U.S. patent application number 10/937616 was filed with the patent office on 2005-06-30 for device for controlled reservoir opening with reinforced reservoir caps.
Invention is credited to Cima, Michael J., Herman, Stephen J., Santini, John T. JR..
Application Number | 20050143715 10/937616 |
Document ID | / |
Family ID | 23135061 |
Filed Date | 2005-06-30 |
United States Patent
Application |
20050143715 |
Kind Code |
A1 |
Cima, Michael J. ; et
al. |
June 30, 2005 |
Device for controlled reservoir opening with reinforced reservoir
caps
Abstract
Device are provided for the controlled release or exposure of
molecules or secondary devices comprising a substrate; a plurality
of reservoirs located in the substrate; reservoir contents
comprising molecules, a secondary device, or both, isolated inside
the reservoirs; reservoir caps positioned on the reservoirs over
the reservoir contents, wherein the reservoir caps (which can
comprise a metal film) are mechanically reinforced with a second
material deposited and patterned on the surface of the metal film
inside the reservoir or on the surface of the metal film outside
the reservoir or on both of said surfaces; and control circuitry
and a power source for disintegrating the reservoir caps to
initiate exposure or release of the reservoir contents in selected
reservoirs.
Inventors: |
Cima, Michael J.;
(Winchester, MA) ; Santini, John T. JR.; (North
Chelmsford, MA) ; Herman, Stephen J.; (Andover,
MA) |
Correspondence
Address: |
SUTHERLAND ASBILL & BRENNAN LLP
999 PEACHTREE STREET, N.E.
ATLANTA
GA
30309
US
|
Family ID: |
23135061 |
Appl. No.: |
10/937616 |
Filed: |
September 9, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10937616 |
Sep 9, 2004 |
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10159550 |
May 31, 2002 |
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6875208 |
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60294818 |
May 31, 2001 |
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Current U.S.
Class: |
604/890.1 ;
137/554; 604/66 |
Current CPC
Class: |
A61K 9/0009 20130101;
Y10T 137/8242 20150401; A61K 9/0097 20130101 |
Class at
Publication: |
604/890.1 ;
604/066; 137/554 |
International
Class: |
A61M 031/00 |
Claims
We claim:
1. A device for the controlled release or exposure of molecules or
secondary devices comprising: a substrate; a plurality of
reservoirs located in the substrate; reservoir contents isolated
inside the reservoirs, wherein the reservoir contents are selected
from the group consisting of molecules, secondary devices, and
combinations thereof; reservoir caps positioned on the reservoirs
over the reservoir contents, wherein the reservoir caps are
mechanically reinforced with a second material deposited and
patterned on the surface of the reservoir caps inside the
reservoir, on the surface of the reservoir caps outside the
reservoir, or on both of said surfaces; and control circuitry and a
power source for disintegrating the reservoir caps to initiate
exposure or release of the reservoir contents in selected
reservoirs.
2. The device of claim 1, wherein the reservoir cap comprises a
metal film.
3. The device of claim 1, wherein the second material is
electrically conductive and patterned onto the surface of the
reservoir cap outside the reservoir.
4. The device of claim 1, wherein the second material is
electrically nonconductive and patterned onto the surface of the
reservoir cap outside the reservoir.
5. The device of claim 1, wherein the second material is
electrically conductive and patterned onto the surface of the
reservoir cap inside the reservoir.
6. The device of claim 1, wherein the second material is
electrically nonconductive and patterned onto the surface of the
reservoir cap inside the reservoir.
7. The device of claim 1, wherein the second material comprises
oxides or nitrides of silicon, titanium, or chromium.
8. The device of claim 1, wherein the second material comprises
carbides, diamond-like materials, photopolymers, or
fluoropolymers.
9. The device of claim 1, wherein the reservoir contents comprise a
therapeutic or prophylactic agent.
10. The device of claim 1, wherein the reservoir contents comprise
molecules selected from the group consisting of enzymes, zeolites,
proteins, nucleic acids, polysaccharides, polymers, and cells.
11. The device of claim 1, wherein the reservoir contents comprises
a sensor or sensing component.
12. The device of claim 1, wherein the reservoir contents comprises
a biosensor.
13. The device of claim 1, wherein the reservoir contents comprises
a glucose sensor.
14. The device of claim 1, further comprising a microprocessor.
15. The device of claim 14, further comprising a source of memory,
a timer, a demultiplexer.
16. The device of claim 1, which is packaged in a biocompatible
material.
17. The device of claim 16, wherein the biocompatible material is
selected from the group consisting of poly(ethylene glycol)s,
polytetrafluoroethylenes, and titanium.
18. A device for the controlled release or exposure of molecules or
secondary devices comprising: a substrate; a plurality of
reservoirs located in the substrate; reservoir contents isolated
inside the reservoirs, wherein the reservoir contents are selected
from the group consisting of drug molecules, sensors, and
combinations thereof; reservoir caps positioned on the reservoirs
over the reservoir contents, the reservoir caps comprising a metal
film mechanically reinforced with a second material deposited and
patterned on the surface of the metal film inside the reservoir, on
the surface of the metal film outside the reservoir, or on both of
said surfaces; and control circuitry and a power source for
disintegrating the reservoir caps to initiate exposure or release
of the reservoir contents in selected reservoirs.
19. A method of releasing or exposing reservoir contents in vivo
comprising the steps of: implanting the device of claim 1 into a
patient; and disintegrating the reservoir cap of at least one
reservoir to open the selected reservoir and release or expose the
reservoir contents therein.
20. The method of claim 19, wherein disintegration of the reservoir
cap is controlled by a preprogrammed microprocessor, by remote
control, by a signal from a biosensor, or by a combination
thereof.
21. A method of releasing or exposing reservoir contents in vivo
comprising the steps of: implanting the device of claim 18 into a
patient; and disintegrating the reservoir cap of at least one
reservoir to open the selected reservoir and release or expose the
reservoir contents therein.
22. The method of claim 21, wherein disintegration of the reservoir
cap is controlled by a preprogrammed microprocessor, by remote
control, by a signal from a biosensor, or by a combination thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of U.S. application Ser. No.
10/159,550, filed May 31, 2002, now U.S. Pat. No. ______. U.S.
application Ser. No. 10/159,550 claims benefit of U.S. Provisional
Application No. 60/294,818, filed May 31, 2001. All of these
applications are incorporated herein by reference in their
entirety.
BACKGROUND OF THE INVENTION
[0002] This invention relates to miniaturized devices for the
controlled exposure or release of molecules such as drugs and/or
secondary devices such as sensors.
[0003] U.S. Pat. No. 5,797,898 to Santini Jr., et al. discloses
microchip delivery devices which have a plurality, typically
hundreds to thousands, of tiny reservoirs in which each reservoir
has a reservoir cap positioned on the reservoir over the molecules,
so that the chemical molecules (e.g., drugs) are released from the
device by diffusion through or upon disintegration of the reservoir
caps. The reservoirs may have caps made of a material that degrades
at a known rate or that has a known permeability (passive release),
or the caps may include a conductive material capable of dissolving
or becoming permeable upon application of an electrical potential
(active release).
[0004] In the active release devices, the reservoir cap can be a
thin metal film. Application of an electric potential causes the
metal film to oxidize and disintegrate, exposing the contents of
the reservoir to the environment at the site of the microchip
device. It would be advantageous to enhance this oxidation and
disintegration across the surface of the metal film, in order to
achieve consistent and reliable exposure of the molecules and
secondary devices contained in the reservoirs. It would be
particularly desirable, for example, to provide microchip devices
that provide highly reliable and precise exposure of drug molecules
located in reservoirs in the microchip delivery devices to the
environment in which the microchip device is implanted. More
generally, it would be desirable to provide devices and methods to
enhance the opening of reservoir caps in microchip devices for the
controlled exposure or release of reservoir contents.
SUMMARY OF THE INVENTION
[0005] Microchip devices and methods of manufacture thereof are
provided to increase the uniformity and reliability of active
exposure and release of microchip reservoir contents. In one
embodiment, the microchip device for the controlled release or
exposure of molecules or secondary devices comprises: (1) a
substrate having a plurality of reservoirs; (2) reservoir contents
comprising molecules, a secondary device, or both, located in the
reservoirs; (3) reservoir caps positioned on the reservoirs over
the reservoir contents; (4) electrical activation means for
disintegrating the reservoir cap to initiate exposure or release of
the reservoir contents in selected reservoirs; and (5) a current
distribution means, a stress induction means, or both, operably
engaged with or integrated into the reservoir cap, to enhance
reservoir cap disintegration.
