Thermal control device for temperature cycling, method for controlling temperature cycling using a thermal control device, and system for controlling temperature of a sample using a thermal control device

Abstract

In one embodiment, a thermal control device (110) adapted for temperature cycling is provided. The thermal control device (110) comprises a thermally conductive heat spreader layer (118) comprising a first side surface and a second side surface. A heater circuit (120) is disposed adjacent to and in thermal contact with at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer (118). At least one thermal interface material layer (114) is disposed adjacent to and in thermal contact with one of the first side surface and the second side surface of the thermally conductive heat spreader layer (118). A cooling block (116) is disposed adjacent to and in thermal contact with the thermal interface material layer (114). The cooling block (116) is adapted to conduct heat energy away from the thermally conductive heat spreader layer (118). A controller is coupled to and adapted to control the heater circuit (120). In another embodiment, a diagnostic test device is provided.

Description

THERMAL CONTROL DEVICE FOR TEMPERATURE CYCLING, METHOD FOR CONTROLLING TEMPERATURE CYCLING USING A THERMAL CONTROL DEVICE, AND SYSTEM FOR CONTROLLING TEMPERATURE OF A SAMPLE USING ATHERMAL CONTROL DEVICEFIELD

[0001] The present disclosure relates to devices, methods and systems including a thermal control device for temperature cycling, such as for a process such as polymerase chain reaction (PCR) test.BACKGROUND

[0002] Devices for tempering (control temperature) samples or reaction mixtures in a controlled way are used in almost all fields of chemistry or biochemistry, whereas basic science is affected in the same manner than industrial development or pharmaceutical production. Since labor time as well as reagents are expensive, development is tending to increase the throughput of production and analysis, while at the same time, to minimize the necessary reaction volumes.

[0003] In general, tempering devices have a thermal block that is in thermal contact with the sample under investigation. The thermal block is tempered to a desired temperature affecting the temperature of the sample, too. The simplest thermal block is a common boilerplate.

[0004] In order to realize an efficient tempering, the device is adapted to heat and cool the samples. For this purpose, the thermal block can be connected with two separate devices or with a single device able to perform both heating and cooling.

[0005] One of many applications for precise thermal tempering a sample includes polymerase chain reaction (PCR) amplification and analyses, where both heating and cooling rates of the reaction are tightly controlled. With PCR, turnaround time (TAT) is also a key attribute, such as in the point of care (POC) and multiplex testing sectors where rapid PCR of a nucleic acid sample aids in diagnostic efficiency.

[0006] US 2013 / 0157271 Al discloses methods and systems for thermal melt analysis on a microfluidic platform. This publication further describes methods and systems using thermal systems including heat spreading devices, including interconnection methods and materials developed to connect heat spreaders to microfluidic devices. This publication also describes methods and systems for controlling, measuring, and calibrating the thermal systems.

[0007] US 2022 / 0258159 Al describes systems for nucleic acid amplification testing. The systems comprise a consumable amplification module and a reader module for receiving the amplification module. The amplification module comprises: a reactor vessel for containing a test sample; a heater comprising a heater element in thermal contact with the reactor vessel and controllable to add heat to the reactor vessel so as to heat the test sample; a temperature sensor for determining the temperature of at least one of the heater element and the test sample; and a heat sink or a heat spreader in thermal contact with the heater. The reader module comprises: a heater controller for selectively controlling the heater element between an on condition and an off condition in response to the determined temperature of the heater element and / or test sample; and an electrical heater interface for connecting the heater controller and the heater. The system comprises a heat sink for subtracting heat from the reactor vessel so as to cool the test sample. The amplification module may comprise the heat sink. The receiver module may comprise the heat sink and a thermal interface, and the amplification module may comprise the heat spreader for thermal contact with the thermal interface.

[0008] US 2019 / 0032114 Al discloses devices for amplifying and detecting analytes, including oligonucleotide targets. The devices may be used for point of care nucleic acid testing. Methods and assays of using the devices are also disclosed.

[0009] What are needed are PCR devices and systems with improved heating and cooling rates. This includes PCR devices and systems that are simplistic in design, such that such devices and systems can easily be deployed to POC workers.SUMMARY

[0010] In one embodiment, a thermal control device adapted for temperature cycling is provided. The thermal control device comprises a thermally conductive heat spreader layer comprising a first side surface and a second side surface. A heater circuit is disposed adjacent to and in thermal contact with at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer. At least one thermal interface material layer is disposed adjacent to and in thermal contact with one of the first side surface and the second side surface of the thermally conductive heat spreader layer. A cooling block is disposed adjacent to and in thermal contact with the thermal interface material layer. The cooling block is adapted to conduct heat energy away from the thermally conductive heat spreader layer. A controller is coupled to and adapted to control the heater circuit.

[0011] In another embodiment, a diagnostic test device is provided. The diagnostic test device comprises a sample chamber and a thermal control device. The thermal control device comprises a thermally conductive heat spreader layer comprising a first side surface and a second side surface. A heater circuit is disposed adjacent to and in thermal contact with at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer. At least one thermal interface material layer is disposed adjacent to and in thermal contact with one of the first side surface and the second side surface of the thermally conductive heat spreader layer. A cooling block is disposed adjacent to and in thermal contact with the thermal interface material layer. The cooling block is adapted to conduct heat energy away from the thermally conductive heat spreader layer. A controller is adapted to control the heater circuit.

