Thermal switch for diagnostic detection chip arrangements and related manufacturing

Abstract

A thermal control device utilizing a thermal switch to facilitate cooling of a biological sample, in particular a biological sample tested with a semiconductor diagnostic detection chip. Such a thermal switch may include a mass made of a thermally conductive material, such as copper or aluminum, that selectively contacts a diagnostic chip or a sample tube by using a movable support driven by a cylinder or servo. Alternatively, the thermal switch may utilize a thermally conductive material that selectively contacts the diagnostic chip or the sample tube by using an inflatable bladder. Alternatively, the thermal switch may utilize a voice coil and a heat sink to selectively contact the diagnostic chip. The thermal control device may also include a thermal overshoot feature, such as a blower or a heat sink disposed proximate the chip or tube. Related methods of assembling and using thermal control devices are also provided herein.

Description

[0001] Cross-references to related applications

[0002] This application was filed on October 18, 2024 as a PCT international application and claims the benefit and priority of U.S. Application No. 63 / 592,087, filed on October 20, 2023, the disclosure of which is incorporated herein by reference in its entirety. This application generally relates to the following: U.S. Application No. 16 / 577,650, filed September 20, 2019, entitled “System, Apparatus, and Method for Sample Processing Using a Semiconductor Detection Chip”; U.S. Application No. 15 / 718,840, filed September 28, 2017, entitled “Fluid Bridge Apparatus and Sample Processing Method”; U.S. Patent No. 6,374,684, filed August 25, 2000, entitled “Fluid Control and Processing System”; U.S. Patent No. 8,048,386, filed February 25, 2002, entitled “Fluid Processing and Control”; and U.S. Application No. 15 / 217,902, filed July 22, 2016, entitled “Thermal Control Apparatus and Method of Use”; each of the above applications is incorporated herein by reference in its entirety for all purposes. Background Technology

[0003] This disclosure generally relates to temperature control devices for thermal cycling of samples in diagnostic detection chip devices, and methods for manufacturing, assembling, and using thermal switches, particularly for rapid cooling.

[0004] In recent years, there has been considerable progress in using semiconductor detection chips to perform fluid sample analysis (e.g., testing of clinical, biological, or environmental samples). A persistent challenge for conventional MEMS technology in diagnostics is the lack of flexible sample preparation front-ends to provide fluid samples suitable for analysis using semiconductor chips. Sample preparation of such fluid samples involves a series of processing steps, including thermal cycling for sample preparation prior to performing detection on the prepared fluid sample using a diagnostic chip. Whether integrated into benchtop instruments, portable analyzers, disposable cartridges, or combinations thereof, this processing typically involves complex components and processing algorithms. In particular, thermal cycling is often one of the most time-consuming processes in sample preparation.

[0005] Conventional methods for processing fluid samples typically involve a significant amount of manual work, while recent approaches have attempted to automate many of the processing steps and may include the use of sample cartridges comprising a series of zones or chambers, each configured to subject the fluid sample to specific processing steps. As the fluid sample flows sequentially from one zone or chamber of the cartridge to the next, it undergoes each processing step according to a specific protocol. However, such systems typically include integrated analytical devices and are generally not well-suited for use with semiconductor chips. Standard methods utilizing semiconductor detection chips, such as “lab-on-a-chip” devices, typically require a considerably complex, time-consuming, and costly effort, necessitating the integration of the chip into a conventional chip package and then into a larger system that utilizes conventional fluid delivery devices to deliver the fluid sample to the chip device. Fluid samples are typically prepared by one or more completely independent systems (often involving manual interaction) and then aspirated into a fluid delivery system for supply to the chip package. These challenges, both before and after the testing process, typically minimize the advantages and benefits of such "lab-on-a-chip" devices and pose practical obstacles to their widespread use and acceptance in diagnostic testing. To make high-functionality MEMS / silicon chip technologies feasible in high-volume diagnostic testing environments, it has been proposed to combine such devices with existing sample cassette techniques for performing sample preparation. While this approach represents a significant advancement in the field, conventional thermal cycling methods are not well-suited for use with semiconductor chips for various reasons.

