Thermal cycler for even heating of one or more samples

Abstract

A thermal transfer device applies a uniform heat to a plurality of samples. The thermal transfer device takes advantage of the natural thermal gradient pattern of a heat exchanging device and arranges the samples along isothermal lines of the heat exchanger. By arranging the samples in this manner, at least two problems are specifically addressed. First, the temperature applied within each sample is uniform. Second, the symmetrical arrangement of the samples guarantees that each sample is exposed to exactly the same conditions as the neighboring samples.

Description

GOVERNMENT LICENSE RIGHTS

This invention was made with Government support under Agreement No. W81XWH-04-9-0010 awarded by the Government. The Government has certain rights in this invention.

FIELD OF THE INVENTION

The invention relates to a method of and apparatus for heating and/or cooling one or more samples. More particularly, the invention relates to a method of and apparatus for uniformly heating and/or cooling all portions of a given sample and/or uniformly heating and/or cooling multiple different samples.

BACKGROUND OF THE INVENTION

There is a large need in multiple industries (from chemical production to pharmaceutical development), chemical and biological research, and diagnostics to perform thermally-driven chemical reactions. Typically, thermally-driven chemical reactions are performed in reaction vessels with separate heater elements that are in direct contact with a vessel. The vessel can be glass, metal, ceramic, or plastic. Heating a sample within the vessel requires the use of a heater.

The vessel occupies a physical footprint, as determined by the physical dimensions of the vessel. The entire sample to be heated within the vessel needs to be subjected to a constant heat, and therefore a constant heat needs to be applied along the entire physical footprint. This requires a heater with a constant thermal gradient across at least the same dimensions as the physical footprint of the vessel. However, heating (or cooling) blocks exhibit variable thermal gradient patterns. For example, most heating blocks exhibit a classic “bulls-eye” thermal gradient pattern with the hottest point in the center, and cooling radially outward toward the edges. This bulls-eye pattern is the result of convection and edge effects. Any vessel positioned across the heater experiences a temperature gradient within the sample, the center portion of the sample being hottest and the end portions being coolest.

FIG. 1 illustrates an exemplary heat exchanger that exhibits a bulls-eye thermal gradient pattern. The heat exchanger 10 can be any conventional heat generating or thermal cycling device, such as a heat spreader coupled to a thermoelectric cooler (TEC). Different sections of the heat exchanger 10 exhibit different temperatures relative to each other. Sections 12, 14, 16, 18, 20, and 22 each represent a different isotherm. All points in an isotherm have substantially the same temperature at a given time or substantially the same mean temperature for a given period of time. In the exemplary bulls-eye pattern shown in FIG. 1, each isotherm forms a ring of the pattern, with the center section 12 being the hottest, and sections 14, 16, 18, 20, and 22 being progressively cooler, with section 22 being the coolest. Containment vessels, or tubes, 30, 32, 34, and 36 store a fluid sample to be heated by the heat exchanger 10. All of the tubes, 30-36 can not occupy the same physical space, so the tubes 30-36 must be positioned across the heat exchanger 10 at different positions. Due to the thermal gradient pattern of the heat exchanger 10, each tube 30-36 is subjected to a different temperature profile. As such, the heat applied to each tube varies as the alignment of the tube relative to the heat exchanger varies. For example, the center portion of the tube 30 is thermally coupled to the section 16 and the ends of the tube 30 are thermally coupled to the section 20. In contrast, the center portion of adjacent tube 32 is thermally coupled to the section 12 and the ends of the tube 32 are thermally coupled to the section 18. As such, each portion of the tube 32 is exposed to a higher temperature than a corresponding portion of the tube 30. This leads to inconsistent temperature protocols applied to the samples stored in each of the tubes 30-36.

For multiple tubes positioned across the heat exchanger 10, not only is there heating variation applied to the different tubes, but the heat applied to a given tube also varies. For example, the center section of the tube is exposed to a higher temperature than the ends of the tube. As such, a sample within the tube is not uniformly heated. In an application using a well-based heating plate with each well holding a sample, a grid arrangement of multiple samples results in the center samples being heated more than the samples located at the periphery.

