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MICROCHIP DEVICES WITH IMPROVED RESERVOIR OPENING
CROSS-REFERENCE TO RELATED APPLICATIONS
Priority is claimed under 35 U.S.C. §119 to U.S. provisional application Ser. No. 60/294,818, filed May 31, 2001.
BACKGROUND OF THE INVENTION
This invention relates to miniaturized devices for the controlled exposure or release of molecules such as drugs and/or secondary devices such as sensors.
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).
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.
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.
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.
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 prestressed 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.
Methods of fabricating and using these devices are also provided.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. la 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. lb shoWs the shape of the reservoir.
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.
FIG. 3 is a perspective diagram of one embodiment of a reservoir covered by a membrane having a current distribution netWork.
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.
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
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.
I. Non-Uniformity of Thin Film Dissolution/Corrosion
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.
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.
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.
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.
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.
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.
II. Methods and Devices for Enhanced Reservoir Cap Disintegration
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.
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 PCT WO 01/12157. 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.
A. Current Distribution Means
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