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Background

Microresevoir Theory

Fabrication (1,2)

Microreservoir actuation

Integrated Microchip device

Advantages

References

How Fabrication involves Biomedical engineering

            The development of device in the biomedical field requires the ability to reproduce the device numerous times using a standard procedure. The task of the biomedical engineer is complicated further by requiring device fabrication procedures to include methods and techniques that can be utilized by other research laboratories. A fabrication method that is only reproducible by a single person uplifts the scientific community much less than a fabrication method that can utilized by anyone.
            The following section on fabrication discusses common techniques that are used in semiconductor technology. These methods can be transferred towards micro- and nano-scale systems that can be utilized for biomedical purposes. Common techniques that are mentioned include photolithography, reactive ion etching (RIE), electron beam evaporation, low pressure chemical vapor deposition and potassium hydroxide etching (KOH etching). Other forms of fabrication certainly exist and should be learned and recognized by a biomedical engineer aiming to research in this field. The benefit of understanding multiple fabrication techniques allows expansion of the user’s options to advance and develop a device or idea.
            The next page will discuss the importance of material selection involved with microreservoir chip systems. (Next page)

Electrochemical microreservoir system (Prototype device) :
           
The prototype devices were 17mm by 17mm by 310µm and contained 34 reservoirs. The size of the device was specifically chosen for ease in handling and viewing. However, the device is capable of being reduced below 2mm based on application. The described device above is capable of housing over 1,000 reservoirs at dimensions 17mm by 17mm

Fabrication procedure [1, 6]

           Initial device prototypes were designed using silicon wafers and microelectronic processing techniques. Specific methods used included ultraviolet photolithography, chemical vapor deposition, electron beam evaporation and reactive ion etching.
            Fabrication starts by depositing approximately 0.12µm of low stress, silicon nitride on both sides of silicon wafers using a vertical tube reactor. The silicon wafers were of <100> oriented, which is a description of the crystal planes existing on the wafer.             Photolithography and electron cyclotron resonance enhanced reactive ion etching (RIE) were used on one surface of the wafer covered by silicon nitride. This step was used to produce a square shape microchip device at dimensions 17mm by 17mm.
            The silicon nitride was used as an etch mask which directs the design or pattern of where the chemical etching will affect. The microchip was submerged in a potassium hydroxide solution at 85 degrees Celsius that anisotropically etched the silicon wafer along the <111> crystal planes creating the square pyramidal structures that form the reservoirs.        The device was etched such that 34 square reservoirs were produced each with a square opening of 480µm by 480µm at the etching surface and an approximately 50 µm by 50 µm square bottom. The etching direction can be imagined as occurring in the form of an inverse pyramid.
            Each reservoir has pyramid shape at a volume of approximately 25nl (Figure b. below). The top portion of the pyramid, or smaller cross-sectional area was covered with the anode material. For this application the anode was a gold membrane that covered the 50µm by 50µm square surface area with a 0.3µm thickness and a 0.01 µm thick chromium adhesion layer. The cathode membrane could be of any conductive material, however gold was chosen for this application as well due to ease of fabrication. The gold electrodes were deposited and patterned over the pre-existing silicon nitride membranes by electron beam evaporation and lift-off. Gold was chosen due to its low reactivity with other substances and resistivity to spontaneous corrosion at variable pH ranges as well as its biocompatibility. Gold is also capable of forming soluble gold chloride complexes in the presence of chloride ions when given an electric potential.

            Figure: Top: A cross-sectional view of the top and side of the prototype microchip. Bottom: A diagram of an anisotropically etched square pyramidal reservoir. (Picture Rights belong to [1, 6]) 

Plasma enhanced chemical vapor deposition at 350 degrees Celsius was used to produce 0.6 µm silicon oxide (SiO2) films over the entire electrode containing surface which included the anode, cathode and bonding pads. The film was used a protective coating over portions of the electrodes to prevent undesired corrosion. The SiO2 film was ideal since it was adherent, non-porous and could isolate the electrode materials from the surrounding electrolyte. SiO2 layers that covered the anode, cathode and bonding pads required removal in order to expose the underlying gold electrode. Electron cyclotron resonance enhanced RIE was used to etch the silicon nitride over these surfaces as well as the thin silicon nitride and chromium membranes that were still located within the reservoir underneath the gold anode membrane.
            Two types of chemicals that are easily detected at low concentrations were selected for proof-of-concept to be inserted in to the device reservoirs. These two chemicals were: fluorescent dye sodium fluorescein and radioactive calcium chloride CaCl2. The first method of reservoir injection was utilizing an inkjet printing technique in combination with a computer-controlled alignment apparatus [7] that is capable of depositing less that 0.2nl of liquid or gel solution. The second method used microsyringe pumps to inject similar volumes of solution in the reservoirs.
            The bottom of the reservoirs were covered with squares of thin adhesive plastic and sealed with waterproof epoxy. The sealed microchips are then packaged and inserted into 100mL of saline solution with or without phosphate buffer. A saturated calomel reference electrode (SCE) is also placed within the solution to hold the anode membrane at a particular potential. An applied potential of +1.04V with respect to SCE was applied for up to 30 seconds to an anode when the release of the enclosed chemical was desired from the corresponding reservoir.