Significant efforts have been made to minimize the temperature gradient applied to a sample or a plurality of samples. Such efforts include addition of a heat spreader, manipulation of the geometry of the heater, electronic control of the heater, and the use of multiple heaters for a given area instead of a single heater. To some extent, these actions have reduced the thermal variability within and between the samples. However, there is still some measure of temperature variation. Further, these approaches increase the complexity and cost of the overall apparatus.

The polymerase chain reaction (PCR) is a technique for the amplification of nucleic acids, such as RNA and DNA, in the laboratory. PCR is a common method of creating copies of specific fragments of DNA. PCR rapidly amplifies a single DNA molecule into many billions of molecules. In one application of the technology, small samples of DNA, such as those found in a strand of hair at a crime scene, can produce sufficient copies to carry out forensic tests.

PCR is typically performed using thermal cycling in which a sample is subjected to a series of heating and cooling steps. Conventional PCR instruments include a PCR tube for holding the sample and a heater coupled to the PCR tube. There are other methods of amplifying nucleic acids, which involve isothermal (a constant temperature) temperature rather than thermal cycling. Regardless of the method, heaters are used to generate the desired temperature or temperatures. The heaters suffer from the thermal gradient patterns described above, and therefore, the PCR protocols are adversely effected.

SUMMARY OF THE INVENTION

A thermal transfer device is not configured to manipulate and modify the inherent nature of the thermal gradient. Instead, the thermal transfer device takes advantage of this natural temperature pattern and arranges the samples along isothermal lines of a heat exchanger. By arranging the samples in this manner, at least two problems are specifically addressed. First, the temperature applied within a given sample is uniform. Second, the symmetrical arrangement of multiple samples guarantees that each sample is exposed to exactly the same conditions as the neighboring samples. This symmetrical arrangement ensures the same “static” and “dynamic” conditions applied to each sample. For example, static conditions refer to the heating and cooling end point temperatures used during a heating, cooling, or thermal cycling process. Dynamic conditions refer to the rate by which the sample is heated and cooled.

In one aspect, an apparatus to apply a uniform heat exchange with a sample is disclosed. The apparatus includes a heat exchanger having a thermal gradient pattern that includes a plurality of isotherms, and a sample container thermally coupled to the heat exchanger, wherein the sample container is configured to hold a fluid sample and the sample container is shaped to align with a specific isotherm of the heat exchanger such that the entire fluid sample is aligned with the specific isotherm to uniformly exchange heat between the entire fluid sample and the specific isotherm. In some embodiments, the thermal gradient pattern is a bulls-eye pattern, and the plurality of isotherms form a series of concentric rings extending radially from a center of the bulls-eye pattern. The heat exchanger can include a Peltier device. The heat exchanger can be a thermal cycler that cycles between a first temperature and a second temperature, thereby heating and cooling the fluid sample within the sample container. Alternatively, the heat exchanger can be a heat generating device or a cooling device. The sample container can be configured as a flow-through container having a first open end and a second open end. The apparatus can also include an input conduit coupled to the first open end of the flow-through container and an output conduit coupled to the second open end of the flow-through container. The heat exchanger can include a channel into which the sample container is positioned.

In another aspect, an apparatus to apply a uniform heat exchange with a plurality of samples is disclosed. The apparatus includes a heat exchanger having a thermal gradient pattern that includes a plurality of isotherms, and a plurality of sample containers thermally coupled to the heat exchanger, wherein each sample container is configured to hold a sample and all of the plurality of sample containers are aligned with a specific isotherm of the heat exchanger such that the entire sample within each sample container is aligned with the specific isotherm to uniformly exchange heat between the entire sample in each of the plurality of sample containers and the specific isotherm.