[0006] Therefore, there is a need for systems and methods to improve the thermal cycling efficiency of fluid samples when used with semiconductor diagnostic chips, particularly those integrated into sample preparation systems such as assay cartridges and modules that perform sample preparation. There is also a need to develop thermal cycling components and methods that are compatible with existing sample handling techniques to allow for seamless integration of diagnostic chips with existing sample preparation techniques. Furthermore, there is a need to perform faster thermal cycling for PCR assays using conductive heat transfer methods that are less susceptible to dust and ambient temperature variations. PCR thermal cycling requires precise temperature control for accurate results. Summary of the Invention

[0007] In general, this disclosure relates to thermal switches for diagnostic detection chip devices, and related manufacturing and usage methods. In some embodiments, and by way of non-limiting example, this disclosure provides thermal control components that can be used for thermal cycling of samples analyzed by diagnostic detection chips and chip devices (also referred to as “chips,” “detection chips,” “semiconductor chips,” and “diagnostic chips”). Various methods are provided to reduce the cost of semiconductor detection chips and chip devices by improving the integration of the semiconductor chip itself throughout the device.

[0008] In a first aspect, this disclosure relates to a thermal control unit that utilizes a block-shaped member made of thermally conductive metal to facilitate cooling via thermal conduction. In some embodiments, the unit includes: a block-shaped member, also referred to as a mass member; a support that supports the mass member made of thermally conductive material so that the mass member is movable within the support, the support having a distal portion engaged adjacent to and / or a chip carrier device supporting the diagnostic chip; and a cylinder coupled to the support and having an air passage through which pressurized air is transmitted to move the block-shaped member in a distal direction, such that the block-shaped member moves within the support and contacts the surface of the diagnostic chip to cool the diagnostic chip via thermal conduction. In some embodiments, the block-shaped member is a metal mass member having protrusions shaped and sized to contact the surface of the diagnostic chip. The thermally conductive material can be a metal, such as copper, or any suitable material. In some embodiments, the thermal control unit further includes a control unit configured to selectively apply pressurized air via a cylinder during one or more cooling portions of the thermal cycle to selectively move the diagnostic chip and engage it with the block. In some embodiments, the thermal control unit further includes a heater positioned adjacent to the diagnostic chip and configured to selectively heat the diagnostic chip during a heating portion of the thermal cycle.

[0009] In another aspect, the present invention relates to a thermal control unit that facilitates cooling by using a flexible thermally conductive material and an expandable bladder. In some embodiments, the thermal control unit includes: a chip carrier device having one or more layers for supporting a semiconductor chip therein; a thermally conductive layer disposed adjacent to a diagnostic chip and movable between a first position spaced apart from the diagnostic chip and a second position contacting the diagnostic chip; and an expandable bladder disposed adjacent to the diagnostic chip, wherein the thermally conductive layer is disposed between the expandable bladder and the diagnostic chip. In some embodiments, the bladder itself is formed of a thermally conductive material. The assembly can be configured such that when the expandable bladder expands, the thermally conductive material contacts the back surface of the diagnostic chip at the second position, and when the expandable bladder contracts, the thermally conductive material is disposed at the first position spaced apart from the back surface of the diagnostic chip. The control unit may also include an air pump coupled to the expandable bladder. In some embodiments, the air pump is disposed on the chip carrier device. In other embodiments, an air pump is disposed within the instrument of a module connected to the chip carrier assembly, and the air pump is removably coupled to the expandable bladder via one or more conduits or openings passing through one or more layers of the chip carrier assembly. The thermally conductive material includes a PGS film or layer. In some embodiments, a control unit is operatively coupled to the air pump and configured to selectively expand the expandable bladder during a cooling portion of a thermal cycle to achieve cooling. In some embodiments, the control unit is also configured to contract the expandable bladder after cooling during a thermal cycle to facilitate heating during a heating portion of the thermal cycle. In some embodiments, the thermal control unit also includes a heater disposed adjacent to the diagnostic chip to achieve heating during a thermal cycle. The controller may also be configured to selectively heat the heater to facilitate heating and selectively expand the expandable bladder to facilitate cooling, cycling between heating and cooling during thermal cycling of the biological sample in contact with the diagnostic chip. The heater may be a thermoelectric cooler, a resistance heater, or any suitable heating element. In some implementations, the heater is thermally coupled to a thermally conductive material to distribute heat on the back of the diagnostic chip.

