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

Abstract

In one embodiment, a thermal control device (110) adapted to temperature cycling is provided. The thermal control device (110) comprises a thermally conductive soaking sheet 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 soaking sheet 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 soaking sheet 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 thermal energy away from the thermally conductive soaking sheet 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

Technical Field

[0001] This disclosure relates to apparatus, methods, and systems including thermal control devices for temperature cycling, such as for processes such as polymerase chain reaction (PCR) testing. Background Technology

[0002] Devices for temperature control of samples or reaction mixtures in a controlled manner are used in almost all fields of chemistry and biochemistry, and basic science, industrial development, and drug production are affected in the same way. Because labor time and reagents are expensive, development tends to increase the throughput of production and analysis while minimizing the necessary reaction quantities.

[0003] Generally, temperature control devices have a hot block that comes into thermal contact with the sample being studied. The hot block is heated to the desired temperature, thus affecting the temperature of the sample. The simplest hot block is the common boiler plate.

[0004] To achieve efficient temperature control, the device is suitable for heating and cooling samples. For this purpose, the hot block can be connected to two separate devices, or to a single device capable of both heating and cooling.

[0005] One of the many applications requiring precise thermoregulation of samples includes polymerase chain reaction (PCR) amplification and analysis, where both the heating and cooling rates of the reaction are strictly controlled. Turnover time (TAT) is also a critical attribute for PCR, such as in the point-of-care (POC) and multiplex testing industries where rapid PCR of nucleic acid samples can enhance diagnostic efficiency.

[0006] US 2013 / 0157271 A1 discloses methods and systems for performing thermal melting analysis on a microfluidic platform. This disclosure further describes methods and systems using a thermal system including a heat exchanger, including interconnection methods and materials developed to connect heat exchangers to the microfluidic device. The disclosure also describes methods and systems for controlling, measuring, and calibrating the thermal system.

[0007] US 2022 / 0258159 A1 describes a system for nucleic acid amplification assays. The system includes a consumable amplification module and a reader module for receiving the amplification module. The amplification module includes: a reactor vessel for containing a test sample; a heater including a heater element that is in thermal contact with the reactor vessel and controllable to add heat to the reactor vessel 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 vaporizer in thermal contact with the heater. The reader module includes: a heater controller for selectively controlling the heater element between an on and off state in response to a determined temperature of the heater element and / or the test sample; and an electric heater interface for connecting the heater controller and the heater. The system includes a heat sink for removing heat from the reactor vessel to cool the test sample. The amplification module may include a heat sink. The receiver module may include a heat sink and a thermal interface, and the amplification module may include a vaporizer for thermal contact with the thermal interface.

[0008] US Patent 2019 / 0032114 A1 discloses a device for amplifying and detecting analytes, including oligonucleotide targets. The device can be used for point-of-care nucleic acid testing. Methods and assays using these devices are also disclosed.

[0009] What is needed are PCR devices and systems with improved heating and cooling rates. This includes PCR devices and systems that are simple in design, making them easy to deploy to POC staff. Summary of the Invention

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

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

[0012] In summary, and without excluding other possible embodiments, the following embodiments are conceivable:

[0013] Example 1: A thermal control device adapted for temperature cycling, the thermal control device comprising:

[0014] A thermally conductive heat spreader layer, comprising a first side surface and a second side surface;

[0015] A heater circuit is configured to be adjacent to and in thermal contact with the first side surface of the thermally conductive heat spreader layer;

[0016] At least one thermal interface material layer is configured to be 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;

[0017] A cooling block, configured to be adjacent to and in thermal contact with the thermal interface material layer, is adapted to conduct heat away from the thermally conductive heat spreader layer; and

[0018] A controller adapted to control the heater circuit.

[0019] Example 2: The thermal control device according to Example 1, wherein the thermally conductive heat spreader layer comprises a synthetic diamond material.

[0020] Example 3: A thermal control device according to any one of the foregoing embodiments, wherein the thermally conductive heat spreader layer comprises a thermally conductive optically transparent material.

[0021] Example 4: A thermal control device according to any one of the preceding embodiments, wherein the thermally conductive heat spreader layer comprises at least one of the group consisting of: sapphire, ceramic, metal, copper, silver, aluminum and gold.

[0022] Example 5: A thermal control device according to any one of the preceding embodiments, wherein the thermally conductive heat spreader layer includes a protective layer disposed toward the processing chamber, the protective layer comprising at least one of the following: a diamond-like carbon layer, a polymer layer, a Kapton layer, a Pyrelin C layer, a paint layer, a gold layer, a platinum layer, a tin layer, a nickel layer, or a nano-coating.

[0023] Example 6: A thermal control device according to any one of the foregoing embodiments, wherein at least one of the heater circuit and the thermal interface material layer includes a protective layer disposed on the surface of the respective heater circuit and thermal interface material layer.

[0024] Example 7: A thermal control device according to any one of the preceding embodiments, wherein the heater circuit is directly deposited on at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer.

[0025] Example 8: A thermal control device according to any one of the preceding embodiments, wherein the heater circuit is configured to be 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.

[0026] Example 9: The thermal control device according to Example 8, wherein the heater circuit is fastened 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).

[0027] Example 10: The thermal control device according to Example 9, wherein the TIM contains an adhesive with self-holding properties.

[0028] Example 11: The thermal control device according to Example 10, wherein the adhesive comprises at least one of pressure-sensitive adhesive and epoxy resin.

[0029] Example 12: The thermal control device according to Example 9, wherein the TIM provides mechanical support for the heat spreader layer.

[0030] Example 13: The thermal control device according to Example 9, wherein the external support device provides mechanical support for the heat spreader layer.

[0031] Example 14: The thermal control device according to Example 13, wherein the external support device includes at least one of the following: screws, clamps, locking attachment devices.

[0032] Example 15: A thermal control device according to any one of the foregoing embodiments, wherein the heater circuit includes at least two electrical contacts for the heater circuit and at least one thermal trace disposed between the at least two contacts.

[0033] Example 16: The thermal control device according to Example 15, wherein the thermal trace includes a resistance heater thermal trace.

[0034] Example 17: The thermal control device according to Example 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.

[0035] Example 18: A thermal control device according to any of the preceding embodiments, wherein the heater circuit is arranged in a pattern across the first side surface or the second side surface of the thermally conductive heat spreader layer.

[0036] Example 19: The thermal control device according to Example 18, wherein the pattern defines an opening adapted to provide an optical window through the heat spreader layer.

[0037] Example 20: The thermal control device according to Example 19, wherein the thermally conductive heat spreader layer includes a layer adapted to reduce reflection at the opening.

[0038] Example 21: A thermal control device according to any one of the preceding embodiments, wherein an optical window aperture is configured to pass through the heat spreader layer, and an optically opaque layer is configured to at least partially surround the optical window aperture to at least reduce light transmission through the optically opaque layer, wherein the optically opaque layer is adapted to reduce the visibility of the TIM toward the processing chamber.

