Electricity: measuring and testing – Determining nonelectric properties by measuring electric... – Particle counting
Utility Patent
1998-09-18
2001-01-02
Metjahic, Safet (Department: 2858)
Electricity: measuring and testing
Determining nonelectric properties by measuring electric...
Particle counting
C324S692000, C422S082020
Utility Patent
active
06169394
ABSTRACT:
BACKGROUND OF THE INVENTION
1. The Field of the Invention
The present invention relates generally to detector systems for measurement of the electrical characteristics of liquids, gases and biological materials. More specifically, the present invention relates to an electrical detector for micro-analysis systems capable of providing conductivity or impedance based measurements on a microscale of particulates in liquids or gases, and biological materials such as living cells.
2. The Relevant Technology
The electrical properties of cells, organelles, and protein solutions are of fundamental interest in the fields of biophysics, physiology, biotechnology, and medicine. Various electrical properties have previously been studied by a variety of methods such as pipette, dielectrophoretic, or electrorotational methods.
In the case of living organisms, pipette based methods suffer the disadvantage of being inherently invasive and require access to the intracellular space. Dielectrophoresis (DP) and electrorotation (ER) are relatively well established techniques for studying dielectric properties such as membrane capacitance and conductance, as well as cytoplasmic permittivity, of individual isolated cells. The DP and ER techniques measure the net force and torque which are generated when the substance of interest is placed in a nonuniform electric field. However, in order to extract the required information, namely the polarization vector, it is necessary to know both the electric field and the distribution of induced forces and moments. The actual electric field is dependent upon the geometry and the materials involved, and can be interpreted to some extent though the use of the measured data along with the appropriate electromagnetic model. The distribution of the internal forces and moments, however, can not be measured directly, but must be inferred from other information, such as a measurement of whole cell velocity, which can be subsequently analyzed using the Stokes approximation. This presents a problem in that a priori models describing the shape of the cell and the constitutive properties within the cell are required to estimate the dielectric parameters.
Recently, developments have been made in the area of microfabricated devices to more efficiently analyze the dielectric properties of small biological systems, particularly different types of cells. For example, a micro-ER device has been developed in which four gold electrodes are electroplated and oriented orthogonally on a glass wafer to create a recording zone on the surface of the wafer. Gimsa et al.,
Biophysical Journal,
vol. 71, p. 495-506 (1996). Although this micro-ER device is capable of somewhat smaller spatial resolution, the device still suffers from the aforementioned difficulties generally associated with ER systems, and in addition, fails to resolve electrical characteristics on a subcellular level.
Electric impedance measurements have previously been demonstrated as an effective technique to characterize dielectric properties of tissues or cell suspensions. The electric impedance of tissues and cells is of interest in part because the impedance is known to vary with the morphology, histopathology, and electrophysiology of certain cells, and can therefore be used to monitor or detect certain pathological conditions or changes in the cells. Prior electric impedance measurement systems for cell layers and tissues have been developed. For example, an impedance sensing system has been developed which performs impedance spectroscopy, i.e., impedance variations in tissue and cell layers measured as a function of applied alternating currents (AC), typically in the range of 20 to 50,000 Hz. Lo et al.,
Biophysical Journal,
vol. 69, p. 2800-2807 (1995). The sensing system was fabricated by sputtering gold onto thin polycarbonate sheets, and photolithography was used to delineate the desired gold patterns on the thin sheets and form the active electrode pairs. Although the Lo system is usefull in providing additional information on the resistive and capacititve properties of cells and cell membranes, the system fails to resolve electrical characteristics on a subcellular level.
Many of the recent medical and drug advances can be tied directly to improvements in chemical and biological analysis systems. These analysis systems are used to study all kinds of chemicals and biological molecules and to screen these particles for efficacy in various medical applications. Such techniques include electrophoresis, gas and liquid chromatography, the various biosensor devices that use proteins, DNA, antibodies, cells, and other biological particulates. Of critical importance to all of these techniques is the detection, monitoring, and transduction methods used to collect, observe, and interpret the signals, separation, or reaction generated by the device. Almost every method for energy transduction has been used to measure and observe signals in these various devices including optical, electrical, mechanical, thermal, chemical, magnetic and others. The most sensitive techniques and those generally used for the various analysis systems, and more specifically, chromatography systems, are optical measurements involving either fluorescence or UV absorption and reflection.
The optical techniques generally used with chromatography systems have several disadvantages. They are generally very bulky, expensive, complex, and often require modification of the sample being detected in order to perform measurements. These optical techniques are also very sensitive to physical movement and require considerable maintenance. While the UV extinction and light scattering techniques are quite robust and allow for a wide variety of sample types, they are also expensive and bulky. For large-scale labs with fixed laboratory equipment, these detection techniques provide high sensitivity and are well characterized and developed, but are not suitable for use with portable equipment, and especially for use with the new generation of microscale analysis systems.
In recent years, development has been made toward integrating a collection of microscale chemical and biological analysis systems on one chip, the so-called lab-on-a-chip design. A number of individual biological and chemical analysis techniques have been demonstrated in a micro-scale system and have been implemented using micromachining technology. These systems include electrophoresis, free-flow electrophoresis, electrical field-flow fractionation (EFFF), polymerase chain reaction (PCR), gas chromatography, liquid chromatography, and hybrid systems.
Unfortunately, most micromachined systems rely on off-chip components to perform the bulk of the detection and signal processing functions. These detection systems are generally the same as those used for the corresponding macro-analysis system with slight modifications for working on the smaller microscale systems. In many cases, after processing the sample using the microscale device, the sample is moved off chip for analysis. Moving the sample off-chip, though, can be very detrimental in terms of resolution for chromatography systems, and measurement quality for other systems.
Thus, there is a need for a simple, inexpensive, and micromachinable detection system with application to a variety of devices and manufacturable on a number of different surfaces.
SUMMARY AND OBJECTS OF THE INVENTION
It is a primary object of the present invention to provide a system for high resolution measurement of the electrical characteristics of biological systems such as cellular and subcellular structures, or of other very small samples of materials.
It is yet another object of the invention to provide a device for the detection of particles which have been separated by a biological or chemical micro-analysis system and which can be incorporated onto the same chip as the micro-analysis system.
A further object of the invention is to provide a conductivity or impedance detector device for particles which have been separated by micro-analysis systems which achieves
Ayliffe H. Edward
Frazier A. Bruno
Rabbitt Richard D.
Metjahic Safet
Solis Jose M.
University of the Utah Research Foundation
Workman & Nydegger & Seeley
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