In yet another aspect, another apparatus to apply a uniform heat exchange with a plurality of samples is disclosed. The apparatus a heat exchanger having a thermal gradient pattern that includes a plurality of isotherms, and a plurality of sample containers thermally coupled to the heat exchanger, wherein each sample container is configured to hold a sample and each of the plurality of sample containers are positioned across the same multiple different isotherms such that corresponding segments of each sample container are aligned with the same one of the multiple different isotherms, thereby uniformly applying a same temperature profile to the fluid samples in all of the plurality of sample containers.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and form a part of this specification, illustrate embodiments of the heat transfer device and, together with the description, serve to explain the principles of the heat transfer device but not limit the heat transfer device to the disclosed examples.

FIG. 1 illustrates an exemplary heat exchanger that exhibits a bulls-eye thermal gradient pattern.

FIG. 2 illustrates a top-down view of a heat transfer device according to an embodiment.

FIG. 3 illustrates a bottoms-up isometric view of the heat transfer device of FIG. 2.

FIG. 4 illustrates the top-down view of FIG. 2 including the heat spreader exhibiting an exemplary bulls-eye thermal gradient pattern.

FIG. 5 illustrates a top-down view of the heat spreader including a plurality of channels.

FIG. 6 illustrates a bottom-up isometric view of an exemplary alternative heat exchanger.

FIG. 7 illustrates a top-down isometric view of the heat exchanger of FIG. 6 which exhibits a nearly linear, slightly curved thermal gradient pattern.

FIG. 8 illustrates a top-down view of a heat transfer device including a plurality of sample holding tubes thermally coupled to a top surface of the alternative heat exchanger.

Embodiments of the heat transfer device are described relative to the several views of the drawings. Where appropriate and only where identical elements are disclosed and shown in more than one drawing, the same reference numeral will be used to represent such identical elements.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

Reference will now be made in detail to the embodiments of the heat transfer device, examples of which are illustrated in the accompanying drawings. While the heat transfer device will be described in conjunction with the embodiments below, it will be understood that they are not intended to limit the heat transfer device to these embodiments and examples. On the contrary, the heat transfer device is intended to cover alternatives, modifications and equivalents, which may be included within the spirit and scope of the heat transfer device as defined by the appended claims. Furthermore, in the following detailed description of the heat transfer device, numerous specific details are set forth in order to more fully illustrate the heat transfer device. However, it will be apparent to one of ordinary skill in the prior art that the heat transfer device may be practiced without these specific details. In other instances, well-known methods and procedures, components and processes haven not been described in detail so as not to unnecessarily obscure aspects of the heat transfer device.

Embodiments of the heat transfer device are directed to one or more sample containers coupled to a heat exchanger. Although reference to a “tube”, “tubing”, or “sample container” is used herein, it is understood that such reference can generally apply to any conventional container, vessel, or structure used to store, hold, and/or transport the sample. In some embodiments, the sample is a fluid sample. The heat exchanger includes at least a first surface onto which the one or more sample containers are thermally coupled. In some embodiments, the first surface includes one or more channels into each of which one of the one or more sample containers is positioned. A shape of the sample container and a shape of the channel match so as to maximize a thermal interface between the two. In other embodiments, the first surface is a flat surface and each sample container either lies directly on the first surface or a thermal interface material is positioned between each sample container and the first surface.

The heat exchanger can be used as either a heating device to heat a sample within each of the sample containers, a cooling device to cool a sample within each of the sample containers, or as both a heating and cooling device to perform a thermal cycling process on a sample within each of the sample containers. Any conventional heating, cooling, or thermal cycling device can be used as the heat exchanger. In an exemplary embodiment, the heat exchanger includes a thermoelectric cooler (TEC) and a heat spreader coupled to the TEC. In this exemplary configuration, a bottom surface of the heat spreader is thermally coupled to the TEC, and a top surface of the heat spreader forms the first surface of the heat exchanger to which the one or more sample containers are thermally coupled. It is understood that the heat exchanger can be comprised of one or more other conventional heating and/or cooling components.