[0012] Summarizing and without excluding further possible embodiments, the following embodiments may be envisaged:Embodiment 1 : A thermal control device adapted for temperature cycling comprising: a thermally conductive heat spreader layer comprising a first side surface and a second side surface;a heater circuit disposed adjacent to and in thermal contact with the first side surface of the thermally conductive heat spreader layer; at least one thermal interface material layer disposed adjacent to and in thermal contact with one of the first side surface and the second side surface of the thermally conductive heat spreader layer; a cooling block disposed adjacent to and in thermal contact with the thermal interface material layer, the cooling block adapted to conduct heat energy away from the thermally conductive heat spreader layer; and a controller adapted to control the heater circuit.Embodiment 2 : The thermal control device of embodiment 1 , wherein the thermally conductive heat spreader layer comprises a synthetic diamond material.Embodiment 3 : The thermal control device of any one of the preceding embodiments, wherein the thermally conductive heat spreader layer comprises a thermally conductive optically transparent material.Embodiment 4: The thermal control device of any one of the preceding embodiments, wherein the thermally conductive heat spreader layer comprises at least one of the group comprising: sapphire, ceramic, a metal, copper, silver, aluminum, and gold.Embodiment 5 : The thermal control device of any one of the preceding embodiments, wherein the thermally conductive heat spreader layer comprises a protective layer disposed towards the process chamber comprising at least one of a diamond like carbon layer, a polymer layer, a Kapton layer, a parylene C layer, a paint layer, a gold layer, a platinum layer, a tin layer, a nickel layer, or a nanocoating layer.Embodiment 6: The thermal control device of any one of the preceding embodiments, wherein at least one of the heater circuit and thermal interface material layer comprises a protective layer disposed on a surface of the respective heater circuit and thermal interface material layer.Embodiment 7 : The thermal control device of any one of the preceding embodiments, wherein the heater circuit is deposited directly on at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer.Embodiment 8 : The thermal control device of any one of the preceding embodiments, wherein the heater circuit is disposed adjacent to and in thermal contact with at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer.Embodiment 9: The thermal control device of embodiment 8, wherein the heater circuit is secured to at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer via a thermal interface material (TIM).Embodiment 10: The thermal control device of embodiment 9, wherein the TIM comprises an adhesive with self-retaining functionality.Embodiment 11 : The thermal control device of embodiment 10, wherein the adhesive comprises at least one of a pressure sensitive adhesive and an epoxy resin.Embodiment 12: The thermal control device of embodiment 9, wherein the TIM provides mechanical support for the heat spreader layer.Embodiment 13 : The thermal control device of embodiment 9, wherein an external support device provides mechanical support for the heat spreader layer.Embodiment 14: The thermal control device of embodiment 13, wherein the external support device comprises at least one of the group: a screw, a clamp, a locking attachment device.Embodiment 15 : The thermal control device of any one of the preceding embodiments, wherein the heater circuit comprises at least two electrical contacts for the heater circuit and at least one thermal trace disposed between the at least two contacts.Embodiment 16: The thermal control device of embodiment 15, wherein the thermal trace comprises a resistive heater thermal trace.Embodiment 17: The thermal control device of embodiment 15, wherein the controller is adapted to control the heater circuit by providing a current control signal or a voltage control signal across the at least two contacts.Embodiment 18: The thermal control device of any one of the preceding embodiments, wherein the heater circuit is disposed in a pattern across the first or second side surface of the thermally conductive heat spreader layer.Embodiment 19: The thermal control device of embodiment 18, wherein the pattern defines an opening adapted to provide an optical window through the heat spreader layer.Embodiment 20: The thermal control device of embodiment 19, wherein the thermally conductive heat spreader layer comprises a layer adapted to reduce reflection at the opening.Embodiment 21 : The thermal control device of any one of the preceding embodiments, wherein an optical window aperture is provided through the heat spreader layer and an opticallynontransparent layer is disposed at least partially surrounding the optical window aperture to at least reduce light transmission through the optically nontransparent layer, wherein the optically nontransparent layer is adapted to reduce the visibility of the TIM against the process chamber.Embodiment 22: The thermal control device of embodiment 21, wherein the optically nontransparent layer comprises an optically opaque coating.Embodiment 23 : The thermal control device of embodiment 22, wherein the optically nontransparent layer comprises a sputtered metal layer.Embodiment 24: The thermal control device of any one of the preceding embodiments, wherein the thermally conductive heat spreader layer is optically transparent.Embodiment 25: The thermal control device of any one of the preceding embodiments, wherein the thermally conductive heat spreader layer is transparent to visible or nonvisible wavelengths.Embodiment 26: The thermal control device of any one of the preceding embodiments, wherein at least one temperature sensor is disposed adjacent at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer.Embodiment 27: The thermal control device of embodiment 26, wherein the sensor circuit comprises at least two electrical contacts for the sensor circuit.Embodiment 28: The thermal control device of embodiment 27, wherein at least one thermal trace is disposed between the at least two contacts for resistive temperature measurement.Embodiment 29: The thermal control device of embodiment 27, wherein a thermal sensor is disposed between the at least two electrical contacts for the sensor circuit.Embodiment 30: The thermal control device of embodiment 28, wherein the sensor is passivated with at least one of a diamond like carbon layer, a polymer layer, a Kapton layer, a parylene C layer, a paint layer, a nanocoating layer, optical antireflection coating, and an electrical non- conductive layer.Embodiment 31 : The thermal control device of embodiment 27, wherein one or multiple commercial sensors are mounted on the heat spreader surface and electrical connected to the electrical contacts for the temperature sensor.Embodiment 32: The thermal control device of embodiment 26, where temperature sensor for control heater circuit is disposed on at least one of the first side surface and the second side surface of the heat spreader layer.Embodiment 33 : The thermal control device of embodiment 32, wherein the temperature sensor is coupled to the at least one of the first side surface and the second side surface of the heat spreader layer via the TIM.Embodiment 34: The thermal control device of embodiment 26, wherein the controller is adapted to receive a signal via the temperature sensor and to control the heater circuit based at least in part on the signal.Embodiment 35 : The thermal control device of any one of the preceding embodiments, wherein the thermal interface material layer is adapted to balance the heating and cooling performance ofthe thermal control element by allowing heat transfer between the thermally conductive heat spreader layer and the cooling block.Embodiment 36: The thermal control device of embodiment 35, wherein the thermal interface material layer comprises a thermal diffusivity within a predetermined range adapted to provide a target heat transfer speed versus a maximum allowed heat loss.Embodiment 37: The thermal control device of embodiment 35, wherein the thermal interface material layer comprises a substantially uniform, constant thickness over one of the first side surface and second side surface to provide a predetermined temperature homogeneity.Embodiment 38: The thermal control device of any one of the preceding embodiments, wherein the thermal interface material layer comprises an adhesive to provide bonding and flexibility between the thermally conductive heat spreader layer and the cooling block.Embodiment 39: The thermal control device of embodiment 38, wherein the adhesive comprises at least one of a pressure sensitive adhesive and an epoxy resin.Embodiment 40: The thermal control device of embodiment 38, wherein the adhesive provides mechanical support for the heat spreader layer.Embodiment 41 : The thermal control device of embodiment 38, wherein an external support device provides mechanical support for the heat spreader layer.Embodiment 42: The thermal control device of embodiment 41, wherein the external support device comprises at least one of the group: a screw, a clamp, a locking attachment device.Embodiment 43 : The thermal control device of any one of the preceding embodiments, wherein the cooling block comprises a passive heatsink.Embodiment 44: The thermal control device of any one of the preceding embodiments, wherein the cooling block comprises an actively temperature controlled cooling block.Embodiment 45: The thermal control device of embodiment 44, wherein the actively controlled cooling block comprises at least one of the group comprising: a heat pipe system, a fluid channel, a fan, a thermoelectric cooler, a variable thermal contact, and a counter-heater element.Embodiment 46: The thermal control device of any one of the preceding embodiments, wherein the controller is adapted to control the heater circuit to provides an upper temperature by heating the heat spreader via providing power to the heater circuit.Embodiment 47: The thermal control device of embodiment 44, wherein a portion of the heat is conducted as waste heat to the cooling block through the thermal interface material layer.Embodiment 48: A diagnostic test device comprising: a sample chamber; and a thermal control device comprising: a thermally conductive heat spreader layer comprising a first side surface and a second side surface; a heater circuit disposed adjacent to and in thermal contact with the first side surface of the thermally conductive heat spreader layer; at least one thermal interface material layer disposed adjacent to and in thermal contact with one of the first side surface and the second side surface of the thermally conductive heat spreader layer;a cooling block disposed adjacent to and in thermal contact with the thermal interface material layer, the cooling block adapted to conduct heat energy away from the thermally conductive heat spreader layer; and a controller adapted to control the heater circuit.Embodiment 49: The diagnostic test device of embodiment 38, wherein the diagnostic test comprises a PCR test.Embodiment 50: The diagnostic test device of any one of the two preceding embodiments, wherein the thermal control device is a thermal control device according to any one of the preceding embodiments referring to a thermal control device.

[0013] The foregoing and other aspects, features, details, utilities, and advantages of the present invention will be apparent from reading the following description and claims, and from reviewing the accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Fig. 1 is an exploded view of an embodiment of a thermal control element suitable for controlling the temperature in one or more adjacent reaction chambers, such as for controlling a temperature for one or more reaction chambers of a PCR instrument.

[0015] Fig. 2 is a perspective view of the heating element shown in Fig. 1 with an exploded view of a portion of the heating element showing the conductive traces of the electrical resistance heater and the temperature sensor element disposed on the heat spreader material, in accordance with certain example embodiments.

[0016] Fig. 3 is a flowchart showing operations of an embodiment of a method of controlling a thermal control element, in accordance with certain example embodiments.

[0017] Fig. 4 is a graph showing an example temperature profile of the thermal control element shown in Fig. 1.

[0018] Fig. 5 is a graph showing simulated temperature profiles for two example thermal control elements used in a PCR process, in accordance with certain example embodiments.

[0019] Fig. 6 is a top view of a thermal control element and an infrared (IR) image of the thermal control element, in accordance with certain example embodiments.