[0039] Example 22: The thermal control device according to Example 21, wherein the optically non-transparent layer includes an optically opaque coating.

[0040] Example 23: The thermal control device according to Example 22, wherein the optically opaque layer comprises a sputtered metal layer.

[0041] Example 24: A thermal control device according to any one of the preceding embodiments, wherein the thermally conductive heat spreader layer is optically transparent.

[0042] Example 25: A thermal control device according to any one of the preceding embodiments, wherein the thermally conductive heat spreader layer is transparent to visible or invisible wavelengths.

[0043] Example 26: A thermal control device according to any one of the preceding embodiments, wherein at least one temperature sensor is disposed adjacent to at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer.

[0044] Example 27: The thermal control device according to Example 26, wherein the sensor circuit includes at least two electrical contacts for the sensor circuit.

[0045] Example 28: The thermal control device according to Example 27, wherein at least one thermal trace is disposed between at least two contacts for resistance temperature measurement.

[0046] Example 29: The thermal control device according to Example 27, wherein the thermal sensor is disposed between the at least two electrical contacts for the sensor circuit.

[0047] Example 30: The thermal control device according to Example 28, wherein the sensor is passivated with at least one of a diamond-like carbon layer, a polymer layer, a Kapton layer, a Pyrelin C layer, a paint layer, a nano-coating, an optical anti-reflective coating, and a non-conductive layer.

[0048] Example 31: The thermal control device according to Example 27, wherein one or more commercial sensors are mounted on the surface of a heat spreader and electrically connected to the electrical contact for the temperature sensor.

[0049] Example 32: The thermal control device according to Example 26, wherein a temperature sensor for controlling the heater circuit is disposed on at least one of the first side surface and the second side surface of the heat spreader layer.

[0050] Example 33: The thermal control device according to Example 32, wherein the temperature sensor is coupled to at least one of the first side surface and the second side surface of the heat spreader layer via the TIM.

[0051] Example 34: The thermal control device according to Example 26, wherein the controller is adapted to receive a signal via the temperature sensor and control the heater circuit at least in part based on the signal.

[0052] Example 35: A thermal control device according to any one of the preceding embodiments, wherein the thermal interface material layer is adapted to balance the heating and cooling performance of the thermal control element by allowing heat transfer between the thermally conductive heat spreader layer and the cooling block.

[0053] Example 36: The thermal control device according to Example 35, wherein the thermal interface material layer has a thermal diffusivity within a predetermined range, the thermal diffusivity being adapted to provide a target heat transfer rate relative to the maximum permissible heat loss.

[0054] Example 37: The thermal control device according to Example 35, wherein the thermal interface material layer has a substantially uniform constant thickness on one of the first side surface and the second side surface to provide predetermined temperature uniformity.

[0055] Example 38: A thermal control device according to any of the preceding embodiments, wherein the thermal interface material layer comprises an adhesive to provide adhesion and flexibility between the thermally conductive heat spreader layer and the cooling block.

[0056] Example 39: The thermal control device according to Example 38, wherein the adhesive comprises at least one of pressure-sensitive adhesive and epoxy resin.

[0057] Example 40: The thermal control device according to Example 38, wherein the adhesive provides mechanical support for the heat spreader layer.

[0058] Example 41: The thermal control device according to Example 38, wherein the external support device provides mechanical support for the heat spreader layer.

[0059] Example 42: The thermal control device according to Example 41, wherein the external support device includes at least one of the following: screws, clamps, locking attachment devices.

[0060] Example 43: A thermal control device according to any one of the preceding embodiments, wherein the cooling block includes a passive radiator.

[0061] Example 44: A thermal control device according to any one of the foregoing embodiments, wherein the cooling block includes an active temperature control cooling block.

[0062] Example 45: The thermal control device according to Example 44, wherein the actively controlled cooling block includes at least one of the following groups: heat pipe system, fluid channel, fan, thermoelectric cooler, variable thermal contact element and anti-heater element.

[0063] Example 46: A thermal control device according to any one of the foregoing embodiments, wherein the controller is adapted to control the heater circuit to provide a higher temperature by heating the heat spreader by providing power to the heater circuit.

[0064] Example 47: The thermal control device according to Example 44, wherein a portion of the heat is conducted to the cooling block as waste heat through the thermal interface material layer.

[0065] Example 48: A diagnostic testing device, comprising:

[0066] Sample chamber; and

[0067] Thermal control device, comprising:

[0068] A thermally conductive heat spreader layer, comprising a first side surface and a second side surface;

[0069] A heater circuit is configured to be adjacent to and in thermal contact with the first side surface of the thermally conductive heat spreader layer;

[0070] At least one thermal interface material layer is configured to be 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;

[0071] A cooling block, configured to be adjacent to and in thermal contact with the thermal interface material layer, is adapted to conduct heat away from the thermally conductive heat spreader layer; and

[0072] A controller adapted to control the heater circuit.

[0073] Example 49: The diagnostic testing apparatus according to Example 38, wherein the diagnostic test includes a PCR test.

[0074] Example 50: A diagnostic testing device according to any one of the preceding two examples, wherein the thermal control device is a thermal control device according to any one of the foregoing examples involving a thermal control device.

[0075] The foregoing and other aspects, features, details, utility, and advantages of the invention will become apparent from reading the following description and claims and from viewing the accompanying drawings. Attached Figure Description

[0076] Figure 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 the temperature of one or more reaction chambers of a PCR instrument).

[0077] Figure 2 is a perspective view of the heating element shown in Figure 1 according to some example embodiments, wherein an exploded view of a portion of the heating element shows the conductive traces of the resistance heater and temperature sensor element disposed on the heat spreader material.

[0078] Figure 3 is a flowchart illustrating an embodiment of a method for controlling a thermal control element according to certain example embodiments.

[0079] Figure 4 is a graph showing an example temperature profile of the thermal control element shown in Figure 1.

[0080] Figure 5 is a graph showing simulated temperature curves for two example thermal control elements used in the PCR process according to certain example embodiments.

[0081] Figure 6 is a top view of a thermal control element according to some example embodiments and an infrared (IR) image of the thermal control element.

[0082] Figure 7 is a block diagram illustrating a pair of thermal control elements arranged along a processing chamber such as a PCR processing chamber according to certain example embodiments.

[0083] Figure 8 is a schematic diagram illustrating the components of an example PCR photometer for detecting transmitted and reflected light. In this embodiment, one or more excitation light signals are generated and directed into a sample chamber, and one or more corresponding emission signals triggered by the one or more excitation light signals are collected and directed to one or more corresponding detectors of the photometer.

[0084] Figure 9A Figure 9B shows a graph of raw photometric data from a PCR instrument using the thermal control elements shown in Figures 1 and 2 (internal control and positive control channels for determining "sexually transmitted infections" under development). The increasing signal after cycles 30…35 indicates successful amplification and demonstrates the feasibility of the technique.

