross-sectional view of a portion
of one embodiment of a device including reservoirs comprising
interior walls having a material to protect the substrate in
vivo.
DETAILED DESCRIPTION OF THE INVENTION
[0031] Improved methods have been developed for fabricating a
multi-reservoir device, such as an implantable micro-reservoir drug
delivery or sensing device. New and improved devices made by these
methods are also provided.
[0032] Herein, where the composition of a multilayer film is given,
the materials composing the layer are listed in order of
deposition, so that, for example, a Ti/Pt/Au multilayer film is
fabricated on a substrate by depositing titanium, then platinum,
then gold.
[0033] As used herein, the terms `comprise,` "comprising,"
"include," and "including" are intended to be open, non-limiting
terms, unless the contrary is expressly indicated.
The Fabrication Methods and Structures
[0034] Reservoir Fabrication
[0035] One method of increasing reservoir volume (and thus device
reservoir density) is to attach/bond two or more substrate portions
together. FIGS. 1A-B illustrates this concept, where first
substrate portion 10 having a first reservoir 12 (FIG. 1A) is
bonded to an additional substrate portion 14 with a
through-substrate hole 16 aligned with the first reservoir to form
a larger substrate 18 and reservoir (FIG. 1B). For simplicity, a
single reservoir is illustrated, but the substrate typically and
preferably includes a plurality of discrete, closely spaced
reservoirs (e.g., in an array).
[0036] In one embodiment, the additional substrate portion is a
glass wafer. Through-wafer holes in glass can be formed by wet
chemical etching, electrochemical discharge drilling, ultrasonic
drilling, laser drilling, electro discharge machining (EDM), or
powder blasting, as known in the art. The glass wafer can be
attached to the silicon wafer by the method of anodic bonding or
the method of eutectic bonding, as described in U.S. Patent
Application Publication No. 2003/0010808.
[0037] In another embodiment, the additional substrate portion is a
silicon wafer. There are several ways to create suitable
through-wafer holes in silicon. In one technique, an etch mask is
deposited and patterned on one side of the wafer to create openings
of the desired size. Deep reactive ion etching (DRIE) is then used
to etch entirely through the wafer. In a variation of this
embodiment, an etch mask is deposited and patterned on both sides
of the wafer. DRIE is then used to etch partially through the
wafer. The wafer is then turned over and DRIE is used to complete
the etching process. This variation may be preferred if the etch
depth is limited, for example, by mass transport limitations. By
using this variation, the required etch depth could be reduced a
factor of two by etching from both sides of the wafer. Suitable
etch masks include photoresist, a metal such as nickel or chromium,
or a dielectric such as thermally grown silicon dioxide. The etch
mask can be removed if necessary after etching is completed.
[0038] Other variations of the method for creating through-holes is
illustrated in FIG. 2. A single crystal silicon wafer 100 with a
surface orientation in the direction of the (100) or (110)
crystalline plane is used as the additional substrate portion.
First, an etch mask 102 is deposited (Step A) and patterned (Step
B) on both sides of the wafer. Suitable etch masks include silicon
nitride or silicon dioxide. Then, an anisotropic silicon etchant,
such as KOH or TMAH, is used to etch cavities in both sides until
the cavities meet (Step C). In an optional variation, an isotropic
silicon etchant is used after the through-wafer hole is created to
widen the hole, or smooth the surfaces of the hole, or both (Step
D). For example, the anisotropic silicon etchant KOH can leave
sharp concave edges because etching occurs along crystallographic
planes. These corners undesirably can serve as stress
concentrators, lowering the strength of the substrate. By using an
isotropic etchant to round these corners, the strength of the
substrate can be increased. Suitable isotropic silicon etchants
include aqueous, gaseous, and plasma-based chemistries. For
example, an aqueous composition including HF and HNO.sub.3 could be
used, as described in Robbins & Schwarz, J. Electrochem. Soc.
106 (1959). Alternatively, gaseous XeF.sub.2 or BrF.sub.3 or a
fluorine-containing plasma could be used.
[0039] The additional substrate portion, containing through-wafer
holes, and the original substrate portion, which could include the
reservoir cap and disintegration circuitry of the device, can be
joined by several methods. In one embodiment, silicon direct
bonding at a temperature of approximately 1000.degree. C., as
described in Tong & Gosele, "Science and Technology of
Semiconductor Wafer Bonding" (John Wiley & Sons, USA) (1999),
is used to join the two wafer, i.e., the two substrate portions. In
another embodiment, an intermediate film is used to join the
wafers. For example, a borosilicate glass could be deposited on one
or both of the wafers by sputtering and the wafers joined by
heating the stack beyond the softening point of the glass.
Alternatively, the borosilicate glass contains an amount of sodium
or lithium to provide mobile ions, and the wafers are joined in an
electrostatic method (anodic bonding) as described in Hanneborg et
al., J. Micromech. Microeng. 2(3) (1992). In yet another
embodiment, the intermediate film consists of a metal (such as
gold) and the wafers are joined by thermocompression bonding, as
described in Tsau, et al., J. Microelectromechanical Systems, 11(6)
(2002). Alternatively, a gold or gold-silicon film is used and the
wafers are joined by the method of Au--Si eutectic bonding, as
known in the art.
[0040] The substrate material can be formed from a variety of
materials. While the methods are described herein often with
reference to using a silicon substrate, non-silicon substrates are
contemplated, which can broaden the range of useful fabrication
methods available for making the devices described herein. Examples
of suitable materials include ceramics, metals, and polymers, and
examples of fabrication methods include Low Temperature Co-Fired
Ceramic (LTCC) methods for ceramics (e.g., aligning/laminating
green ceramics and then firing them) and thermo-compression molding
for polymers.
[0041] In another aspect, as shown in FIG. 13, it may be desirable
to provide the interior sidewalls of the reservoirs with a
protective surface, e.g., by coating the interior sidewalls or to
otherwise provide a favorable surface chemistry. Single crystal
silicon, for instance, is known to be etched under in vivo
conditions. So, to protect this surface, it may be desirable to
physically deposit or chemically grow on the sidewalls a protective
material. In one embodiment, a metal such as gold or platinum is
deposited on the sidewalls by physical vapor deposition. In another
embodiment, a metal is deposited on the sidewalls and annealed to
form a silicide. In yet another embodiment, silicon dioxide is
thermally grown on the sidewalls to provide a hydrophilic surface
that would promote wetting when the reservoir is filled with drug.
In a further embodiment, the reservoir sidewalls are coated with
titanium or silicon nitride. In still another embodiment, the
silicon sidewalls are doped with an impurity to improve resistance
to etching under in vivo conditions. For instance, boron at high
levels of doping would be an example of a dopant that would
decrease dissolution/etching when exposed to chemicals or to fluids
in a human or other mammalian body. In a further embodiment, the
sidewalls have one or more layers of material deposited on them.
This can be highly useful or even necessary to protect the walls of
the reservoir exposed to a range of chemicals, drugs, and/or in
vivo fluids. Examples of coating materials include diamond-like
carbon, silicon carbide, and other carbides.