The heat exchanger, and in particular the first surface of the heat exchanger, exhibits a thermal gradient due to convection and edge effects. As such, a thermal gradient pattern is formed on the heat exchanger, and when coupled to the one or more sample containers, each sample container is exposed to a portion of the thermal gradient pattern. The thermal gradient pattern is comprised of isotherms, or bands, that have substantially the same temperature. Each isotherm is defined by a specific geometry on the first surface of the heat exchanger. Changing the “temperature” of the heat exchanger changes the temperature of each isotherm in the thermal gradient pattern. For example, raising the average temperature of the heat exchanger raises the temperature of each of the isotherms, where each isotherm retains its thermal distinctiveness from each of the other isotherms. In some embodiments, the thermal gradient pattern forms a “bulls-eye” pattern, where each “ring” in the bulls-eye pattern is an isotherm. For a given average temperature of the heat exchanger, each isotherm in the bulls-eye pattern has a different temperature. In a heating application, a center section of the bulls-eye pattern is the hottest, and each isotherm ring extending radially from the center is progressively cooler, with the outer ring (isotherm) being the coolest. A width of an isotherm can be the same or different than a width of one or more other isotherms in the bulls-eye pattern. It is understood that the heat exchanger may exhibit thermal gradient patterns other than a bulls-eye pattern.

One of the isotherms of the thermal gradient pattern is selected, and the one or more sample containers are shaped to match a contour of the selected isotherm. The one or more sample containers are aligned with and thermally coupled to the selected isotherm. In this manner, the sample maintained within the sample container is exposed to a uniform temperature because the sample container is exposed to a uniform temperature of the selected isotherm. Further, since all of the one or more sample containers are thermally coupled to the same selected isotherm, the samples maintained in all of the one or more sample containers are exposed to the uniform temperature.

FIG. 2 illustrates a top-down view of a heat transfer device according to an embodiment. FIG. 3 illustrates a bottoms-up isometric view of the heat transfer device of FIG. 2. The heat transfer device 100 includes a plurality of sample holding containers, or tubes, 130, 140, 150, and 160 thermally coupled to a heat exchanger. It is understood that more or less than four sample holding tubes can be used. The heat exchanger includes a heat spreader 110 thermally coupled to a TEC 170. The TEC 170 includes electrical leads 172 and 174 for coupling to power. A temperature of the TEC can be raised or lowered to a desired temperature or between various temperatures as in thermal cycling. A bottom surface of the heat spreader 110 is thermally coupled to a top surface of the TEC 170. A top surface of the heat spreader 110 is thermally coupled to the tubes 130, 140, 150, 160. Although the heat transfer device 100 is described as having a heat exchanger that includes a heat spreader and a TEC, the heat exchanger can be any conventional heating, cooling, or thermal cycling device.

In this exemplary configuration, a heat exchanger exhibits a bulls-eye thermal gradient pattern. It is understood that the heat transfer device can be configured to operate with alternative thermal gradient patterns. Different sections of the heat exchanger exhibit different temperatures relative to each other. These different temperatures are manifested as isotherms at the top surface of the heat spreader 110. In the bulls-eye thermal gradient pattern, each isotherm forms a radially symmetric concentric ring. FIG. 4 illustrates the top-down view of FIG. 2 including the heat spreader 110 exhibiting an exemplary bulls-eye thermal gradient pattern. The exemplary bulls-eye thermal gradient pattern includes isotherms 112, 114, 116, 118, and 120. All points in a given isotherm have substantially the same temperature at a given time or substantially the same mean temperature for a given period of time. In the exemplary bulls-eye pattern shown in FIG. 4, each isotherm forms a ring of the bulls-eye pattern. During a heating application, the center isotherm 112 is the hottest, and isotherms 114, 116, 118, and 120 are progressively cooler, with isotherm 120 being the coolest.