[0085] Figure 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 the temperature of one or more reaction chambers of a PCR instrument). Detailed Implementation

[0086] The following description of the invention is provided as a facilitating teaching of the invention in its best, currently known embodiments. Therefore, those skilled in the art will recognize and understand that many changes can be made to various aspects of the invention described herein while still obtaining the beneficial results of the invention. It will also be apparent that some of the desired beneficial effects of the invention can be obtained by selecting some features of the invention without utilizing others. Therefore, those skilled in the art will recognize that many modifications and alterations to the invention are possible and even desirable in some cases, and are part of the invention. Thus, the following description is provided to illustrate the principles of the invention, and not to limit it.

[0087] As used throughout, unless the context clearly indicates otherwise, the singular forms “a,” “one,” and “the” include a plural of the referred objects. Thus, for example, unless the context clearly indicates otherwise, a reference to a “one” component may include two or more such components. Furthermore, the terms “proximal” and “distal” are used to describe articles or parts of articles positioned closer to and further away from the user or operator (such as a surgeon), respectively. Thus, for example, the tip or free end of a device may be referred to as the distal end, while the generally opposite end or handle may be referred to as the proximal end.

[0088] All directional references (e.g., up, down, upward, downward, left, right, leftward, rightward, top, bottom, above, below, vertical, horizontal, clockwise, and counterclockwise) are for identification purposes only to aid the reader in understanding this disclosure and do not impose limitations, particularly regarding the location, orientation, or use of the invention. Engagement references (e.g., attachment, coupling, connection, etc.) should be interpreted broadly and may include intermediate members between connected elements and relative movement between elements. Therefore, engagement references do not necessarily imply that two elements are directly connected and in a fixed relationship with each other.

[0089] A range may be expressed herein as from “about” a particular value and / or to “about” another particular value. When expressing such a range, the other aspect includes from one particular value and / or to another particular value. Similarly, when a value is expressed as an approximation using the antecedent “about,” it should be understood that the particular value forms the other aspect. It should also be understood that the endpoints of each range are significant both relative to and independent of the other endpoint.

[0090] As used herein, the terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both scenarios in which the event or situation occurs and scenarios in which the event or situation does not occur.

[0091] As used in this article, the term "substantially" can be applied to modify any quantity representation that allows for change without altering its underlying functionality.

[0092] Many devices exist for cyclically temperature-controlled samples. The phrase thermal cycling refers to the cyclical change of temperature, such as that of a sample. Cyclic temperature changes can include situations where the temperature at the start of a cycle is the same as the temperature at the end of the cycle, or situations where the cycle varies slightly in temperature. In one embodiment, for example, a cycle can include overlapping temperature shifts between cycles. In an example of overlapping temperature shifts, temperatures in different cycles may overlap, but the start and / or stop temperatures are different. For example, in an example of overlapping temperature shifts, each temperature may change by 0.1°C, and the start and end temperatures between cycles are not the same. A temperature cycle includes phases of heating, cooling (temperature ramping), and phases of substantially constant temperature (where the temperature remains relatively constant or sub-cycles around a temperature level (e.g., by 0.2°C)). The change of temperature over time is summarized by the phrase "thermal cycling scheme."

[0093] If the device can simultaneously temperature-regulate assemblies of multiple samples (e.g., consumable sample arrays such as multiple tubes), and the results of experiments within the multiple samples should be comparable, then the thermal cycling of the samples at the center and edges of the assembly can be substantially the same. Furthermore, it may be desirable to perform a temperature ramp in the thermal cycling scheme when a constant temperature phase is reached, regardless of whether the temperatures of the multiple samples are overridden.

[0094] As described above, turnaround time is a critical attribute for polymerase chain reaction (PCR) testing, especially in the point-of-care (POC) and multiplex testing industries. In the context of PCR testing, rapid and controlled PCR thermal cyclers are well-suited to provide extremely fast and accurate heating and cooling rates for POC and high-throughput PCR cycler platforms, such as during single or simultaneous PCR amplification of one or more samples.

[0095] Figure 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 the temperature of one or more reaction chambers of a PCR instrument). In this embodiment, the thermal control element 110 includes a heating element 112, a thermal interface material (TIM) 114 (also referred to as a “thermal interface material layer”), and a cooling block 116. The thermal control device may also be referred to as a “thermal control element”.

[0096] Heating element 112 includes a thermally conductive vapor chamber 118, also referred to as a "vapor chamber layer," coupled to heater circuit 120. The thermally conductive material is one with good thermal conductivity. An ideal vapor chamber for cyclic applications also has a low heat capacity to allow for rapid temperature changes. In heat transfer analysis, the ratio of thermal conductivity to heat capacity is also defined as thermal diffusivity.

[0097] α = k / ( p * Cp)

[0098] Where k is the thermal conductivity (measured in W / (m'K)), pc p The volumetric heat capacity is expressed in J / (m³). 3 Measurements are taken in units of 'K'. The SI unit for thermal diffusivity is m. 2 / s.

[0099] Materials with high thermal diffusivity can rapidly adjust their temperature to that of their surroundings because they conduct heat quickly relative to their thermal volume. Thermally diffusive materials are those with good thermal conductivity, and this is not theoretically constrained; most materials with good electrical conductivity also have good thermal diffusivity. Other materials, such as diamond, have good thermal diffusivity but not good electrical conductivity.

[0100] On the other hand, while they have much smaller thermal diffusivity, depending on the application, there are also some plastics, ceramics, and polymers that may possess sufficient thermal properties. Plastics have diffusivity up to α = 0.2 mm. 2 The ceramic exhibits a thermal diffusivity of up to α = 0.4 mm / s. 2 Thermal diffusivity / s.

[0101] Various materials with good thermal conductivity are available and suitable for vapor chamber 118, such as synthetic materials (e.g., CVD) diamond, copper, aluminum, or silver. Synthetic diamond has a diameter of approximately >2'100 mm. 2 The thermal diffusivity per second (below 110℃) is k = 1500 WmK, Cp = 0.02 kJ / kgK, and approximately 3515 lg / m 3 The density of copper, for example, is approximately α = 107 mm. 2 With a thermal diffusivity of α / s, silver has an α = 166 mm² / s. 2 The thermal diffusivity is 93.10 mm / s, while aluminum has a thermal diffusivity of approximately 93.10 mm / s. 2 Thermal diffusivity / s (all at 300 K). Note that in most cases, metallic materials are not pure but alloys, and the thermal conductivity of the material will depend on the composition of the alloy.

[0102] In one embodiment, the vapor chamber 118 is substantially planar, and substantially planar generally refers to a cubic vapor chamber having a top-view cross-sectional area A, a length l, a width w, and a height h, with typical dimensions of l = 1 - 50 mm, w = 1 - 50 mm, and h = 0.1 - 1 mm. In other embodiments, the vapor chamber 118 may not be planar; for example, parallel curved or spherical plates may be used.