[0042] Reservoir Cap Fabrication
[0043] In some embodiments, a reservoir cap material that is
electrically favorable for device operation is incompatible with
certain (additional or optional) fabrication steps. U.S. Patent
Application Publication No. 2004/0121486 A1 to Uhland, et al.
describes the use of reservoirs caps made of conductors such as
titanium or silicon doped with an impurity. However, where
fabrication includes depositing the reservoir cap material on a
suspended dielectric membrane and then removing the membrane from
underneath by plasma etching with a fluorine-containing gas such as
CF.sub.4 or CHF.sub.3, as described in U.S. Pat. No. 5,797,898,
then a reservoir cap made of titanium or silicon would be partially
or completely etched during reactive ion etching to remove the
dielectric membrane, as it is known in the art that titanium and
silicon are chemically etched in plasmas containing fluorine. One
method of preventing the reservoir cap from being etched is to add
a protective layer of material that would not be chemically etched
in fluorine-containing plasma. Examples of suitable layers include
noble metals such as gold, platinum, or iridium, or alloys thereof.
The layer is desirably thick enough to form a contiguous layer, but
not so thick that the electrical resistance of the reservoir cap is
significantly affected. For example, a suitable thickness and
composition for a protective layer would be 40 nm of platinum for a
reservoir cap with an initial thickness and composition of 300 nm
titanium. In addition, an adhesion layer such as titanium or
chromium preferably may be included between the dielectric material
and the protective layer. One example of a suitable thickness and
composition for this adhesion layer would be 10 nm of titanium.
Other thicknesses of the reservoir cap layer and the protective
layers are contemplated.
[0044] Similarly, it may be desirable to partially or completely
passivate or protect the reservoir cap before implantation by
depositing a dielectric such as silicon dioxide on its surface, as
described in U.S. Pat. No. 5,797,898. Silicon dioxide is typically
patterned by using hydrofluoric acid, which also attacks titanium.
A reservoir cap made of titanium would be partially or completely
etched through during hydrofluoric acid etching while the
passivation layer is being patterned. As described above, a
protective layer can be added to the reservoir cap. Examples of
suitable layers include noble metals such as gold, platinum, or
iridium, or alloys thereof. Again, an adhesion layer such as
titanium preferably can be added between the passivating dielectric
material and the protective layer.
[0045] FIG. 3A illustrates substrate 10, reservoir 12, and
unprotected reservoir cap 110, which is made of titanium. FIG. 3B
illustrates substrate 10, reservoir 12, and protected reservoir cap
112. As detailed in FIG. 3C, the protected reservoir cap 112
includes reservoir cap 102 between layers of protective platinum
104a, 104b and titanium adhesion layers 106a, 106b. If a protective
layer of noble metal, such as platinum, is added to both sides of
the original reservoir cap, then a reservoir cap comprising a
reactive material, such as titanium, is protected from oxidation or
reaction with the environment. The protective layers on both sides
can have equal thickness, but other ratios of thickness may also be
appropriate. Similarly, the adhesion layers on both sides can have
equal thickness, but other ratios of thickness may also be
appropriate. These protective layers on the reservoir cap may, in
some embodiments, also provide a level of mechanical support to the
reservoir cap structure. In a preferred embodiment, the protective
layer(s) are made of a conductive noble metal film and the primary
reservoir cap layer is a conductive non-noble metal layer.
Typically the thickness of each protective layer is less than about
20% of the thickness of the reservoir cap layer. In one embodiment,
protected reservoir cap 112 comprises 12.5 nm Ti/40 nm Pt/300 nm
Ti/40 nm Pt/12.5 nm Ti.
[0046] In one embodiment, the stack of layers forming protected
reservoir cap 112 is deposited in one process step by a physical
vapor deposition method, such as evaporation or sputtering. If a
noble metal such as platinum is deposited as part of the reservoir
cap, methods of patterning the reservoir cap by wet chemical
etching may be limited, as platinum is resistant to many chemical
etchants. Moreover, a multilayer or alloy film can be difficult to
pattern by wet chemical etching when the layers of the film cannot
all be etched by the same etchant. For example, consider a
reservoir cap partially or completely comprising a gold-silicon
alloy. An aqueous solution of KI+I.sub.2 is commonly used to etch
gold, and aqueous potassium hydroxide is commonly used to etch
silicon, but these are not be suitable etchants for certain other
materials. It is common to pattern multilayer or alloy films with
the liftoff process.
[0047] In the liftoff process, one or more layers of photoresist
are deposited and patterned before film deposition, and windows are
opened where the film is desired on the substrate. After film
deposition, the photoresist is removed in a solvent, leaving the
film remaining where it is desired on the finished device. The
advantage of the liftoff process is that a multilayer or alloy film
can be patterned without chemically etching each component of the
film.
[0048] Variation on the liftoff process are known in the art. For
example, U.S. Pat. No. 4,024,293 to Hatzakis discloses a method of
using a bilayer stack of two photoresists, developed in two
different developers that are mutually exclusive. In addition, U.S.
Pat. No. 3,934,057 to Moreau discloses a method of using a stack of
two or more layers of photoresist that have successively decreasing
solubility in a single developer. This process also leaves an
overhang that is favorable for performing the liftoff process.
Bilayer lift-off resists are commercially available. See e.g.,
http://www.microchem.com/products/lor.htm. There are also
single-layer photoresists that form an overhanging slope favorable
to lift off. The extent of the overhang is determined by the
exposure time and developing time.
[0049] These photoresist methods can be used to pattern a reservoir
cap such as those containing a gold-silicon alloy, or a multilayer
film comprising platinum and titanium. The liftoff process is well
suited to film deposition by evaporation; however, problems can
arise when using the liftoff process with sputtering. Sputter
deposition is preferred for some applications because of its
capability for high processing throughput and conformal substrate
coating. However, some material tends to deposit on the sidewalls
of the photoresist because sputter deposition is not a
line-of-sight deposition process. When the liftoff process is
completed by removing the photoresist, the material sputtered under
the photoresist overhang can remain, and this remaining material
can interfere in the subsequent deposition of another film. FIG. 4
illustrates this process: bilayer stack of two photoresists 122a,
122b is deposited onto substrate 120, creating overhang 123 (Step
A); reservoir cap material 124 is sputtered onto the substrate and
photoresist, including onto the photoresist sidewall 125 (Step B);
and photoresist is removed, leaving reservoir cap 128 and extra
material 126, called a tag or wing (Step C).
[0050] When combining sputter deposition with a liftoff process, it
is desirable to produce features with smooth sidewalls. It is noted
that in this paragraph, the term "sidewalls" does not refer to the
inner surface of the reservoirs in the substrate, but rather refers
to metal deposition and patterning processes of features, typically
on top of the substrate, the surfaces of the feature (e.g.,
reservoir cap) that are other than parallel to the substrate
surface. That is, it may be desirable to have features with smooth
contours, transitions, or edges, rather than abrupt changes in
surface topography or sharp edges of features, so that these
features are then easily covered with another film, such as a
dielectric or additional conductive layer. Illustrations of
"favorable" and "unfavorable" sidewalls are shown in FIGS. 5A-C. In
these figures, substrate 120 has feature 130, with different
sidewalls 132a, 132b, and 132c, covered by material layer 134 using
physical vapor deposition (PVD) or chemical vapor deposition (CYD).
The "favorable/unfavorable" classification is based on the
desirability of depositing multiple layers of material on top of
each other while achieving good contact/continuity between the
layers. The exact slope angle required to make a favorable
connection depends on the material being deposited over the slope
and the method of deposition. Based on these objectives, FIGS. 5A
and 5B would generally be considered to illustrate unfavorable
sidewalls, and FIG. 5C would generally be considered to illustrate
favorable sidewalls. There are, however, device designs and
fabrication methods where the embodiments of FIG. 5A or 5B would be
considered favorable, for example, where continuity in the
deposited film is unnecessary or undesirable.