Sample holding tubes 130, 140, 150, 160 are shaped to match the circular contour of the isotherm 118, and the sample holding tubes 130, 140, 150, 160 are aligned with and thermally coupled to the isotherm 118. It is understood that selection of isotherm 118 is for exemplary purposes only and that any of the isotherms 112, 114, 116, 118, 120 can be selected. Due to the uniform temperature of the isotherm 118, each of the sample holding tubes 130, 140, 150, 160 are subjected to the same temperature, or temperature profile in the case of a thermal cycling application. Such temperature conditions are referred to as “static” conditions.

Subjecting each fluid sample to the same temperature profile also results in consistent “dynamic” temperature conditions being applied to each fluid sample. Dynamic conditions include the rate of temperature change applied to each fluid sample. By positioning the tubes 130, 140, 150, 160 on the same isotherm(s), each fluid sample heats or cools at the same rate relative to each other. In contrast, if one or more tubes are positioned across different isotherms than the other tubes, as in FIG. 1, the fluid samples may eventually all reach the same temperature, but each fluid sample heats or cools at different rates to reach the same temperature. In PCR applications for example, where multiple temperature cycles are required, the cycle time is determined by the fluid sample with the slowest temperature change rate. Further, the fluid sample with the fastest temperature change rate may overshoot or undershoot the target temperature while waiting for the fluid sample experiencing the slowest temperature change rate to cath up. This condition is reduced if not eliminated by positioning all fluid samples across the same isotherm(s).

Referring to FIG. 2, each of the sample holding tubes 130, 140, 150, 160 are configured as flow-through tubes including an inlet end and an outlet end. The inlet end of the sample holding tube 130 is coupled to an inlet tube 132. A valve tube 136 is coupled to the inlet tube 132. The outlet end of the sample holding tube 130 is coupled to an outlet tube 134. A valve tube 138 is coupled to the outlet tube 134. In some embodiments, the sample holding tube 130, the inlet tube 132, and the outlet tube 134 are made of the same thermally conductive material. In some embodiments, the tubes 130, 132, 134 form a single integrated tube. Since the tubes 130, 132, 134 are each thermally coupled to the heat spreader 110, the tubes 130, 132, 134 must be able to withstand at least the temperature range generated by the isotherm 118. The tubes 130, 132, 134 must also be able to withstand repeated heating and cooling as experienced during a thermal cycling application. In some embodiments, the valve tubes 136 and 138 are made of a different material than the tubes 130, 132, 134. Since the valve tubes 136 and 138 are not thermally coupled to the heat spreader, the valve tubes 136 and 138 do not require as high a thermal tolerance as the tubes 130, 132, 134. Also, each valve tube 136 and 138 includes a valve mechanism by which fluid flow into and out of the sample holding tube 130 is regulated. In one embodiment, the valve tubes 136 and 138 are made of a flexible material to enable a pinch valve to be implemented. It is understood that other valve mechanisms can be implemented. In other embodiments, the valve tubes 136 and 138 are made of the same material as the tubes 130, 132, 134.

In some embodiments, the fluid flow into and out of the sample holding tube 130 is regulated so that the fluid sample is positioned completely within the tube 130 during the heating and/or cooling steps. None of the fluid sample is positioned in the adjacent tubes 132 and 134. Maintaining the entire fluid sample within the sample holding tube 130 ensures that the entire fluid sample is subjected to the same isotherm, in this case isotherm 118. As tubes 132 and 134 extend across multiple isotherms, in this case isotherms 118 and 120, any fluid sample positioned in the tubes 132 and/or 134 is subjected to a non-uniform temperature. Positioning the entire fluid sample within only the tube 130 can be accomplished by inserting a specific volume of buffer solution into the inlet tubing before and again after the fluid sample, and tightly regulating the fluid flow through the tubing such that buffer solution is positioned in tubes 132 and 134 while fluid sample is positioned in the sample holding tube 130. In some embodiments, microfluidic circuitry including valve mechanisms and fluid pumps is used to regulate the fluid flow through the tubes.