[0103] In some embodiments, the heat spreader 118 may be described as "without recesses" to emphasize that the heat spreader 118 has a continuous top-view cross-sectional area A that is not interrupted by recesses. In other words, the heat spreader 118 without recesses has a flat surface, at least in the area in thermal contact with adjacent device parts.

[0104] The phrase "thermal contact" between two components is used to emphasize that the physical contact between the two components can be optimized or aimed at a relatively high thermal conductivity. In other words, "thermal contact" is an improved / optimized "physical contact" that is suitable for improving thermal conductivity between the two components. Since air is a poor conductor of heat, the amount of air between the two components in thermal contact should be minimized. There are several possibilities for minimizing the air in the contact area between the two solid materials, and these possibilities can be classified into two groups: direct thermal contact and indirect thermal contact.

[0105] One variation of indirect thermal contact utilizes a paste with high thermal conductivity (e.g., thermal grease) as a connector between two components. Another variation typically uses a flexible, thermally conductive foil, such as graphite foil, as the interface material between the two components. Such graphite foil can smooth out any roughness of the components and reduce mechanical stress caused by thermal expansion.

[0106] On the other hand, mechanical force can be applied so that direct thermal contact is sufficient, and no additional interface material is required between the two components. Both contact areas can be as flat as possible or matched in shape to minimize air gaps between the components. It should be noted that even for embodiments with indirect thermal contact, applying mechanical force to press the two components together may be advantageous, as this can further improve thermal conductivity.

[0107] In one variation, the heat spreader 118 is in direct or indirect thermal contact with the cooling block 116 (e.g., via a thermal interface material (TIM) 114). The TIM 114 includes a thermal bonding material, which may include one or more such materials, such as, but not limited to, thermal grease, thermal paste, thermal adhesive, graphite foil, etc. If desired, multiple layers may comprise a primary thermal bonding material (e.g., a polymer, graphite, etc.), and one or more additional components, such as thermal grease, thermal adhesive, etc., may be used as additional interface materials between any components.

[0108] The thermal interface material (TIM) 114 may include a thermal bonding material suitable for providing a predetermined thermal conductivity or thermal resistance, and may be further combined with one or more additional thermal bonding materials having different (e.g., higher or lower) thermal conductivity or thermal resistance.

[0109] In one embodiment, the vapor chamber 118 comprises a synthetic diamond material, such as, but not limited to, chemical vapor deposition (CVD) diamond. The CVD diamond vapor chamber can operate at temperatures, for example, between 50°C and 110°C. In other embodiments, the vapor chamber 118 may comprise other materials, such as, but not limited to, sapphire, ceramic, copper, silver, aluminum, etc. Synthetic diamond (such as CVD diamond) provides relative temperature uniformity, high thermal conductivity, sufficient stiffness to allow for thin, low-mass materials requiring relatively little energy for heating and cooling, and a low coefficient of thermal expansion to reduce stress on one or more components of the heating element 112 and increase lifetime. Synthetic CVD diamond can also provide optical transparency, enabling one or more optical sensors to optically detect light emission through the material, such as using a photometer. In the case of diamond materials with high refractive indices, an additional anti-reflective coating (on one or both sides) can increase optical efficiency.

[0110] When a non-optically transparent material (such as copper, aluminum, ceramic, or silver) is used as the 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 implementations, the heater element can be disposed on more surface of the heat spreader layer 118 than shown in FIG. 1. In this embodiment, the heater element can be located on the entire surface, and good temperature uniformity can be achieved even when using a material with low thermal conductivity. This allows the use of materials with relatively lower performance compared to diamond to achieve similar or satisfactory thermal performance (but without an optical window).

[0111] When a conductive heat spreader material (such as copper, aluminum or silver) is used as the heat spreader layer 118, an additional insulating layer can be provided between the resistance heater and the heat spreader layer 118 to prevent electrical conduction into the heat spreader layer 118.

[0112] The vapor chamber layer 118, including synthetic diamond or other similar surfaces, is chemically inert and can be easily cleaned. However, in cases where the vapor chamber layer 118 is not chemically inert, a protective layer may be disposed on the outer surface of the vapor chamber layer 118. Examples of protective layers include, but are not limited to, diamond-like carbon (DLC) layers, polymers (e.g., Kapton, Pyrelin C, paints, adhesives), ceramic gold (Au), platinum (Pt), tin (Sn), nickel (Ni), nanocoatings, etc.

[0113] Using a lower stiffness material as the heat spreader layer 118 can provide a relatively high thermal mass material, although a higher thermal mass material may result in a relatively slower overall system or higher power consumption.

[0114] The heating element 112 further includes a heater circuit 120, such as a resistance heater circuit deposited on the surface of the heat spreader material. In one embodiment, for example, the heater circuit 120 may be directly sputtered onto the surface of the heat spreader 118. In another embodiment, a conductive material layer may be deposited on the surface and etched to form the heater circuit 120 on the surface of the 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 is not necessarily disposed directly on the heat spreader material. For example, the electric heater element may be disposed on a polyimide layer having a pressure-sensitive adhesive. The pressure-sensitive adhesive can secure the heater element to the heat spreader material.

[0115] The heater circuit 120 includes a pair of contacts adapted to supply electrical energy to the heater circuit 120 and to supply heat to the adjacent heat spreader material. The heater circuit 120 is patterned along the surface of the heat spreader 118 and is adapted to efficiently supply heat to the heat spreader material during application by maintaining good temperature uniformity on the surface. To find a suitable pattern for the circuit, tools such as the finite element method (FEM) can be used.

[0116] In this embodiment, heater circuitry 120 is deposited on the surface of vapor chamber 118 in a pattern defining openings. The openings provide optical windows through the optically transparent vapor chamber. The optical windows can provide openings suitable for visible or invisible wavelengths, such as infrared (IR) or ultraviolet (UV) light.

[0117] The heating element 112 further includes a temperature sensor element deposited on the same or opposite surfaces 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 includes 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 to control the temperature of the heating element 112 by controlling the inputs (such as current) provided to the heater circuit 120.

[0118] A thermal interface material 114 with defined 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. In the event of electrical exposure of the heater and sensor rails, the thermal interface material 114 may have electrically insulating and at least partially thermally conductive properties. In other embodiments, the heater and sensor rails may be covered, such as with a passivation layer (e.g., Capton, Pyrene C, paint, ceramic, polymer, etc.), and a conductive material (such as a conductive adhesive or grease) may be used as the thermal interface material layer 114.

[0119] Depending on the target rate of heat loss relative to the maximum permissible heat loss, the thermal diffusivity of the thermal interface material 114 can be within a predetermined range. In one embodiment, the thermal interface material layer 114 has a uniform, constant thickness throughout the surface to maintain acceptable temperature uniformity.