[0020] Fig. 7 is a block diagram showing a pair of thermal control elements disposed along a process chamber, such as a PCR process chamber, in accordance with certain example embodiments.

[0021] Fig. 8 is a schematic diagram showing elements of an example PCR photometer for transmitted light and reflecting light detection. In this embodiment, one or more excitation optical signals are generated and directed into a sample chamber and one or more corresponding emission signals triggered by the one or more excitation optical signals are collected and directed to one or more corresponding detectors of a photometer.

[0022] Figs. 9A and 9B show graphs of photometer raw data from a PCR instrument using a thermal control element as shown in Figs. 1 and 2 (Internal-control and positive control channels of in development assay “sexual transmitted infections”). The increasing signal after cycle 30...35 shows successful amplification and proves the feasibility of this technology.

[0023] Fig. 10 is a plan view of another embodiment of a thermal control element suitable for controlling the temperature in one or more adjacent reaction chambers, such as for controlling a temperature for one or more reaction chambers of a PCR instrument.DETAILED DESCRIPTION

[0024] The following description of the invention is provided as an enabling teaching of the invention in its best, currently known embodiment. To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various aspects of theinvention described herein, while still obtaining the beneficial results of the present invention. It will also be apparent that some of the desired benefits of the present invention can be obtained by selecting some of the features of the present invention without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the present invention are possible and can even be desirable in certain circumstances and are a part of the present invention. Thus, the following description is provided as illustrative of the principles of the present invention and not in limitation thereof.

[0025] As used throughout, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a” component can include two or more such components unless the context indicates otherwise. Also, the words “proximal” and “distal” are used to describe items or portions of items that are situated closer to and away from, respectively, a user or operator such as a surgeon. Thus, for example, the tip or free end of a device may be referred to as the distal end, whereas the generally opposing end or handle may be referred to as the proximal end.

[0026] All directional references (e.g., upper, lower, upward, downward, left, right, leftward, rightward, top, bottom, above, below, vertical, horizontal, clockwise, and counterclockwise) are only used for identification purposes to aid the reader’s understanding of the present disclosure, and do not create limitations, particularly as to the position, orientation, or use of the invention. Joinder references (e.g., attached, coupled, connected, and the like) are to be construed broadly and may include intermediate members between a connection of elements and relative movement between elements. As such, joinder references do not necessarily infer that two elements are directly connected and in fixed relation to each other.

[0027] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular valueforms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0028] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0029] The term “substantially” as used herein may be applied to modify any quantitative representation which could permissibly vary without resulting in a change in the basic function to which it is related.

[0030] There are many devices available to temper a sample in a cyclic fashion. The phrase thermocycling refers to a cyclic variation in temperature, such as of a sample. The cyclic variation in temperature may include where the temperature at the beginning of one cycle is the same as the temperature at the end of the cycle or where the cycles vary slightly in temperature. In one embodiment, for example the cycles may include an overlapping temperature shift from cycle to cycle. In an overlapping temperature shift example, the temperatures in different cycles may overlap, but with different starting and / or stopping temperatures. For example, in an overlapping temperature shift example, each temperature may be changed by 0.1 °C and the start and end temperatures between cycles are not the same. One temperature cycle comprises phases of heating, cooling (temperature ramps) and phases of substantially constant temperature in which the temperature is held relatively constant or is sub-cycled (e.g., by 0.2°C) around a temperature level. The temperature variation with time is summarized by the phrase “thermocycling protocol."

[0031] If the device is able to simultaneously temper an assembly of multiple samples, e.g., a consumable sample array such as multiple tubes, and the results of the experiments within the multiple samples should be comparable, the thermocycling of the samples in the center of the assembly and at the border of the assembly may be substantially identical. Moreover, it may be desirable to perform the temperature ramps of the thermocycling protocol with or withoutovershooting the temperatures of the multiple samples when reaching the phases of constant temperature.

[0032] As described above, for polymerase chain reaction (PCR) tests the turnaround time is a key attribute, especially in the point-of-care (POC) and multiplex testing sectors. In the context of a PCR test, a fast and controllable PCR thermocycler is adapted to provide extremely fast and accurate heating and cooling rates for POC and high throughput PCR cycler platforms, such as in a single or simultaneous PCR amplification process with one or multiple samples.

[0033] Fig. 1 is an exploded view of an embodiment of a thermal control element 110 suitable for controlling the temperature in one or more adjacent reaction chambers, such as for controlling a temperature for one or more reaction chambers of a PCR instrument. In this embodiment, the thermal control element 110 comprises a heating element 112, a thermal interface material (TIM) 114, also referred to as “thermal interface material layer”, and a cooling block 116. The thermal control device may also be referred to as “thermal control element”.

[0034] The heating element 112 comprises a thermally conductive heat spreader 118, also referred to as “heat spreader layer”, coupled to a heater circuit 120. Thermally conductive materials are materials that have a good thermal conductivity. An ideal heat spreader for cycling applications has also low thermal capacity to enable fast changes in temperature. In heat transfer analysis the ratio of thermal conductivity and heat capacity is also defined as thermal diffusivity: a = k / ( p * Cp) where k is the thermal conductivity, measured in W / (m'K), p cpis the volumetric heat capacity, measured in J / (m3'K). The SI unit of the thermal diffusivity is m2 / s.

[0035] Substances with high thermal diffusivities rapidly adjust their temperatures to that of their surroundings, because they conduct heat quickly in comparison to their thermal bulk. Thermally diffusive materials are materials having a good thermal conductivity, and without being bound to theory, most materials having a good electrical conductance also have a good thermal diffusivity,too. Other materials, such as diamond, have good thermal diffusivity without having good electrical conductance.

[0036] On the other hand, although they have much smaller thermal diffusivities, there are also some plastics, ceramics and polymers that may have sufficient thermal properties depending on the application. Plastics have thermal diffusivities of up to a = 0.2 mm2 / s, ceramics of up to a = 0.4 mm2 / s.

[0037] There is a plurality of materials that have a good thermal conductance and that are suitable for the heat spreader 118, e.g., synthetic substances (e.g., CVD) diamond, copper, aluminum or silver. Synthetic diamond has a thermal diffusivity of about >2’ 100 mm2 / s (below 110°C), k = 1500 WmK, Cp = 0.02 kJ / kgK, and a density of about 3515 lg / m3. Copper for example has a thermal diffusivity of about a = 107mm2 / s, silver of about a = 166 mm2 / s, whereas aluminum has about 93 10 mm2 / s (all at 300 K). Note that in the majority of cases the metallic materials are not pure but alloys, whereas the thermal conductance of the material will be depending on the composition of the alloy.

[0038] In one embodiment, the heat spreader layer 118 is substantially planar, whereas substantially planar summarizes cuboid heat spreader layers with a top-view cross section area A, a length 1, a width w and a height h, having the typical dimensions of 1 = 1 - 50 mm, w = 1 - 50 mm, and h = 0.1 - 1 mm. In other embodiments, the heat spreader layer 118 may not be planar, for example, parallel curved or spherical plates may be used.

[0039] In certain embodiments, the heat spreader 118 can be described as "free of recesses" to emphasize that the heat spreader layer 118 has a continuous top-view cross section area A that is uninterrupted by recesses. In other words, a heat spreader layer 118 that is free of recesses has a planar surface at least in the area of thermal contact with the neighboring device parts.

[0040] The phrase "thermal contact" between two components is used to emphasize that the physical contact between two components can be optimized or targeted towards a relatively high thermal conductance. In other words, a "thermal contact" is an improved / optimized "physicalcontact" adapted to improve the thermal conductance between two components. Since air is a poor thermal conductor, the amount of air between two components in thermal contact is as small as reasonably possible. There are several possibilities to minimize air in the contact zone of two solid state materials, whereas these possibilities can be classified in two groups, namely a direct thermal contact and an indirect thermal contact.