[0006] The device can further include a cathode, wherein the
reservoir caps each comprise a thin metal film which is an anode,
the electrical activation means comprises a means for applying an
electric potential between the cathode and the anode effective to
cause the reservoir cap disintegration to occur electrochemically.
The device can, alternatively or in addition, further include at
least one resistor operably adjacent the reservoir caps, wherein
the electrical activation means comprises a means for applying an
electric current through the resistor effective to cause the
reservoir cap disintegration to occur thermally.
[0007] In one embodiment, the current distribution means can
comprise a current distribution network mounted on or integrated
into the reservoir cap. In another embodiment, the current
distribution means can include an electrochemically plated metal
layer on the outer surface of the reservoir cap, wherein the metal
layer has increased surface roughness relative to the outer surface
of the reservoir cap. The stress induction means can comprise a
pre-stressed structure attached to or integrated into the reservoir
cap, the pre-stressed structure providing a force substantially
perpendicular to the surface of the reservoir cap. In one
embodiment, the pre-stressed structure comprises a bilayer
cantilever beam. In other embodiments, the pre-stressed structure
has a spring, coil, or cross structure.
[0008] Methods of fabricating and using these devices are also
provided.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1a is perspective diagram of one embodiment of a
microchip chemical delivery device, in partial cross-section
showing chemical filled reservoirs and membrane reservoir caps, and
FIG. 1b shows the shape of the reservoir.
[0010] FIG. 2 is a graph showing cyclic voltammetry data for gold
in 0.145 M NaCl solution (pH=5.5-6.0), wherein the current peak at
1.0-1.2 volts is associated with the active dissolution of
gold.
[0011] FIG. 3 is a perspective diagram of one embodiment of a
reservoir covered by a membrane having a current distribution
network.
[0012] FIG. 4 is a plan view of twelve possible designs of springs
to fabricate onto the reservoir caps of microchip devices, wherein
the springs serve as stress-inducing structures to facilitate
disintegration/rupture of the reservoir caps.
[0013] FIG. 5 is a cross-sectional view of one embodiment of a
microchip device having a spring stress inducing structure.
DETAILED DESCRIPTION OF THE INVENTION
[0014] It has been discovered that reservoir cap opening in
microchip devices can be enhanced by a number of means. Generally
speaking, these means include a current distribution means, a
stress induction means, or both, operably engaged with or
integrated into the reservoir cap, to enhance reservoir cap
disintegration.
[0015] I. Non-Uniformity of Thin Film Dissolution/Corrosion
[0016] Experiments have shown that the electrochemical dissolution
rate of some metal membranes may not be uniform or complete across
the surface of the membrane. Scanning electron micrographs taken of
a partially dissolved gold membrane show the corners and edges of
the membrane can corrode more than the interior surface, leaving
for example a "flap" of gold still attached to one edge of the
electrode. Such a flap may fold over and expose the reservoir
opening or may remain in place and partially occlude the reservoir.
Other membranes may corrode or dissolve to a certain thickness and
then stop before the membrane is structurally weak enough to fall
apart or disintegrate. This "residual" membrane may have enough
strength to remain intact, thereby hindering or preventing the
opening of the reservoir and the release of molecules or exposure
of devices contained therein.
[0017] It is hypothesized that non-uniform or incomplete corrosion
of thin metal membranes, such as those serving as reservoir caps,
is due to one or a combination of five causes. The first cause is
the presence of a non-uniform potential distribution across the
surface of the membrane. The potential near the edge is fixed by
the material (e.g., glass, silicon) covering the trace (e.g., gold)
that supplies electric current to the membrane. However, the
electrical resistivity of the membrane rises as it thins during the
corrosion process, thus causing the electrical potential to vary
across the exposed portion of the membrane, with the lowest
potential occurring near the center of the membrane. The potential
may become sufficiently low so that the gold corrosion reaction is
no longer possible. For example, the potential vs. current diagram
shown in FIG. 2 for a gold membrane in a dilute saline solution
shows the current peak around 1.0-1.2 volts, which indicates gold
corrosion is occurring. The diagram shows that a small decrease in
electric potential will cause the corrosion reaction to
dramatically decrease or even stop, as indicated by a sharp drop in
current. This phenomenon is similar to non-uniform deposition
during metal plating processes where the potential drop along metal
traces influences the local deposition rate of metal.
[0018] The second suspected cause of variation in the rate and
degree of metal membrane corrosion is the possible presence of
local variations in the composition of the electrolyte at the
surface of the metal film. The corrosion process can cause local
variations in the composition, pH, and/or temperature of the
electrolyte when transport of reactants to the metal surface and/or
transport of products away from the metal surface are limited. Such
variations in the electrolyte may then result in local surface
corrosion rates that differ significantly from corrosion rates of
the metal exposed to the bulk electrolyte. Such variations in the
electrolyte often occur in or near physical defects such as pits,
cracks, crevices, or hillocks, or fabricated structures such as
trenches, holes, the interface between two layers of material, or
any other location where mass transport may be hindered.
[0019] The third possible cause of variation in the rate and degree
of uniformity of corrosion of thin metal membranes in microchips is
related to their structural morphology, in particular grain size
within the metal. For example, gold thin films have been shown to
corrode preferentially in grain boundaries with an applied
potential in dilute saline solutions (Santini, "A Controlled
Release Microchip", Ph.D. Thesis, Massachusetts Institute of
Technology, 1999). Increased rates of corrosion in metal grain
boundaries can cause portions of the metal film to be isolated from
the source of electric potential, resulting in the local stoppage
of corrosion. This is a particularly common problem for metal films
whose thickness is only one grain thick, because corrosion through
the thickness of the membrane or thin film can occur faster than
the bulk of the membrane corrodes, which can hinder the passage of
current through the membrane and stop the corrosion of the membrane
prematurely, thereby potentially leaving portions of the metal
membrane un-corroded and intact to hinder chemical release from the
reservoirs of the microchip.
[0020] The fourth cause is changing internal stress in the metal
membrane. Internal mechanical stress in the metal film can
influence the corrosion rate. As the film is disintegrated, the
force of this stress increases inversely with the decreasing
thickness of the film, thereby creating micro-fractures, which
expose more surface area to be disintegrated. In addition, stresses
at the corners or along the edges of the membrane may be much
higher than other regions of the membrane, leading to non-uniform,
stress dependent variations in corrosion of the membrane.
[0021] The fifth cause of variation is related to the fabrication
of thin metal film electrodes. The electron beam and sputtering
processes used to deposit thin metal films result in surfaces that
are relatively smooth on the atomic scale. This yields inefficient
charge transfer and low currents for the geometric areas occupied
by the film. In addition, the microfabrication processes used to
make the microchip devices may introduce contaminants that adhere
strongly to the metal electrode surfaces. Contaminants and the
smooth surface of the electrodes can create non-uniform corrosion
of the membrane electrodes. Specifically, when an anodic potential
sufficient to corrode the metal is applied to the membrane, only a
small amount of corrosion occurs until the surface roughens.
Instabilities are created when localized regions (for example, the
corners of the membrane) roughen before the remainder of the film.
These regions have a much higher charge transfer rate and corrode
faster. The entire process leads to non-uniform corrosion of the
membrane. Removal of these contaminants and roughening of the metal
surface will generally result in better electrochemical activity
and corrosion.
[0022] II. Methods and Devices for Enhanced Reservoir Cap
Disintegration
[0023] In a preferred embodiment, the microchip device for the
controlled release or exposure of molecules or secondary devices
comprise: (1) a substrate having a plurality of reservoirs; (2)
reservoir contents comprising molecules, a secondary device, or
both, located in the reservoirs; (3) reservoir caps positioned on
the reservoirs over the reservoir contents; (4) electrical
activation means for disintegrating the reservoir cap to initiate
exposure or release of the reservoir contents in selected
reservoirs; and a current distribution means, a stress induction
means, or both, operably engaged with or integrated into the
reservoir cap, to enhance reservoir cap disintegration.