[0120] In one embodiment, the thermal interface material layer 114 provides mechanical functionality, such as, but not limited to: an adhesive layer to provide adhesion and flexibility between the heat spreader layer 118 and the cooling block 116 during device lifetime; mechanical stability, which maintains mechanical accuracy under load, temperature, and during device lifetime; low fluorescence at the target wavelength (e.g., 402 to 800 nm); ease of application (e.g., sheet rather than liquid adhesive); ease of storage (room temperature, long storage lifetime); and / or providing a dielectric layer.

[0121] Cooling block 116 is thermally coupled to heating element 112 via thermal interface layer 114. Cooling block 116 may include a passive radiator or an actively controlled cooling block. In an actively controlled cooling block embodiment, for example, 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, cooling block 116 may contain one or more materials, such as, but not limited to, copper, aluminum, silver, etc., to provide good thermal conductivity. In other embodiments, cooling block 116 does not need to contain a bulk material, but may include a system (such as a heat pipe system) or use fluid channels for cooling. For actively controlled cooling blocks, the temperature may be controlled using elements such as fans, thermoelectric coolers (TECs), variable thermal contacts with the radiator, and anti-heater elements that preheat cooling block 116 to operating temperature.

[0122] In one embodiment, the cooling block 116 is cooled by air or by a flow of water. Intermittent fin assemblies can provide a large surface area, while a solid substrate represents the area of ​​thermal contact with the thermal interface material 114. The cooling block 116 dissipates heat to the surrounding environment. Because this dissipation process is most effective for large temperature differences between the ambient atmosphere and the cooling block 116, the device can actively cool the surrounding environment. This can be achieved either by an airflow generated by a fan or by a liquid flow generated, such as by a peristaltic pump.

[0123] During the cooling of the heat spreader layer 118, a large amount of heat is dissipated in a short period of time. The thermal diffusivity of the heat spreader layer 118 and the thermal interface material layer 114 controls the heat dissipation from the heat spreader layer 118 to the cooling block 116, thereby reducing the temperature of the heat spreader layer 118.

[0124] The thermal control element 110 provides higher temperatures by heating the heat spreader 118 via supplying electricity 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. The thermal characteristics of the system can be customized by changing one or more properties of the thermal interface material 114.

[0125] The thermal control element 110 provides a lower temperature by reducing or eliminating the power destined for the heater circuit 120. The heat from the heat spreader 118 is then dissipated to the cooling block 116 via the thermal interface material 114.

[0126] The temperature of the thermal control element 110 can be controlled between a higher and a lower temperature by controlling the power supplied to the heater circuit 120 of the heating element 112.

[0127] In addition to providing a heat sink, the cooling block 116 and / or the thermal interface material 114 also provide structural stability to the heat spreader layer 118 and the corresponding resistance and temperature sensor traces. By providing structural support to the heat spreader layer 118, a relatively thin layer of heat spreader material can be provided to facilitate rapid heat conduction within this layer, without requiring the heat spreader layer 118 to provide mechanical support for the layer and the corresponding traces, except for optical windows that are not directly supported by the thermal interface material 114 and the cooling block 116. Optical windows can be applied to both heat spreaders 118 (on both sides of the consumable material) for light transmission applications, to one side for light reflection applications, or not applied to the heat spreader layer 118 for non-real-time detection after PCR. In combination with the absence of optical windows, other quantitative methods such as electrochemical detection can also be used for real-time or non-real-time detection.

[0128] Compared to other existing technologies for rapid PCR cycling, embodiments of the thermal control element 110 offer a flow-free design. This means that rapid changes in temperature levels do not require active mechanical fluid movement. This eliminates the possibility of incomplete fluid transfer within the heater / cooler zone and the possibility of changes or bubble formation within the optical window. The absence of movement within the thermal control element 110 also eliminates the effects of temporary reductions or ambiguous thermal contact with fluids within the processing chamber (such as the PCR chamber), and provides continuous thermal control of the fluid within the chamber due to the constant pressure in the fluid chamber, unaffected by variable boundary conditions.

[0129] In one embodiment, the device is further adapted to monitor the reaction chamber (e.g., nucleic acid amplification) in real time.

[0130] All nucleic acid amplification methods known in the art (such as any nucleic acid amplification reaction requiring temperature control) are applicable. These reactions include conventional polymerase chain reaction (PCR), ligase chain reaction (LCR), polymerase ligase chain reaction, Gap-LCR, repair chain reaction, 3SR, strand displacement amplification (SDA), transcription-mediated amplification (TMA), or Qβ amplification. Other methods include multiplex PCR, long-fragment PCR, single-cell PCR, rapid cycling PCR, methylation-specific PCR (MSP), hot-start PCR, high-fidelity PCR, rapid amplification of polymorphic DNA (RAPD), rapid cDNA end amplification (RACE), differential display PCR, nested PCR, assembly PCR, asymmetric PCR, etc.

[0131] Typically, nucleic acid amplification is monitored in real time using fluorescent dyes known to those skilled in the art. For measuring the fluorescence signal, all kinds of optical devices are suitable, such as, but not limited to, CCD cameras or photometers that can be used with or without additional optical components such as lenses, optical filters, or folding mirrors.

[0132] If the optical device is oriented below the heat spreader layer 118, for example, to monitor the fluorescence intensity of one or more samples through bottom holes in the cooling block 116 and the thermal interface layer 114 and through optical windows in the heat spreader layer 118.

[0133] Figure 2 is a perspective view of the heating element 112 shown in Figure 1, wherein an exploded view of a portion of the heating element 112 shows conductive traces of a resistance heater 122 and a temperature sensor element 124 disposed on a heat spreader material. In this embodiment, the resistance heater 122 includes a pair of terminals disposed along the edge of the heating element 112 to provide an electrical power connection. Multiple individual resistance heater traces (e.g., in...) Figure 1 The four heater traces (as shown in the embodiment of Figure 2) are arranged along the surface of the heat spreader material, thereby forming a pattern around the periphery of the heat spreader material that is adapted to provide heat to the heat spreader material. In the embodiment of Figure 2, for example, the heating element 112 includes a plurality of individual traces arranged in parallel between the pair of terminals. This reduces the number of contacts required for the same number of traces. One or more trace designs can be designed using simulations such as FEM simulations to achieve sufficient thermal uniformity. In this embodiment, the pattern of the resistive heater traces defines an opening that provides an optical window 126 through the heating element 112, such as an optical window 126 for photometer readings. The temperature sensor element 124 also includes a pair of terminals arranged along the edge of the heating element 112 and adapted to provide an electrical connection to a controller. In one embodiment, the controller is adapted to determine a change in the properties of the heating element 112, such as a change in electrical properties (e.g., a change in resistance). The temperature sensor traces are arranged along the surface of the heat spreader material and coupled between the pair of temperature sensor element terminals. In this embodiment, the temperature sensor element traces are arranged around the periphery of an opening adjacent to the inner traces of the plurality of resistive heater traces, and are adapted to determine the temperature along the surface of the heating element 112. The sensor traces can be positioned across the entire surface, in a specific target region, or as a standard tortuous thin-layer layout at characteristic dots. In the thermal model, the absence of heating functionality in the sensor region can be considered. This can be achieved by overheating in the region adjacent to the sensor or by locally removing the cooling block 116 in the sensor region. Typically, a good design can be quickly found using finite element method simulation.

