A commentary by:
- ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½John T. Santini, Jr. (Graduate Student, Dept. of Chemical Engineering),
- ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½Michael J. Cima (Sumitomo Electric Industries Professor of Ceramic Processing),
- ï¿½ï¿½ï¿½ï¿½ï¿½ï¿½Robert Langer (Kenneth J. Germeshausen Professor of Chemical and Biomedical Engineering).
We've developed a microchip that has the ability to store a large number of drugs or chemicals, control the time at which release begins, and control the rate at which the chemicals are released, all without moving parts. The microchip could be integrated with a tiny power supply and controlled by a microprocessor, remote control, or biosensors. This microchip technology has potential uses in areas such as medical diagnostics, chemical detection, combinatorial chemistry, drug delivery, cosmetics, and entertainment.
What are the microchip's applications?
The microchip could be used in any application where precise amounts of one or more compounds must be released at specific times and at specific rates. For example, this technology could be used to develop hand-held devices for medical diagnostics or chemical detection and microfluidic devices for combinatorial chemistry or microbiology.
In drug delivery applications, for example, this microchip may someday be used in the development of an autonomous, controlled release implant ("pharmacy-on-a-chip") or a highly controllable tablet ("smart tablet") for oral drug delivery.
Although the prototype microchip requires contact with a small amount of solution to operate, we have ideas for developing chips that can function without contacting a solution. This may lead to the development of microchips for use in televisions or jewelry that release scents in response to signals sent through television cable or changes in the skin's salinity, respectively.
What is novel about the microchip?
It is the first device of its kind enabling the storage of one or more compounds inside of the microchip in any form(solid, liquid, or gel), with the release of the compounds achieved on demand and with no moving parts.
What sparked the invention of the microchip?
Dr. Robert Langer, Kenneth J. Germeshausen Professor of Chemical and Biomedical Engineering at MIT, conceived of the microchip idea while watching a documentary on the mass production of microchips. He envisioned numerous applications for a microchip that could controllably release chemicals or drugs. He thought, for example, that it may be possible to create a microchip that would be placed in televisions that could release scents corresponding to the picture shown on the screen.
What was an exciting moment in the research?
Witnessing the first demonstration of the release of a compound from the microchip was exciting. However, there were not many sudden leaps. Instead, progress over the years has been steady. We encountered numerous technical challenges along the way such as material selection, process design, and reservoir filling issues, but we were able to develop solutions for each of these.
How does the microchip work?
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 volt) 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 volt 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.
How are the reservoirs controlled individually?
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" by directing power to a particular reservoir based on a code sent to the demultiplexer by a microprocessor or remote control.
Size of the prototype device
The prototype device is approximately the size of a United States dime. A device this size could theoretically contain over 1000 reservoirs. However, the microchips could easily be made much smaller or much larger, depending on the particular application.
Our respective contributions to the project
Dr. Robert Langer, Kenneth J. Germeshausen Professor of Chemical and Biomedical Engineering at MIT, conceived of the microchip idea while watching a documentary on the mass production of microchips. He envisioned numerous applications for a microchip that could controllably release chemicals or drugs.
He contacted Dr. Michael Cima, Sumitomo Electric Industries Professor of Ceramic Processing at MIT, about collaborating on the development of such a technology. Dr. Cima proposed that the microchip's release mechanism be based on the electrochemical dissolution of a thin metal membrane.
While still a junior at the University of Michigan, John T. Santini Jr., now a doctoral student in chemical engineering at MIT, began work on the project in 1993 as a student in the MIT Materials Processing Center's Summer Scholars Program. Beginning with the initial microchip concept, John developed a process for fabricating controlled release microchips, designed experiments demonstrating proof-of-principle release of chemicals from prototype microchips, and found solutions for a number of the technical challenges that were encountered while developing the prototype device.
What were some of the technical challenges encountered while developing the microchip and how were they overcome?
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. We desired to find 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 the metal 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 or PBS) 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. 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.)
The fabrication of unsupported gold membranes involved several 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 (>700ï¿½ï¿½ï¿½C) 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 of these cases, the challenge was to determine the processing conditions that resulted in the formation of a defect free, low stress gold membrane. To reduce defects, we fabricated the devices in a low particulate environment (class 100 cleanroom) and rearranged processing steps so that the devices were never exposed to temperatures above 350ï¿½ï¿½ï¿½C after the gold was deposited. To reduce the stress in the gold membrane, we deposited the silicon nitride support layer 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.
Gold anodes exposed to a chloride containing solution will corrode when an electrical voltage of approximately +1 volt is applied. However, there are some portions of each anode that must be protected from unwanted corrosion, such as those parts of the anode not directly covering the reservoir. This protection can be achieved by an adherent, low porosity coating that isolates the electrode materials from the surrounding solution.
Silicon dioxide (SiO2) was selected as a model protective coating for the prototype device because it is a material commonly used in microfabrication processes and its physical properties can be tailored to a particular application by selecting appropriate processing conditions. The challenge was to determine the processing conditions that resulted in an adherent, low porosity coating. We demonstrated experimentally, and verified with the scientific literature, that SiO2deposited by chemical vapor deposition (CVD) at low temperatures (<100ï¿½ï¿½ï¿½C) tends to be porous and is non-adherent when placed in solution. In addition, high temperature (>700ï¿½ï¿½ï¿½C) deposition or annealing of SiO2 results in denser (less porous) SiO2, but may also lead to thermal grooving and the formation of voids (pinholes) in the gold membrane anodes. We found that plasma enhanced chemical vapor deposition (PECVD) at moderate temperatures (350ï¿½ï¿½ï¿½C) addresses these problems and produces SiO2 films possessing adequate density and adhesion with negligible gold void formation. More importantly, examination of prototype microchips by light microscopy revealed that this coating provides adequate corrosion protection to the underlying gold.
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. We solved this problem by applying inkjet printing and micro-injection techniques to fill the reservoirs. For the inkjet printing process, we used a computer-controlled positioning apparatus developed in Dr. Cima's lab to position an inkjet printhead directly above a reservoir.
The inkjet printhead was then used to deposit a number of drops into the reservoir through the large (500 mm) reservoir opening on the backside of the microchip. The 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 that chemical in the filling solution, we can calculate the amount of chemical deposited in each reservoir with either filling method.
Has this microchip technology been patented?
A broad United States patent (#5,797,898) covering this microchip technology was issued on August 25, 1998 to John T. Santini Jr., Michael J. Cima, Robert Langer, and Achim M. Gï¿½ï¿½pferich, an MIT visiting scientist during the early stages of the project now at the Lehrstuhl Fï¿½ï¿½r Pharmazeutische Technologie Universitï¿½ï¿½ï¿½ï¿½ï¿½ï¿½t Erlangen-Nï¿½ï¿½rnberg. 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 Gï¿½ï¿½pferich).