[0024] As used herein, the terms "electrical activation" in
reference to means for disintegrating refers to reservoir cap
disintegration that is initiated by application of an electrical
current or potential. This disintegration can be primarily as due
to electrochemical action or thermal action (i.e., can occur
electrochemically or thermally). Electrochemical disintegration
occurs when the microchip device is in the presence of an
electrolytic solution and comprises a cathode and an anodic
reservoir cap (e.g., a thin metal film) and the electrical
activation means applies an electric potential between the cathode
and the anode effective to cause the reservoir cap to corrode and
fall apart, as described for example in U.S. Pat. No. 5,797,898.
Thermal activation occurs when the microchip device comprises at
least one resistor (i.e., resistive heater) operably adjacent the
reservoir cap and the electrical activation means applies an
electric current through the resistor effective to heat the
reservoir cap or contents enough to cause the reservoir cap to
rupture, melt, or otherwise lose structural integrity, as described
in U.S. Pat. No. 6,527,762. The device also can be configured so
that the heating induces stress forces in the reservoir cap to
facilitate mechanical failure. By "operably adjacent" is meant that
the resistor is inside the reservoir, or attached to or otherwise
sufficiently near the reservoir cap, to transfer an effective
amount of heat to the reservoir cap or to the reservoir contents.
These types of disintegration can occur together. For example,
heating at the reservoir cap can increase the rate of the
electrochemical reaction.
[0025] A. Current Distribution Means
[0026] The current distribution means includes, but is not limited
to, structures designed to disperse electrical current and/or
thermal energy uniformly across the reservoir cap, as well as
structures that increase the exchange current density of reservoir
caps that operate as electrodes. Representative current
distribution means include current distribution networks and
electrochemically plated metal layers (on the outer surface of the
reservoir cap) that have increased surface roughness relative to
the outer surface of the reservoir cap.
[0027] Current Distribution Networks
[0028] Effective disintegration is enhanced by providing the thin
film with a current distribution network, such as one comprised of
a plurality of traces attached to the outer surface of the thin
film. The traces (which are strips of metal or another conductor
fabricated onto the reservoir caps) and the thin film can be formed
of the same material, such as gold, or the traces can be formed of
a first material that corrodes at a different rate than a second
material of which the thin film is formed. The traces could also be
made of a conducting material that does not corrode, such as
platinum, titanium, or silicon doped with ionic species.
Alternatively, the traces can be coated with a passivating layer,
such as one formed of silicon nitride, silicon oxide, or titanium
oxide, to aid in the uniform distribution of the corrosion current
across the surface of the thin film.
[0029] When electrochemical disintegration is to be employed, the
current distribution network is a low electrical resistance path on
top of, under, or near the membrane (reservoir cap). The current
distribution network continues to conduct electricity throughout
the duration of the corrosion process, even if the majority of the
thin film or membrane anode is losing or has lost its ability to
conduct electricity. When thermal disintegration is to be used, the
current distribution network is a high electrical resistance path
on top of, under, or near the membrane (reservoir cap). That is, it
is essentially a resistor that heats the reservoir cap material or
the reservoir contents.
[0030] In a preferred embodiment, a current distribution network is
provided on or below the metal membrane (reservoir cap) in order to
corrode the metal membrane more uniformly, minimizing the effects
of some or all of the non-uniformity factors described above. One
embodiment of this network is shown in FIG. 3, which shows current
distribution network 10 (which is composed of numerous network
traces) fabricated on top of the metal membrane 12 covering
reservoir 14. Main trace 16, on substrate 18, provides current to
the current distribution network 10 and metal membrane 12. A wide
variety of network topologies are suitable. The main traces and
network traces can be fabricated from the same or different
materials.
[0031] The network traces can be current conductor paths that
either do not corrode at the potential applied to the membrane or
are so thick that their change in resistivity does not change
significantly over the period during which they are corroded. Thus,
the voltage drop along these traces is insignificant over the
period in which the membrane is corroding. The traces simply act as
current distribution "busses." These traces can be located either
on top of or below the membrane.
[0032] The trace spacing should be chosen to insure that the
potential affected zone of the membrane is always close to one of
the traces. This spacing can be established by measurement of the
membrane resistivity as a function of thickness and by knowledge of
the membrane thickness at which the membrane no longer retains
structural integrity. The membrane resistivity will rise rapidly as
the film becomes thinner. The resistivity at the failure thickness
and the applied current density will establish the potential drop
over film between the traces. This current distribution network
will also form numerous crevices along the surface of the membrane.
If crevice corrosion is indeed a significant contributor to
corrosion for the particular metal/electrolyte system, then this
process will allow the membrane to corrode more reproducibly by
increasing the surface areas at which the membrane will corrode,
perforate, and thereby expose and release molecules or devices from
the reservoir.
[0033] In another preferred embodiment, a current distribution
network is provided on top of the metal membrane (reservoir cap) by
suitably patterning an insulating layer, in order to allow the
portions of the membrane below the insulating layer to corrode
slower, enabling those portions of the membrane to remain at the
corrosion potential and distribute the corrosion current to
neighboring exposed membrane surfaces as they become thinner.
Preferred materials for such non-conducting layers include oxides
and nitrides of silicon, titanium, and chromium, carbides,
diamond-like materials, and certain organic compounds such as
photopolymers (photoresists, polyimide), fluoropolymers (e.g.
TEFLON.TM.) and some epoxies.
[0034] Distribution Network Traces
[0035] The traces may be composed of several different types of
materials. In one embodiment, the network traces are composed of
the same material as the membrane or film, such as gold or other
metals described above. In this embodiment, however, the traces are
substantially thicker in cross-sectional area, such that the traces
will corrode when the potential is applied, but the change in
resistivity will be small compared to that which occurs in the
membrane.
[0036] In another embodiment, the network traces are fabricated
from a metal that does not corrode at the same potential as the
membrane material. For example, platinum or titanium trace
materials can be used with gold membranes.
[0037] In still another embodiment, the network traces are metal
coated with a passivating layer to prevent degradation or
corrosion. In a preferred form of this embodiment, gold network
traces are coated with silicon oxide or silicon nitride
dielectrics. In another variation, a current distribution network
is provided on top of the metal membrane (reservoir cap) by
patterning an insulating layer, in order to allow the portions of
the membrane below the current distribution network to corrode
slower, enabling those portions of the membrane to remain at the
corrosion potential and distribute the corrosion current to
neighboring exposed membrane surfaces as they become thinner.
Preferred materials for such non-conducting layers include oxides
and nitrides of silicon, titanium, and chromium, carbides,
diamond-like materials, and certain organic compounds such as
fluoropolymers (e.g. polytetrafluoroethylene) and some epoxies.
[0038] Increased Surface Roughness
[0039] In another embodiment, the current distribution means
includes a reservoir cap or a layer thereon having a roughened
metal surface for distributing current uniformly across the surface
of the anode. The roughened surface transfers charge efficiently
and should result in more uniform corrosion. Typically, the
roughening method involves either repeated potential cycling
through the metal oxide formation and stripping regions or repeated
cycling in a metal complexing solution such as that containing a
halide salt. The first method drives oxygen many atomic lengths
into the surface and then removes it, potentially in combination
with some metal. The latter method specifically dissolves and
redeposits metal.