[0051] Favorable feature sidewalls can be achieved by using any of
several techniques. In one embodiment of the bilayer liftoff
process, shown in FIG. 6A, the bottom photoresist 140 is laterally
etched to a sufficient distance that a negligible amount of
material 142 is deposited on the sidewall of the bottom
photoresist. In another embodiment, shown in FIG. 6B, the conformal
nature of sputter deposition is adjusted by decreasing the pressure
in the vacuum chamber during deposition or by incorporating a
collimator, as described in U.S. Pat. No. 4,824,544 to Mikalesen,
et al., resulting in layer 144 having a more steeply angled
sidewall and a negligible amount of material 144 deposited on the
sidewall of the bottom photoresist 140.
[0052] In a further embodiment, a microfabrication process has been
developed applicable to making metal films for a variety of
purposes, not limited to medical devices or to micro-reservoir
devices, but would be broadly applicable to any microfabricated
device that includes metal layers (e.g., integrated circuits for
computers and other electronic devices). Advantageously, the
process provides a way to produce a metal film or patterned metal
feature with a thickness variation within a single metal layer,
without subsequently etching the metal layer. In a preferred
embodiment, the method is used to form reservoir caps, traces, for
both. The process provides continuous metal films deposited with
varying thicknesses, with a smooth transition from one thickness to
another. Advantageously, it can be performed in one metal
deposition step. In one embodiment, a bilayer of photoresist is
applied to a substrate and the lower (liftoff) resist is then
completely etched away in select areas to form one or more
"bridges" composed of the upper (imaging) resist. These one or more
bridges then can be used to make a continuous metal film of varying
thickness and a smooth contour. This concept is illustrated in
FIGS. 12A-B, where substrate 200 has bilayer photoresist comprising
imaging resist 202 and liftoff resist 204, which is etched to form
bridge 206. Metal layer 208 can then be deposited, where bridge 206
has influenced the thickness of the metal layer therebelow. The
thickness and variation of the thickness can be controlled by the
choice of the metal deposition method (e.g., e-beam, sputtering,
ion beam), the conditions that affect directionality (e.g., process
pressure and temperature), the width of the bridge, and the rate of
metal deposition. Multiple bridges and varying shapes of bridges
can readily be created (e.g., by patterning of the photoresist) to
further control thickness variations across the metal surface
area.
[0053] Fabrication of Traces
[0054] The term "traces," as used herein, is used to describe the
on-chip (i.e., on substrate) wiring or conductive features that
electrically connect the reservoir cap to other features elsewhere
on the chip.
[0055] To form an operable electric circuit through the reservoir
caps as described in U.S. Patent Application Publication No.
2004/0121486 A1 to Uhland, et al., the reservoir caps are connected
to a power source and to control electronics, on or off the device.
It is desirable to keep the power requirements low for an
implantable device. If a certain electrical current is required to
rupture the reservoir cap, then the total voltage required for
activation is proportional to this current and the total resistance
in the circuit. It is therefore desirable to reduce the resistance
of the circuitry in series with the reservoir cap.
[0056] Traces with a favorably low resistance can be constructed by
depositing materials with a low electrical resistivity and by using
features that are as wide or as thick as possible. For example,
low-resistivity materials such as gold, silver, copper, or aluminum
are appropriate materials, while gold is preferred for an
implantable device due to its biocompatibility and biostability.
The maximum width of the traces is necessarily limited by the space
available on the substrate surface of the microchip. The maximum
thickness may be limited by the deposition and patterning processes
used to fabricate the traces.
[0057] In some cases, substrate surface area limitations (e.g.,
where the substrate surface area is small and contains an array of
many closely packed reservoirs) may impact the number and placement
of the traces. In such instances, the traces can be overlaid if an
appropriate insulator or dielectric material is deposited between
the overlaid traces. In such cases, the traces typically would be
connected electrically through vias for operation.
[0058] When it is necessary to fabricate a conducting feature in
electrical contact with another conducting feature of the
micro-reservoir device, techniques known in the art can be used or
adapted to promote good physical and electrical contact. For
example, a separate adhesion layer can be included to promote
adhesion of the electrical trace to a dielectric layer, but may not
be needed or desirable in all embodiments. Adhesion can be promoted
by using adhesion layers on the contacting surfaces. For example, a
layer comprising 12.5 m Ti/2000 nm Au/12.5 nm Ti may be deposited
and patterned as a trace feature. Following this step, an
additional layer comprising 12.5 nm Ti/2000 nm Au can be deposited
over the first metal layer, where the titanium is used as an
adhesion layer. Other layer thicknesses are contemplated. Another
way of promoting a good physical and electrical contact is to
perform an in situ sputter clean immediately before the second
metal layer is deposited by sputter deposition. It is necessary to
maintain a vacuum in the deposition chamber between the cleaning
and deposition steps to avoid contamination. In this approach,
intermediate adhesion layers are not always necessary, and so, for
example, a layer comprising 2000 nm Au can be deposited over a
layer comprising 12.5 nm Ti/2000 nm Au. If a gold trace surface is
absolutely (atomically) clean (e.g., with in situ sputtering), a Ti
or other adhesion layer may not be needed.
[0059] In one embodiment, the trace features can be patterned by
combining sputter deposition with a liftoff process. As described
above, this combination may produce "tags" or "wings" of material
at the edge of features. As illustrated in FIG. 7, a useful way to
remove these tags 152 is to deposit a mask layer 154 over the trace
material 150 (Step A). This mask layer 154 is desirably thinner
than the trace material 150. Suitable ratios of thickness range
from about 1:5 to about 1:1000. After deposition and liftoff, both
layers are exposed to an etchant that etches the trace material.
Because the mask layer is of sufficient thickness over most of the
feature to protect the trace material, the majority of the trace
material is not etched. However, in the areas at the edge of the
feature, the thickness of both the mask layer and the trace
material is reduced. The trace material is therefore vulnerable to
etching in these areas, and the tags remaining after liftoff 152
will be removed, leaving sloped sidewalls 156 (Step B). In a
typical embodiment, the thickness and materials are 2 .mu.m Au for
the trace material and 12.5 n Ti for the mask layer. It is
possible, but not necessary, for the mask layer to also serve as an
adhesion layer to a dielectric layer that is deposited later.
[0060] In another approach, the liftoff tag is formed but removed
in a step of the process. In one embodiment, ultrasonication is
used after metal liftoff, but before nitride removal. For example,
the ultrasonication step could be performed in water or in a dilute
Au etch or a dilute Ti etch solution. If the nitride membrane alone
is found to break due to the ultrasonication, then the reservoir
could be partially etched with KOH to leave a thick SiN.sub.X/Si
membrane and sonicate after metal deposition and before completion
of the KOH etch. See FIG. 10. Alternatively, the entire reservoir
could be etched in KOH at the end of the process (i.e., after tag
removal). In another embodiment, the device is sonicated to remove
the tags when the reservoirs and nitride membrane are present, with
the reservoir being filled (at least temporarily) with a material
that can provide support to the membrane, as photoresist or another
polymer. See FIG. 11.