[0041] One variant of indirect thermal contact utilizes a paste having a high thermal conductance as linker between the two components, e.g., thermal grease. In another variant of indirect thermal contact typically a soft, thermally conductive foil, e.g., a graphite foil is used as an interface material between the two components. Such a graphite foil can even a certain roughness of the components and reduces the mechanical stress due to thermal expansion.

[0042] On the other hand, a mechanical force may be applied such that a direct thermal contact is sufficient and no additional interface materials between the two components are needed. Both contact areas can be as flat as possible or matched in shape to minimize the air gap between the components. Note that it may be advantageous to apply a mechanical force to press together the two components even for the embodiments with indirect thermal contact, because this can further improve the thermal conductance.

[0043] In a variant, the heat spreader 118 is in thermal contact with the cooling block 116 either in a direct thermal contact or an indirect thermal contact, such as via thermal interface material (TIM) 114. The TIM 114 comprises a thermal connecting material that may comprise one or more such material, such as but not limited to thermal grease, thermal paste, thermal adhesive, graphite foils, or the like. If desired, a plurality of layers may include a primary thermal connecting material (e.g., polymer, graphite, or the like) and one or more additional component, such as a thermal grease, a thermal adhesive, or similar, may be used as an additional interface material between any of the components.

[0044] The thermal interface material (TIM) 114 may comprise a thermal connecting material adapted to provide a predetermined thermal conductivity or thermal resistance and may be furthercombined with one or more additional thermal connecting material with a different (e.g., higher or lower) thermal conductance or thermal resistance.

[0045] In one embodiment, the heat spreader 118 comprises a synthetic diamond material, such as but not limited to a chemical vapor deposited (CVD) diamond material. The CVD diamond heat spreader may be operated e.g. at temperatures in between 50°C to 110°C. In other embodiments, the heat spreader 118 may comprise other materials, such as but not limited to sapphire, ceramic, copper, silver, aluminum, or the like. Synthetic diamond, such as CVD diamond, provides relative temperature homogeneity, high thermal conductivity, stiffness sufficient to allow a thin, low mass material that requires relatively less energy to heat and cool, a low coefficient of thermal expansion to reduce stress and increase lifetime of one or more components of the heating element 112. Synthetic CVD diamond may also provide optical transparency such that one or more optical sensors may be able to optically detect luminescence through the material, such as with a photometer. Additional anti-reflection coating (on one or both sides) can increase the light efficiency in case of diamond material with high refractive index.

[0046] Where a non-optically transparent material, such as copper, aluminum, ceramic, or silver, is used as a heat spreader layer 118, an optical window may or may not be provided (e.g., an optical window cut, etched, or otherwise removed from the material of the heat spreader layer 118). In such an implementation, the heater element may be disposed over more of the surface of the heat spreader layer 118 than shown in Fig. 1. In this embodiment, the heater element can be located over the entire surface and can be beneficial to reach good temperature homogeneity, even with a less thermally conductive material. Doing so can allow use of a relatively low performance material compared to diamond to reach similar or satisfactory thermal performance (but without an optical window).

[0047] Where a conductive heat spreader material, such as copper, aluminum, or silver, is used as a heat spreader layer 118, an additional insulation layer may be provided between an electricalresistance heater and the heat spreader layer 118 to prevent electrical conduction into the heat spreader layer 118.

[0048] A heat spreader layer 118 comprising a synthetic diamond or other similar surfaces are inert against chemicals and can be easily cleaned. Where the heat spreader layer 118 is not chemically inert, however, a protection layer may be disposed on an exterior surface of the heat spreader layer 118. Examples of protection layers include, but are not limited to, diamond like carbon (DLC) layer, polymer (e.g., Kapton, Parylene C, paint, adhesives), ceramics gold (Au), platinum (Pt), tin (Sn), nickel (Ni), nanocoatings, or the like.

[0049] Where a lower stiffness material is used as the heat spreader layer 118, a relatively higher thermal mass material may be provided although the higher thermal mass material may provide a relatively slower overall system or higher power consumption.

[0050] The heating element 112 further comprises a heater circuit 120, such as an electrical resistance heater circuit deposited onto a surface of the heat spreader material. In one embodiment, for example, the heater circuit 120 may be sputtered directly onto the surface of the heat spreader 118. In another embodiment, a layer of conductive material may be deposited on the surface and etched to form the heater circuit 120 on the surface of heat spreader material. In yet another embodiment, the heater circuit 120 may be formed on a layer disposed adjacent to the heat spreader material layer and not necessarily disposed directly onto the heat spreader material. For example, an electrical heater element can be disposed on a polyimide layer with pressure sensitive adhesive. The pressure sensitive adhesive can secure the heater element to the heat spreader material.

[0051] The heater circuit 120 comprises a pair of contacts adapted to provide electrical energy to the heater circuit 120 and provide heat to the adjacent heat spreader material. The heater circuit 120 is disposed in a pattern along a surface of the heat spreader 118 and is adapted to efficiently provide heat to the heat spreader material by maintaining good temperature homogeneity on the surface during application. To find suitable patterns for circuit, tools like Finite Element Method (FEM) or similar could be used.

[0052] The heater circuit 120, in this embodiment, is deposited on the surface of the heat spreader 118 in a pattern defining an opening. The opening provides an optical window through an optically transparent heat spreader. The optical window may provide an opening suitable for visible wavelengths or non-visible wavelengths, such as infrared (IR) or ultraviolet (UV) light.

[0053] The heating element 112 further comprises a temperature sensor element deposited on the same or opposing surface of the heat spreader material. In one embodiment, for example, a platinum sensor circuit is deposited onto the surface of the heat spreader material. The temperature sensor element comprises a pair of contacts for detecting a temperature sensing signal from the temperature sensor element. The temperature sensor element is adapted to detect the temperature at one or more locations along the surface of the heat spreader material. A controller (not shown in the Figures) may be provided to detect the temperature sensing signal as a feedback signal and control the temperature of the heating element 112 by controlling an input, such as a current, provided to the heater circuit 120.

[0054] A thermal interface material 114 with determined thermal properties is disposed between the heating element 112 and the cooling block 116 of the thermal control element 110. The thermal interface material 114 balances the heating and cooling performance of the thermal control element 110 by allowing heat transfer between the heating element 112 and the cooling block 116. Where the heater and sensor tracks are electrically exposed, the thermal interface material 114 may comprises an electrically insulative and at least partially thermally conductive property. In other embodiments, the heater and sensor tracks may be covered, such as with a passivation layer (e.g., capton, parylene C, paint, ceramics, polymers, or the like) an electrically conductive material such as an electrically conductive adhesive or grease may be used as the thermal interface material layer 114.

[0055] Thermal diffusivity of the thermal interface material 114 may be within a predetermined range depending on a target speed versus a maximum allowed heat loss. The thermal interfacematerial layer 114, in one embodiment, comprises a uniform, constant thickness over the surface to maintain acceptable temperature homogeneity.

[0056] In one embodiment, the thermal interface material layer 114 provides mechanical functionality, such as but not limited to an adhesive layer to provide bonding and flexibility between the heat spreader layer 118 and the cooling block 116 over the device lifetime, a mechanical stability that maintains mechanical accuracy over load, temperatures, and device lifetime, low fluorescence in a target wavelength (e.g., 402-800 nm), ease of application (e.g., a sheet instead of a liquid adhesive), easy storage (room temperature, long storage life), and / or to provide a dielectric layer.