[0040] In one embodiment, roughening of the metal anode surface is
obtained by plating a small amount of metal under conditions that
should yield a nonepitaxial film. In the case of gold anodes, for
example, a solution containing a mildly oxidizing, non-halide
containing electrolyte such as HNO.sub.3, KNO.sub.3,
H.sub.2SO.sub.4, Na.sub.2SO.sub.4 is prepared at a concentration
between 0.01 and 5 M. To this solution, a small amount of
HAuCl.sub.4 or other gold salt is added. The concentration of the
gold salt should be in the range of 1 to 500 nM per cm.sup.2 of
gold surface area on the device of interest. This concentration
range ensures that no more than a few hundred atomic layers of gold
will be deposited. The gold-containing device is then externally
connected to a potential source such as a potentiostat. The device
is then immersed in the above solution along with a counter and
working electrode. The counter electrode is a clean, large surface
area gold wire, sheet or mesh, which can act as an additional gold
ion source. The most useful reference electrodes for this procedure
are non-halide containing electrodes such as
Hg.vertline.Hg.sub.2SO.sub.4.vertline.K.sub- .2SO.sub.4 or
Hg.vertline.HgO.vertline.NaOH. Physically isolating the reference
electrode by placing it in a beaker connected by a salt bridge or
Luggin capillary will minimize contamination. After immersion and
electrical connection, a potential waveform (i.e., a square,
triangular, or saw-tooth) is applied to the system using the
standard three-electrode electrochemical cell geometry. This
waveform scan or step is bounded by an upper potential limit of 1.0
to 2.0 V and a lower limit of -0.5 to 0.5 V. The upper limit is in
the range where some oxide formation will occur. The lower limit is
below the oxide-stripping region and also below the gold reduction
region. The presence of the small quantity of gold salt in the
solution prevents substantial dissolution of gold and provides
material to be plated on the existing gold surface. After continued
potential cycling for a period of 10 seconds to 1 hour, the cycling
is stopped at the lower potential limit. The device is then
withdrawn from the gold solution under potential control at this
lower limit. This will ensure that the open circuit potential does
not allow removal or oxidation of the gold immediately before
withdrawal.
[0041] Electrochemical dissolution of a reservoir cap can be
enhanced by cleaning and roughening the electrode surface. Examples
of techniques for surfacing roughening include (1) increasing the
electrode surface area by electrochemically plating metal onto the
surface of the electrode prior to use, and (2) repeatedly cycling
the metal electrode through the oxide formation and stripping
potentials.
[0042] B. Stress Induction Means
[0043] Internal stress in the reservoir cap can be controlled,
induced, and distributed by several techniques. When the metal film
is fabricated, its initial tension can be adjusted by varying the
shape of the support layer used in the deposition of the metal. For
example, a flat support will result in a higher residual stress
than a concave or convex support layer because the flat support
will produce a tighter film when the film cools. Also, additional
thickness of metal could be added to known high stress areas, such
as corners, to extend the time required for sufficient
disintegration in these areas where disintegration would occur at a
faster rate due to the combination of the primary [electro]
corrosion and the stress which is creating micro fractures. The
stress can be controlled by patterning another material (conducting
or non-conducting) on either or both sides of the metal film. This
process would retard disintegration selectively and would reinforce
the metal film in specific locations. For example, a pattern of the
top surface dielectric that is used to insulate the electrical
conductors that has rounded corners where it terminates at the
periphery of the metal caps would produce less localized stress
than sharp (e.g., 90.degree.) corners. A pattern that extended over
the central area of the metal cap could also distribute loading,
thereby reducing local stress concentration.
[0044] Another factor that will control the magnitude and sign
(tension vs. compression) of these stresses is the thermal
processing history of the film. Thermal stresses can develop from a
difference in thermal expansion between the film and the substrate
on cooling the film from process temperature(s) to room
temperature. By controlling the thermal cycle and engineering
specific thermal mismatch differences, one can target specific
stressed states.
[0045] In one embodiment, the stress inducing means comprises a
pre-stressed structure that enhances reservoir cap opening, for
example, as the reservoir cap thermally or electrochemically
disintegrates. The pre-stressed structure preferably provides a
force substantially perpendicular to the surface of the reservoir
cap.
[0046] The pre-stressed structure can be a member attached to
(e.g., built upon) or integrated into the reservoir cap. Residual
stress in the structure, in its simplest form, a cantilever beam,
loads the membrane. The intact membrane counteracts the stress. As
the membrane corrodes and weakens, the stress introduced by the
structure exceeds the yield strength of the corroded membrane and
the structure penetrates the membrane.
[0047] In one embodiment, the pre-stressed structure is a
cantilever beam, e.g., located on a thin film anode. This beam will
cause the reservoir to open if the anode corrodes or dissolves to a
certain thickness and then stops before the membrane is
structurally weak enough to fall apart. In other embodiments, the
pre-stressed structure can comprise a single layer of material
having a stress gradient, or the pre-stressed structure can
comprise a spring, coil, or cross design (see FIGS. 4 and 5), as
well as a variety of other configurations.
[0048] In another approach, a structure is fabricated as a
composite of two layers having residual stress of opposite sign.
That is, one layer having a built-in tensile stress, while the
other having a compressive stress. The means to control stress in
thin films deposited during microfabrication is well known. For
example, the stress of films deposited using plasma-enhanced
chemical vapor deposition (PECVD) is controlled by controlling the
temperature of the deposition, and the composition of the gases
used to form the film. A suitable structure can be formed of a
composite layer of silicon dioxide having a compressive stress, and
a layer of silicon nitride having a tensile stress.
[0049] By controlling internal stress levels and the distribution
of internal stresses in the metal film, a more consistent corrosion
result can be achieved. Stress levels can be controlled by, for
example, varying the dimensions of the metal film (including
thickness), its grain size and crystal orientation, the film's
intrinsic stress (affected by parameters such as temperature,
pressure, and method of deposition), and its initial tension
loading, as well as by selective patterning of other materials on
the top and/or bottom surfaces of the metal film to direct the
stress loading of the film (while still exposing a sufficient
amount of metal film to achieve effective disintegration).
[0050] C. Controlled Morphology of the Metal Membrane
[0051] Where grain boundary corrosion is a dominant cause of
non-uniform corrosion and molecule release, reliability and
uniformity can be improved by changing the structural morphology
(i.e., average grain size distribution and grain orientation
distribution) of the metal membrane itself. Specifically,
decreasing the size of the metal grains with respect to the
thickness of the membrane should improve corrosion of the membrane,
and thus opening of the reservoir and release of molecules. This
grain size change will increase the proportion of the membrane mass
and metal surface area consisting of grain boundaries with respect
to the mass and metal surface area consisting of grains. Therefore,
preferential corrosion of the grain boundaries will cause a larger
portion of the membrane to corrode, leaving a membrane that is
weaker and more likely to open after corrosion by an applied
potential.
[0052] There are numerous methods (e.g., plasma-deposition or
evaporation-deposition) with several parameters (e.g., impurity
level, temperature, and deposition potential) to keep grain sizes
small in thin films. See for example, Thompson, "Grain Growth in
Thin Metal Films," Annu. Rev. Mater. Sci., 20: 45-68 (1990); King
& Harris, "Grain Growth Suppression and Enhancement by
Interdiffusion in Thin Metal Films", Mat. Res. Soc. Symp. Proc.,
343: 3-42 (1994). In one embodiment, the metal is deposited at a
higher base pressure (e.g., lower base vacuum), which typically is
greater than 10.sup.-5 Torr. This allows oxygen and other
impurities in the deposition chamber to be incorporated into the
metal film. These impurities can slow grain boundary mobility and
grain growth. Impurities can also be introduced into grain
structure by solution doping. "Impurities" present in solution are
capable of strongly influencing the grain growth rate, since they
will tend to segregate to the grain boundaries and exert a drag
force on boundary motion. These impurities can also be in the form
of precipitates. The grain boundaries must move past the
precipitates during growth, which results in a local increase in
interfacial energy that acts as an impeding force on the grain
boundary.
[0053] The thermal processing of the metal film is a critical
factor that dictates the average grain size and the size
distribution because grain boundary mobility is strongly
temperature dependent, M.sup.grain.varies.exp.sup.(-E/kT).
Therefore, grain size can be kept small by limiting thermal
processing of the thin film after deposition, as high temperatures
can induce high grain growth rates, i.e., large grains. Maintaining
low temperatures during processing, T<0.2*T.sup.Melt, will
promote a smaller average grain size (10 to 100 nm), while higher
temperatures, T>0.2*T.sup.Melt, will yield larger grains
(.gtoreq.1000 nm).
[0054] Since corrosion may occur primarily at the "amorphous" grain
boundaries, the gold film may preferably be amorphous rather than
polycrystalline. This may be achieved by impurity doping and/or
rapid cooling in excess of 10.sup.8 K/sec during processing
(Schaffer, et al., The Science and Design of Engineering Materials,
p. 225, Irwin Inc. (Chicago 1995)). Another potential method for
producing amorphous metal films involves bombarding the metal film
during deposition with an ion beam.
