WO2007082466A1

WO2007082466A1 - A capillary heating device

Info

Publication number: WO2007082466A1
Application number: PCT/CN2007/000161
Authority: WO
Inventors: Min Guo; Keyue Shen; Cheng Zhou; Xiaosheng Guan; Jing Cheng
Original assignee: Capitalbio Corporation; Tsinghua University
Priority date: 2006-01-19
Filing date: 2007-01-16
Publication date: 2007-07-26
Also published as: CN101004287B; CN101004287A

Abstract

A capillary heating device comprises a capillary tube for passing fluid, a resistive heating element (4) for heating the capillary tube, and a temperature regulation element for modifying the temperature of the capillary tube. The temperature regulation element can either be sandwiched between the resistive heating element (4) and the outer surface of the capillary tube, or wraps around the resistive heating element (4) and the capillary tube.

Description

A CAPILLARY HEATING DEVICE

TECHNICAL FIELD

[0001] This application relates to a capillary heating device for heating a capillary and fluid contained therein. The device uses a temperature regulation element to control the temperature along the length of the capillary tube.

BACKGROUND

[0002] Temperature control of capillary tubes is critical in various applications such as microfluidic devices. Because different portions of the capillary tubes are frequently exposed to different environmental variations, it is often difficult to maintain homogeneous temperature along the entire length of the capillary tube. Accordingly, there is a need for a capillary heating device that meets the needs for homogenous temperature control. There is also a need for a capillary heating device that creates a desired temperature profile on or along the capillary tube.

[0003] The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.

BRIEF SUMMARY OF THE INVENTION

[0004] The present invention provides a capillary heating device comprising: a capillary tube, a resistive heating element that is configured to increase the temperature of the capillary tube, and a temperature regulation element that is configured to modify the temperature profile of the capillary tube.

[0005] In some embodiments, the temperature regulation element comprises one or more layers, the resistive heating element comprises one or more layers, wherein at least one layer of the temperature regulation element is sandwiched between one layer of the resistive heating element and the outer surface of the capillary tube. In some embodiments, the temperature regulation element comprises one or more layers, the resistive heating element comprises one or more layers, wherein at least one layer of the temperature regulation element wraps around a layer of the resistive heating element, which in turn wraps around the capillary tube. In some embodiments, the capillary heating device further comprises one or more of the following: 1) a heating circuit, 2) a temperature sensing circuit, and 3) a controller. [0006] In some embodiments, the resistive heating element comprises electric conductive material selected from the group consisting of metals, non-metallic materials, chemical compounds, or combination thereof. The resistive heating element in some embodiments is connected to a heating circuit, for example via an electrically conductive copper foil ring. In some embodiments, the resistance of the resistive heating element monotonically changes with its temperature. In some embodiments, the resistive heating element is part of (or connected to) a temperature control device comprising a resistive heating element, a temperature sensing circuit, a heating circuit, and a controller, wherein the resistance of the resistive heating element monotonically changes with its temperature, wherein the temperature sensing circuit is configured to determine the temperature of the resistive heating element, wherein the heating circuit is configured to heat the resistive heating element, and wherein the controller is configured to control the activation of the temperature sensing circuit and the heating circuit.

[0007] In some embodiments, the thickness of the layers of the temperature regulation element is uneven, and may be designed (for example by adjusting the thickness of a layer or by altering the number of layers) according to a desired temperature profile of the capillary tube. In some embodiments, the distribution or thermal conductivitiy of the temperature regulation element is uneven (for example by using materials having different thermal conductivities), and may be designed according to the desired temperature profile of the capillary tube. In some embodiments, the temperature regulation element may be configured to modify the temperature profile along the length of the capillary tube, for example, to maintain a homogeneous temperature distribution along the length of the capillary tube. Alternatively, the temperature regulation element may be configured to create a temperature gradient along the length of the capillary tube.

[0008] In some embodiments when homogenous temperature distribution along the length of the capillary tube is desired, the temperature regulation element may comprise at least one layer of low thermal conductive material, the two ends of the layer of the low thermal conductive material along the capillary tube being thicker than the portion in the middle portion of layer. When the temperature regulation element comprises at least one layer of high thermal conductive material, the two ends of the layer of the low thermal conductive material along the capillary tube is thinner than the portion in the middle portion of the layer.

