MIT Microchip Releases Chemicals, Drugs On Demand
Ask MIT researchers John Santini, Michael Cima, and Robert Langer about potential applications for the microchip they're reporting in the Jan. 28, 1999 issue of Nature, and settle back for an enthusiastic tour of a future that ranges from jewelry that emits different scents depending on your mood to drug delivery systems that could be swallowed or implanted under the skin and programmed for the delivery of precise amounts of drugs at specific times.
The chip behind their excitement, the first of its kind, can store and release different chemicals on demand from tiny reservoirs built into its silicon structure. Apply a small electrical voltage to a given reservoir, and the thin gold cap covering it dissolves, releasing the chemical inside.
"The Nature paper shows that this basic concept works," said Cima, Sumitomo Electric Industries Professor of Ceramic Processing at the Institute. "The next step is to do the engineering to make this into a real application."
How it Works
Technical Challenges
The dime-sized prototype contains 34 reservoirs, each the size of a pinprick and capable of holding about 25 nanoliters of chemical in solid, liquid, or gel form. There is room for more than 1,000 such reservoirs, potentially thousands more if the reservoirs are made small enough. The prototype apparatus contains 34 wires, connecting the circuitry of each reservoir to an external power source. The researchers say that it should be possible, however, to make a device that's completely self-powered. That would involve fitting the chip with a small battery and a microprocessor. The chip could then be either preprogrammed for the release of pharmaceuticals, triggered by remote control, or activated by an on-chip biosensor.
The chip could also be cheap. "We're making them right now in a research lab for about $20 each," Cima said. "With process optimization and larger batches, I could easily see making them for a few dollars each, or even less."
Another intriguing medical application is diagnostics. Today's diagnostic tests involve adding precise amounts of chemicals in a precise order to fluids like blood and saliva. As a result, samples must be sent to a lab, where it can take hours to days to get results. A microchip preprogrammed to release the proper chemicals at the right times and in the right order could be fitted to the end of a probe, swirled in a vial of fluid at the bedside, and deliver results in real time.
Think of this chip as the ultimate drug delivery system. Yes, the small drug quantities delivered limit the usefulness of the device. Stability will be another issue to solve, since implantable drugs are maintained at body temperature. However, there are many potential drugs (and diagnostics) that are quite stable at physiologic temperature and work in very small doses, e.g. hormones and biopharmaceuticals. Since the device is implantable, one could envision applications where tissue-specific controlled delivery can now be achieved.
In any case the developers believe the benefits of a "drug chip" far outweigh its limitations. Most implants and patches currently on the market deliver drugs continuously over time; the new chip would allow control of both the amount of drug released and delivery schedule, Santini said. For example, some infertility treatments require wearing a small pump that delivers pulses of certain hormones every 90 minutes for weeks at a time via a catheter inserted through the skin. Those hormones could potentially be incorporated into a chip—along with sensing and control functions—to release the contents of specific reservoirs at specific times.
"The applications, I think, are unlimited," Professor Langer said. "The question is, which applications are the best?"
The microchip contains a large number of reservoirs, each covered by a thin membrane of a material that serves as an anode in an electrochemical reaction. There are other electrodes on the surface of the microchip that serve as cathodes in an electrochemical reaction. Each reservoir is filled with a compound for release. When release from a particular reservoir is desired, an electrical voltage (approximately 1 V) is applied between the anode covering that reservoir and a cathode. The anode membrane dissolves due to an electrochemical reaction. This reservoir is now open, allowing the material inside to diffuse out into the surrounding fluid. Each reservoir on the microchip can be activated and opened individually, allowing complex release patterns to be achieved. In the prototype device, the membrane anodes and the cathodes are made of a thin layer (approximately 0.3 mm) of gold. Application of approximately 1 V to the gold membrane anode in a solution containing a small amount of chloride ion (such as that found in any biological fluid) causes the membrane to dissolve in less than 10 seconds. The material in the reservoir is then free to release into the surrounding fluid.
Each reservoir on the prototype microchip can be activated individually because each anode has its own independent connection to the power source. As the number of reservoirs on a microchip becomes large, it should be possible to connect each anode to the power supply through a demultiplexer. The demultiplexer serves as a "routing station," directing power to a particular reservoir based on a code sent to the demultiplexer by a microprocessor or remote control.