[0061] Protective Features
[0062] U.S. Pat. No. 6,123,861 describes the use of a suspended
dielectric membrane upon which a reservoir cap is fabricated, where
the membrane is subsequently removed by etching. U.S. Patent
Application Publication No. 2004/0121486 A1 to Uhland, et al.
describes a method of operating reservoir caps by matrix
addressing, where two conductive layers, comprising rows and
columns, are separated by an intermediate dielectric layer. In some
cases, however, the reservoir cap may not be compatible with the
process used to deposit this dielectric layer. For example, for a
reservoir cap partially or completely comprising a gold-silicon
alloy at the eutectic composition, the melting point of the alloy
is approximately 363.degree. C. Therefore, this reservoir cap would
be incompatible with a dielectric layer of silicon dioxide or
silicon nitride deposited by the method of chemical vapor
deposition around 350.degree. C. or higher. It therefore would be
desirable to fabricate a reservoir cap of such material after the
dielectric layer has been deposited and patterned. In this case,
the intermediate dielectric layer is deposited on the suspended
dielectric membrane before being partially removed in preparation
for the fabrication of the reservoir cap.
[0063] If the suspended membrane is attacked by the etching method
used to pattern the intermediate dielectric layer, however, it can
be difficult to stop the etch precisely on the suspended membrane,
and the integrity of the membrane may be compromised by partial or
complete etching. For example, the suspended dielectric membrane
may be fabricated from silicon-rich silicon nitride deposited by
LPCVD, as described in U.S. Pat. No. 5,797,898, and the
intermediate dielectric layer may be fabricated from silicon
dioxide, as described in U.S. Patent Application Publication No.
2004/0121486, that is deposited by PECVD and etched by reactive ion
etching using CF.sub.4. In this case, the method used to etch the
dielectric layer will also attack the suspended membrane.
[0064] This problem can be avoided by fabricating a protective
feature on the suspended membrane before the dielectric layer is
deposited. This protective feature may comprise a layer or layers
that can serve as an etch stop. For example, a layer comprising 5
nm Ti/300 nm Au/5 nm Ti can be deposited on the suspended membrane
by the method of sputter deposition with liftoff, as described
herein. In this multilayer film, the gold layer serves as an etch
stop and the titanium serves as an adhesion layer. A dielectric
layer can be deposited over this protective feature. When this
dielectric layer is selectively or completely etched, for example
by plasma etching with a fluorine-containing gas such as CF.sub.4,
the gold, which is not chemically etched by CF.sub.4, serves as an
etch stop. This modification protects the suspended dielectric
membrane when a passivating dielectric layer is deposited and
patterned over it. The protective feature can be partially or
completely removed after the passivation layer is etched and before
the reservoir cap is fabricated. The protective feature can also
serve as an electrical connection between the traces and the
reservoir cap.
[0065] Dielectric Layers
[0066] U.S. Pat. No. 5,797,898 describes the use of a dielectric
film as a passivation layer to cover conductive layers on a drug
delivery microchip. In addition, U.S. Patent Application
Publication No. 2004/0121486 A1 to Uhland, et al. describes the use
of a dielectric film to separate two conductive layers on a
substrate of a micro-reservoir device. As with conductive films, it
is desirable to fabricate these dielectric films with sloping
sidewalls to promote good physical and electrical connections
between conductive films.
[0067] One way to achieve sloping sidewalls in a dielectric film is
to use an isotropic wet or dry chemical etch, which ideally
produces sidewalls in the approximate shape of an arc. One example
of this type of etching is the etching of silicon dioxide in
hydrofluoric acid. Another way to achieve sloping sidewalls is to
use an anisotropic etch, as is possible with reactive ion etching,
and to use a organic etch mask that is etched in O.sub.2. This type
of organic etch masks includes standard positive-type and
negative-type photoresists. By including O.sub.2 in the reactive
ion etching feed gases, the organic etch mask will be slightly
eroded during etching. The resulting sidewall in the dielectric
will have a slope that is favorable for later deposition of
materials. An example of this type of etching is the reactive ion
etching of a silicon dioxide film using 15 sccm CF.sub.4, 2 sccm
O.sub.2, and 15 sccm He, at a pressure of 20 mtorr and a plasma
power of 100 W. Variations of this process are contemplated.
[0068] Biostability
[0069] When a multi-reservoir medical device is to be implanted in
the body, e.g., for drug delivery or biosensing, the device
desirably is formed of or coated with a material that protects both
the device in vivo and the patient. In one embodiment, a protective
coating is deposited on the device. In one embodiment, the
protective coating consists of silicon dioxide deposited by CVD.
The silicon dioxide layer electrically insulates conductive layers
(e.g., traces) from the body. In another embodiment, the protective
coating includes an ion barrier, such as silicon nitride. Edell,
IEEE Trans. Biomedical Eng., BME-33(2) (1986) describes a layer of
silicon dioxide deposited by CVD, followed by a layer of silicon
nitride deposited by CVD. The silicon nitride serves as a barrier
to sodium ions in the body, and the silicon dioxide layer insulates
the silicon nitride layer from electrical potential on the device.
The silicon dioxide improves the performance of the passivation
layer because silicon nitride exposed to an electrical potential in
an electrolyte is known to anodize and dissolve. In still another
embodiment, the protective coating comprises a layer of silicon
carbide deposited by CVD. Silicon carbide is harder than either
silicon dioxide or silicon nitride and can therefore be used as a
scratch-resistant coating. Silicon carbide is also more resistant
to harsh chemical environments than either silicon dioxide or
silicon nitride, as described in Flannery, Sensor & Actuators,
A70 (1998). Other suitable coating materials include silicon
oxycarbide (U.S. Pat. No. 5,755,759 to Cogan), titanium oxide,
tantalum oxide (Christensen, et al, J. Micromechanics
Microengineering, 9(2) (1999)), diamond-like carbon (U.S. Pat. No.
6,572,935 to He), and ultrananocrystalline diamond (U.S. Patent
Application Publication No. 2003/0080085 to Greenberg).
[0070] In still further embodiments, the protective coating
comprises or consists of a biocompatible metal layer.
Representative examples include platinum, gold, iridium, titanium,
or alloys thereof. In one embodiment, this metal is deposited on
the part of the substrate that is exposed in vivo, as described in
Hammerle, et al., Biomaterials, 23(3) (2002). If the metal has a
sufficiently high resistivity and the layer is sufficiently thin,
the amount of electrical current passing between reservoir caps
during operation, or electrical cross-talk, is not significant. In
another embodiment, the deposition of this metal layer also forms
the reservoir caps. In yet another embodiment, openings are
patterned in the metal layer around each reservoir to eliminate
cross-talk. In yet another embodiment, a dielectric layer is first
deposited on the microchip, followed by the metal, so that
cross-talk is eliminated. As used herein "cross-talk" refers to and
includes unwanted electrical interference, short-circuits, stray or
induced currents, and the like.
EXEMPLARY EMBODIMENTS
[0071] In one embodiment, the construction of a multi-reservoir
(micro-reservoirs) device begins by fabricating an array of
reservoirs in a silicon substrate leaving a suspended dielectric
membrane. This is described, for example, in U.S. Pat. No.
5,797,898 and No. 6,123,861. Then other layers/features (e.g.,
conductive layers, dielectric layers) are constructed on the
surface of the substrate, preferably using one or more of the
techniques described above.
[0072] In one embodiment, traces with sloped sidewalls are
fabricated by combining sputter deposition with a liftoff process.
The reservoir caps are then fabricated by combining sputter
cleaning and sputter deposition with a liftoff process. A
passivating layer is deposited and patterned to open windows over
the reservoir caps and over bond pads elsewhere on the substrate.
In a preferred embodiment, the traces comprise 12.5 nm Ti/2000 nm
Au/12.5 nm Ti, the reservoir cap comprises 12.5 nm Ti/40 nm Pt/300
nm Ti/40 nm Pt/12.5 nm Ti, and the passivating layer comprises 0.6
.mu.m silicon oxide deposited by PECVD at 350.degree. C. Anodic
bonding is then used to attach a patterned Pyrex wafer, which
serves as an additional substrate portion to increase reservoir
volume.