[0057] The cooling block 116 is thermally coupled to the heating element 112 via the thermal interface layer 114. The cooling block 116 may comprise a passive heatsink or an actively controlled cooling block. In an actively controlled cooling block embodiment, for example, the cooling block 116 is maintained at a constant temperature or within a temperature range, such as between 30°C and 40°C. In some embodiments, for example, the cooling block 116 may comprise one or more materials such as, but not limited to, copper, aluminum, silver, or the like to provide good thermal conductivity. In other embodiments, the cooling block 116 need not comprise a bulk material but may include a system such as a heat-pipe system or use fluid channels for cooling. For active controlled cooling blocks, the temperature can be controlled with elements such as a fan, a thermoelectric cooler (TEC), a variable thermal contact to a heat sink, a counter-heater element to preheat the cooling block 116 to an operational temperature.

[0058] In one embodiment, the cooling block 116 is cooled by air or by water flow. An interstitial assembly of fins can provide a large surface area, whereas the solid base plate represents the thermal contact area with the thermal interface material 114. The cooling block 116 dissipates heat to the surrounding. Since this dissipative process is most effective for large temperature differences between the surrounding atmosphere and the cooling block 116, the device may actively cool the1 surrounding. This can be done either by air flow produced by a fan or by liquid flow, such as produced by a peristaltic pump.

[0059] During the cooling of the heat spreader layer 118 a large amount of heat is dissipated in a short time. The thermal diffusivity of the heat spreader layer 118 and the thermal interface material layer 114 control the heat dissipation from the heat spreader layer 118 to the cooling block 116 to reduce the temperature of the heat spreader layer 118.

[0060] The thermal control element 110 provides an upper temperature by heating the heat spreader 118 via providing power to the heater circuit 120. A portion of the heat is conducted as waste heat to the cooling block 116 through the thermal interface material 114. Varying one or more property of the thermal interface material 114 can customize the system heat characteristic.

[0061] The thermal control element 110 provides a lower temperature by reducing or eliminating the power to the heater circuit 120. Heat of the heat spreader 118 is then dissipated through the thermal interface material 114 to the cooling block 116.

[0062] The temperature of the thermal control element 110 can be controlled between the upper and lower temperatures by controlling the power to the heater circuit 120 of the heating element 112.

[0063] In addition to providing a heatsink, the cooling block 116 and / or the thermal interface material 114 also provides structural stability for the heat spreader layer 118 and corresponding electrical resistance and temperature sensor traces. By providing a structural support for the heat spreader layer 118, relatively thin heat spreader material layers can be provided for fast thermal conduction in the layer without the requirement of the heat spreader layer 118 to provide mechanical support for the layer and the corresponding traces except for an optical window not directly supported by the thermal interface material 114 and the cooling block 116. The optical window can be applied on both heat spreader 118 (both side of consumable) for through light applications, on one side for reflected light applications or on none of the heat spreader 118, for non-real time detection after completed PCR. In combination with none optical window, otherquantification methods like electrochemical detection are also possible for real time or non-real time detection.

[0064] In contrast to other state of the art technologies for fast PCR-cycling, embodiments of the thermal control element 110 provides a flow free design. Meaning to change temperature levels fast no active, mechanical fluid movement is needed. This eliminates the possibility of incomplete fluid transfer within the heater / cooler zones and the possibility of variation or air bubble formation within the optical window. The lack of movement within the thermal control element 110 also eliminates the effect of temporary reduced or undefined thermal contact to the fluid within a process chamber, such as in a PCR chamber, and also provides a continuous thermal control over fluid within a chamber due to a constant pressure on the fluid pocket without influence of variable boundary conditions.

[0065] In one embodiment, a device is further adapted to monitor a reaction chamber (e.g., nucleic acid amplifications) in real-time.

[0066] All nucleic acid amplifications known in the art are applicable, such as any nucleic acid amplification reaction that requires tempering of the reaction. Such reactions include the conventional polymerase chain reaction (PCR), the Ligase Chain Reaction (LCR), Polymerase Ligase Chain Reaction, Gap-LCR, Repair Chain Reaction, 3 SR, strand displacement amplification (SDA), transcription mediated amplification (TMA) or Q0 -amplification. Also included are multiplex PCR, long-range PCR, single-cell PCR, fast-cycling PCR, methylation-specific PCR (MSP), hot start PCR, high-fidelity PCR, rapid amplified polymorphic DNA analysis (RAPD), rapid amplification of cDNA ends (RACE), differential display PCR, nested PCR, assembly PCR, asymmetric PCR, and the like.

[0067] In general, nucleic acid amplifications are monitored in real-time using fluorescence dyes known to someone skilled in the art. To measure the fluorescence signals all kinds of optical devices are suitable, such as but not limited to CCD cameras or photometers that may be utilized with and without additional optical components like lenses, optical filters, or folding mirrors.

[0068] If the optical device is oriented below the heat spreader layer 118, e.g., to monitor the fluorescence intensity of the one or more samples through bottom holes in the cooling block 116 and the thermal interface layer 114, and through an optical window in the heat spreader layer 118.

[0069] Fig. 2 is a perspective view of the heating element 112 shown in Fig. 1 with an exploded view of a portion of heating element 112 showing the conductive traces of the electrical resistance heater 122 and the temperature sensor element 124 disposed on the heat spreader material. In this embodiment, the electrical resistance heater 122 comprises a pair of terminals disposed along an edge of the heating element 112 to provide for an electrical power source connection. A plurality of individual electrical resistance heater traces (e.g., four heater traces in the embodiment shown in Figs. 1 and 2) are disposed along the surface of the heat spreader material forming a pattern around a perimeter of the heat spreader material adapted to provide heat to the heat spreader material. In the embodiment of Fig. 2, for example, the heating element 112 comprises a plurality of individual traces disposed in parallel between the pair of terminals. This reduces the number of contacts required for the same number of traces. A simulation, such as FEM-simulation, may be used to design one or more trace designs to achieve sufficient thermal homogeneity. In this embodiment, the pattern of the electrical resistance heater traces defines an opening that provides an optical window 126 through the heating element 112, e. g. an optical window 126 for photometer reading. The temperature sensor element 124 also comprises a pair of terminals disposed along the edge of the heating element 112 and adapted to provide an electrical connection to the controller. In one embodiment, the controller is adapted to determine a change in a property of the heating element 112, such as a change in an electrical property (e.g., a change in electrical resistance). A temperature sensor trace is disposed along the surface of the heat spreader material and is coupled between the pair of temperature sensor element terminals. In this embodiment, the temperature sensor element trace is disposed along a perimeter of the opening adjacent to the inner trace of the plurality of electrical resistance heater traces and is adapted to determine a temperature along the surface of the heating element 112. The sensor traces can be located all over the surface, in a certain area from interest or as a standard meander thin layer layout on a characteristic spot. The lack ofheating functionality in the region of the sensor can be considered in the thermal model. This can be done by overheating in the region next to the sensor or local removal of the cooling block 116 in the region of the sensor. Typically, a good design can promptly be found with help of finite element method simulations.

[0070] If the optical system is not compatible with the thermal interface material 114 (e.g. due disturbing luminescence of used materials) an aperture can be sputtered between the traces. In one embodiment, the same material as for the traces can be used with a minimum required gap for electrical insulation between the traces. Another option is a not transparent passivation layer on the traces (e.g., painting) to decouple the optical system from the thermal interface material 114.

[0071] The traces may comprise platinum or similar material used for resistance thermometer applied with thin or thick film technology. An optional titanium connection layer between diamond and platinum can be used to increase adhesion strength. To protect the traces a passivation layer can be applied. Example materials include glass, polyimide, Parylene C or similar. The thermal interface material 114 itself can also be used as passivation layer itself.

[0072] Contacting of the traces can be done via soldering, klettwelding, welding, Pogo pins, connectors or similar methods.