[0009] In some embodiments, the temperature regulation element comprises multiple separate portions. For example, in some embodiments, the temperature regulation element comprises two separate portions located at the two ends of the capillary tube, each portion comprising at least one layer of a low thermal conductive material.

[0010] In some embodiments, the ratio of the length to the largest cross section of the capillary tube is more than about 2:1, including for example more than about any of 3:1, 4:1, 5:1, 10:1, 15:1, 20:1. In some embodiments, the largest cross section of the capillary tube is about 10 mm to about 0.002 mm, including for example about 5 mm to about 0.01 mm, about 1 mm to about 0.1 mm. In some embodiments, the thickness of the capillary tube is about 5 mm to about 0.001 mm, including for example about 2 mm to about 0.01 mm, about 1 mm to about 0.05 mm. In some embodiments, the length of the capillary tube is about 0.05 to about 5 mm, including for example about 0.5 to about 1 mm.

[0011] The capillary heating device may be integrated into systems (such as microfluidic devices). The invention thus also provides systems (such as microfluidic devices) comprising a capillary heating device described herein. In some embodiments, the system is automated. Also provided are kits comprising the capillary heating device described herein.

BRIEF DESCRIPTION OF THE FIGURES

[0012] Figure 1 provides a schematic diagram of an exemplary capillary heating device. [0013] Figure 2 provides gel electrophoresis showing results of PCR reactions using an exemplary capillary heating device of the present invention. Lanes 1 and 2 show PCR results using conventional PCR methods. Lanes 4 and 5 show PCR results using the capillary heating device of the present invention. Lanes 3 and 6 show blank controls of PCR reactions for lanes 1, 2 and 4, 5, respectively.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention provides a capillary heating device that allows the creation of a temperature profile along a capillary tube. Specifically, the capillary heating device comprises a capillary tube, a resistive heating element, and a temperature regulation element. The resistive heating element is configured to increase the temperature of the capillary tube, and the temperature regulation element is configured to modify the temperature profile (i.e., to adjust the temperature) of the capillary tube. The device can heat a fluid when the fluid is passing through the capillary tube. It is simple in structure and easy to be integrated. The device allows temperature in the capillary tube to be raised or lowered rapidly, with low energy consumption due to its small size and small heat capacity. [0015] "Temperature profile" used herein refers to desired temperatures at specific points of the capillary tube. Frequently, a temperature profile along the length of the capillary tube is desired. In some embodiments, the temperature profile is a homogenous temperature along the length of the capillary tube. In some embodiments the temperature profile is a temperature gradient along the length of the capillary tube. As described in further details below, the present invention utilizes a temperature regulation element to modify the temperature profile of the capillary tube. [0016] When fluid flows through a capillary tube, the regions at the two ends of the capillary tube cannot be wrapped completed by a resistive heating element, thereby forming a "cold zone." Accordingly, a temperature gradient along the capillary tube is created. The temperature regulation element is used to compensate for the temperature gradient and maintain homogeneous temperature along the length of the capillary tube. For example, when the temperature regulation material is a good thermal conductor, it can serve as an effective balance of the temperature distribution in the heating area and make the temperature more uniform and evenly. Similarly, when the layer of the high thermal-conductive temperature regulation material is thinner at the two ends of the capillary tube, a homogeneous temperature profile can be created along the capillary tube. The same effect can be achieved by wrapping the two ends of the capillary tube with temperature regulation material that has poor thermal conductivity. Similarly, when the layer of the low thermal-conductive temperature regulation material is thicker at the two ends of the capillary tube, a homogeneous temperature profile can be created along the capillary tube.

[0017] In some embodiments when the two ends of the capillary tube are wrapped with insulating temperature regulation materials, the temperature of the two ends can even be higher than that of the middle portion of the capillary tube. By altering the thickness or nature of the temperature regulation element, a desired temperature profile (such as a temperature gradient) can be established. [0018] The capillary tube, the resistive heating element, and the temperature regulation element may be present in different arrangements. For example, in some embodiments, a layer of the temperature regulation element is sandwiched between a layer of the resistive heating element and the exterior wall of the capillary tube. The temperature regulation element may further comprise additional layers of temperature regulation materials. These other layers may also be sandwiched between the layer of the resistive heating element and the exterior wall of the capillary tube. Alternatively, these additional layers may wrap around one or more layers of the resistive heating element. For example, the device may comprise one or multiple layers of resistive heating element wrapping around multiple layers of temperature regulation materials, which in turn wrap around the capillary tube. Alternatively, the different layers of the temperature regulation materials may be intercalated with different layers of resistive heating materials.