[0073] One specific example of this process is shown in FIG. 8A,
with steps evenly numbered 30 through 46. The fabrication begins by
depositing 200 nm low-stress nitride by Low Pressure Chemical Vapor
Deposition (LPCVD) on a double side polished silicon wafer (30).
The Nitride is patterned with photoresist and then etched using
Reactive Ion Etching (RIE) techniques (32). The etching gases are
CF.sub.4 and O.sub.2. After stripping the photoresist, the wafers
are then anisotropically etched using 28% Potassium Hydroxide (KOH)
solution. The patterned silicon nitride serves as an etch mask for
the chemical etching of the exposed silicon (34). The metal traces
are then deposited and patterned by liftoff (36). Alternatively,
the metal traces can also be deposited and etched with a liquid
etchant. After a quick O.sub.2 plasma to clean the wafers, the
reservoir cap is then deposited and patterned using lift off (38).
The wafers are then passivated with 0.6 .mu.m thick silicon dioxide
layer (40). The passivation layer is deposited with Plasma Enhanced
Chemical Vapor Deposition (PECVD) using silane and nitrous oxide
gases. The passivation layer is etched with RIE using CHF.sub.3 and
Ar gases (42). The backside nitride is etched from under the
reservoir cap by RIE (44). The silicon wafer is then anodically
bonded to a patterned Pyrex wafer (46). The anodic bonding
temperature and voltage are 340.degree. C. and 1000V, respectively.
FIG. 5B illustrates the final device architecture, with the circled
area in the upper structure shown enlarged to illustrate the
structural details. Variations and modifications are this process
are contemplated, including the use of different materials,
different combinations of materials, different techniques for
building and removing materials from select regions, and different
proportions of the layers and shapes of the reservoir.
[0074] In another embodiment, the reservoir caps are fabricated by
combining sputter deposition with a liftoff process. Traces are
then fabricated by combining sputter cleaning and sputter
deposition with a liftoff process. An intermediate dielectric layer
is deposited and patterned to open windows over selective parts of
the reservoirs caps and traces. In a variation, additional traces
are fabricated in a second conductive layer by combining sputter
cleaning and sputter deposition with a liftoff process. The
sequence of depositing an intermediate dielectric layer and an
additional conductive layer could be continued as desired to create
additional traces.
[0075] In yet another embodiment, protective features are
fabricated by deposition and patterning. Traces are then fabricated
by combining sputter cleaning and sputter deposition with a liftoff
process. A passivating layer is deposited and patterned to open
windows over the protective features and over bond pads elsewhere
on the substrate. The protective layer is removed from over the
suspended membrane by wet chemical etching. The reservoir caps are
fabricated by combining sputter cleaning and sputter deposition
with a liftoff process. Anodic bonding is then used to attach a
patterned glass (e.g., PYREX.TM.) wafer, which serves as an
additional substrate portion.
[0076] One specific example of this process is shown in FIGS. 9A-B,
with steps evenly numbered 52 through 74. The fabrication begins by
depositing 200 nm low stress nitride by LPCVD on a double side
polished silicon wafer (52). The nitride is patterned with
photoresist and then etched using RIE techniques (54). The etching
RIE gases are CF.sub.4 and O.sub.2. After stripping the
photoresist, the wafers are then anisotropically etched using a 28%
potassium hydroxide (KOH) solution. The patterned silicon nitride
serves as an etch mask for the chemical etching of the exposed
silicon (56). Circular openings are used to reduce reservoir size
variation caused by angular misalignment. The diameter is
approximately 775 .mu.m to allow for lateral (111) plane etching.
The link metal layer is then deposited and patterned (58). The
thickness/materials of the link layer is/are 12.5 nm Ti/0.3 .mu.m
Au/12.5 nm Ti. The link layer is used to electrically connect the
traces to the reservoir cap. ID marks next to the bond pads are
created in this step. The link layer is etched with a diluted
HF/KI-based Au etch/diluted HF. A 300 nm dielectric layer is
deposited by PECVD and etched with BHF (60). This dielectric layer
is used as an etch "STOP". The trace metal layer is then deposited
by sputtering. The thickness of the metal stack is 12.5 nm Ti/2.0
.mu.m Au/12.5 nm Ti. The trace metal layer is etched by a series of
sequential etches. For example, three etch steps could be used:
dilute HF/KI-based Au etch/dilute HF (62). The link and ID marks
are protected during etching by the STOP dielectric features. A
passivation layer is then deposited by PECVD. The
thickness/materials of the layer is/are 1.0 .mu.m oxide/1.0 .mu.m
nitride/1.0 .mu.m oxide. The passivation layer is then etched using
RIE and BHF (64). This etching step can be finished using BHF to
avoid etching LPCVD nitride if possible. The suspended nitride is
protected during etching by the link metal feature. The ID marks
next to the wells are created in this step. The link metal layer is
then etched by dilute HF/KI based Au etch/dilute HF (66). The link
feature is removed directly over the reservoir cap, but tabs remain
to electrically connect the reservoir cap at the end of the
process. The reservoir cap is then deposited using lift off (68). A
sputter clean step is done prior to the reservoir cap deposition to
provide a good metal contact. The silicon nitride and titanium is
then removed under the reservoir cap using RIE (70). A conformal
coating layer is deposited to passivate the chip (72). Finally, the
silicon wafer is anodically bonded to a patterned Pyrex wafer (74).
The anodic bonding temperature and voltage is 340.degree. C. and
1000V, respectively.
Additional Device and Component Details
[0077] The Substrate and Reservoirs
[0078] The substrate is the structural body (e.g., part of a
device) in which, or on which, the reservoirs are formed. A
reservoir can be a well, a container, or other space in which
reservoir contents are stored. MEMS methods, micromolding, and
micromachining techniques known in the art can be used to fabricate
the substrate/reservoirs from a variety of materials. See, for
example, U.S. Pat. No. 6,123,861 and U.S. Patent Application
Publication No. 2002/0107470. Examples of suitable substrate
materials include silicon, metals, ceramics, semiconductors, and
degradable and non-degradable polymers. In one embodiment, the
substrate serves as the support or base for a drug delivery or
biosensing microchip.
[0079] The substrate can have a variety of shapes, or shaped
surfaces. The substrate may consist of only one material, or may be
a composite or multi-laminate material, that is, composed of
several layers of the same or different substrate materials that
are bonded together. Preferably, the substrate is hermetic, that is
impermeable (at least during the time of use of the reservoir
device) to the molecules to be delivered and to surrounding gases
or fluids (e.g., water, blood, electrolytes or other
solutions).
[0080] The substrate thickness can vary. For example, the thickness
of a device may vary from approximately 10 .mu.m to several
millimeters (e.g., 500 .mu.m). Total substrate thickness and
reservoir volume can be increased by bonding or attaching wafers or
layers of substrate materials together. The device thickness may
affect the volume of each reservoir and/or may affect the maximum
number of reservoirs that can be incorporated onto a substrate. The
size and number of substrates and reservoirs can be selected to
accommodate the quantity and volume of drug formulation needed for
a particular application, although other constraints such as
manufacturing limitations or total device size limitations (e.g.,
for implantation into a patient) also may come into play. For
example, devices for in vivo applications desirably would be small
enough to be implanted using minimally invasive procedures.