Electrothermal microreservoir system

Fabrication Procedure [9]

            The device’s primary components include reservoirs, a reservoir membrane (previously termed the anode membrane in the electrochemical based device), and metal traces for directing electric current to the membranes. A cross sectional view of the device can be seen below.

            Figure: Cross sectional diagram of microchip device and reservoir for an electrothermal based device. (Picture rights belong to [9])

The process of fabrication is similar to that of the electrochemical based device. A 0.2µm layer of silicon nitride is deposited on both sides of a <100> oriented silicon wafer by low pressure chemical vapor deposition (LPCVD) to insulate metal features and support electrode membranes. An etch mask is created along the silicon nitride layer using photolithography and reactive ion etching (RIE) that outlines the areas desired for reservoirs. KOH etching at 80 degrees Celsius is used to produce the pyramid shaped reservoirs with a volume of approximately 120nL at dimensions of 800 µm x 800 µm and 50 µm x 50 µm for the large and small openings, respectively. The traces (the path leading current to the anode membrane) is created by sputter depositing an Au (gold) layer with a Ti (titanium) adhesion layer and using wet etching to form patterns. The metal membranes are formed by combining sputter deposition with a liftoff process to cover the necessary areas of the silicon nitride layer. A passivation layer is deposited on the entire surface and is removed only over anode membrane areas by photolithography and RIE. The pre-existing silicon nitride membranes under the reservoir membranes are removed by RIE.

Two types of materials were chosen for the reservoir membrane: Au and a Pt/Ti/Pt (platinum/ titanium/ platinum) combination. Pt is used to protect the Ti during etching steps that remove silicon nitride. Selection of membrane composition is the critical fabrication step that determines device functionality. The trace composition is not as critical and does not significantly affect the membrane effectiveness.  A scanning electron micrograph shown below shows an Au membrane over the 50 µm by 50 µm reservoir. 

            Figure: A scanning electron micrograph of a reservoir membrane made of Au. (Picture rights belong to [9]).

There were two experimental designed microchips: the first contained 100 reservoirs and the second contained 24 reservoirs. In experimental designs for a microchip consisting of 100 reservoirs, the thicknesses of the traces were 10nm Ti/ 2 µm Au/ 10 nm Ti for reservoir membrane thicknesses of 300nm Au or 20nm Pt/ 300nm Ti/ 20n Pt. These 100 reservoir microchips were also covered with a passivation layer of thickness 1 µm silicon oxide/ 1 µm silicon nitride/ 1 µm silicon oxide. For the second experimental microchip consisting of 24 reservoirs, the trace thickness was 10nm Ti/ 600nm Au/ 10nm Ti for a reservoir thickness of 40nm Pt/ 300nm Ti/ 40nn Pt with no passivation layer. Below is a photograph of both devices, showing the back and front of the device.

            Figure: Top: 24 reservoir microchip, Bottom: 100 reservoir microchip that show the front side (left) and the back side (right). The front side consists of the reservoir membranes and traces, while the back side contains the reservoirs. (Picture rights belong to [9])

           
            Each reservoir was filled from the back side with 100 nL of a fluorescein/ mannitol formulation that could easily be detected and quantified. Reservoir filling was done using a custom, automated filling microsyringe pump. The reservoir backsides were covered using fitted, reflowed paraffin. Microchips were placed on printed circuit boards that electrically connected wire bonds to each trace. Voltage can be discharged through the circuit using a ribbon cable to initiate membrane activation or opening. The microchip and circuit board was tested in vitro for functionality using a customized enclosure that could provide an inlet and outlet flow of fluids. The entire in vitro testing system can be seen in the figure below.

             Figure: In vitro testing system used to assess the functionality of the electrothermal based microchip. (Picture Rights belong to [9]) 

            Opening of the membrane occurs when current is passed through the traces and into the membrane rapidly heating the membrane till the point of degradation. The degradation exposes the chemicals or drugs within the corresponding reservoir.

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