[0019] In some embodiments, a layer of temperature regulation material wraps around a layer of resistive heating element material, which in turn wraps around the capillary tube. The resistive heating element may comprise additional layers of resistive heating materials. These other layers may also be sandwiched between the layer of temperature regulation element and the exterior wall of the capillary tube. For example, the device may comprise one or multiple layers of temperature regulation materials wrapping around multiple layers of resistive heating materials, which in turn wrap around the capillary tube. Alternatively, the different layers of the resistive heating materials may be intercalated with different layers of temperature regulation materials. [0020] In some embodiments, there is provided a capillary heating device comprising: a) at least one capillary tube for passing a fluid; b) at least one resistive heating element, and c) a temperature regulation element sandwiched between the resistive heating element and the exterior wall of the capillary tube. In some embodiments, there is provided a capillary heating device comprising: a) at least one capillary tube for passing a fluid; b) at least one resistive heating element, wherein the resistive heating element wraps around the exterior wall of the capillary tube; and c) a temperature regulation element, wherein the temperature regulation element is located outside of the resistive heating element and wraps around the resistive heating element.

[0021] "Layer" used herein refers to a surface outside of the capillary tube. A layer can be, for example, a sheet of materials, a thin film formed by methods such as evaporation or sputtering, a surface formed by aligning wires, or wires winding around the capillary tube. In some embodiments, the layer is continuous. In some embodiments, the layer is discontinuous. For example, the layer may comprise two or more separate portions. Suitable thickness for a single layer (such as a film) includes, for example, about 10^"2 to about 10^"9 meters. In some embodiments, the layer is preformed and tightly wrap around the capillary tube. In some embodiments, the layer is formed by winding wires around the tube. Suitable cross sections for the wires include, for example, about 10^" to about 10^"9 meters.

[0022] A layer "wraps around" a capillary tube or another layer of a different nature if the inner surface of the layer is in direct contact with the outer surface of the capillary tube or the other layer. The contact can be partial or complete. A layer is "sandwiched" between the a layer of a different nature and the outer surface of the capillary tube if the inner surface of the layer is in direct contact with the capillary tube and the outer surface of the layer is in direct contact with the other layer of a different nature. When multiple layers of the same nature (e.g., multiple layers of the resistive heating materials or multiple layers of the temperature regulation materials) are piled together, each layer will be considered to be in direct contact with another layer of a different nature or the outer surface of the capillary tube if the inner surface or outer surface of one of the layers in the pile is in direct contact with the other layer of a different nature or the outer surface of the capillary tube. [0023] The capillary tube, the resistive heating element, and the temperature regulation layer can be joined together by any methods known in the art. For example, the layers can be joined together by wrapping, winding, sputtering, deposition, chemical synthesis, etc.

[0024] "Capillary tube" used herein refers to close-ended or open-ended capillaries. The term "capillary tube" used herein thus includes both capillary tubes and capillary channels. In some embodiments, the ratio of the length to the largest cross section of the capillary tube is more than about 2:1, including for example more than about any of 3:1, 4:1, 5:1, 10:1, 15:1, 20:1. In some embodiments, the largest cross section of the capillary tube is about 10 mm to about 0.002 mm, including for example about 5 mm to about 0.01 mm, about 1 mm to about 0.1 mm. In some embodiments, the thickness of the capillary tube is about 5 mm to about 0.001 mm, including for example about 2 mm to about 0.01 mm, about 1 mm to about 0.05 mm. In some embodiments, the length of the capillary tube is about 0.05 to about 5 mm, including for example about 0.5 mm to about 1 mm.

