Gas and liquid contact apparatus – With external supply or removal of heat – Plural distinct contact zones
Reexamination Certificate
2001-10-23
2003-03-18
Riley, Jezia (Department: 1637)
Gas and liquid contact apparatus
With external supply or removal of heat
Plural distinct contact zones
C261S151000, C261S152000, C261S153000, C261S155000, C261S004000, C261S006000, C261S091000, C261S091000
Reexamination Certificate
active
06533255
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a heating apparatus for biological/chemical samples, which device includes PCR thermal cyclers. The present invention relates also to a method of heating biological/chemical samples, which method includes PCR.
2. Description of the Related Art
The polymerase chain reaction (PCR) has become a widely used tool in molecular biology. This technique allows one to quickly and easily amplify segments of nucleic acid for further investigation and analysis. Roughly two types of automated PCR instruments are conventionally available on the market.
The first type is based on a robotic arm (such as RoboCycler™ from Stratagene). In this type, temperature control is accomplished by using a stationary heating block, and samples are transferred mechanically between blocks set at different temperatures according to programmed steps. The samples are moved by the robotic arm in either a circular or linear direction. The heating blocks comprise wells in which test tubes (or micro titer plate) are fitted, and it is normally necessary to fill the wells with either water or mineral oil for sufficient heat transfer.
The second type is a fully integrated and dedicated PCR thermocycler. The PCR thermocycler relies on a thermoelectric element for the Peltier effect to provide rapid change of temperature. Depending on the direction of electric current, the thermoelectric element can either heat or cool a sample on demand. Thermo-cycling parameters are programmed into a temperature controller.
The first type uses at least three heating blocks whose temperatures are set at 55° C., 72° C., and 94° C., respectively. The second type uses a thermocycler with a heating block whose temperature is controlled to change to 55° C., 72° C., and 94° C. in one cycle. Conventional heating blocks have a plurality of wells for receiving test tubes, and the heating blocks heat the test tubes with an electric resistance, for example, and cool them by circulating a liquid through elaborate channels inside the heating blocks or by a thermoelectric element, for example. The fluid for cooling is commonly a water-based medium. The elaborate channels for cooling are machined into the holding blocks to allow either tap water or refrigerated water to circulate throughout. Although such a setup can give very high cooling rates, high costs are associated with this system and make this type of configuration unacceptable. Thus, a combination of an electric resistance and a thermoelectric element provided in a metal heating block is the most frequently used configuration.
The holding block is specifically machined to fit a particular brand of test tubes in order to provide a maximized contacting surface to enhance heat transfer. The holding blocks are made interchangeable to accommodate an assortment of different test tubes or microtiter plates from different vendors. Even if the surface of the holding block is precisely machined, the area actually contacting each sample holder (i.e., test tube or microtiter plate) may vary due to minor imperfections in plastic injection molding. A variety of methods are employed to alleviate this problem, including force clamping and adding mineral oil, to fill the gap between the surface of a holding block and the surface of a sample holder. As the number of samples subjected to the holding block increases, means to ensure temperature uniformity between different samples become important.
Further, the heating block itself has temperature distribution. If the heating block has 96 wells, wells at different corners may have different temperatures.
Although heat transfer difference may occur at contacting surfaces between test tubes and respective wells, and uneven heat diffusion may occur within the heating block, there is no way to verify the accuracy of the temperature. Users must rely on a temperature indicator installed in the heating block.
In addition, the wells of the heating block are designed specifically for particular test tubes, and thus, a 96-well format heating block cannot be used for any other format PCR plates such as a 384-well format. Further, one heating block holds only one PCR plate.
SUMMARY OF THE INVENTION
To guarantee the success of experiments and allow users to directly compare samples from the same run or different runs at different times using the same program, it is essential to have all samples reach the same temperature during each cycle. The uniformity of heating and cooling rates across the entire holding block surface, as well as the physical fit between wells and test tubes, are very important.
In accordance with the present invention, an improved polymerase chain reaction thermal cycler can be implemented based on liquid metals. The invention is based on the realization that liquid metals have a comparable heat conductivity and capacity to that of metal and at the same time are not confined to having a pre-defined shape. This enables the use of sample test tubes from different vendors without switching test tube holding blocks. Precise temperature control and rapid temperature cycling is carried out by liquid metals. In addition, pumping and switching of liquid metal can be based on magnetohydrodynamics. Furthermore, in one embodiment, multiple plates can be treated at one time when using a large liquid metal bath. By using a large liquid metal bath comprising a plurality of heating and cooling sections, which bath has a length sufficient to complete PCR cycles without physically circulating test tubes in the bath, continuous input of samples and continuous output of PCR products can be performed simultaneously, resulting in surprisingly high productivity.
The present invention can be adapted to any type of heating and cooling device for biological/chemical samples which require accurate temperature control. The claimed invention is directed to an apparatus for temperature control of samples comprising at least one container containing liquid metal, said container having an upper open area where the liquid metal thermally contacts one or more of the samples for temperature control thereof; and a temperature control device for heating the liquid metal, whereby said liquid metal remains in a liquid state and does not significantly evaporate during heating.
The container containing the liquid metal may be either a plastic or metal container. The temperature control device for heating the liquid metal may be the heat block of a thermal cycler.
A variety of liquid metal compositions may be used in the practice of the claimed invention. Compositions containing gallium may be preferred. A most preferred composition may be a 75.5% gallium/24.5% indium alloy.
The apparatus of the presently claimed invention may include a plurality of containers containing liquid metal and one sample container. The sample container may then be moved through a series of containers containing liquid metal by any convenient means such as manually or mechanically, for example, by use of a robotic arm.
Alternatively, the liquid metal may be moved through the sample container. The liquid metal at a first temperature may be replaced by liquid metal of a second temperature. Movement of the liquid metal, either within the sample container or its injection and removal from the sample container may be accomplished by a conventional pump. Alternatively, movement of the liquid metal may be accomplished by magnetohydrodynamics in either AC or DC mode. Of course, gravity may also be used to move the liquid metal.
The containers containing liquid metal may also be linked to other apparatus for sample treatment such as a robotic liquid handler and dispenser, a cell incubator and/or a detection system such as a Luminex 100, for example.
The claimed apparatus may be used in a method of incubating one or more biological/chemical samples at a pre-determined temperature comprising contacting the one or more biological/chemical samples with a container containing liquid metal at the pre-determined temperature for a given time peri
Chu Charles Y.
Mitsuhashi Masato
Hitachi Chemical Research Center Inc.
Knobbe Martens Olson & Bear LLP
Riley Jezia
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