[0081] The substrate includes at least two and preferably tens or
hundreds of reservoirs. For example, one reservoir could be
provided for each daily dose of drug required, for example, over a
3-, 8-, or 12-month course of treatment. The substrate could
include, for example, 300 to 400 reservoirs.
[0082] In one embodiment, the reservoir has a volume equal to or
less than 500 .mu.L (e.g., less than 250 .mu.L, less than 100
.mu.L, less than 50 .mu.L, less than 25 .mu.L, less than 10 .mu.L,
etc.) and greater than about 1 nL (e.g., greater than 5 nL, greater
than 10 nL, greater than about 25 nL, greater than about 50 nL,
greater than about 1 .mu.L, etc.).
[0083] Reservoir Contents
[0084] The reservoir contents are essentially any object or
material that needs to be isolated (e.g., protected from) the
environment outside of the reservoir until a selected point in
time, when its release or exposure is desired. In various
embodiments, the reservoir contents comprise (a quantity of)
molecules, a secondary device, or a combination thereof. Proper
functioning of certain reservoir contents, such as a catalyst or
sensor, generally does not require release from the reservoir;
rather their intended function, e.g., catalysis or sensing, occurs
upon exposure of the reservoir contents to the environment outside
of the reservoir after opening of the reservoir cap. Thus, the
catalyst molecules or sensing component can be released or can
remain immobilized within the open reservoir. Other reservoir
contents such as drug molecules often may need to be released from
the reservoir in order to pass from the device and be delivered to
a site in vivo to exert a therapeutic effect on a patient. However,
the drug molecules may be retained for certain in vitro
applications.
[0085] Molecules
[0086] The reservoir contents can include essentially any natural
or synthetic, organic or inorganic molecule or mixture thereof. The
molecules may be in essentially any form, such as a pure solid or
liquid, a gel or hydrogel, a solution, an emulsion, a slurry, or a
suspension. The molecules of interest may be mixed with other
materials to control or enhance the rate and/or time of release
from an opened reservoir. In various embodiments, the molecules may
be in the form of solid mixtures, including amorphous and
crystalline mixed powders, monolithic solid mixtures, lyophilized
powders, and solid interpenetrating networks. In other embodiments,
the molecules are in liquid-comprising forms, such as solutions,
emulsions, colloidal suspensions, slurries, or gel mixtures such as
hydrogels.
[0087] For in vivo applications, the chemical molecule can be a
therapeutic, prophylactic, or diagnostic agent. As used herein, the
term "drug" includes any therapeutic or prophylactic agent (e.g.,
an active ingredient). The drug can comprise small molecules, large
(i.e., macro-) molecules, or a combination thereof, having a
bioactive effect. In one embodiment, the large molecule drug is a
protein or a peptide. In various other embodiments, the drug can be
selected from amino acids, vaccines, antiviral agents, gene
delivery vectors, interleukin inhibitors, immunomodulators,
neurotropic factors, neuroprotective agents, antineoplastic agents,
chemotherapeutic agents, polysaccharides, anti-coagulants (e.g.,
LMWH, pentasaccharides), antibiotics (e.g., immunuosuppressants),
analgesic agents, and vitamins. In one embodiment, the drug is a
protein. Examples of suitable types of proteins include,
glycoproteins, enzymes (e.g., proteolyic enzymes), hormones or
other analogs (e.g., LHRH, steroids, corticosteroids, growth
factors), antibodies (e.g., anti-VEGF antibodies, tumor necrosis
factor inhibitors), cytokines (e.g., .alpha.-, .beta.-, or
.gamma.-interferons), interleukins (e.g., IL-2, IL-10), and
diabetes/obesity-related therapeutics (e.g., insulin, exenatide,
PYY, GLP-1 and its analogs). In one embodiment, the drug is a
gonadotropin-releasing (LHRH) hormone analog, such as leuprolide.
In another exemplary embodiment, the drug comprises parathyroid
hormone, such as a human parathyroid hormone or its analogs, e.g.,
hPTH(1-84) or hPTH(1-34). In a further embodiment, the drug is
selected from nucleosides, nucleotides, and analogs and conjugates
thereof. In yet another embodiment, the drug comprises a peptide
with natriuretic activity, such as atrial natriuretic peptide
(ANP), B-type (or brain) natriuretic peptide (BNP), C-type
natriuretic peptide (CNP), or dendroaspis natriuretic peptide
(DNP). In still another embodiment, the drug is selected from
diuretics, vasodilators, inotropic agents, anti-arrhythmic agents,
Ca.sup.+ channel blocking agents, anti-adrenergics/sympatholytics,
and renin angiotensin system antagonists. In one embodiment, the
drug is a VEGF inhibitor, VEGF antibody, VEGF antibody fragment, or
another anti-angiogenic agent. Examples include an aptamer, such as
MACUGEN.TM. (Pfizer/Eyetech) (pegaptanib sodium)) or LUCENTIS.TM.
(Genetech/Novartis) (rhuFab VEGF, or ranibizumab), which could be
used in the prevention of choroidal neovascularization. In yet a
further embodiment, the drug is a prostaglandin, a prostacyclin, or
another drug effective in the treatment of peripheral vascular
disease. In various other embodiments, the drug is selected from
tumor necrosis factors (TNF), TNF antagonists (e.g., ENBREL.TM.),
angiogenic agents (e.g., VEGF), and anti-inflammatory agents (e.g.,
dexamethasone).
[0088] In one embodiment, a device is used to deliver a drug
systemically to a patient in need thereof. In another embodiment,
the construction and placement of the microchip in a patient
enables the local or regional release of drugs that may be too
potent for systemic delivery of an effective dose. The reservoir
contents in one reservoir or in one device can include a single
drug or a combination of two or more drugs, and the reservoir
contents can further include pharmaceutically acceptable
carriers.
[0089] The molecules can be provided as part of a "release system,"
as taught in U.S. Pat. No. 5,797,898, the degradation, dissolution,
or diffusion properties of which can provide a method for
controlling the release rate of the molecules. The release system
may include one or more pharmaceutical excipients. Suitable
pharmaceutically acceptable excipients include most carriers
approved for parenteral administration, including various aqueous
solutions (e.g., saline, Ringer's, Hank's, and solutions of
glucose, lactose, dextrose, ethanol, glycerol, albumin, and the
like). Examples of other excipients and diluents include calcium
carbonate and sugars. Other excipients may be used to maintain the
drug in suspensions as an aid to reservoir filling, stability, or
release. Depending on the properties of the drug, such excipients
may be aqueous or non-aqueous, hydrophobic or hydrophilic, polar or
non-polar, protic or aprotic. Such excipients generally have low
reactivity. See e.g., U.S. Pat. No. 6,264,990 to Knepp et al. The
release system optionally includes stabilizers, antioxidants,
antimicrobials, preservatives, buffering agents, surfactants, and
other additives useful for storing and releasing molecules from the
reservoirs in vivo.
[0090] The release system may provide a more continuous or
consistent release profile (e.g., pulsatile) or constant plasma
level as needed to enhance a therapeutic effect, for example.
Pulsatile release can be achieved from an individual reservoir,
from a plurality of reservoirs, or a combination thereof. For
example, where each reservoir provides only a single pulse,
multiple pulses (i.e. pulsatile release) are achieved by temporally
staggering the single pulse release from each of several
reservoirs. Alternatively, multiple pulses can be achieved from a
single reservoir by incorporating several layers of a release
system and other materials into a single reservoir. Continuous
release can be achieved by incorporating a release system that
degrades, dissolves, or allows diffusion of molecules through it
over an extended period. In addition, continuous release can be
approximated by releasing several pulses of molecules in rapid
succession ("digital" release, analogous to the digital storage and
reproduction of music). The active release systems described herein
can be used alone or on combination with passive release systems
known in the art, for example, as described in U.S. Pat. No.