The microchip's release mechanism is based on the electrochemical dissolution of a thin membrane anode covering a reservoir filled with the chemical to be released. Therefore, a major challenge in the development of the controlled release microchip involved the selection of the material to be used as the membrane material. The MIT group needed a material that could be easily deposited and patterned, be integrated with standard microfabrication processes, provide a barrier between the chemical in the reservoir and the fluid surrounding the device, and quickly dissolve with the application of a small electrical voltage. Given these criteria, metals appeared to be the best candidates for the membrane material in the prototype device.
Copper was initially chosen because it met all of the selection criteria. However, copper would spontaneously corrode in the chloride containing solutions (such as phosphate buffered saline solution) used in the proof-of-principle release experiments, allowing the chemical in the reservoirs to release prematurely. Therefore, the challenge was to find a material that met the above criteria and was chemically inert, except with an applied electrical voltage. "We took a major step forward in the development of the prototype microchip when we discovered gold as an excellent candidate for the membrane material," Langer stated. "Gold is known for its ability to resist corrosion in all but a few highly corrosive solutions. We demonstrated experimentally, and verified by a small number of papers in the literature, that gold corrodes readily in solutions containing a small amount of chloride ion when an electrical voltage of approximately +1 volt (relative to a saturated calomel reference electrode) is applied.
"However, gold membranes will not corrode and open in these same solutions without an applied electrical voltage, no matter how long they are in contact. Therefore, gold was selected as the model membrane material for the prototype controlled release microchips. In addition to its unique electrochemical properties, gold has also been shown in the literature to be biocompatible."
Fabricating the unsupported gold membranes also involved processing challenges. Defects (such as pinholes) in the gold membrane can be caused by the presence of particulates during the deposition process or by processing the gold at high (>700°C) temperatures. Such defects can enable chemicals to leak out of the reservoir or cause the membranes to rupture in response to small stresses. In addition, stresses present in the silicon nitride membrane that serves as a support for the gold membrane during most of the fabrication process can affect the quality of the gold membrane. If the silicon nitride membrane is under high compressive stress, the nitride and gold membranes tend to buckle and fold. If the silicon nitride membrane is under high tensile stress, the nitride and gold membranes are pulled so tightly that they rupture easily.
In each case, the challenge was to determine the processing conditions that resulted in the formation of a defect free, low stress gold membrane. To reduce defects, devices were fabricated in a low particulate environment (class 100 cleanroom) and rearranged processing steps so that the devices were never exposed to temperatures above 350°C after the gold was deposited. To reduce the stress in the gold membrane, the silicon nitride support layer was deposited at conditions that resulted in a relatively stress-free silicon nitride membrane. These process modifications resulted in higher device yields and stronger, defect free membranes.
Finally, the microchip reservoirs were so small that they could not be filled with chemicals by conventional methods because surface tension and capillary forces were dominant at this size scale. The challenge was to find a way to accurately fill the prototype reservoirs, each of which had an extremely small volume of approximately 25 nanoliters. The problem was solved by applying inkjet printing and micro-injection techniques to fill the reservoirs. The inkjet printhead was used to deposit a number of drops into the reservoir through the large (500 mm) reservoir opening on the backside of the microchip. Drops from the inkjet printhead were about 50-60 mm in diameter, so they easily fit through the 500 mm reservoir opening. For the micro-injection process, the plunger of a micro-syringe was manipulated by a computer-controlled piston. A 200 mm diameter needle on the micro-syringe was inserted into the large opening of a reservoir. When the needle was correctly positioned using a microscope, the plunger of the micro-syringe was depressed by the piston to fill the reservoir with nanoliter volumes of a solution containing the chemical to be released. "Therefore, if we know the concentration of the chemical in the filling solution, we can calculate the amount of chemical deposited in each reservoir with either filling method," Langer added.
A broad U.S. patent (5,797,898) covering this microchip technology was issued on Aug. 25, 1998 to John T. Santini Jr., Michael J. Cima, Robert Langer, and Achim M. Gvpferich, an MIT visiting scientist during the early stages of the project now at the Lehrstuhl Fuer Pharmazeutische Technologie Universitdt Erlangen-Nuernberg. There are currently two patents pending; a U.S. patent on the fabrication of the microchips (Santini, Cima, and Langer), and a foreign patent covering all aspects of the microchip technology (Santini, Cima, Langer, and Gvpferich).
For more information: Robert Langer, professor, Dept. of Chemical Engineering, Room E25-342, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139. Tel: 617-253-3107. Email: rlanger@mit.edu.