[0025] The resistive heating element allows the capillary tube to be heated. By applying voltage and current to the resistive heating element and producing a Joule heat from the resistance, the capillary tube and fluid contained within is heated by the Joule heat. The resistive heating element is made of a conductive material which may be any of metals, non-metallic compounds, or combination thereof with a defined resistance. Materials suitable for the resistive heating element include, for example, copper, aluminum, aurum, argent, and alloy. The resistive heating element can be of any shape that is compatible with the capillary tube. For example, in some embodiments when the resistive heating element is in direct contact with the capillary tube, the resistive heating element can be in the shape of wires winding around the outer surface of the capillary tube. The wires can have a defined cross sectional shape. The largest cross section of the wires can be about 10^"2 to about 10^"9 meters. Alternatively, the resistive heating element can be wires aligned at the outer surface of the capillary tube. In some embodiments, the resistive heating element can be in the shape of a sheet or film wrapping around the capillary tube. The thickness of the sheet or film can be about 10^"2 to about 10^"9 meters. In some embodiments, the resistive heating element is covered with an insulation layer. In some embodiments, the resistive heating element comprises multiple layers. [0026] The resistive heating element may be connected to a heating circuit. In some embodiments, the resistive heating element is connected to a temperature sensing circuit or a controller. In some embodiments, the resistive heating element is also part of a temperature control device, such as a temperature control device described in copending PCT application entitled METHODS AND DEVICES FOR CONTROLLING TEMPERATURE WITHOUT TEMPERATURE SENSOR, which is incorporated herein in its entirety (Attorney Docket No. 51457-20049.40) based on Chinese Patent Application CN200510135478.6.

[0027] In some embodiments, the resistive heating element is part of a temperature control device comprising (and in some embodiments consisting of or consisting essentially of): a resistive heating element, a temperature sensing circuit, a heating circuit, and a controller, wherein the resistance of the resistive heating element monotonically changes with its temperature, wherein the temperature sensing circuit is configured to determine the temperature of the resistive heating element, wherein the heating circuit is configured to heat the resistive heating element, and wherein the controller is configured to control the activation of the temperature sensing circuit and the heating circuit. In some embodiments, the resistive heating element is connected with four wires arranged sequentially, wherein the two distal wires are connected to the heating circuit, wherein the two middle wires are connected to the temperature sensing circuit, and wherein the connection points of the two middle wires on the resistive heating element are substantially far from each other.

[0028] In some embodiments, the resistive heating element is part of a temperature control device comprising (and in some embodiments consisting of or consisting essentially of): a) a resistive heating element, wherein the resistance of the resistive heating element monotonically changes with its temperature, b) a temperature sensing circuit configured to determine the temperature of the resistive heating element, comprising a first electric switch, a precision constant current source, a voltage differential amplifier, and an analog/digital converter, c) a heating circuit configured to heat the resistive heating element, comprising a second electric switch and a constant voltage source, and d) a controller configured to control the activation of the temperature sensing circuit and the heating circuit, wherein the output end of the amplifier is connected to the input end of the analog/digital converter, wherein the output end of the analog/digital converter is connected to the input end of the controller. In some embodiments, the resistive heating element is connected with four wires arranged sequentially, wherein the two distal wires are connected to the heating circuit, wherein the two middle wires are connected to the temperature sensing circuit, and wherein the connection points of the two middle wires on the resistive heating element are substantially far from each other. [0029] The temperature regulation elements described herein are made of temperature regulation materials. "Temperature regulation material" as used herein refers to materials with a defined thermal conductivity, and can be either thermal conductive or thermal non-conductive. By choosing a material with a specific thermal conductivity, thickness of the layer(s) of the temperature regulation materials, or arrangement of the temperature regulation materials on the device, a desired temperature profile can be created at different sites of the capillary tube or along the length of the capillary tube. [0030] When the temperature regulation element is configured to modify the temperature profile along the length of the capillary tube, the thickness of the layers of the temperature regulation material along the length of the capillary tube can be adjusted. This can be achieved by altering the thickness of a layer of the temperature regulation material, or the number of layers of the temperature regulation material. For example, in some embodiments when the temperature regulation element is configured to maintain a homogeneous temperature distribution along the length of the capillary tube and the temperature regulation element comprises a layer of low thermal conductive material, the layer(s) of the low thermal conductive temperature regulation material at the two ends of the capillary tube may be thicker than those at the middle portion of the capillary tube. When the temperature regulation element comprises a layer of high thermal conductive material, the layer(s) of the high thermal conductive temperature regulation material at the two ends of the capillary tube may be the same or thinner than those at the middle portion of the capillary tube. In one embodiment, the temperature regulation element comprises two separate located at the two ends of the capillary tube, each portion comprising at least one layer of a low thermal conductive material. [0031] In some embodiments, different temperature regulation materials can be used along the capillary tube. For example, the thermal conductivity of the temperature regulation material at the two ends of the capillary tube may be lower than that of the material in the middle of the capillary tube. Other configurations can be readily designed based on the teaching of the present invention and the desired temperature profiles.