[0010] On the other hand, this disclosure relates to a thermal control unit that facilitates cooling via a movable heat sink. In some embodiments, the thermal control unit includes: a heat sink comprising a mass member made of a thermally conductive material, wherein the heat sink includes a protrusion sized and dimensioned to engage a surface of a diagnostic chip; a movable support supporting the heat sink and configured to move the heat sink between a plurality of positions; and a controller configured to move the movable support between a plurality of positions, including a first position spaced apart from the diagnostic chip for heating and a second position in contact with the surface of the diagnostic chip for cooling. The thermally conductive material may be a metal, such as aluminum. In some embodiments, the thermally conductive material includes any of the following: aluminum, black anodized aluminum; or a combination of aluminum and black anodized aluminum.

[0011] On the other hand, the thermal control unit may include one or more features for suppressing thermal overshoot. Thermal overshoot refers to a temperature rebound that occurs once the diagnostic chip reaches its target temperature during cooling, after the thermally conductive material loses contact with the diagnostic chip. In some embodiments, one or more features for suppressing thermal overshoot may include a blower that directs air to the surface of the diagnostic chip after cooling to suppress thermal overshoot after the heatsink is removed from the surface of the diagnostic chip. In some embodiments, the blower includes a fan that directs air directly to the surface of the diagnostic chip through an air outlet disposed in a protrusion of the heatsink. In some embodiments, one or more features for suppressing thermal overshoot include maintaining the heatsink in close proximity to the surface of the diagnostic chip after cooling to suppress thermal overshoot. In some embodiments, the proximity distance to the surface of the diagnostic chip is 3 mm or less. In some embodiments, the proximity distance to the surface of the diagnostic chip is between 0 mm and 0.5 mm. In some embodiments, the control unit determines the number of “close proximity positions” for suppressing overshoot based on the overshoot magnitude. The "adjacent locations" have varying levels of cooling rates, with higher cooling capacities closer to the chip, and cooling capacity decreasing as the thermally conductive material moves away from the diagnostic chip. The advantage of the control unit lies in utilizing these "adjacent locations" to cool the diagnostic chip and suppress overshoot.

[0012] In some embodiments, the thermal control unit is entirely located on the instrument of the module that is connected to the chip carrier assembly supporting the diagnostic chip, which is attached to the sample cassette inserted into the module. In some embodiments, particularly those related to an expandable capsule configuration, varying pressures can be used for expansion to ensure proportional heating and / or cooling effects. Different pressures will allow for proportional capsule deflection, thereby allowing for a proportional contact area between the chip and the flexible conductive material propelled by the capsule. This will allow for regulation of the cooling rate and even the heating rate, and helps mitigate overshoot. Furthermore, once full contact is achieved, the thermal contact resistance can be varied by altering the force applied to the chip in this case, which can then be sustained.

[0013] Another method is a method for cooling a diagnostic chip, comprising the steps of: (a) bringing the surface of the diagnostic chip into contact with a heat sink, the heat sink including a mass made of a thermally conductive material, wherein the heat sink includes a protrusion sized and dimensioned to engage with the surface of the diagnostic chip; (b) terminating the contact between the surface of the diagnostic chip and the heat sink; and (c) repeating steps (a) and (b) at least once more. In some embodiments, step (a) lasts for at least 10 milliseconds. In some embodiments, step (b) lasts for at least 10 milliseconds.

[0014] Another aspect is a method for cooling a diagnostic chip, the method comprising the steps of: (a) vibrating a heat sink comprising a mass member made of a thermally conductive material, wherein the heat sink includes a protrusion sized and dimensioned to engage the surface of the diagnostic chip within the thermal boundary of the diagnostic chip; (b) increasing the distance between the diagnostic chip and the heat sink such that the heat sink does not vibrate within the thermal boundary of the diagnostic chip; and (c) repeating steps (a) and (b) at least once more. In some embodiments, step (a) lasts for at least 10 milliseconds. In some embodiments, step (b) lasts for at least 10 milliseconds. In some embodiments, during step (b), the vibration of the heat sink cools the heat sink itself, unaffected by the thermally conductive material that cooled the diagnostic chip in step (a). In some embodiments, during step (a), the cooling rate of the diagnostic chip is inversely proportional to the distance between the surfaces of the heat sink and the diagnostic chip.