[0134] If the optical system is incompatible with the thermal interface material 114 (e.g., due to the interfering luminescence of the material used), orifices can be sputtered between the traces. In one embodiment, the same material used for the traces can be used, with a minimum required gap between the traces for electrical insulation. Another option is to add a non-transparent passivation layer (e.g., paint) to the traces to separate the optical system from the thermal interface material 114.

[0135] The trace may contain platinum or similar materials for resistance thermometers used in thin-film or thick-film applications. An optional titanium bonding layer between the diamond and platinum can be used to increase adhesion strength. To protect the trace, a passivation layer may be applied. Example materials include glass, polyimide, pyrene C, etc. Thermal interface material 114 can also be used as the passivation layer itself.

[0136] The contact of the traces can be made by means of soldering, Klett soldering, welding, spring pins, connectors or similar methods.

[0137] In some embodiments, the heat spreader 118 and / or the heating element material provide protection against chemicals, such as those that may be used adjacent to the equipment during the process.

[0138] The controller is coupled to the terminals of the temperature sensor element and is adapted to provide an electrical power signal to the terminals and determine the 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 the power input to the terminals of the resistance heater based on the temperature determination to control the heating (or cooling) profile of the heating element 112.

[0139] Figure 3 is a flowchart illustrating the operation of an embodiment of a method for controlling a thermal control element 110 according to certain example embodiments. In block (302), a thermal control element 110 is provided. In this embodiment, the thermal control element 110 includes a heating element 112, a thermal interface material (TIM) 114, and a cooling block 116. The thermal control element 110 may be positioned adjacent to a processing chamber or may form part of a processing chamber.

[0140] Heating element 112 includes a heat spreader layer 118 and heating circuitry 120. A controller is adapted in block (304) to determine the temperature of the heat spreader layer 118 via a temperature sensor element (such as temperature sensor element 124 shown in Figures 1 and 2). The controller is further adapted in block (306) 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 temperature range. The predetermined temperature or temperature range changes during the duration of the cycle, and the controller is adapted to heat or cool the heat spreader layer 118 during the thermal cycle. In block (308), the controller is adapted to provide a power signal to the heating element 112 or increase that power signal when the controller determines that the temperature of the heat spreader layer is less than the predetermined temperature or temperature range, thereby increasing the temperature of the heat spreader layer 118 according to the desired curve of the thermal cycle until it reaches the predetermined temperature or temperature range. If the controller determines, based on the desired curve of the thermal cycle, that the temperature of the heat spreader 118 is within or at a predetermined temperature or a predetermined temperature range, the controller is adapted to maintain the electrical power signal to the heater element in block (310) to maintain the temperature of the heat spreader 118, thereby maintaining the temperature of the heat spreader 118 according to the curve of the thermal cycle. If the controller determines that the temperature is above the predetermined temperature or a predetermined temperature range, the controller is adapted to reduce or eliminate the electrical power signal to the heating element 112 in block (312) to allow the heat energy of the heat spreader 118 to dissipate to the cooling block 116 via the thermal interface material (TIM) 114, thereby cooling the heat spreader 118 according to the curve of the thermal cycle. In one embodiment, an appropriate controller setting is selected (e.g., a proportional-integral-derivative controller or its derivative). As discussed above with reference 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 118 to the cooling block 116.

[0141] Figure 4 is a graph illustrating an example temperature profile of the thermal control element 110 shown in Figure 1. Specifically, the profile in Figure 4 shows the temperature 128 of the vapor chamber 118 changing over time 130. In this example, a calibrated internal platinum temperature sensor is used to set and measure controlled linear heating and cooling rates. Nonlinear heating and cooling profiles are possible and will provide faster ramp times. Higher ramp rates, especially for heating, can be achieved through fine-tuning. In thermal lifetime testing, 200,000 cycles were performed using the temperature profile depicted in Figure 4, achieving a linear heating and cooling rate of + / - 50 °C / sec. In comparison, a conventional PCR analyzer using TEC technology has a heating rate of approximately 5 °C / s and a cooling rate of approximately 2.5 °C / s. Compared to conventional PCR cyclers based on TEC technology, the temperature profile shown in Figure 4 for the thermal control element 110 offers approximately 10 times the performance in heating and approximately 20 times the performance in cooling.

[0142] Figure 5 is a graph illustrating simulated temperature profiles for two example thermal control elements 110 used in a PCR process according to certain example embodiments. Specifically, the curves in Figure 5 show the temperature 128 of the vapor chamber 118 changing over time 130. In this example, the first thermal control element 110 includes a diamond (0.2 mm thick) vapor chamber layer 118 with sputtered heater and sensor traces, and a reference... Figure 1 The cooling system described in Figure 3 is used. The temperature profile of the first thermal control element 110 is shown as a dashed line for a single PCR cycle in Figure 5 (indicated by reference numeral 132). The temperature profile of the first thermal control element 110 is first heated to a first process temperature of approximately 95°C within approximately 0.7 s and maintained at 95°C for approximately 2.5 seconds. The temperature of the first thermal control element 110 is then 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 cycle time of approximately 13.5 seconds ends (indicated by reference numeral 134).

[0143] The second thermal control element 110 similarly includes a diamond (0.2 mm thick) heat spreader layer 118 with sputtered heaters and sensor traces, and a cooling system that further includes overheating and undercooling as shown in the temperature profiles. The temperature profiles for the second thermal control element 110 are shown as solid lines for a single PCR cycle in Figure 5 (indicated by reference numeral 136). The temperature profile of the second thermal control element 110 is first heated to approximately 100°C, above the first process temperature of approximately 95°C, and then restored to the first process temperature of 95°C for approximately 2.7 seconds (heating, overshoot, restoration to 95°C, and holding at 95°C). The temperature of the second thermal control element 110 decreases over a period of approximately 1.1 seconds to approximately 50°C, below the process temperature of approximately 60°C. The process of restoring the temperature profile to approximately 60°C lasts for 6.6 seconds until the end of a cycle time of approximately 11.2 seconds (indicated by reference numeral 138), thereby achieving a faster cycle time compared to the first thermal control element 110 by maintaining the same temperature level within the fluid deposited in the simulation example.