[0055] Effective disintegration is enhanced by controlling the size
of the grains in the metal film. For example, the longest dimension
of metal grains possibly may be made smaller than the thickness of
the film. Small grain size can be achieved, for example, by forming
the metal film via deposition at a high base pressure (i.e., lower
base vacuum). Large grain size, if desired, can be achieved by
deposition of the metal film at high vacuum. Grain size may also be
modified by impacting the thin film with an ion beam during
deposition. Small grain size can be maintained by avoiding exposure
to high temperatures following deposition of the metal film, while
grains can be made larger by post-deposition heat treatment.
[0056] III. The Basic Microchip Devices
[0057] As used herein, a "microchip" is a miniaturized device
fabricated using methods commonly applied to the manufacture of
integrated circuits such as ultraviolet (UV) photolithography,
reactive ion etching, and electron beam evaporation, as described,
for example, by Wolf & Tauber, Silicon Processing for the VLSI
Era, Volume 1--Process Technology (Lattice Press, Sunset Beach,
Calif., 1986); and Jaeger, Introduction to Microelectronic
Fabrication, Volume V in The Modular Series on Solid State Devices
(Addison-Wesley, Reading, Mass., 1988), as well as MEMS methods
that are not standard in making computer microchips, including
those described, for example, in PCT WO 01/41736; Madou,
Fundamentals of Microfabrication (CRC Press 1997); and other
micromolding and micromachining techniques known in the art. The
microchips provide control over the rate the molecules are released
as well as the time at which release begins. The time of release
can be controlled actively or passively.
[0058] The microchip fabrication procedure allows the manufacture
of devices with primary dimensions (length of a side if square or
rectangular, or diameter if circular) ranging from less than a
millimeter to several centimeters. Typical device thicknesses range
from 300 to 550 .mu.m. However, the thickness of the device can
vary from approximately 10 .mu.m to several centimeters, depending
on the device's application. Total device thickness and reservoir
volume can also be increased by bonding (for example, by anodic
bonding) or attaching (for example, by adhesives) additional
silicon wafers or other substrate materials (such as glasses or
plastics) having openings or apertures that align with the
reservoirs to the fabricated microchip device. In general, changing
the device thickness affects the volume of each reservoir and may
affect the maximum number of reservoirs that may be incorporated
onto a microchip. In vivo applications of the device typically
require devices having a primary dimension of 5 cm or smaller.
Devices for in vivo applications may be made small enough to be
swallowed or implanted using minimally invasive procedures. Smaller
in vivo devices (on the order of a millimeter) can be implanted
using a catheter or other injectable means. Devices for in vitro
applications have fewer size restrictions and, if necessary, can be
made much larger than the dimension ranges for in vivo devices.
[0059] IV. Device Components and Materials
[0060] Each device consists of a substrate, reservoirs, and a
release system containing, enclosing, or layered with the molecules
to be delivered. The device further includes a reservoir cap to
control the release or exposure time of the molecules or devices
contained in the reservoirs, and typically includes control
circuitry and a power source for active microchips. The substrate,
reservoirs, release system, reservoir contents, control circuitry
and power source are substantially as described in U.S. Pat. No.
5,797,898 and No. 6,123,861, as well as PCT WO 02/30401, WO
02/30264, WO 01/91902, WO 01/64344, WO 01/41736, WO 01/35928, and
WO 01/12157.
[0061] A. The Substrate
[0062] The substrate contains the etched, machined, or molded
reservoirs and serves as the support for the microchip. Any
material which can serve as a support, is suitable for etching,
machining, or molding, and is impermeable (during the time scale of
the microchip's use) to the molecules to be delivered and to the
surrounding fluids (e.g., water, blood, electrolytes or other
solutions) may be used as a substrate. Examples of substrate
materials include metals, ceramics, semiconductors, and degradable
and non-degradable polymers. Biocompatibility of the substrate
material is preferred, but not required. For in vivo applications,
non-biocompatible materials may be encapsulated or contained in a
biocompatible material, such as poly(ethylene glycol),
polytetrafluoroethylene-like materials, or titanium, before use.
One example of a strong, non-degradable, easily etched substrate
that is impermeable to the molecules to be delivered and the
surrounding fluids is silicon. In another embodiment, the substrate
is made of a strong material that degrades or dissolves over a
defined period of time into biocompatible components. This
embodiment is preferred for in vivo applications where the device
is implanted and physical removal of the device at a later time is
not feasible or recommended, for example, brain implants. An
example of a class of strong, biocompatible materials are the
poly(anhydride-co-imides) described in Uhrich et al., "Synthesis
and characterization of degradable poly(anhydride-co-imides)",
Macromolecules, 28: 184-93 (1995). Another group of biocompatible
polymers suitable for use as a substrate material includes PLA
[poly(lactic acid)], PGA [poly(glycolic acid)], and PLGA
[poly(lactic-co-glycolic acid)].
[0063] B. Molecules and Secondary Devices (Reservoir Contents)
[0064] The reservoirs contain molecules, secondary devices, or
combinations thereof, that need to be protected from surrounding
environmental components until their release or exposure is
desired. Proper functioning of certain reservoir contents, such as
a catalyst or sensor, generally does not require their 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.
[0065] Molecules
[0066] The reservoir contents can include essentially any natural
or synthetic, organic or inorganic molecule or mixture thereof, for
release (i.e., delivery) or retained and exposed. The molecules
(i.e., chemicals) may be in pure solid, liquid, or gel form, or
mixed with other materials that affect the release rate and/or
time. Chemicals may be in the form of solid mixtures including, but
not limited to, amorphous and crystalline mixed powders, monolithic
solid mixtures, lyophilized powders, and solid interpenetrating
networks; in the form of liquid mixtures including, but not limited
to, solutions, emulsions, colloidal suspensions, and slurries; and
in the form of gel mixtures including, but not limited to,
hydrogels.
[0067] For in vivo applications, the chemical preferably is a
therapeutic, prophylactic, or diagnostic agent. In one embodiment,
the microchip device is used to deliver drugs 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. As used herein, "drugs" include any
therapeutic, prophylactic or diagnostic agent, including organic or
inorganic molecules, proteins, nucleic acids, polysaccharides and
synthetic organic molecules, having a bioactive effect.
Representative examples include analgesics, steroids, cytokines,
psychotropic agents, chemotherapeutic agents, and hormones
anesthetics, vaccines, metabolites, sugars, immunomodulators,
antioxidants, ion channel regulators, and antibiotics. An example
of a diagnostic agent is an imaging agent such as a contrast agent.
The drugs can be in the form of a single drug or drug mixtures and
can include pharmaceutically acceptable carriers.
[0068] In another embodiment, molecules are released in vitro in
any system 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.
[0069] In another embodiment, the molecules to be released are
perfumes, fragrances, dyes, coloring agents, sweeteners, or a
variety of other compounds, which for example, may be useful to
release as a function of temperature change.
[0070] In other embodiments, the reservoirs contain immobilized
molecules. Examples include any chemical species which can be
involved in a reaction, including, but not limited to, reagents;
catalysts, including enzymes, metals, and zeolites; proteins;
nucleic acids; polysaccharides; polymers; cells, as well as organic
or inorganic molecules, including diagnostic agents.
[0071] Formulations of molecules to be released also may contain
stabilizers and anti-oxidants to preserver the integrity of the
drug or other molecules.
[0072] Molecules to be delivered may be inserted into the
reservoirs in their pure form, as a liquid solution or gel, or as a
material that quickly vaporizes. Alternatively, the molecules may
be encapsulated within or by a release system. As used herein,
"release system" includes both the situation where the molecules
are in pure form, as either a solid, liquid, or vapor, or are
formulated in a matrix formed of a degradable material or a
material that releases incorporated molecules by diffusion out of
or disintegration of the matrix. The degradation, dissolution, or
diffusion properties of the release system can provide a method for
controlling the release rate of the molecules. The molecules can be
homogeneously or heterogeneously distributed within the release
system. Selection of the release system is dependent on the desired
rate of release of the molecules.
[0073] Both non-degradable and degradable release systems can be
used for delivery of molecules. Suitable release systems include
polymers, polymeric matrices, non-polymeric matrices, and inorganic
and organic excipients and diluents. Examples of such excipients
and diluents include calcium carbonate and sugar. Release systems
may be natural or synthetic, although synthetic release systems are
preferred due to the better characterization of release profiles.