[0015] Another method is a method for cooling a diagnostic chip, comprising the steps of: (a) bringing the surface of the diagnostic chip into contact with a heat sink, the heat sink including a mass made of a thermally conductive material, wherein the heat sink includes a protrusion sized and dimensioned to engage with the surface of the diagnostic chip; (b) terminating the contact between the surface of the diagnostic chip and the heat sink; and (c) repeating steps (a) and (b) at least once more. In some embodiments, the method is followed by the steps of: (a) vibrating the heat sink including the mass made of a thermally conductive material, wherein the heat sink includes a protrusion sized and dimensioned to engage the surface of the diagnostic chip within the thermal boundary of the diagnostic chip; (b) increasing the distance between the diagnostic chip and the heat sink such that the heat sink does not vibrate within the thermal boundary of the diagnostic chip; and (c) repeating steps (a) and (b) at least once more.

[0016] Another aspect is a method for performing thermal control operations on a diagnostic chip, the method comprising: moving a heat sink toward the surface of the diagnostic chip; holding the heat sink within the thermal boundary of the diagnostic chip; removing the heat sink from the surface of the diagnostic chip; holding the heat sink outside the thermal boundary of the diagnostic chip; and repeating at least once more the steps of moving the heat sink toward the surface of the diagnostic chip, holding the heat sink within the thermal boundary of the diagnostic chip, removing the heat sink from the surface of the diagnostic chip, and holding the heat sink outside the thermal boundary of the diagnostic chip; wherein the heat sink includes a mass made of a thermally conductive material and a protrusion portion sized and dimensioned to engage the surface of the diagnostic chip, and wherein, when the heat sink is within the thermal boundary of the diagnostic chip, the heat sink cools the diagnostic chip. In some embodiments, removing the heat sink from the surface of the diagnostic chip results in moving the heat sink outside the thermal boundary of the diagnostic chip. In some embodiments, a controller controls the movement of the heat sink to control the temperature of the diagnostic chip to a predetermined temperature or temperature range. In some embodiments, the duty cycle may be in the range of 0% to 100%. In some implementations, the heat sink is moved toward the surface of the diagnostic chip and held within the thermal boundary of the diagnostic chip for a total of at least 10 milliseconds. In some implementations, the heat sink is removed from the surface of the diagnostic chip and held outside the thermal boundary of the diagnostic chip for a total of at least 10 milliseconds. Attached Figure Description

[0017] Figure 1 This is a schematic diagram of a sample cartridge and a module associated with an instrument interface according to some embodiments of the present invention. The sample cartridge is fluidly connected to a chip carrier device supporting a semiconductor diagnostic chip, and the module has an electrical interface connector for operating the diagnostic chip and a thermal component for thermal cycling.

[0018] Figure 2A The illustration shows an instrument interface board of a module according to some embodiments, the instrument interface board having an array of electrical contacts for contacting electrical contact pads of a chip device, and as shown in the figure. Figure 2B The thermal component shown is used for thermal cycling.

[0019] Figure 3 The illustration shows a detailed diagram of the fluid connection between the sample box and the chip carrier device according to some embodiments.

[0020] Figures 4A to 4E The illustration shows a method for manufacturing and assembling a diagnostic chip device according to some embodiments.

[0021] Figures 5A to 5D The illustration shows a method for manufacturing and assembling a diagnostic chip device according to some embodiments.

[0022] Figures 6A to 6C The illustration shows a method for manufacturing and assembling a diagnostic chip device according to some embodiments.

[0023] Figures 7A to 7C The illustration shows a method for manufacturing and assembling a diagnostic chip device according to some embodiments.

[0024] Figure 8 The illustration shows a previous diagnostic chip device and instrument interface according to some embodiments.

[0025] Figures 9A to 9C The illustration shows an integrated diagnostic chip and chip device according to some embodiments.

[0026] Figure 10A An idealized thermal profile is shown according to some embodiments, in which a square wave is controlled to cycle between increasing and decreasing temperatures.