5,797,898. For example, the reservoir cap can be removed by
electrothermal ablation as described herein to expose a passive
release system that only begins its passive release after the
reservoir cap has been actively removed. Alternatively, a given
substrate can include both passive and active release
reservoirs.
[0091] For in vitro applications, the molecules can be any of a
wide range of molecules where the controlled release of a small
(milligram to nanogram) amount of one or more molecules is
required, for example, in the fields of analytic chemistry or
medical diagnostics. Molecules can be effective as pH buffering
agents, diagnostic reagents, and reagents in complex reactions such
as the polymerase chain reaction or other nucleic acid
amplification procedures. In various other embodiments, the
molecules to be released are fragrances or scents, dyes or other
coloring agents, sweeteners or other concentrated flavoring agents,
or a variety of other compounds. In yet other embodiments, the
reservoirs contain immobilized molecules. Examples include any
chemical species which can be involved in a reaction, including
reagents, catalysts (e.g., enzymes, metals, and zeolites),
proteins, nucleic acids, polysaccharides, cells, and polymers, as
well as organic or inorganic molecules which can function as a
diagnostic agent.
[0092] Secondary Devices
[0093] As used herein, unless explicitly indicated otherwise, the
term "secondary device" includes any device or a component thereof
which can be located in a reservoir. In one embodiment, the
secondary device is a sensor or sensing component thereof. As used
herein, a "sensing component" includes a component utilized in
measuring or analyzing the presence, absence, or change in a
chemical or ionic species, energy, or one or more physical
properties (e.g., pH, pressure) at a site. Types of sensors include
biosensors, chemical sensors, physical sensors, or optical sensors.
Examples of biosensors that could be adapted for use in/with the
reservoir devices described herein include those taught in U.S.
Pat. No. 6,486,588; U.S. Pat. No. 6,475,170; and U.S. Pat. No.
6,237,398. Secondary devices are further described in U.S. Pat. No.
6,551,838.
[0094] Examples of sensing components include components utilized
in measuring or analyzing the presence, absence, or change in a
drug, chemical, or ionic species, energy (or light), or one or more
physical properties (e.g., pH, pressure) at a site. In one
embodiment, a device is provided for implantation in a patient
(e.g., a human or other mammal) and the reservoir contents
comprises at least one sensor indicative of a physiological
condition in the patient. For example, the sensor could monitor the
concentration of glucose, urea, calcium, or a hormone present in
the blood, plasma, interstitial fluid, or other bodily fluid of the
patient.
[0095] In one embodiment, the device includes one or more MEMS
gyroscopes, attached to or integrated into the device, e.g., on or
in a substrate portion. For example, the gyro could be employed in
a sensor application, e.g., telematics or biomechanics.
[0096] Several options exist for receiving and analyzing data
obtained with secondary devices located within the primary device,
which can be a microchip device or another device. Devices may be
controlled by local microprocessors or remote control. Biosensor
information may provide input to the controller to determine the
time and type of activation automatically, with human intervention,
or a combination thereof. For example, the operation of an
implantable drug delivery system (or other controlled
release/controlled reservoir exposure system) can be controlled by
an on-board microprocessor (i.e., within the package of the
implantable device). The output signal from the device, after
conditioning by suitable circuitry if needed, will be acquired by
the microprocessor. After analysis and processing, the output
signal can be stored in a writeable computer memory chip, and/or
can be sent (e.g., wirelessly) to a remote location away from the
implantable device. Power can be supplied to the implantable device
locally by a battery or remotely by wireless transmission. See,
e.g., U.S. Patent Application Publication No. 2002/0072784.
[0097] In one embodiment, a device is provided having reservoir
contents that include drug molecules for release and a
sensor/sensing component. For example, the sensor or sensing
component can be located in a reservoir or can be attached to the
device substrate. The sensor can operably communicate with the
device, e.g., through a microprocessor, to control or modify the
drug release variables, including dosage amount and frequency, time
of release, effective rate of release, selection of drug or drug
combination, and the like. The sensor or sensing component detects
(or not) the species or property at the site of in vivo
implantation and further may relay a signal to the microprocessor
used for controlling release from the device. Such a signal could
provide feedback on and/or finely control the release of a drug. In
another embodiment, the device includes one or more biosensors
(which may be sealed in reservoirs until needed for use) that are
capable of detecting and/or measuring signals within the body of a
patient.
[0098] As used herein, the term "biosensor" includes sensing
devices that transduce the chemical potential of an analyte of
interest into an electrical signal, as well as electrodes that
measure electrical signals directly or indirectly (e.g., by
converting a mechanical or thermal energy into an electrical
signal). For example, the biosensor may measure intrinsic
electrical signals (EKG, EEG, or other neural signals), pressure,
temperature, pH, or loads on tissue structures at various in vivo
locations. The electrical signal from the biosensor can then be
measured, for example by a microprocessor/controller, which then
can transmit the information to a remote controller, another local
controller, or both. For example, the system can be used to relay
or record information on the patient's vital signs or the implant
environment, such as drug concentration.
[0099] Reservoir Caps
[0100] As used herein, the term "reservoir cap" includes a membrane
or other structure suitable for separating the contents of a
reservoir from the environment outside of the reservoir. It
generally is self-supporting across the reservoir opening, although
caps having additional structures to provide mechanical support to
the cap can be fabricated. Selectively removing the reservoir cap
or making it permeable will then "expose" the contents of the
reservoir to the environment (or selected components thereof
surrounding the reservoir. In preferred embodiments, the reservoir
cap is selectively disintegrated. As used herein, the term
"disintegrate" is used broadly to include without limitation
degrading, dissolving, rupturing, fracturing or some other form of
mechanical failure, as well as a loss of structural integrity due
to a chemical reaction (e.g., electrochemical degradation) or phase
change (e.g., melting) in response to a change in temperature,
unless a specific one of these mechanisms is indicated. In one
specific embodiment, the "disintegration" is by an electrochemical
activation technique, such as described in U.S. Pat. No. 5,797,898.
In another specific embodiment, the "disintegration" is by an
electro-thermal ablation technique, such as described in U.S.
Patent Application Publication No. 2004/0121486 A1 to Uhland, et
al. In the latter technique, the reservoir cap is formed of a
conductive material, such as a metal film, through which an
electrical current can be passed to electrothermally ablate it, as
described in U.S. Patent Application Publication No. 2004/0121486
A1 to Uhland, et al. Representative examples of suitable reservoir
cap materials include gold, copper, aluminum, silver, platinum,
titanium, palladium, various alloys (e.g., Au/Si, Au/Ge, Pt--Ir,
Ni--Ti, Pt--Si, SS 304, SS 316), and silicon doped with an impurity
to increase electrical conductivity, as known in the art. In one
embodiment, the reservoir cap is in the form of a thin metal film.
In one embodiment, the reservoir cap is part of a multiple layer
structure, for example, the reservoir cap can be made of multiple
metal layers, such as a multi-layer/laminate structure of
platinum/titanium/platinum. The reservoir cap is operably (i.e.,
electrically) connected to an electrical input lead and to an
electrical output lead, to facilitate flow of an electrical current
through the reservoir cap. When an effective amount of an
electrical current is applied through the leads and reservoir cap,
the temperature of the reservoir cap is locally increased due to
resistive heating, and the heat generated within the reservoir cap
increases the temperature sufficiently to cause the reservoir cap
to be electrothermally ablated (i.e., ruptured/disintegrated).