The release system is selected based on the period over which
release is desired, generally in the range of at least one to
twelve months for in vivo applications. In contrast, release times
as short as a few seconds may be desirable for some in vitro
applications. In some cases, continuous (constant) release from a
reservoir may be most useful. In other cases, pulsed (variable)
release from a reservoir may provide results that are more
effective.
[0074] 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.
[0075] 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).
[0076] Active and passive release systems can be combined. For
example, a metal film or membrane reservoir cap, which is removed
actively, can cover a passive release system that only begins its
passive release after the metal film has been actively removed.
Alternatively, a given substrate can include both passive and
active release reservoirs.
[0077] The release system material can be selected so that
molecules of various molecular weights are released from a
reservoir by diffusion out or through the material or degradation
of the material. Biodegradable polymers, bioerodible hydrogels, and
protein delivery systems are preferred for release of molecules by
diffusion, degradation, or dissolution. In general, these materials
degrade or dissolve either by enzymatic hydrolysis or exposure to
water in vivo or in vitro, or by surface or bulk erosion.
Representative synthetic, biodegradable polymers include polyamides
such as poly(amino acids) and polypeptides; polyesters such as
poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic
acid), and polycaprolactone; polyanhydrides; polyorthoesters;
polycarbonates; and chemical derivatives thereof (substitutions,
additions of chemical groups, for example, alkyl, alkylene,
hydroxylations, oxidations, and other modifications routinely made
by those skilled in the art), copolymers and mixtures thereof.
Representative synthetic, non-degradable polymers include
polyethers such as poly(ethylene oxide), poly(ethylene glycol), and
poly(tetramethylene oxide); vinyl polymers--polyacrylates and
polymethacrylates such as methyl, ethyl, other alkyl, hydroxyethyl
methacrylate, acrylic and methacrylic acids, and others such as
poly(vinyl alcohol), poly(vinyl pyrolidone), and poly(vinyl
acetate); polyurethanes; cellulose and its derivatives such as
alkyl, hydroxyalkyl, ethers, esters, nitrocellulose, and various
cellulose acetates; polysiloxanes; and any chemical derivatives
thereof (substitutions, additions of chemical groups, for example,
alkyl, alkylene, hydroxylations, oxidations, and other
modifications routinely made by those skilled in the art),
copolymers and mixtures thereof.
[0078] Secondary Devices
[0079] As used herein, unless explicitly indicated otherwise, the
term "secondary device" includes, but is not limited to, any device
and component thereof which can be located in or designed to
operably communicate with one or more reservoirs in a microchip
device. In a preferred embodiment, the secondary device is a sensor
or sensing component. As used herein, a "sensing component"
includes, but is not limited to, 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. Secondary
devices are further described in PCT WO 01/64344.
[0080] 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 a preferred
embodiment, the microchip device is implantable in a patient (e.g.,
a human or other mammal) and includes sensors for monitoring the
levels of glucose or urea in blood and other body fluids.
[0081] There are several different options for receiving and
analyzing data obtained with devices located in the microchip
devices. Typically, the operation of the microchip system will be
controlled by an on-board (i.e., within the package)
microprocessor. 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
microchip. Power can be supplied to the microchip system locally by
a microbattery or remotely by wireless transmission.
[0082] D. Reservoir Caps
[0083] The reservoir cap is positioned on the reservoir over the
molecules to be released. In one embodiment, a reservoir cap is
positioned on top of the release systems contained in one or more
reservoirs.
[0084] Metal Films
[0085] In a preferred embodiment, the reservoir cap is in the form
of a thin metal film (also herein referred to as a metal membrane).
Representative examples, of suitable metal materials include
copper, gold, silver, zinc, and combinations thereof. The reservoir
cap optionally can be coated with an overcoat material, for example
to protect the metal from premature degradation until the overcoat
material has been substantially removed by dissolving, eroding,
biodegrading, oxidizing, or otherwise degrading, such as upon
exposure to water in vivo or in vitro. Representative suitable
degradable materials include synthetic or natural biodegradable
polymers.
[0086] The metal films may be reinforced with a pattern of a second
material (frequently dissimilar to the metal) deposited onto
surfaces of the film in order to strengthen the film and/or to
distribute mechanical stress. The second material can be deposited
on the surface adjacent the reservoir (i.e., the inner surface) or
distal the reservoir (i.e., the outer surface).
[0087] For thermal disintegration, the reservoir cap can be a
non-conducting material.
[0088] E. Device Packaging, Control Circuitry, and Power Source
[0089] Microelectronic device packages are typically made of an
insulating or dielectric material such as aluminum oxide or silicon
nitride. Their purpose is to allow all components of the device to
be placed in close proximity and to facilitate the interconnection
of components to power sources and to each other. For in vivo
applications of the delivery device, the entire package, including
all components (i.e., the device, the microprocessor, and the power
source), are contained, coated, or encapsulated in a biocompatible
material such as poly(ethylene glycol),
polytetrafluoroethylene-like materials, or titanium. The materials
requirements for in vitro applications may be less stringent and
depend on the particular situation.
[0090] The control circuitry typically consists of a timer, a
demultiplexer, a microprocessor, an input source (for example, a
memory source, a signal receiver or a biosensor), and a power
source. The timer and demultiplexer circuitry can be designed and
incorporated directly onto the surface of the microchip during
electrode fabrication. The criteria for selection of a
microprocessor are small size, low power requirement, and the
ability to translate the output from memory sources, signal
receivers, or biosensors into an address for the direction of power
through the demultiplexer to a specific reservoir on the delivery
device. Selection of a source of input to the microprocessor such
as memory sources, signal receivers, or biosensors depends on the
delivery device's particular application and whether device
operation is preprogrammed, controlled by remote means, or
controlled by feedback from its environment (i.e.,
biofeedback).
[0091] The criteria for selection of a power source are small size,
sufficient power capacity, ability to be integrated into the
control circuitry, ability to be recharged, and the length of time
before recharging is necessary. Several lithium-based, rechargeable
microbatteries have been described in Jones & Akridge,
"Development and performance of a rechargeable thin-film
solid-state microbattery", J. Power Sources, 54: 3-67 (1995); and
Bates et al., "New amorphous thin-film lithium electrolyte and
rechargeable microbattery", IEEE 35.sup.th International Power
Sources Symposium, pp. 337-39 (1992). These batteries are typically
only ten microns thick and occupy 1 cm.sup.2 of area. One or more
of these batteries can be incorporated directly onto the delivery
device. Alternatively, a capacitor can be charged by transduction
of microwave, RF, or sonic energy.
[0092] V. Methods of Device Fabrication
[0093] The microchip devices can be made using the methods
described below, alone or in combination with known methods, such
the microfabrication techniques described in U.S. Pat. Nos.
5,797,898 and 6,123,861, to Santini, et al. Other methods are
described in PCT WO 01/41736. For example, the substrate can be
formed from polymer, ceramic, or metal, e.g., by compression
molding powders or slurries of polymer, ceramic, metal, or
combinations thereof. Other forming methods useful with these
materials include injection molding, thermoforming, casting,
machining, and other methods known to those skilled in the art.
Substrates formed using these methods can be formed (e.g., molded)
to have the reservoirs or the reservoirs can be added in subsequent
steps, such as by etching.
[0094] Exemplary processes are described below.
[0095] A. Fabrication of Substrates with Reservoirs
[0096] In one method of microchip manufacture, fabrication begins
by depositing and photolithographically patterning a material,
typically an insulating or dielectric material, onto the substrate
to serve as an etch mask during reservoir etching. Typical
insulating materials for use as a mask include silicon nitride,
silicon dioxide, and some polymers, such as polyimide. In a
preferred embodiment, a thin film (approximately 1000-3000 .ANG.)
of low stress, silicon-rich nitride is deposited on both sides of a
silicon wafer in a Vertical Tube Reactor (VTR). Alternatively, a
stoichiometric, polycrystalline silicon nitride (Si.sub.3N.sub.4)
can be deposited by Low Pressure Chemical Vapor Deposition (LPCVD),
or amorphous silicon nitride can be deposited by Plasma Enhanced
Chemical Vapor Deposition (PECVD). Reservoirs are patterned into
the silicon nitride film on one side of the wafer by ultraviolet
photolithography and either plasma etching or a chemical etch
consisting of hot phosphoric acid or buffered hydrofluoric acid.