[0144] Figure 6 shows a top view (left side of Figure 6) of the thermal control element 110 according to some example embodiments and an infrared (IR) image of the thermal control element 110 (right side of Figure 6). An IR camera is used to evaluate temperature accuracy and uniformity, as well as the temperature distribution pattern. The displayed temperature distribution is affected by the material emissivity, the IR transparency of the ACSLED sticker used, and IR reflection. This measurement is used to identify potential maximum / minimum temperature regions. Subsequently, three measurement points 140 (point 1, point 2, and point 3) are selected based on the extreme points in the IR camera measurement within the relevant area (= 10 x 10 mm) for the cobas® Liat® system. At these characteristic points, additional measurements are performed using three miniature thermocouple sensors. In this example, readings are determined for two process temperatures. At the first process temperature of 55°C, temperature uniformity of < 0.3°C and temperature accuracy of -0.2°C, measured as the average of the three measurement points (point 1, point 2, and point 3), are achieved. Temperature uniformity of <0.4℃ and temperature accuracy of -0.3℃, measured as the average of three measurement points (point 1, point 2, and point 3), were achieved at a second process temperature of 88℃. Absolute deviations in accuracy may also be partly due to measurement errors (caused by the difficulty of surface measurements), which are typically affected by ambient temperature (despite insulation from the environment). Measurement results are summarized in Table 1.

[0145]

[0146] Table 1: Measurement results of temperature using an IR camera

[0147] Figure 7 is a block diagram illustrating a pair of thermal control elements 110 disposed along a processing chamber 142, such as a PCR processing chamber, and defining at least a portion of the processing chamber according to some example embodiments. The thermal control elements 110 are adapted to heat a processing fluid within the processing chamber 142. In this embodiment, each thermal control element 110 includes a heat spreader layer 118 disposed directly adjacent to the processing chamber 142 and defining at least a portion of the processing chamber. A heater element 144 is disposed adjacent to the heat spreader layer 118 on the side of the heat spreader layer 118 opposite to the processing chamber 142. A thermal interface / insulation layer 114 is disposed adjacent to the heater element 144, and a cooling block 116 is disposed on the opposite side of the thermal interface / insulation layer 114. In this embodiment, a thermal resistance 146 is disposed between the heater element 144 and the heat spreader layer 118. The location of the consumable material (pipe, fluid) between the pair of thermal control elements 110 is indicated by reference numeral 142. The cutout for the optional optical window 126 (e.g., an optical window for light-transmitting applications) is simplified in Figure 7.

[0148] In this embodiment, cooling block 116 provides constant cooling, such as via a heat sink. In the embodiment shown in FIG. 6, for example, cooling block 116 can be maintained at a minimum temperature of approximately 40°C. As discussed above, cooling block 116 can alternatively be actively cooled via a controller, resulting in increased heat dissipation within thermal control element 110, but at the cost of more complex components.

[0149] The higher temperature of each thermal control element 110 is achieved by heating the heat spreader layer 118 by supplying electricity to the heater element 144. A portion of the heat is dissipated as waste heat to the cooling block 116 through the thermal interface / insulation layer 114. The thermal interface / insulation layer 114 limits the waste heat dissipation to the cooling block 116.

[0150] The lower temperature of each thermal control element 110 is achieved by eliminating or reducing the power supplied to the heater element 144 and allowing heat to dissipate through the thermal interface / insulation layer 114.

[0151] By utilizing the controlled properties of the thermal interface / insulation layer 114 and optionally the thermal resistance 146 of the heat spreader 118, system characteristics can be controlled.

[0152] Figure 8 is a schematic diagram illustrating the components of the transmitted light detection system 148 and the reflected light detection system 150, wherein the temperature profile of the sample 152 or sample chamber is controlled using a thermal control device 110, such as that described herein. In a first embodiment of the transmitted 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 a filter and one or more of a lens 158. The light signal excites the sample 152 within the sample chamber or container. As shown in Figure 8, the resulting sample emission signal 160 is provided to the detector 162. In this embodiment, the thermal control device 110 may include a pair of opposing optical windows 126 that allow the excitation light signal 160 to be directed to the sample 152 and allow the sample emission light signal 160 to be transmitted to the detector 162 in a transmission configuration.

[0153] Figure 8 also illustrates a second reflected light detection system 150, wherein a light source 154 provides an excitation light signal 156. The excitation light signal 156 is directed to a sample 152 via one or more of a filter and one or more of a lens 158. The light signal excites the sample 152 within a sample chamber or container. The resulting sample emission signal 160 is reflected back toward a detector 162. In this embodiment, a single optical window 126 may allow both the excitation light signal 160 and the sample emission signal 156 to pass through.

[0154] Figure 9A shows a graph of raw photometer data from a PCR instrument using the thermal control element 110 shown in Figures 1 and 2. The graph corresponds to the LED excitation light channels: amber 164, blue 166, green 168, red 170, and UV green 172. As shown in each channel graph in the individual channel graphs, the raw photometer data successfully identified the increasing light signal over a certain number of cycles (typically between 30 and 35 PCR cycles).

[0155] Each figure shows the photometer detector reading 174 for the corresponding light channel at the end of each PCR cycle 176. Before cycles 30 to 35, there is no significant increase in the detected signal because noise is higher than the signal increase. In fact, the signal intensity approximately doubles between cycles. Between approximately cycles 30 and 35, the signal increase is high enough to clearly see the change. After one signal increase (green channel in this example), saturation begins. Based on the shape of the signal increase, a characteristic value (e.g., CT value) can be calculated using an algorithm. The lower the CT value, the higher the initial concentration of the target DNA that can be determined.

[0156] Figure 9A shows five similar plots detected using another optical channel, each targeting a different target. One of these channels serves as an internal control, and another is a reading of the target DNA sequence. In this example, a positive control is used to simulate the amount of the target DNA sequence. PCR-only tubes from a sexually transmitted infection (STI) assay were used to generate the plots. A PCR time of approximately 11:13 [min:ss] was achieved, compared to 12:21 [min:ss] in the existing cobas® Liat® system.