[0027] Figure 10B The thermal profile of a semiconductor diagnostic chip is shown without the application of any thermal components, demonstrating a gradual cooling process from an increased temperature to a decreased temperature.

[0028] Figure 11 A chip and interface assembly including a thermal control component are shown according to some embodiments, the thermal control component having a thermal switch defined by a copper block.

[0029] Figure 12 A conventional thermal profile of a semiconductor diagnostic chip is shown compared with that obtained by using some embodiments. Figure 11 The comparison of improved thermal profiles provided by the thermal switch.

[0030] Figure 13 Another thermal control component according to some embodiments is shown, which includes a thermal switch using an expandable bladder.

[0031] Figure 14 A side view of a thermal control component using an expandable bladder-like thermal switch is shown according to some embodiments.

[0032] Figures 15A to 15B Cross-sectional and detailed views of a thermal control component using an expandable bladder-like thermal switch according to some embodiments are shown.

[0033] Figures 16A to 16D A side view of a variable-expansion expandable bladder with variable thermal resistance is shown according to some embodiments.

[0034] Figure 17 A thermal cross-section of a semiconductor diagnostic chip utilizing an expandable bladder thermal switch is shown according to some embodiments.

[0035] Figures 18A to 18C Various views of a chip carrier device having a semiconductor diagnostic chip are shown according to some embodiments.

[0036] Figures 19A to 19B The application of a thermal switch defined by a movable heat sink during heating and cooling is shown according to some embodiments.

[0037] Figures 20A to 20B Views of a thermal control unit with thermal overshoot characteristics during heating and cooling, according to some embodiments, are shown respectively.

[0038] Figure 21 The use according to some implementation methods is shown. Figure 20A The thermal profile of the thermal control components is cooled.

[0039] Figure 22 A chip and interface assembly including a thermal control component according to some embodiments are shown. The thermal control component has a thermal switch defined by a heat sink that operates in conjunction with a voice coil.

[0040] Figure 23 The use according to some implementation methods is shown. Figure 22 The thermal profile of the chip is cooled by thermal control components and a multi-step cooling method.

[0041] Figure 24 The use according to some implementation methods is shown. Figure 22 Thermal control components and Figure 23 The multi-step cooling method involves repeatedly cooling the thermal profile of the silicon chip. Detailed Implementation

[0042] Various embodiments will be described in detail with reference to the accompanying drawings, wherein the same reference numerals denote the same parts and components throughout the views. Reference to the various embodiments does not limit the scope of the appended claims. Furthermore, any examples set forth in this specification are not intended to be limiting, and merely illustrate some of the many possible embodiments for use in the appended claims.

[0043] This disclosure generally relates to systems, apparatus, and methods for controlling the temperature of diagnostic chips, particularly when disposed in a chip carrier device attached to a sample cartridge within a diagnostic module, for thermal cycling.

[0044] I. Overview

[0045] In one aspect, the present invention relates to a thermal component including a thermal switch for improving cooling of a semiconductor diagnostic chip during cooling, thereby improving the efficiency of thermal cycling. In some embodiments, the thermal component is designed to engage with the thermal switch by engaging the diagnostic chip disposed within a chip carrier assembly. The chip carrier assembly includes one or more fluid conduits fluidly connected to one or more ports of a sample cartridge to facilitate the delivery of a processed fluid sample from the cartridge through the one or more fluid conduits into the chip carrier assembly, and further to the semiconductor chip within the chip carrier assembly. The sample cartridge is received by a module that facilitates operation of the sample cartridge to perform processing and deliver the processed fluid sample into the chip carrier assembly, and the module includes an instrument interface electrically connected to the chip carrier assembly to facilitate operation of the semiconductor chip carried within the chip carrier assembly and to operate the thermal component to perform thermal cycling.

[0046] A. Chip

[0047] As described herein, the term "chip" can refer to the chip itself or a chip device including the chip, an underlying support substrate, and a nearby electrical interface electrically connected to the chip. Typically, the chip includes a silicon sensor element having an active surface that hermetically engages with a flow cell filled with a prepared fluid sample. In some embodiments, the chip device is designed and configured to be carried within a chip carrier device having integrated flow cell and fluid control features for compatibility with the sample handling modules described above. The chip device can be fitted into a recess in the chip carrier device, or can be pressed into a recess and secured by a friction fit. The chip, already secured within the chip carrier device, is provided to the user, or the end user can assemble the chip within the chip carrier device.