The sample holding tubes 140, 150, 160 are coupled to inlet and outlet tubing in a manner similar to the sample holding tube 130. Specifically, an inlet end of the sample holding tube 140 is coupled to an inlet tube 142. A valve tube 146 is coupled to the inlet tube 142. An outlet end of the sample holding tube 140 is coupled to an outlet tube 144. A valve tube 148 is coupled to the outlet tube 144. An inlet end of the sample holding tube 150 is coupled to an inlet tube 152. A valve tube 156 is coupled to the inlet tube 152. An outlet end of the sample holding tube 150 is coupled to an outlet tube 154. A valve tube 158 is coupled to the outlet tube 154. An inlet end of the sample holding tube 160 is coupled to an inlet tube 162. A valve tube 166 is coupled to the inlet tube 162. An outlet end of the sample holding tube 160 is coupled to an outlet tube 164. A valve tube 168 is coupled to the outlet tube 164. The tubes 140, 142, 144, 146, 148, the tubes 150, 152, 154, 156, 158, and the tubes 160, 162, 164, 166, 168 can be configured similarly as and fluidically coupled similarly as the tubes 130, 132, 134, 136, 138.

As described above, the heat transfer device 100 is configured such that a fluid sample is positioned entirely within the sample holding tubes 130, 140, 150, 160 so that all fluid samples are subjected to a uniform temperature or temperature profile, and rate of temperature change. This is accomplished by regulating the fluid flow through the tubing such the fluid sample to be heated, cooled, or thermal cycled is positioned only in that portion of the tubing that lies in a single isotherm. In an alternative embodiment, flow of the fluid sample is regulated so that the fluid sample is positioned in all portions of the tubing that are thermally coupled to the heat exchanger. As applied to FIGS. 2 and 4, a fluid sample is positioned in the sample holding tube 130 and also in the portion of the inlet tube 132 and the outlet tube 134 that is thermally coupled to the heat spreader 110. In this case, the fluid sample is exposed to the isotherms 118 and 120. Although not ideal, the fluid sample is exposed to a smaller temperature range than a tube positioned across the entire heat spreader, as in FIG. 1. Further, the fluid sample in each of the tubes 130, 132, 134, the tubes 140, 142, 144, the tubes 150, 152, 154, and the tubes 160, 162, 164 are all exposed to the same temperature profile. This is preferable to the configuration where one or more tubes filled with fluid sample are exposed to different temperature profiles, such as the tubes in FIG. 1. Also, although the fluid sample may be positioned across multiple isotherms, in this case isotherms 118 and 120, the majority of the fluid sample is positioned across a single isotherm, in this case isotherm 118. Some applications many require less rigorous temperature control where this alternative configuration is sufficient to achieve the desired results. This alternative configuration provides improved throughput since a larger tubing volume can heat, cool, or thermal cycle a larger fluid sample volume.

In some embodiments, the top surface of the heat spreader 110 is a flat surface and the tubes 130, 132, 134, the tubes 140, 142, 144, the tubes 150, 152, 154, and the tubes 160, 162, 164 are thermally coupled to the flat surface either by direct contact or via an intermediate thermal interface material. In other embodiments, the top surface of the heat spreader 110 is configured with channels into which the tubes 130, 132, 134, the tubes 140, 142, 144, the tubes 150, 152, 154, and the tubes 160, 162, 164 fit. FIG. 5 illustrates a top-down view of the heat spreader 110 including a plurality of channels. Specifically, the top surface of the heat spreader 110 includes channels 182, 184, 186, and 188. The shape and contour of the channels 182, 184, 186, 188 are configured to match the shape and contour of the tubes 130, 132, 134, the tubes 140, 142, 144, the tubes 150, 152, 154, and the tubes 160, 162, 164, respectively. In this manner, the tubes 130, 132, 134 are positioned within the channel 182, the tubes 140, 142, 144 are positioned within the channel 184, the tubes 150, 152, 154 are positioned within the channel 186, and the tubes 160, 162, 164 are positioned within the channel 188. The tubes are thermally coupled to the inner surface of the channels either by direct contact or via an intermediate thermal interface material.