[0073] In some embodiments, the heat spreader 118 and / or heating element materials provide protection against chemicals such as those that may be used in a process adjacent to the device.

[0074] A controller is coupled to the temperature sensor element terminals and is adapted to provide an electrical power signal to the terminals and determine a temperature along the surface of the heating element 112 by determining a change in one or more electrical properties (e.g., a change in resistance of the temperature sensor element trace). The controller is also adapted to control a power input to the electrical resistance heater terminals based on the temperature determination to control a heating (or cooling) profile of the heating element 112.

[0075] Fig. 3 is a flowchart showing operations of an embodiment of a method of controlling a thermal control element 110, in accordance with certain example embodiments. In block (302), a thermal control element 110 is provided. In this embodiment, the thermal control element 110 comprises a heating element 112, a thermal interface material (TIM) 114, and a cooling block 116. The thermal control element 110 may be disposed adjacent to a process chamber or may form a portion of a process chamber.

[0076] The heating element 112 comprises a heat spreader layer 118 and a heating circuit 120. A controller is adapted to determine a temperature of the heating spreader layer 118 in block (304) via a temperature sensor element, such as the temperature sensor element 124 shown in Figs. 1 and 2. The controller is further adapted to determine whether the temperature of the heat spreader layer 118 is less than, equal to, or greater than a predetermined temperature or a predetermined range of temperatures in block (306). The predetermined temperature or range of temperatures change over the duration of a cycle, and the controller is adapted to heat or cool the heat spreader layer 118 over the course of a thermocycle. In block (308), the controller is adapted to provide or increase a power signal to the heating element 112 when the controller determines that the heat spreader layer temperature is less than the predetermined temperature or range of temperatures and thereby increase the temperature of the heat spreader layer 118 until it reaches the predetermined temperature or range of temperatures according to a desired profile of a thermocycle. If the controller determines that the temperature of the heat spreader layer 118 is at or within a margin of the predetermined temperature or predetermined range of temperatures according to the desired profile of the thermocycle, the controller is adapted to maintain the electrical power signal to the heater element to maintain the temperature of the heat spreader layer 118 in block (310) thereby maintaining the temperature of the heat spreader layer 118 according to the profile of the thermocycle. If the controller determines that the temperature is above the predetermined temperature or predetermined range of temperatures, the controller is adapted to reduce or eliminate the electrical power signal to the heating element 112 in block (312) to allow thermal energy of the heat spreader layer 118 to dissipate via the thermal interface material (TIM) 114 tothe cooling block 116 thereby cooling the heat spreader layer 118 according to the profile of the thermocycle. In one embodiment, appropriate controller settings are chosen (e.g., proportional- integral-derivative controller or its derivatives). As discussed above with respect to Fig. 1, one or more properties of the thermal interface material 114 can be used to control the heat dissipation from the heat spreader layer 118 to the cooling block 116.

[0077] Fig. 4 is a graph showing an example temperature profile of the thermal control element 110 shown in Fig. 1. Specifically, the graph of Figure 4 shows the temperature 128 of the heat spreader 118 as a function of time 130. In this example, a controlled, linear heating and cooling rate was set and measured with a calibrated internal platinum temperature sensor. Nonlinear heating and cooling profiles are possible and would provide a quicker ramp time. With fine tuning higher ramp rates could be achieved, especially for heating. In a thermal lifetime test 200,000 cycles were performed with the temperature profile pictured in Fig. 4, and a linear heating and cooling rate of + / - 50°C / sec was achieved. In comparison, state of the art PCR-analyzer with TEC- technologies have a heating rate of about 5°C / s and cooling rate of about 2.5°C / s. The temperature profile shown for the thermal control element 110 shown in Fig. 4 provided a performance approximately 10 times faster in heating and approximately 20 times faster in cooling compared to the current state of the art PCR cyclers based on TEC technology.

[0078] Fig. 5 is a graph showing simulated temperature profiles for two example thermal control elements 110 used in a PCR process, in accordance with certain example embodiments. Specifically, the graph of Figure 5 shows the temperature 128 of the heat spreader 118 as a function of time 130. In this example, a first thermal control element 110 comprises a diamond (0.2 mm thickness) heat spreader layer 118 with sputtered heater and sensor traces and a cooling system described with reference to Figs. 1 through 3. The temperature profile for this first thermal control element 110 is shown in dotted line for a single PCR cycle in the graph of Fig. 5 (denoted by reference number 132). The temperature profile of this first thermal control element 110 is first heated to a first process temperature of approximately 95°C within approximately 0.7 s and ismaintained at the 95°C for a first process step of approximately 2.5 seconds. The temperature of the first thermal control element 110 is reduced to a second process temperature of approximately 60°C over a period of approximately 0.4 seconds. The temperature profile is maintained at the second process temperature for approximately 9.9 seconds until the end of cycle time of approximately 13.5 seconds (denoted by reference number 134).

[0079] A second thermal control element 110 similarly comprises a diamond (0.2 mm thickness) heat spreader layer 118 with sputtered heater and sensor traces and a cooling system further comprising overheating and subcooling as shown in the temperature profile. The temperature profile for this second thermal control element 110 is shown in solid line for a single PCR cycle in the graph of Fig. 5 (denoted by reference number 136). The temperature profile of this second thermal control element 110 is first heated to approximately 100°C, above the first process temperature of approximately 95°C and is allowed to revert toward the first process temperature of 95°C for a first process step of approximately 2.7 seconds (heating, overshooting, revert to 95°C, holding at 95°C). The temperature of the second thermal control element 110 is reduced to a temperature of approximately 50°C below the process temperature of approximately 60°C over a period of approximately 1.1 seconds. The temperature profile is allowed to revert to the process temperature of approximately 60°C for 6.6 seconds until the end of cycle time of approximately 11.2 seconds achieving a quicker cycle time than the first thermal control element 110 by maintaining same temperature levels within the fluid deposited in the simulation example (denoted by reference number 138).

[0080] Fig. 6 shows a top view of a thermal control element 110 (left side of Figure 6) and an infrared (IR) image of the thermal control element 110 (right side of Figure 6), in accordance with certain example embodiments. An IR camera was used to assess temperature accuracy and homogeneity and the pattern of temperature distribution. Displayed temperature distribution is impacted by material emission coefficient, IR transparency of used ACSLED-sticker, and IR reflection. The measurement was used to identify potential max. / min. temperature areas.Subsequently, three measurement spots 140 (Spot 1, Spot 2, and Spot 3) were chosen according extreme points in IR-camera measurements within relevant area for a cobas® Liat® system (= 10x10 mm). At these characteristic points additional measurements with three MicroThermocouple sensors were performed. In this example, readings were determined for two process temperatures. At a first process temperature of 55°C, a temperature homogeneity of < 0.3°C and a temperature accuracy measured as a mean over the three measurement spots Spot 1, Spot 2, and Spot 3 of -0.2°C were achieved. At a second process temperature of 88°C, a temperature homogeneity of < 0.4°C and a temperature accuracy measured as a mean over the three measurement spots Spot 1, Spot 2, and Spot 3 of -0.3°C were achieved. The absolute deviation in accuracy can partially also be induced by measurement error due the difficult surface measurement, which are often affected by ambient temperature (despite insulation to ambient). The measurement results are summarized In Table 1 :Table 1: Measurement results of temperature measurement with IR camera

[0081] Fig. 7 is a block diagram showing a pair of thermal control elements 110 disposed along and defining at least a portion of a process chamber 142, such as a PCR process chamber, in accordance with certain example embodiments. The thermal control elements 110 are adapted to heat process fluid within the process chamber 142. In this embodiment, each thermal control element 110 comprises a heat spreader layer 118 disposed directly adjacent to and defining at least a portion of the process chamber 142. A heater element 144 is disposed adjacent the heat spreader layer 118 on opposing sides of the heat spreader layer 118 from the process chamber 142. The thermal interface / thermal insulation layer 114 is disposed adjacent the heater element 144, and the cooling block 116 is disposed on the opposing side of the thermal interface / thermal insulation layer114. In this embodiment, a thermal resistance 146 is disposed in between the heater element 144 and the heat spreader layer 118. Indicated with reference number 142 is the location of the consumable between the pair of thermal control elements 110 (Tube, fluid). The cutout for the optional optical windows 126, e.g. an optical window for through light applications, is simplified in Fig. 7.