[0101] In another embodiment, multiple reservoir caps may be
located over an individual reservoir and supported by a grid
structure, as described in U.S. Patent Application No. 60/606,387,
which is incorporated herein by reference. Such multiple caps allow
a larger area of the reservoir to be exposed than may be feasible
using a single large cap. For example, opening a large cap may
require more power or generation of more heat that could damage
tissue or sensors compared to opening several smaller caps. Smaller
caps may be opened simultaneously or sequentially.
[0102] Means for Controlling Reservoir Opening
[0103] The multi-reservoir device includes a control means to
control the time at which the reservoir cap is disintegrated to
release or expose the reservoir contents (e.g., to initiate drug
release from the device and into the patient's body, or to permit
sensor exposure in vivo).
[0104] In one embodiment, the means for controllably releasing the
drug provides selective actuation of each reservoir, which is done
under the control of a microprocessor. Preferably, such means
includes an input source, a microprocessor, a timer, a
demultiplexer (or multiplexer), and a power source. As used herein,
the term "demultiplexer" also refers to multiplexers. The power
source provides energy to activate the selected reservoir, i.e.,
trigger release of drug from the particular reservoir desired for a
given dose. The microprocessor can be programmed to initiate the
disintegration or permeabilization of the reservoir cap in response
at a pre-selected time or in response to one or more of signals or
measured parameters, including receipt of a signal from another
device (for example by remote control or wireless methods) or
detection of a particular condition using a sensor such as a
biosensor.
[0105] The medical device can also be activated or powered using
wireless means, for example, as described in U.S. 2002/0072784 A1
to Sheppard et al.
[0106] In one embodiment, the medical device includes a substrate
having a two-dimensional array of reservoirs arranged therein, a
release system comprising drug contained in the reservoirs, anode
reservoir caps covering each of the reservoirs, cathodes positioned
on the substrate near the anodes, and means for actively
controlling disintegration of the reservoir caps. The energy drives
a reaction between selected anodes and cathodes. Upon application
of a small potential between the electrodes, electrons pass from
the anode to the cathode through the external circuit causing the
anode material (reservoir cap) to oxidize and dissolve into the
surrounding fluids, exposing the release system containing the drug
for delivery to the surrounding fluids, e.g., in vivo. For example,
the microprocessor can direct power to specific electrode pairs
through a demultiplexer as directed by an EPROM, remote control, or
biosensor.
[0107] In another embodiment, the activation energy initiates a
thermally driven rupturing or permeabilization process, for
example, as described in U.S. Pat. No. 6,527,762. For example, the
means for controlling release can actively disintegrate or
permeabilize a reservoir cap using a resistive heater. The
resistive heater can cause the reservoir cap to undergo a phase
change or fracture, for example, as a result of thermal expansion
of the reservoir cap or release system, thereby rupturing the
reservoir cap and releasing the drug from the selected reservoir.
The application of electric current to the resistive heater can be
delivered and controlled using components as described above for
use in the electrochemical disintegration embodiment. For example,
a microprocessor can direct current to select reservoirs at desired
intervals.
[0108] In yet another embodiment, control means controls
electro-thermal ablation of the reservoir cap. For example, the
drug delivery device could include a reservoir cap formed of an
electrically conductive material, which prevents the reservoir
contents from passing out from the device; an electrical input lead
connected to the reservoir cap; an electrical output lead connected
to the reservoir cap; and a control means to deliver an effective
amount of electrical current through the reservoir cap, via the
input lead and output lead, to heat and rupture the reservoir cap
to release the drug. In one embodiment, the reservoir cap and
conductive leads are formed of the same material, where the
temperature of the reservoir cap increases locally under applied
current because the reservoir cap is suspended in a medium that is
less thermally conductive than the substrate. Alternatively, the
reservoir cap and conductive leads are formed of the same material,
and the reservoir cap has a smaller cross-sectional area in the
direction of electric current flow, where the increase in current
density through the reservoir cap causes an increase in localized
heating. The reservoir cap alternatively can be formed of a
material that is different from the material forming the leads,
wherein the material forming the reservoir cap has a different
electrical resistivity, thermal diffusivity, thermal conductivity,
and/or a lower melting temperature than the material forming the
leads. Various combinations of these embodiments can be employed as
described in U.S. Patent Application Publication No. 2004/0121486
A1 to Uhland, et al.
[0109] In one embodiment, the drug delivery device utilizes an
accelerated release mechanism. In one embodiment, a positive
displacement feature can be included to facilitate release of the
drug from the reservoirs. For example, the device may include an
osmotic engine or water-swellable component, which can be used to
drive a drug formulation from the reservoirs. For example, such a
feature can provide very fast release of drug the efficacy of which
is dependent on a fast pharmacokinetic pulsatile profile. As used
herein, the term "accelerated release" refers to an increase in the
transport rate of drug out of the reservoir relative to the
transport rate of the drug solely by diffusion down its own
chemical gradient. The terms also refer to expelling reservoir
contents that would not otherwise egress from an open reservoir,
i.e., where no or negligible diffusion could occur.
Operation and Use of the Devices
[0110] The devices made by the methods described herein can be used
in a wide variety of applications. Preferred applications include
the controlled delivery of a drug, biosensing, or a combination
thereof. Embodiments for some of these applications are described
below.
[0111] In one embodiment, a microchip device is provided for
implantation into a patient, such as a human or other vertebrate
animal, for controlled drug delivery. In one embodiment, the
microchip device can be implanted in vivo using standard surgical
or minimally-invasive implantation techniques. Such microchip
devices are especially useful for drug therapies in which one needs
to very precisely control the exact amount, rate, and/or time of
delivery of the drug. Exemplary drug delivery applications include
the delivery of potent molecules, including, hormones (e.g., PTH),
steroids, cytokines, chemotherapeutics, vaccines, gene delivery
vectors, anti-VEGF aptamers, and certain analgesic agents.
[0112] In other embodiments, the device described herein is
incorporated into a variety of other types and designs of
implantable medical devices, such as the cardiac sensing and
neurostimulation. In another example, it could be incorporated into
another medical device, in which the present devices and systems
release drug into a carrier fluid that then flows to a desired site
of administration, as illustrated for example in U.S. Pat. No.
6,491,666.
[0113] The devices also have numerous in vivo, in vitro, and
commercial diagnostic applications. The devices are capable of
delivering precisely metered quantities of molecules and thus are
useful for in vitro applications, such as analytical chemistry,
drug discovery, and medical diagnostics, as well as biological
applications such as the delivery of factors to cell cultures. In
still other non-medical applications, the devices are used to
control release of fragrances, dyes, or other useful chemicals.
Other methods of using the devices for controlled release of
molecules, as well as for controlled exposure or release of
secondary devices, are described in U.S. Pat. No. 5,797,898; U.S.
Pat. No. 6,123,861; U.S. Pat. No. 6,527,762; U.S. Pat. No.
6,491,666; U.S. Pat. No. 6,551,838 and U.S. Patent Application
Publications No. 2002/0072784; No. 2002/0107470; No. 2002/0151776;
No. 2002/0099359; and No. 2003/0010808.
[0114] Patents and publications cited herein and the materials for
which they are cited are specifically incorporated by reference.
Modifications and variations of the methods and devices described
herein will be obvious to those skilled in the art from the
foregoing detailed description. Such modifications and variations
are intended to come within the scope of the appended claims.
* * * * *
References