Liquid chromatograph on a chip

Details Liquid chromatograph on a chip Liquid chromatograph on a chip

1999-09-17

2001-07-10

Therkorn, Ernest G. (Department: 1723)

Liquid purification or separation

With means to add treating material

Chromatography

C210S656000, C204S451000, C204S601000, C422S070000

Reexamination Certificate

active

06258263

ABSTRACT:

FIELD OF THE INVENTION
The invention generally relates to microelectromechanical system (MEMS) devices and methods of making the same, and more particularly, to a chromatograph micromachined using MEMS technology.
BACKGROUND OF THE INVENTION
Liquid chromatography is one of the most widely used techniques for separation and analysis of liquid samples. Liquid chromatographs are used as the apparatus for analyzing samples. Liquid chromatography is a method of chemical separation that involves passage of a liquid phase through a solid phase and relies on subtle chemical interactions to resolve complex mixtures into pure compounds. In a liquid chromatograph, a sample is mixed with a carrier. The components of the sample are separated while flowing through a separation column, and sample components are fixed and identified by referring to a resulting chromatogram. A liquid chromatograph employs a material that is located in a separation column and selected depending on a sample to be analyzed. This material comprises the stationary phase of the liquid chromatograph. The liquid phase carrier transports the sample through the stationary phase. Thermodynamic differences in the interaction of components of the sample with the mobile (liquid) and stationary (usually a solid) phases causes the components to separate. This phenomenon produces a chromatogram which can subsequently be used to identify the components of the sample.
Certain stationary phases utilize relative ionic bond strength to cause the components of a sample to separate. Ion exchange is typically used for separation and determination of organic and inorganic ions in complex mixtures. In ion exchange separation, the stationary phase has charge-bearing functional groups. The sample components then compete with the mobile phase ion for ionic sites on the stationary phase. This bonding allows one to tailor the surface chemistry of this phase to give virtually any desired interaction.
Conventional chromatographs are bulky pieces of lab equipment. Such cumbersome pieces of equipment are also not amenable to transport and/or use at remote locations. Other important practical problems associated with conventional chromatographs include high-solvent consumption and long analysis time. As such, they cannot be used for on-line process control and real time data monitoring on a continual basis. Typically, an assay run through these liquid chromatographic systems can require from at least thirty minutes to over sixty minutes to complete a sample analysis. For example, analysis of amino acids is an arduous and lengthy process because of the many components to be analyzed. The standard assay of amino acids can take up to thirty minutes and the physiological fluid assay may require as much as 110 to 140 minutes to complete.
The time required for processing creates additional problems. Chemical sensor technology for on-line sensing is currently lagging behind needs, particulary in the chemical and pharmaceutical industries, in environmental monitoring, and for a wide range of medical applications. Due to the length of time on-line or real time detection is not an option for most applications. This limitation can have profound consequences. For example, in the chemical process industry, product quality and process safety are often directly influenced by the speed with which accurate and reliable chemical composition data can be obtained. The traditional approach to on-line chemical detection has been to develop highly selective sensors. While this approach has had some noticeable successes, it has also been plagued with a variety of difficulties, primarily in developing suitable selective sensors for the enormous variety of problems faced. Thus, it would be advantageous to shorten the time required to analyze a sample.
One method by which the analyzing time of a conventional liquid chromatograph can be shortened is by reducing the size of resin particles filled in the separation column. However, one problem with this size reduction of the resin particles is that they have a tendency to pack together. Once this compaction occurs, gravity is unable to singularly urge the liquid or mobile phase of the chromatograph through the separation column. This problem has been overcome through the use of a highly pressurized system to force the liquid phase to pass through the solid phase in the chromatographic column. This sort of chromatography is referred to as “high pressure” or “high performance” liquid chromatography (HPLC). However, the reductions in size of resin particles does not involve a corresponding reduction in the size of the chromatographic equipment to a degree that would facilitate use of the chromatograph for remote sensing.
One method of reducing the size of the chromatograph and other such devices is through the application of microelectromechanical systems (MEMS) technology. New applications and uses for microelectromechanical systems are continuously being developed. Many of these systems typically include one or more microactuated devices that are batch micromachined into silicon wafers or other substrates in part using many of the photolithographic batch fabrication techniques developed for fabricating electronic devices, except that the etching is expanded into the third dimension. Microactuated devices typically include movable members or components that are either driven by an electrical stimulus to perform mechanical tasks or are sensory elements that generate an input into an electronic system in response to a physical stimulus or condition. In addition, by virtue of the commonality of many manufacturing processes, control and other support electronics may also be fabricated onto the same substrates as the microactuated devices, thereby providing single chip solutions for many microelectroinechanical applications.
The general approach in trying to miniaturize a chromatograph, or any other device, involves copying the function of the device as it exists on a macro-scale. On a macro-scale, efficiency in a chromatograph is enhanced by minimizing the distance that molecules of sample have to travel prior to being adsorbed onto the surfaces of the solid particles that are normally present in chromatographic systems. The primary way to achieve this minimization is to reduce the diameter of the separation column.
However, reducing the size of a chromatograph by using microelectromechanical system technology can result in additional drawbacks. Such a miniaturized chromatograph will be unable to utilize the filled column solid phase which is found in high performance liquid chromatography (HPLC), any filler particles being simply too large for the separation component of the chromatograph. As a result, open tubular liquid chromatography (OTLC) is often used as an alternative approach to the conventional filled column of HPLC. Studies have demonstrated that OTLC can provide results in some aspects comparable, and in some aspects greatly superior, to those typically attained using the conventional HPLC apparatus. For a good performance, an OTLC column must be made very narrow (less than 10 micrometers in diameter) which at the same time requires an adequate sample injection system and detector cell of comparably small volumes. This small size of the separation column makes OTLC amenable for use in a chromatograph fabricated using MEMS technology.
Another problem that immediately presents itself upon such a severe reduction in size of the separation column, is the increased pressures that occur across the device. Most of the problems and limitations in the development of OTLC micro-channels are related to the high pressure involved in pumping liquids through the miniature structures, which are typically formed as shallow cavities isotropically or anisotropically etched in silicon. In a macro-system chromatograph, there is essentially no limitation on the pressure drop because a pump can be built to a size sufficient to pump the carrier through the separation column in a very uniform velocity profile. In reducing a chromatograph to t

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