A controlled release microchip
Author(s)Santini, John Thomas, 1972-
Massachusetts Institute of Technology. Dept. of Chemical Engineering.
Robert S. Langer and Michael J. Cima.
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It is well known that the method by which a drug is delivered can have a significant effect on the drug's therapeutic efficacy. There exist numerous cases where constant release is not the optimal method of drug delivery; instead, delivery of pulses of drug at variable time intervals is the preferred method. This method is commonly referred to as pulsatile delivery, and it is preferred in some cases because it closely mimics the way in which the human body naturally produces the compounds. The objectives of this thesis were to design, fabricate, and characterize a microchip capable of achieving both pulsatile and continuous release of multiple chemical substances on demand. Each prototype microchip consisted of an array of reservoirs etched into and extending through a silicon wafer. Each reservoir was covered on one end by a thin conductive membrane that served as the anode in an electrochemical reaction. The reservoir was filled with chemicals through the other side of the reservoir and was then sealed. The proposed release mechanism had no moving parts and was based on the electrochemical dissolution of a thin anode membrane covering each reservoir. Each reservoir was independently addressable, and the electric potential was applied to an anode membrane using wires and a potentiostat. Future integration of microelectronic components may allow reservoirs to be opened on demand by a preprogrammed microprocessor, remote control, or by biosensors and biofeedback controllers. Potential advantages of the microchip for the release of drugs and other chemicals may include its small size, low power consumption, and the absence of moving parts. Such microchips may find application in a wide array of fields such as drug delivery, medical diagnostics, chemical detection. industrial process monitoring and control, and micro-scale chemical synthesis. A process was developed for producing prototype microchips using microfabrication methods such as ultraviolet photolithography, chemical vapor deposition (CYD), reactive ion etching (RTE), and electron beam evaporation. An important component of this process was a procedure for making thin ( I 000-3000 [angstroms]), unsupported, metal membrane anodes on silicon. In addition, the fabrication process was designed so that the chemicals to be released would !lever be exposed to solvents, acids, bases, or high temperatures. This was accomplished by completing all device fabrication steps before reservoir filling. This important process feature would be especially useful when dealing with easily denatured molecules such as proteins or DNA. Gold was selected as the model membrane and electrode material for the prototype controlled release microchips primarily due to its unique electrochemical properties. It is easily deposited and patterned, has a low reactivity with other substances, and resists spontaneous corrosion in most aqueous solutions over the entire pH range. However, the presence of a small amount of chloride ion in solution creates an electric potential/pH region that thermodynamically favors the dissolution of gold as water soluble gold chloride complexes. Experiments showed that gold thin films are rapidly corroded in saline solution and that corrosion occurs preferentially in the grain boundaries. Release studies were conducted to demonstrate that single and multiple substances could be released from microchip devices on demand. Sodium fluorescein (a fluorescent dye) and radioactive calcium (in the form, 45CaCI) were chosen as model substances for release due to their simplicity of detection in solution. Prototype devices were filled with one or both substances, sealed, and submerged in either phosphate buffered saline or 0.145 M NaCl solution. A potential of+ 1.04 volts relative to a saturated calomel reference electrode (SCE) was applied between a gold membrane anode covering a filled reservoir and a cathode. Electrochemical dissolution of the gold membrane anode typically occurred within 10-20 seconds of application of the potential. Once the reservoir was opened, the compound in the reservoir was able to diffuse into the surrounding solution and was detected by fluorescence spectroscopy or scintillation counting. This process was repeated to obtain multiple releases from a single device. Disintegration refers to the "falling apart" of a gold membrane over a reservoir resulting from gold corrosion and possibly. applied physical stresses. The visualization of the membrane disintegration process was achieved by videotaping the corrosion of gold membranes through a microscope. The observations from these in situ membrane disintegration experiments were then combined with gold corrosion concepts and data to develop a qualitative mechanism for the disintegration of thin. gold membranes covering chemical reservoirs. Future work should focus on materials science issues, microelectronics fabrication and packaging, and in vivo studies.
Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1999."September 1999."Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Dept. of Chemical Engineering.
Massachusetts Institute of Technology