[0157] Figure 9B shows the temperature logs of a diamond circulator, where reference numeral 178 indicates the temperature log of a reference temperature, reference numeral 180 indicates the temperature log of the heat spreader 118 of the first thermal control element 110, reference numeral 182 indicates the temperature log of the heat spreader 118 of the second thermal control element 110, and reference numerals 184 and 186 indicate the temperature logs of the cooling blocks 116 of the first and second thermal control elements 110, respectively. Figure 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 the temperature of one or more reaction chambers in a PCR instrument). In this embodiment, the thermal control element 110 includes a heating element 112 comprising a resistive heater 122 disposed on the heat spreader material and conductive traces of a temperature sensor element 124. In this embodiment, the resistive heater 122 includes a pair of terminals, such as pads for electrical contacts 188, disposed along the edge of the heating element 112 to provide an electrical power connection. Multiple individual resistance heater traces (e.g., the four heater traces in the embodiment shown in FIG. 10) are arranged along the surface of the heat spreader material, thereby forming a pattern around the periphery 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 includes multiple individual traces arranged in parallel between the pair of terminals. This reduces the number of contacts required for the same number of traces. Simulation (such as FEM simulation) can be used to design one or more trace designs to achieve sufficient thermal uniformity. In this embodiment, the pattern of the resistance heater traces defines an opening that provides an optical window 126 through the heating element 112. The temperature sensor element 124 also includes a pair of terminals, such as pads for electrical contacts 188, arranged along the edge of the heating element 112 and adapted to provide an electrical connection to a controller. In one embodiment, the controller is adapted to determine a change in the properties of the heating element 112, such as a change in electrical properties (e.g., a change in resistance). The temperature sensor traces are arranged along the surface of the heat spreader material and coupled between the pair of temperature sensor element terminals. In this embodiment, the temperature sensor element traces are arranged around the periphery of an opening adjacent to the inner traces of the plurality of resistive heater traces, and are adapted to determine the temperature along the surface of the heating element 112. The sensor traces can be positioned across the entire surface, in a specific target region, or as a standard tortuous thin-layer layout at characteristic dots. In the thermal model, the absence of heating functionality in the sensor region can be considered. This can be achieved by overheating in the region adjacent to the sensor or by locally removing the cooling block 116 in the sensor region. Typically, a good design can be quickly found using finite element method simulation.

[0158] If the optical system is incompatible with the thermal interface material 114 (e.g., due to the interfering luminescence of the material used), an aperture 190 can be defined between the traces by one or more layers (such as sputtered layers). In one embodiment, the same material used for the traces can be used, with a minimum required gap between the traces for electrical insulation, for example, a distance of 0.05 mm from the heater circuit 120. Another option is to use a non-transparent passivation layer (e.g., paint) on the traces to separate the optical system from the thermal interface material 114. The aperture 190 can reduce the visibility of the TIM 114.

[0159] In this embodiment, the trace may comprise platinum or a similar material for resistance thermometers used in thin-film or thick-film applications. An optional titanium bonding layer between the diamond and platinum may be used to increase adhesion strength. To protect the trace, a passivation layer may be applied. Example materials include glass, polyimide, pyrene C, etc. The thermal interface material 114 may also be used as the passivation layer itself.

[0160] The contact of the traces can be made by means of soldering, Klett soldering, welding, spring pins, connectors or similar methods.

[0161] In some embodiments, the heat spreader and / or heating element material provides protection against chemicals, such as those that may be used adjacent to the equipment during the process.

[0162] The controller is coupled to the terminals of the temperature sensor element and is adapted to provide an electrical power signal to the terminals and determine the 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 the power input to the terminals of the resistance heater based on the temperature determination to control the heating (or cooling) profile of the heating element 112.

[0163] In the embodiment of FIG. 10, for example, the optical aperture is defined between the trace and the optical window aperture by one or more layers surrounding the optical window aperture (and defining the optical window aperture in this example). In this embodiment, the one or more layers include a sputtered platinum layer deposited on the surface of the heat spreader layer 118. The platinum layer at least reduces light and can prevent light from being transmitted through the heat spreader layer 118 in the region surrounding the intended optical window aperture. In cases where the TIM 114 of the thermal control device 110 or other components may interfere with (e.g., via fluorescence or luminescence in response to a light signal) the light signal received from the sample chamber, the platinum or other layer can prevent or reduce the transmission of interfering light signals through the heat spreader layer 118.

[0164] List of reference numerals

[0165]

Claims

1. A thermal control device (110) adjustable for temperature cycling, the thermal control device comprising: A thermally conductive heat spreader layer (118) includes a first side surface and a second side surface; A heater circuit (120) is configured to be 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 configured to be 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 configured to be adjacent to and in thermal contact with the thermal interface material layer (114), the cooling block (116) being adapted to conduct heat 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) according to claim 1, wherein the thermally conductive heat spreader layer (118) comprises at least one material selected from the group consisting of: synthetic diamond material; thermally conductive optically transparent material; sapphire; ceramic; metal; copper; silver; aluminum; gold.

3. The thermal control device (110) according to claim 1, wherein the thermally conductive heat spreader layer (118) includes a protective layer disposed toward the processing chamber (142), the protective layer comprising at least one of the following: a diamond-like carbon layer, a polymer layer, a Kapton layer, a Pyrelin C layer, a paint layer, a gold layer, a platinum layer, a tin layer, a nickel layer, or a nano-coating.

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

5. The thermal control device (110) according to claim 1, wherein the heater circuit (120) is directly deposited 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) according to claim 1, wherein the heater circuit (120) is fastened to at least one of the first side surface and the second side surface of the thermally conductive heat spreader layer (118) via a thermal interface material (TIM) (114), wherein the TIM (114) comprises an adhesive having a self-holding function, 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) according to claim 1, wherein the heater circuit (120) includes 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) according to claim 1, wherein the heater circuit (120) is configured with a pattern across the first side surface or the 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) includes a layer adapted to reduce reflections at the opening.

9. The thermal control device (110) according to claim 1, wherein the optical window aperture is configured to pass through the heat spreader layer (118), and the optically opaque layer is configured to at least partially surround the optical window aperture to at least reduce light transmission through the optically opaque layer, wherein the optically opaque layer is adapted to reduce the visibility of the TIM to the processing chamber (142), wherein the optically opaque layer comprises an optically opaque coating.

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

11. The thermal control device (110) according to claim 1, wherein at least one temperature sensor is disposed adjacent to 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 includes 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 the thermal sensor is disposed between the at least two electrical contacts.

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

13. The thermal control device (110) according to 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) has a thermal diffusivity within a predetermined range, the thermal diffusivity being adapted to provide a target heat transfer rate relative to a maximum permissible heat loss, and / or wherein the thermal interface material layer (114) has a substantially uniform constant thickness on one of the first side surface and the second side surface to provide predetermined temperature uniformity.

14. The thermal control device (110) according to claim 1, wherein the thermal interface material layer (114) comprises an adhesive to provide adhesion 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 heat sink and / or wherein the cooling block (116) comprises an actively temperature controlled cooling block, wherein an actively controlled cooling block comprises at least one of the group comprising: Heat pipe systems, fluid channels, fans, thermoelectric coolers, variable thermal contacts, and anti-heater elements.

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

17. A diagnostic testing device, comprising: Sample chamber; as well as Thermal control device (110), comprising: A thermally conductive heat spreader layer (118) includes a first side surface and a second side surface; A heater circuit (120) is configured to be 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 configured to be 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 configured to be adjacent to and in thermal contact with the thermal interface material layer (114), the cooling block (116) being adapted to conduct heat away from the thermally conductive heat spreader layer (118); and A controller adapted to control the heater circuit (120).

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