The patterned silicon nitride serves as an etch mask for the
chemical etching of the exposed silicon by a concentrated potassium
hydroxide solution (approximately 20-40% KOH by weight at a
temperature of 75-90.degree. C.). Alternatively, the reservoirs can
be etched into the substrate by dry etching techniques such as
reactive ion etching or ion beam etching. These techniques are
commonly used in the fabrication of microelectronic devices, as
reviewed, for example, by Wolf et al. (1986), Jaeger (1988), and
Madou (1997). Use of these microfabrication techniques allows the
incorporation of hundreds to thousands of reservoirs on a single
microchip. The spacing between each reservoir depends on its
particular application and whether the device is a passive or
active device. In a passive device, the reservoirs may be less than
one micron apart. In an active device, the distance between the
reservoirs may be slightly larger (greater than approximately 1 to
10 .mu.m) due, for example to the space occupied by circuitry on or
near each reservoir. Reservoirs can be made in nearly any shape and
depth, and need not pass completely through the substrate. In a
preferred embodiment, the reservoirs are etched into a (100)
oriented, silicon substrate by potassium hydroxide, in the shape of
a square pyramid having side walls sloped at 54.7.degree., and pass
completely through the substrate (approximately 525 .mu.m thick) to
the silicon nitride film on the other side of the substrate,
forming a silicon nitride membrane. (Here, the silicon nitride film
serves as a potassium hydroxide etch stop.) The pyramidal shape
allows easy filling of the reservoirs through the large opening of
the reservoir (approximately 800 .mu.m by 800 .mu.m for a 525 .mu.m
thick wafer) on the patterned side of the substrate, release
through the small opening of the reservoir (approximately 50 .mu.m
by 50 .mu.m) on the other side of the substrate, and provides a
large cavity inside the device for storing the drugs or other
molecules to be delivered.
[0097] In a preferred embodiment of the active devices, resistors
are integrated into the device. Typically, thin-film resistors are
conveniently integrated with the reservoir during the manufacturing
process, as the resistors commonly are made by deposition and
patterning methods that are used to manufacture the reservoirs as
described herein. Alternatively, small chip resistors can be
surface mounted in close proximity to the reservoir.
[0098] B. Fabrication of Active Timed-Release Reservoir Caps
[0099] In a preferred embodiment, photoresist is patterned in the
form of electrodes on the surface of the substrate having the
reservoirs covered by the thin membrane of insulating or dielectric
material. The photoresist is developed such that the area directly
over the covered opening of the reservoir is left uncovered by
photoresist and is in the shape of an anode. A thin film of
conductive material capable of dissolving into solution or forming
soluble ions or oxidation compounds upon the application of an
electric potential is deposited over the entire surface using
deposition techniques such as chemical vapor deposition, electron
or ion beam evaporation, sputtering, spin coating, and other
techniques known in the art. Exemplary materials include metals
such as copper, gold, silver, and zinc, and some polymers, such as
disclosed by Kwon et al. (1991) and Bae et al. (1994). After film
deposition, the photoresist is stripped from the substrate. This
removes the deposited film, except in those areas not covered by
photoresist (lift-off technique). This leaves conducting material
on the surface of the substrate in the form of electrodes. An
alternative method involves depositing the conductive material over
the entire surface of the device, patterning photoresist on top of
the conductive film using UV or infrared (IR) photolithography, so
that the photoresist lies over the reservoirs in the shape of
anodes, and etching the unmasked conductive material using plasma,
ion beam, or chemical etching techniques. The photoresist is then
stripped, leaving conductive film anodes covering the reservoirs.
The thickness of the conductive film typically, but not
necessarily, is between about 0.05 and several microns. The anode
serves as the reservoir cap and the placement of the cathodes on
the device is dependent upon the device's application and method of
electric potential control.
[0100] Alternatively, a reservoir cap material can be deposited
that disintegrates, cracks, or ruptures in response to changes in
the temperature of the cap material itself or in response to a
temperature-induced pressure increase in the reservoir. Such caps
can be made using techniques such as, but not limited to, spin
coating, solvent casting, evaporation, chemical vapor deposition,
sputtering, or other deposition methods known in the art. The
contents of such as reservoir contains at least one material that
expands or vaporizes when exposed to heat produced by a source
within or in thermal communication with the reservoir or the
material. Representative examples of such sources that can transmit
energy to the material include resistive heating elements,
piezeoelectric elements, capacitive discharge (spark) elements, and
combinations thereof.
[0101] An insulating or dielectric material such as silicon oxide
(SiO.sub.X) or silicon nitride (SiN.sub.X) is deposited over the
entire surface of the device by methods such as chemical vapor
deposition (CVD), electron or ion beam evaporation, sputtering, or
spin coating. Photoresist is patterned on top of the dielectric to
protect it from etching except on the cathodes and the portions of
the anodes directly over each reservoir. The dielectric material
can be etched by plasma, ion beam, or chemical etching techniques.
The purpose of this film is to protect the electrodes from
corrosion, degradation, or dissolution in all areas where electrode
film removal is not necessary for release.
[0102] The electrodes are positioned in such a way that when an
electric potential is applied between an anode and a cathode, the
unprotected (not covered by dielectric) portion of the anode
reservoir cap oxidizes to form soluble compounds or ions that
dissolve into solution, exposing the reservoir contents to the
surrounding fluids. The molecules are released from the reservoir
at a rate dependent upon the degradation or dissolution rate of a
degradable release system or the rate of diffusion of the molecules
out of or through a non-degradable release system.
[0103] Alternatively, one or more resistors are positioned in the
reservoirs or near the cap material so that passing a current
through the resistor will change the temperature of the contents of
the reservoir or the temperature of the cap material. A sufficient
temperature change causes the reservoir to open by rupturing the
cap due to an increase in the pressure in the reservoir, a change
in the cap material itself based on its physical properties (e.g.,
volume changes with temperature related to its coefficient of
thermal expansion), or a combination thereof.
[0104] C. Removal of the Insulator Membrane (Reservoir Etch
Stop)
[0105] The thin membrane of insulating or dielectric material
covering the reservoir used as a mask and an etch stop during
reservoir fabrication must be removed from the active timed release
device before filling the reservoir and from the passive timed
release device (if the reservoir extends completely through the
substrate) after filling reservoir. The membrane may be removed in
two ways. First, the membrane can be removed by an ion beam or
reactive ion plasma. In a preferred embodiment, the silicon nitride
used as the insulating material can be removed by reactive ion
plasma composed of oxygen and fluorine containing gases such as
CHF.sub.3 or CF.sub.4. Second, the membrane can be removed by
chemical etching. For example, buffered hydrofluoric acid (BHF or
BOE) can be used to etch silicon dioxide and hot phosphoric acid
can be used to etch silicon nitride.
[0106] D. Reservoir Filling
[0107] The release system containing the molecules for delivery is
inserted into the large opening of the reservoir by injection,
inkjet printing, screen printing, or spin coating. Each reservoir
can contain a different molecule and dosage. Similarly, the release
kinetics of the molecule in each reservoir can be varied by the
choice of the release system and cap materials. In addition, the
mixing or layering of release system and cap materials in each
reservoir can be used to tailor the release kinetics to the needs
of a particular application.
[0108] The distribution over the microchip of reservoirs filled
with the release system containing the molecules to be delivered
can vary depending on the medical needs of the patient or other
requirements of the system. For applications in drug delivery, for
example, the drugs in each of the rows can differ from each other.
One row may contain a hormone and another row may contain a
metabolite. In addition, the release system can differ within each
row to release a drug at a high rate from one reservoir and a slow
rate from another reservoir. The dosages can also vary within each
row. For those devices having deep (greater than 10 .mu.m)
reservoirs or reservoirs with large (greater than 50 .mu.m)
openings, differences in reservoir loading can be achieved by
injection or inkjet printing of different amounts of material
directly into each reservoir. Variation between reservoirs is
achieved in devices having shallow (less than 10 .mu.m) reservoirs,
reservoirs that do not pass completely through the substrate, or
reservoirs with small (less than 50 .mu.m) openings by a repeated,
step-wise process of masking selected reservoirs, spin coating, and
etching, as described above regarding the fabrication by spin
coating of passive timed release reservoir caps. Preferably, the
release system and molecules to be delivered are mixed before
application to the reservoirs. Although injection, inkjet printing
and spin coating are the preferred methods of filling reservoirs,
it is understood that each reservoir can be filled individually by
capillary action, by pulling or pushing the material into the
reservoir using a vacuum or other pressure gradient, by melting the
material into the reservoir, by centrifugation and related
processes, by manually packing solids into the reservoir, or by any
combination of these or similar reservoir filling techniques.