It is understood that the heat transfer device can be configured to operate with a heat exchanger exhibiting alternative thermal gradient patterns. FIG. 6 illustrates a bottom-up isometric view of an exemplary alternative heat exchanger 210 including a heat spreader 208 and a heating and/or cooling element 206. FIG. 7 illustrates a top-down isometric view of the heat exchanger 210 which exhibits a nearly linear, slightly curved thermal gradient pattern. The thermal gradient pattern shown in FIG. 7 is centered about the heating and/or cooling element 206. This exemplary thermal gradient pattern includes isotherms 212, 214, 216, and 218. During a heating application, the center isotherm 212 is the hottest, and the isotherms 214, 216, and 218 are progressively cooler, with isotherm 218 being the coolest.

FIG. 8 illustrates a top-down view of a heat transfer device 200 including a plurality of sample holding tubes 230, 240, 250, and 260 thermally coupled to a top surface of the heat exchanger 210. Sample holding tubes 230, 240, 250, 260 are shaped to match the near linear contour of the isotherm 216, and the sample holding tubes 230, 240, 250, 260 are aligned with and thermally coupled to the isotherm 216. It is understood that selection of isotherm 216 is for exemplary purposes only and that any of the isotherms 212, 214, 216, 218 can be selected. Due to the uniform temperature of the isotherm 216, each of the sample holding tubes 230, 240, 250, 260 are subjected to the same temperature, or temperature profile, and temperature rate change in the case of a thermal cycling application.

In operation, a thermal gradient pattern of an heat exchanger is determined, including the shape and contour of various isotherms. One of the isotherms is selected for performing a heating, cooling, or thermal cycling process. One or more sample holding tubes are shaped and contoured to match the selected isotherm, and the one or more sample holding tubes are aligned and thermally coupled to the selected isotherm. The one or more sample holding tubes are then coupled to microfluidic circuitry that regulates fluid flow through the one or more sample holding tubes. A fluid sample is input and positioned within each of the sample holding tubes. A heating, cooling, or thermal cycling process is then applied to the sample by setting the selected isotherm to a desired temperature. In the case of a thermal cycling process, the selected isotherm is adjusted between multiple different temperatures, each temperature maintained for a desired period of time. In some embodiments, the thermal cycling process is used to perform PCR. Once the heating, cooling, or thermal cycling process is completed, the fluid samples are output from the one or more sample holding tubes via the microfluidic circuitry.

The heat transfer device can be used as a thermal cycling device that cycles between heating and cooling steps. The heat transfer device can be alternatively used as either a heating device or a cooling device, without cycling between heating and cooling.

The sample holding containers are described above as flow-through tubes with an open input end and an open output end. Alternatively, a sample holding container includes an open end and a closed end, where the fluid sample is both input and output via the open end.

The heat transfer device has been described in terms of specific embodiments incorporating details to facilitate the understanding of the principles of construction and operation of the heat transfer device. The specific configurations shown and the methodologies described in relation to the various modules and the interconnections therebetween are for exemplary purposes only. Such reference herein to specific embodiments and details thereof is not intended to limit the scope of the claims appended hereto. It will be apparent to those skilled in the art that modifications may be made in the embodiment chosen for illustration without departing from the spirit and scope of the heat transfer device.

Claims

1. An apparatus to apply a uniform heat exchange with a sample, the apparatus comprising:

a. a heat exchanger having a thermal gradient pattern that includes a plurality of isotherms; and

b. a sample container thermally coupled to the heat exchanger, wherein the sample container is configured to hold a fluid sample and the sample container is shaped to align with a specific isotherm of the heat exchanger such that the entire fluid sample is aligned with the specific isotherm to uniformly exchange heat between the entire fluid sample and the specific isotherm.

2. The apparatus of claim 1 wherein the thermal gradient pattern is a bulls-eye pattern, and the plurality of isotherms form a series of concentric rings extending radially from a center of the bulls-eye pattern.