[0082] The cooling block 116 in this embodiment provides a constant cooling, such as via a heatsink. In the embodiment shown in Fig. 6, for example, the cooling block 116 may be maintained at a minimum temperature of approximately 40°C. As discussed above, the cooling block 116 may alternatively be actively cooled via a controller resulting in an increased heat dissipation within the thermal control element 110 but at a cost of a more complex assembly.

[0083] An upper temperature of each thermal control element 110 is achieved via heating the heat spreader layer 118 by providing power to the heater element 144. A portion of the heat is dissipated as waste heat through the thermal interface / thermal insulation layer 114 to the cooling block 116. The thermal interface / thermal insulation layer 114 limits the amount of waste heat dissipated to the cooling block 116.

[0084] A lower temperature of each thermal control element 110 is achieved with eliminating or reducing the power provided to the heater element 144 and allowing heat to dissipate through the thermal interface / thermal insulation layer 114.

[0085] With controlled properties of the thermal interface / thermal insulation layer 114 and, optionally, thermal resistance 146 to the heat spreader 118, a system characteristic can be controlled.

[0086] Fig. 8 is a schematic diagram showing elements of a transmission light detection system 148 and a reflecting light detection system 150 in which a temperature profile of a sample 152 or sample chamber is controlled by use of a thermal control device 110 such as described herein. In a first embodiment of a transmission light detection system 148, a light source 154 provides an excitation light signal 156. The light signal is directed to the sample via one or more of filter(s)and lens(es) 158. The light signal excites the sample 152 within a sample chamber or receptacle. A resultant sample emission signal 160 is provided to a detector 162 as shown in Fig. 8. In this embodiment, a thermal control device 110 may comprise a pair of opposing optical windows 126 allowing the excitation light signal 160 to be directed to the sample 152 and to allow a sample emission light signal 160 to pass to a detector 162 in a transmission configuration.

[0087] Fig. 8 also shows a second, reflecting light detection system 150 in which a light source 154 provides an excitation light signal 156. The excitation light signal 156 is directed to the sample 152 via one or more of filter(s) and lens(es) 158. The light signal excites the sample 152 within a sample chamber or receptacle. A resultant sample emission signal 160 is reflected back toward a detector 162. In this embodiment, a single optical window 126 may allow the excitation light signal 160 and the sample emission signal 156 to pass.

[0088] Fig. 9 A shows graphs of photometer raw data from a PCR instrument using a thermal control element 110 as shown in Figs. 1 and 2. The graphs correspond to amber 164, blue 166, green 168, red 170, and UV green 172 LED excitation light channels. As shown in each of the individual channel graphs, the photometer raw data successfully identified increasing light signals over a number of cycles, generally between 30 and 35 PCR cycles.

[0089] Each graph shows the photometer detector reading 174 at the end of each PCR cycle 176 for the corresponding light channels. Before the 30-35 cycle range there is no clear increase in the detected signal, because the noise is higher than the signal increase. In fact the signal strength approximately doubles from cycle to cycle. Between about cycle 30 and 35, the signal increase is high enough to clearly see the change. After one signal increase (green channel in this example), saturation starts. According to the shape of the signal increase, characteristic values (e.g., CT- value) can be calculated with an algorithm. The lower the CT-value, the higher the initial concentration of the target DNA can be determined.

[0090] Fig. 9 A shows five similar graphs, each for a different target, detected with another optical channel. One of these channels is an internal control, and the other channels are readings for targetDNA sequences. In this example, a positive control was used to simulate the content of the target DNA sequence. To generate the graphs, PCR-only tubes from a sexually transmitted infection (STI) assay were used. PCR time was around 11:13 [min:ss] was achieved compared to 12:21 [min:ss] in a prior cobas® Liat® system.

[0091] Fig. 9B shows a temperature log of the diamond cycler, wherein reference number 178 denotes the temperature log of a reference temperature, reference number 180 denotes the temperature log of the heat spreader 118 of a first thermal control element 110, wherein reference number 182 denotes the temperature log of the heat spreader 118 of a second thermal control element 110 and wherein reference numbers 184 and 186 denotes the temperature log of the cooling blocks 116 of the first and second thermal control element 110, respectively. Fig. 10 is a plan view of another embodiment of a thermal control element 110 suitable for controlling the temperature in one or more adjacent reaction chambers, such as for controlling a temperature for one or more reaction chambers of a PCR instrument. In this embodiment, the thermal control element 110 comprises a heating element 112 comprising conductive traces of an electrical resistance heater 122 and the temperature sensor element 124 disposed on a heat spreader material. In this embodiment, the electrical resistance heater 122 comprises a pair of terminals, e.g. pads for electrical contact 188, disposed along an edge of the heating element 112 to provide for an electrical power source connection. A plurality of individual electrical resistance heater traces (e.g., four heater traces in the embodiment shown in Fig. 10) are disposed along the surface of the heat spreader material forming a pattern around a perimeter of the heat spreader material adapted to provide heat to the heat spreader material. In the embodiment of Fig. 10, for example, the heating element 112 comprises a plurality of individual traces disposed in parallel between the pair of terminals. This reduces the number of contacts required for the same number of traces. A simulation, such as FEM-simulation, may be used to design one or more trace designs to achieve sufficient thermal homogeneity. In this embodiment, the pattern of the electrical resistance heater traces defines an opening that provides an optical window 126 through the heating element 112. The temperature sensor element 124 also comprises a pair of terminals, e.g. pads for electricalcontact 188, disposed along the edge of the heating element 112 and adapted to provide an electrical connection to the controller. In one embodiment, the controller is adapted to determine a change in a property of the heating element 112, such as a change in an electrical property (e.g., a change in electrical resistance). A temperature sensor trace is disposed along the surface of the heat spreader material and is coupled between the pair of temperature sensor element terminals. In this embodiment, the temperature sensor element trace is disposed along a perimeter of the opening adjacent to the inner trace of the plurality of electrical resistance heater traces and is adapted to determine a temperature along the surface of the heating element 112. The sensor traces can be located all over the surface, in a certain area from interest or as a standard meander thin layer layout on a characteristic spot. The lack of heating functionality in the region of the sensor can be considered in the thermal model. This can be done by overheating in the region next to the sensor or local removal of the cooling block 116 in the region of the sensor. Typically, a good design can promptly be found with help of finite element method simulations.

[0092] If the optical system is not compatible with the thermal interface material 114 (e.g. due disturbing luminescence of used materials) an aperture 190 can defined by one or more layers (such as sputtered layers) between the traces. In one embodiment, the same material as for the traces can be used with a minimum required gap for electrical insulation between the traces, e.g. with a distance of 0.05 mm to the heater circuit 120. Another option is a not transparent passivation layer on the traces (e.g., painting) to decouple the optical system from the thermal interface material 114. The aperture 190 may reduce visibility of the TIM 114.

[0093] In the embodiment, the traces may comprise platinum or similar material used for resistance thermometer applied with thin or thick film technology. An optional titanium connection layer between diamond and platinum can be used to increase adhesion strength. To protect the traces a passivation layer can be applied. Example materials include glass, polyimide, Parylene C or similar. The thermal interface material 114 itself can also be used as passivation layer itself.