[0109] E. Device Packaging, Control Circuitry, and Power Source
[0110] The openings through which the reservoirs of passive and
active devices are filled are sealed by wafer bonding or with a
waterproof epoxy or other appropriate material impervious to the
surrounding fluids. For in vitro applications, the entire unit,
except for the face of the device containing the reservoirs and
electrodes, is encased in a material appropriate for the system.
For in vivo applications, the unit is preferably encapsulated in a
biocompatible material such as poly(ethylene glycol) or
polytetrafluoroethylene.
[0111] The mechanism for release of molecules by the active
timed-release device does not depend on multiple parts fitted or
glued together which must retract or dislodge. Control of the time
of release of each reservoir can be achieved by a preprogrammed
microprocessor, by remote control, by a signal from a biosensor, or
by any combination of these methods.
[0112] First, a microprocessor is used in conjunction with a source
of memory such as programmable read only memory (PROM), a timer, a
demultiplexer, and a power source such as a microbattery, which is
described, for example, by Jones et al. (1995) and Bates et al.
(1992). The pre-selected release pattern is written in
machine-readable form directly into the PROM by the user (e.g., the
physician). These instructions are read from the PROM by the
microprocessor, which takes appropriate action, such as starting a
timer. When the time for release has been reached as indicated by
the timer, the microprocessor sends a signal corresponding to the
address (location) of a particular reservoir to the demultiplexer.
The demultiplexer routes an input, such as an electric potential or
current, to the reservoir addressed by the microprocessor. A
microbattery provides the power to operate the PROM, timer, and
microprocessor, and provides the electric potential or current
input that is directed to a particular reservoir by the
demultiplexer. The manufacture, size, and location of each of these
components are dependent upon the requirements of a particular
application. In a preferred embodiment, the memory, timer,
microprocessor, and demultiplexer circuitry is integrated directly
onto the surface of the chip. The microbattery is attached to the
other side of the chip and is connected to the device circuitry by
vias or thin wires. However, in some cases, it is possible to use
separate, prefabricated, component chips for memory, timing,
processing, and demultiplexing. These are attached to the backside
of the miniaturized delivery device, or carrier substrate, with the
battery. The size and type of prefabricated chips used depends on
the overall dimensions of the delivery device and the number of
reservoirs.
[0113] Second, activation of a particular reservoir by the
application of an electric potential or current can be controlled
externally by remote control. Much of the circuitry used for remote
control is the same as that used in the preprogrammed method. The
main difference is that the function of the PROM as a source of the
dosing regime is replaced by a signal receiver. A signal (e.g.,
radio wave, microwave, low power laser, or ultrasound) is sent to
the receiver by an external source, for example, a computer or an
ultrasound generator. The signal is received by the microprocessor
where it is translated into a reservoir address. Power is then
directed through the demultiplexer to the reservoir having the
appropriate address.
[0114] Third, a biosensor, which may or may not be integrated into
the microchip, can detect molecules in the surrounding fluids or
temperature or pressure. When the concentration of the molecules
reaches a certain value or when a tissue temperature or fluid
pressure is reached, the sensor sends a signal to the
microprocessor to activate one or more reservoirs. The
microprocessor directs power through the demultiplexer to the
particular reservoir(s).
[0115] F. Electric Potential or Current Control Methods
[0116] The reservoir caps of an active device are anodes that
oxidize to form soluble compounds and ions when a potential is
applied between the anode and a cathode. For a given electrode
material and electrolyte, there exists a range of electric
potentials over which these oxidation reactions are
thermodynamically and kinetically favorable. In order to
reproducibly oxidize and open the reservoir caps of the device, the
anode potential must be maintained within this favorable potential
range.
[0117] There exist two primary control methods for maintaining an
electrode within a specific potential range. The first method is
called potentiostatic control. As the name indicates, the potential
is kept constant during reservoir activation. Control of the
potential is typically accomplished by incorporating a third
electrode into the system that has a known, constant potential,
called a reference electrode. The reference electrode can take the
form of an external probe whose tip is typically placed within one
to three millimeters of the anode surface. The potential of the
anode is measured and controlled with respect to the known
potential of a reference electrode such as a saturated calomel
electrode (SCE), a silver/silver chloride (Ag/AgCl) electrode, or
sometimes a platinum wire. In a preferred embodiment of
potentiostatic control, a thin film reference electrode and
potential feedback controller circuitry could be fabricated
directly onto the surface of the microchip. For example, a
microfabricated Ag/AgCl reference electrode integrated with a
microchip device would enable the device to maintain the anode
potential of an activated reservoir within the oxidation regime
until the reservoir was completely opened. The second method is
called galvanostatic control. As the name indicates, the current is
kept constant during reservoir activation. One drawback of this
method of control is that there is more than one stable potential
for a given current density. However, if the current density versus
potential behavior is well characterized for the microchip device
in a particular electrolyte system, the current density that will
maintain the anode in the oxidation regime will be known. In this
case, the galvanostatic method of potential control would be
preferable to the potentiostatic control, because galvanostatic
control does not require a reference electrode.
[0118] Alternatively, corrosion can be achieved using less
complicated means of controlling the potential. A reference
electrode is not needed if the potential between the anode and the
cathode is periodically swept through a range of potential such
that the potential difference between the anode and the electrolyte
needed for oxidative corrosion is achieved during the sweep. In
other words, if the reference electrode is eliminated and the
electrical potential is swept back and forth (i.e., cycled) over a
suitable range, then the anode will experience the potential
required for corrosion at least a fraction of the time. Corrosion
will thus occur.
[0119] Another method of reservoir opening and chemical release is
based on rupturing the reservoir cap due to a change in the
temperature of the materials in the reservoir or a change in the
temperature of the material forming the reservoir cap. In a
preferred embodiment, such temperature changes are induced using
thin film resistors integrated onto the microchip itself or small,
prefabricated chip resistors surface mounted onto the microchip or
its associated packaging. The temperature change may be controlled
by the amount of current that is passed through the resistor and
the thermal properties of the material inside the reservoir or the
reservoir cap material. Control over the amount of current applied
and its duration of application can be controlled by a
microprocessor, remote control, biosensor, or a combination of
these devices.
[0120] VI. Microchip Device Applications
[0121] The microchip device systems can be used in a wide variety
of applications. The applications can be ex vivo or in vitro, but
more preferably are for in vivo applications, particularly
following non- or minimally-invasive implantation.
[0122] Preferred applications for using the devices and systems
include the controlled delivery of a drug to sites within the body
of a human or animal, biosensing, or a combination thereof. The
microchip systems are especially useful for drug therapies in which
it is desired to control the exact amount, rate, and/or time of
delivery of the drug. Preferred drug delivery applications include
the delivery of potent compounds, including both small and large
molecules, such as hormones, steroids, chemotherapy medications,
vaccines, gene delivery vectors, and some strong analgesic
agents.
[0123] The microchips can be implanted into the body of a human or
other animal via surgical procedures or injection, or swallowed,
and can deliver many different drugs, at varying rates and varying
times. In another embodiment, the microchip 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. As used herein, the term "biosensor"
includes, but is not limited to, 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 blood
gases, drug concentration, or temperature.
[0124] The system also has a variety uses that are not limited to
implantation. For example, the reservoir contents may include a
sensor for detecting a chemical or biological molecule at the site
in which the microchip is placed, and the telemetry system
transmits a status of the sensor detection to the remote
controller. Such a site could be in vivo or in vitro. The chemical
or biological molecule could, for example, be associated with a
chemical or biological weapon, and the system used in an early
warning/detection system.
[0125] Active microchip 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. The microchip devices have numerous in vivo, in vitro, and
commercial diagnostic applications. The microchips are capable of
delivering precisely metered quantities of molecules and thus are
useful for in vitro applications, such as analytical chemistry and
medical diagnostics, as well as biological applications such as the
delivery of factors to cell cultures.
[0126] 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.
* * * * *