[0032] The device described herein can find many applications. For example, in some embodiments, the device is used to carry out PCR reaction in a capillary tube. In some embodiments, the device is used to carry out hybridization reaction in the capillary tube. In some embodiments, the device is used to carry out electrophoresis within the capillary tube. [0033] The device described herein can be integrated into a system (such as a microfluidic device). The present invention thus also provides a microfluidic device comprising the capillary heating device. In some embodiments, the microfluidic device is automated. In some embodiments, there is provided a kit comprising a capillary heating device.

[0034] Also provided are methods of manufacturing the capillary heating devices and microfluidic devices described herein. The capillary heating device can be made by methods known in the art, including for example sputtering, welding, and etching.

[0035] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples, including the size and ratio of the various elements described herein, should not be construed as limiting the scope of the invention.

EXAMPLE

[0036] Figure 1 provides an example of using the capillary heating device to control temperature of a nucleic acid amplification reaction in a glass capillary tube. The glass capillary has an inside diameter of 1 mm. The thickness of the outside wall was 0.2 mm, and the total volume of the capillary tube was 25 micro liters. Resistive heating element 4 was a coil of copper wire coated with a polyimide insulating layer and with a diameter of 60 um, which tightly wound around the capillary tube. The two ends of the copper wire 5 were welded onto two copper foil ring 2, which were used as the transition points for the copper wire connecting to the heating circuit. A 50 μm copper foil 3, which serves as the temperature regulation element, wrapped around the wound copper wire. A control circuit controlled and calibrated the temperature of the capillary heating device. The DNA fragment of the T-HCV (Hepatitis C virus) gene cloned into the T vector was amplified within half an hour. The result is shown in Figure 2.

Claims

CLAIMSWhat is claimed is:

1. A capillary heating device, comprising: a capillary tube, a resistive heating element that is configured to increase the temperature of the capillary tube, and a temperature regulation element that is configured to modify the temperature profile of the capillary tube.

2. The capillary heating device of claim 1, wherein the temperature regulation element comprises one or more layers, wherein the resistive heating element comprises one or more layers, wherein at least one layer of the temperature regulation element is sandwiched between one layer of the resistive heating element and the exterior wall of the capillary tube.

3. The capillary heating device of claim 1, wherein the temperature regulation element comprises one or more layers, wherein the resistive heating element comprises one or more layers, wherein at least one layer of the temperature regulation element wraps around a layer of the resistive heating element, which in turn wraps around the capillary tube.

4. The capillary heating device of claim 2 or claim 3, wherein the thickness of at least one layer of the temperature regulation element is uneven.

5. The capillary heating device of claim 4, wherein the temperature regulation element comprises at least one layer of low thermal conductive material.

6. The capillary heating device of claim 5, wherein the two ends of the layer of the low thermal conductive material along the capillary tube is thicker than the middle portion of layer.

7. The capillary heating device of claim 4, wherein the temperature regulation element comprises at least one layer of high thermal conductive material.

8. The capillary heating device of claim 7, wherein the two ends of the layer of the low thermal conductive material along the capillary tube is thinner than the middle portion of the layer.

9. The capillary heating device of claim 1, wherein the temperature regulation element is configured to modify the temperature profile along the length of the capillary tube.

10. The capillary heating device of claim 9, wherein the temperature regulation element is configured to maintain a homogeneous temperature distribution along the length of the capillary tube.

11. The capillary heating device of claim 1, wherein the temperature regulation element comprises two portions, wherein each portion comprise at least one layer of a low thermal conductive material, and wherein each portion are located at the two ends of the capillary tube.

12. The capillary heating device of claim 1, wherein the ratio of the length to the largest cross section of the capillary tube is more than about 2:1.

13. The capillary heating device of claim 1, wherein the largest cross section of the capillary tube is about 10 mm to about 0.002 mm.

14. The capillary heating device of claim 1, wherein the thickness of the capillary tube is about 5 mm to about 0.001 mm.

15. The capillary heating device of claim 1, wherein the resistive heating element comprises electric conductive material selected from the group consisting of metals, non-metallic materials, chemical compounds, or combination thereof.

16. The capillary heating device of claim 1, wherein the resistive heating device comprises sheets or wires.

17. The capillary heating device of claim 1, further comprising a heating circuit connected to the resistive heating element.

18. The capillary heating device of claim 17, wherein the heating circuit is connected to the resistive heating element via electrically conductive copper foil ring.