Chemistry: molecular biology and microbiology – Apparatus – Mutation or genetic engineering apparatus
Reexamination Certificate
1999-04-21
2003-03-25
Siew, Jeffrey (Department: 1637)
Chemistry: molecular biology and microbiology
Apparatus
Mutation or genetic engineering apparatus
C435S006120, C435S007100, C435S091100, C435S091200, C422S068100, C422S098000, C422S091000, C204S155000, C204S164000, C204S450000, C204S459000, C204S600000
Reexamination Certificate
active
06537799
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention generally relates to microfluidic systems. More particularly, the present invention provides a technique, including methods and devices, for providing and controlling heat to fluid in a channel of a microfluidic system in an efficient manner. Merely by way of example, the invention is applied to a polymerase chain reaction process, commonly termed PCR, but it will be recognized that the invention has a much wider range of applicability. The invention also provides techniques for monitoring and controlling a variety of process parameters using resistivity and/or conductivity measurements.
There has been a growing interest in the manufacture and use of microfluidic systems for the acquisition of chemical and biochemical information. Techniques commonly associated with the semiconductor electronics industry, such as photolithography, wet chemical etching, etc., are being used in the fabrication of these microfluidic systems. The term, “microfluidic”, refers to a system or device or “chip” having channels and chambers which are generally fabricated at the micron or submicron scale, e.g., having at least one cross-sectional dimension in the range of from about 0.1 &mgr;m to about 500 &mgr;m. Early discussions of the use of planar chip technology for the fabrication of microfluidic systems are provided in Manz et al.,
Trends in Anal. Chem.
(1990) 10(5):144-149 and Manz et al.,
Adv. in Chromatog.
(1993) 33:1-66, which describe the fabrication of such fluidic devices and particularly microcapillary devices, in silicon and glass substrates.
Applications of microfluidic systems are myriad. For example, International Patent Appln. WO 96/04547, published Feb. 15, 1996, describes the use of microfluidic systems for capillary electrophoresis, liquid chromatography, flow injection analysis, and chemical reaction and synthesis. U.S. Pat. No. 5,800,690, assigned to the present assignee, discloses wide ranging applications of microfluidic systems in rapidly assaying large number of compounds for their effects on chemical, and preferably, biochemical systems. The phrase, “biochemical system,” generally refers to a chemical interaction which involves molecules of the type generally found within living organisms. Such interactions include the full range of catabolic and anabolic reactions which occur in living systems including enzymatic, binding, signaling and other reactions. Biochemical systems of particular interest include, e.g., receptor-ligand interactions, enzyme-substrate interactions, cellular signaling pathways, transport reactions involving model barrier systems (e.g., cells or membrane fractions) for bio-availability screening, and a variety of other general systems.
Many chemical or biological systems also desire control over processing parameters such as temperature, concentration of reagents, buffers, salts and other materials, and the like. In particular, some chemical or biological systems require processes to be carried out at controlled or varied temperature. In providing such a controlled temperature in miniaturized fluidic systems, external heating elements have generally been used. Such heating elements typically include external resistive heating coils or material, which provide heat to the fluidic system in a conductive manner. This heating unit attaches itself directly to an external portion of the chip to globally heat the chip and to provide a uniform temperature distribution to be present on the chip. This heating unit, however, is cumbersome. It also complicates chip manufacturing and often affects quality and reliability of the chip. Additionally, the resistive heating element often fails, which can damage the chip, equipment, and the environment. Furthermore, the resistive heating element generally cannot effectively control heat supplied to the chip, which often causes large undesirable temperature gradients and fluctuations in the chip. Accordingly, the resistive heating element applied directly to the chip is extremely limited (e.g., cannot heat locally) and unreliable in controlling process temperature in the chip.
Larger scale temperature controllers have also been used to control reaction temperatures within a reaction vessel, including, e.g., hot-plates, water baths, and the like. These larger temperature control elements have been commonly employed in biological and chemical laboratory environments to heat fluid in beakers, test tubes, and the like. Unfortunately, such controllers are not well suited to providing accurate control of temperature within a microfluidic system. In fact, such global heating systems heat the entire material region of the microfluidic device and cannot be used to selectively apply heat to specific regions of the microfluidic device, e.g., specific channels or chambers. Additionally, these large temperature controllers, e.g., hot plates, often require large resistive heating elements, which transfer heat via conduction. These resistive heating elements possess a large characteristic response time, which often relates to a long time to heat or cool material within a reaction vessel in contact therewith in some applications. Accordingly, hot plates can be extremely limited for use in heating fluid in microfluidic applications.
Other process parameters in the microfluidic system such as fluid concentration, pH, and the like typically cannot be controlled by way of conventional techniques. A user of the microfluidic system often verifies fluid concentration or pH at the fluid source (e.g., bottle), but the user generally cannot monitor such fluid parameters while the fluid in being used in the microfluidic system using conventional techniques. In fact, there is simply no easy or efficient way to check these parameters once the fluid enters into channels or processing chambers of the microfluidic system. Accordingly, it is often difficult, if not impossible, to verify the integrity of a process by monitoring these process parameters.
From the above, it is seen that a technique for selectively controlling a variety of process parameters in a microfluidic system that is easy, efficient, and safe is highly desirable.
SUMMARY OF THE INVENTION
According to the present invention, techniques including methods and devices for controlling process parameters such as fluid temperature, concentration and the like of material (e.g., fluid) in a microfluidic system is provided. The present invention uses, for example, electric current applied through the material for heating purposes. Since only a small volume of the material is heated, the material can be successively heated and cooled by controlling the application of electric current to the material for a variety of chemical and biological applications, e.g., PCR and others. Additionally, the invention provides techniques for monitoring process parameters such as temperature, fluid concentration, pH, and the like during a process step. Accordingly, an in-situ technique for monitoring these process parameters is provided.
In one aspect, the present invention provides a microfluidic system having a controlled temperature element. In particular, the system comprises a substrate having at least a first fluid-filled microscale channel disposed therein. The system also includes a means for elevating a temperature of the fluid in the first portion of the channel, by applying a first controlled electrical current or voltage through the first portion of the channel. The current is optionally applied through the first channel or through a second channel intersecting the first channel. Regions may be selectively heated by providing those regions with different, e.g., narrower cross-sectional areas, to increase the current density in those regions, and thus, the heat generated from that current.
In a related aspect, the present invention provides a microfluidic system having one or more thermal elements included therein. The system comprises a first channel defined in a substrate, where the channel includes a first end and a second end. A first energy sour
Chow Calvin Y. H.
Kopf-Sill Anne R.
Parce J. Wallace
Caliper Technologies Corp.
Shaver Gulshan H.
Siew Jeffrey
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