[0094] Contacting of the traces can be done via soldering, klettwelding, welding, Pogo pins, connectors or similar methods.

[0095] In some embodiments, the heat spreader and / or heating element materials provide protection against chemicals such as those that may be used in a process adjacent to the device.

[0096] A controller is coupled to the temperature sensor element terminals and is adapted to provide an electrical power signal to the terminals and determine a temperature along the surface of the heating element 112 by determining a change in one or more electrical properties (e.g., a change in resistance of the temperature sensor element trace). The controller is also adapted to control a power input to the electrical resistance heater terminals based on the temperature determination to control a heating (or cooling) profile of the heating element 112.

[0097] In the embodiment of Fig. 10, for example, the optical opening aperture is defined by one or more layers surrounding the optical window aperture (and in this example defining the optical window aperture) between the traces and the optical window aperture. In this embodiment, the one or more layers comprises a sputtered platinum layer deposited on the surface of the heat spreader layer 118. The platinum layer at least reduces and may prevent light from transmitting through the heat spreader layer 118 in the region surrounding the intended optical window aperture. Where the TIM 114 or other component of the thermal control device 110 may interfere (e.g., via fluorescence or luminescence in response to a light signal) with the optical signal received from a sample chamber, the platinum or other layer may prevent or reduce interfering light signals from being transmitted through the heat spreader layer 118.List of reference number thermal control element heating element thermal interface material cooling block heat spreader heater circuit electrical resistance heater temperature sensor element optical window temperature time temperature profile of first thermal control element end of cycle without overheating / subcooling temperature profile of second thermal control element end of cycle with overheating / subcooling measurement spot process chamber heater element thermal resistance transmission light detection system reflecting light detection system sample light source excitation light signal filter(s) and lens(es) sample emission signal detector amber LED excitation light channelblue LED excitation light channel green LED excitation light channel red LED excitation light channel UV green LED excitation light channel photometer detector reading cycle reference temperature temperature log of first thermal control element temperature log of second thermal control element temperature log of first cooling block temperature log of second cooling block pads for electrical contact aperture

Claims

CLAIMS1. A thermal control device (110) adapted for temperature cycling comprising: a thermally conductive heat spreader layer (118) comprising a first side surface and a second side surface; a heater circuit (120) disposed adjacent to and in thermal contact with at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer (118); at least one thermal interface material layer (114) disposed adjacent to and in thermal contact with one of the first side surface and the second side surface of the thermally conductive heat spreader layer (118); a cooling block (116) disposed adjacent to and in thermal contact with the thermal interface material layer (114), the cooling block (116) adapted to conduct heat energy away from the thermally conductive heat spreader layer (118); and a controller adapted to control the heater circuit (120).

2. The thermal control device (110) of claim 1, wherein the thermally conductive heat spreader layer (118) comprises at least one material selected from the group consisting of: a synthetic diamond material; a thermally conductive optically transparent material; sapphire; ceramic; a metal; copper; silver; aluminum; gold.

3. The thermal control device (110) of claim 1, wherein the thermally conductive heat spreader layer (118) comprises a protective layer disposed towards the process chamber (142) comprising at least one of a diamond like carbon layer, a polymer layer, a Kapton layer, a parylene C layer, a paint layer, a gold layer, a platinum layer, a tin layer, a nickel layer, or a nanocoating layer.

4. The thermal control device (110) of claim 1, wherein at least one of the heater circuit (120) and the thermal interface material layer (118) comprises a protective layer disposed on a surface of the respective heater circuit (120) and the thermal interface material layer (114).

5. The thermal control device (110) of claim 1, wherein the heater circuit (120) is deposited directly on at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer (118).

6. The thermal control device (110) of claim 1 , wherein the heater circuit (120) is secured to at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer (118) via the thermal interface material (TIM) (114), wherein the TIM (114) comprises an adhesive with self-retaining functionality, wherein the TIM (114) provides mechanical support for the heat spreader layer (118) and / or wherein an external support device provides mechanical support for the heat spreader layer (118).

7. The thermal control device (110) of claim 1, wherein the heater circuit (120) comprises at least two electrical contacts for the controller and at least one thermal trace disposed between the at least two contacts, wherein the controller is adapted to control the heater circuit (120) by providing a current control signal or a voltage control signal across the at least two contacts.

8. The thermal control device (110) of claim 1, wherein the heater circuit (120) is disposed in a pattern across the first or second side surface of the thermally conductive heat spreader layer (118), wherein the pattern defines an opening adapted to provide an optical window (126) through the heat spreader layer (118), wherein the thermally conductive heat spreader layer (118) comprises a layer adapted to reduce reflection at the opening.

9. The thermal control device (110) of claim 1, wherein an optical window aperture is provided through the heat spreader layer (118) and an optically nontransparent layer is disposed at least partially surrounding the optical window aperture to at least reduce light transmission through the optically nontransparent layer, wherein the optically nontransparent layer is adapted to reduce the visibility of the TIM against the process chamber (142), wherein the optically nontransparent layer comprises an optically opaque coating.

10. The thermal control device (110) of claim 1, wherein the thermally conductive heat spreader layer (118) is transparent to visible or nonvisible wavelengths.

11. The thermal control device (110) of claim 1, wherein at least one temperature sensor is disposed adjacent at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer (118), wherein the temperature sensor comprises at least two electrical contacts for the controller, wherein at least one thermal trace is disposed between the at least two contacts for resistive temperature measurement and / or wherein a thermal sensor is disposed between the at least two electrical contacts.

12. The thermal control device (110) of claim 11, wherein the controller is adapted to receive a signal via the temperature sensor and to control the heater circuit (120) based at least in part on the signal.

13. The thermal control device (110) of claim 1, wherein the thermal interface material layer (114) is adapted to balance the heating and cooling performance of the thermal control element (110) by allowing heat transfer between the thermally conductive heat spreader layer (118) and the cooling block (116), wherein the thermal interface material layer (114) comprises a thermal diffusivity within a predetermined range adapted to provide a target heat transfer speed versus a maximum allowed heat loss and / or, wherein the thermal interface material layer (114) comprisesa substantially uniform, constant thickness over one of the first side surface and second side surface to provide a predetermined temperature homogeneity.

14. The thermal control device (110) of claim 1, wherein the thermal interface material layer (114) comprises an adhesive to provide bonding and flexibility between the thermally conductive heat spreader layer (118) and the cooling block (116), wherein the adhesive provides mechanical support for the heat spreader layer (118) and / or wherein an external support device provides mechanical support for the heat spreader layer (118).

15. The thermal control device (110) of claim 1, wherein the cooling block (116) comprises a passive heatsink and / or wherein the cooling block (116) comprises an actively temperature controlled cooling block, wherein the actively controlled cooling block comprises at least one of the group comprising: a heat pipe system, a fluid channel, a fan, a thermoelectric cooler, a variable thermal contact, and a counter-heater element.

16. The thermal control device (110) of claim 1, wherein the controller is adapted to control the heater circuit (120) to provides an upper temperature by heating the heat spreader (118) via providing power to the heater circuit (120), wherein a portion of the heat is conducted as waste heat to the cooling block (116) through the thermal interface material layer (114).

17. A diagnostic test device comprising: a sample chamber; and a thermal control device (110) comprising: a thermally conductive heat spreader layer (118) comprising a first side surface and a second side surface;a heater circuit (120) disposed adjacent to and in thermal contact with at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer (118); at least one thermal interface material layer (114) disposed adjacent to and in thermal contact with one of the first side surface and the second side surface of the thermally conductive heat spreader layer (118); a cooling block (116) disposed adjacent to and in thermal contact with the thermal interface material layer (114), the cooling block (116) adapted to conduct heat energy away from the thermally conductive heat spreader layer (118); and a controller adapted to control the heater circuit (120).

Images