3. The apparatus of claim 1 wherein the heat exchanger comprises a Peltier device.

4. The apparatus of claim 1 wherein the heat exchanger comprises a thermal cycler that cycles between a first temperature and a second temperature, thereby heating and cooling the fluid sample within the sample container.

5. The apparatus of claim 1 wherein the heat exchanger comprises a heat generating device.

6. The apparatus of claim 1 wherein the heat exchanger comprises a cooling device.

7. The apparatus of claim 1 wherein the sample container is configured as a flow-through container having a first open end and a second open end.

8. The apparatus of claim 5 further comprising an input conduit coupled to the first open end of the flow-through container and an output conduit coupled to the second open end of the flow-through container.

9. The apparatus of claim 1 wherein the heat exchanger includes a channel into which the sample container is positioned.

10. An apparatus to apply a uniform heat exchange with a plurality of samples, the apparatus comprising:

a. a heat exchanger having a thermal gradient pattern that includes a plurality of isotherms; and

b. a plurality of sample containers thermally coupled to the heat exchanger, wherein each sample container is configured to hold a sample and all of the plurality of sample containers are aligned with a specific isotherm of the heat exchanger such that the entire sample within each sample container is aligned with the specific isotherm to uniformly exchange heat between the entire sample in each of the plurality of sample containers and the specific isotherm.

11. The apparatus of claim 10 wherein the thermal gradient pattern is a bulls-eye pattern, and the plurality of isotherms form a series of concentric rings extending radially from a center of the bulls-eye pattern.

12. The apparatus of claim 10 wherein the heat exchanger comprises a Peltier device.

13. The apparatus of claim 10 wherein the heat exchanger comprises a thermal cycler that cycles between a first temperature and a second temperature, thereby heating and cooling the fluid sample within each of the plurality of sample containers.

14. The apparatus of claim 10 wherein the heat exchanger comprises a heat generating device.

15. The apparatus of claim 10 wherein the heat exchanger comprises a cooling device.

16. The apparatus of claim 10 wherein one or more of the plurality of sample containers are configured as flow-through containers having a first open end and a second open end.

17. The apparatus of claim 16 further comprising an input conduit coupled to the first open end of each flow-through container and an output conduit coupled to the second open end of each flow-through container.

18. The apparatus of claim 10 wherein the heat exchanger includes a plurality of channels into each of which one of the plurality of sample containers is positioned.

19. An apparatus to apply a uniform heat exchange with a plurality of samples, the apparatus comprising:

a. a heat exchanger having a thermal gradient pattern that includes a plurality of isotherms; and

b. a plurality of sample containers thermally coupled to the heat exchanger, wherein each sample container is configured to hold a sample and each of the plurality of sample containers are positioned across the same multiple different isotherms such that corresponding segments of each sample container are aligned with the same one of the multiple different isotherms, thereby uniformly applying a same temperature profile to the fluid samples in all of the plurality of sample containers.

20. The apparatus of claim 19 wherein the thermal gradient pattern is a bulls-eye pattern, and the plurality of isotherms form a series of concentric rings extending radially from a center of the bulls-eye pattern.

21. The apparatus of claim 19 wherein the heat exchanger comprises a Peltier device.

22. The apparatus of claim 19 wherein the heat exchanger comprises a thermal cycler that cycles between a first temperature and a second temperature, thereby heating and cooling the fluid sample within each of the plurality of sample containers.

23. The apparatus of claim 19 wherein the heat exchanger comprises a heat generating device.

24. The apparatus of claim 19 wherein the heat exchanger comprises a cooling device.

25. The apparatus of claim 19 wherein one or more of the plurality of sample containers are configured as flow-through containers having a first open end and a second open end.

26. The apparatus of claim 25 further comprising an input conduit coupled to the first open end of each flow-through container and an output conduit coupled to the second open end of each flow-through container.

27. The apparatus of claim 19 wherein the heat exchanger includes a plurality of channels into each of which one of the plurality of sample containers is positioned.