[0048] In some embodiments, semiconductor diagnostic chips are configured to perform sequencing of nucleic acid target molecules via nanopore sequencing, which detects changes in conductivity without requiring optical excitation or detection. The underlying technology of such chips can be further understood by referring to U.S. Patent No. 8,986,928. In some embodiments, semiconductor diagnostic chips analyze other properties of target molecules in a sample, such as molecular weight and similar characteristics. Such technology can be further understood by referring to the following article: Ding Xiaoyun et al., Surface acoustic wave microfluidics. Lab Chip; 13(18): 3626-3649. In some embodiments, semiconductor diagnostic chips use surface plasmon resonance to provide analysis of target molecules, such as in Biocore provided by GE Healthcare UK Limited. TM The references used in the system and those described in its Biocore Sensor System Handbook (see gelifesciences.com / biacore) are all incorporated herein by reference in their entirety.

[0049] Typically, the chip is a semiconductor diagnostic detection chip, including but not limited to CMOS, ISFET, bulk acoustic wave, non-bulk acoustic wave chips, piezoelectric acoustic wave chips, and aperture array sensor chips. While semiconductor diagnostic chips are preferred, it should be understood that the concepts described herein are applicable to any type of chip suitable for use in performing the processing or analysis of fluid samples.

[0050] B. Chip carrier device

[0051] Chip carrier devices are adapted to fluidly couple semiconductor chips to sample cartridges, as described herein. In some embodiments, the chip carrier device includes an electrical interface adapted to interface with an instrument interface board of a sample processing module that operates the sample processing cartridge. It should be understood that the chip carrier device can be configured for use with any type of chip. In some embodiments, the chip carrier device is designed to allow analysis of biological fluid samples with the chip via electrical operation of the chip through the module's instrument interface. This is achieved through electrical probe contact pads of the chip device that are electrically connected to the module's instrument interface.

[0052] The above configuration enables a more seamless transition between processing fluid samples using sample cartridges and subsequent processing or analysis of fluid samples using chips within a chip carrier device. This configuration facilitates the industrial development of semiconductor chip devices by standardizing sample handling or preparation and the delivery of processed samples to the chip device. Sample preparation, performed manually, can be time-consuming and labor-intensive, and its development in next-generation chip devices can be challenging. By utilizing chip carrier devices instead of reaction tubes, users can prepare samples within sample cartridges and subsequently deliver the prepared samples to an attached chip carrier device for analysis using a semiconductor chip device housed within the chip carrier. This configuration accelerates semiconductor chip development by utilizing existing sample preparation processes originally configured for PCR detection and allowing such processes to be used with chip devices.

[0053] In some embodiments, the chip carrier device may include one or more processing features in fluid communication with one or more fluid flow channels, such as one or more chambers, filters, traps, membranes, ports, and windows, to allow additional processing steps during the delivery of the fluid sample to a second sample processing device. Such chambers may be configured for use with an amplification chamber to perform nucleic acid amplification, filtration, chromatography, hybridization, incubation, chemical treatments such as bisulfite treatment, etc. In some embodiments, the chamber allows the accumulation of a large portion, or even all, of the fluid sample for further processing or analysis according to a specific protocol.

[0054] C. Sample box

[0055] The sample cartridge can be any of the following devices configured to perform one or more process steps related to the preparation and / or analysis of a biological fluid sample according to any of the methods described herein. In some embodiments, the sample cartridge is configured to perform at least sample preparation. The sample cartridge can also be configured to perform additional processes, such as detecting target nucleic acids in a nucleic acid amplification assay (NAAT), for example, a polymerase chain reaction (PCR) assay, by using a reaction tube attached to the sample cartridge. The preparation of fluid samples typically involves a series of processing steps, which, depending on the specific protocol, may include chemical, electrical, mechanical, thermal, optical, or acoustic processing steps. These steps can be used to perform various sample preparation functions such as cell capture, cell lysis, analyte binding, and binding of unwanted materials.

[0056] Sample cartridges suitable for use with the present invention include one or more delivery ports through which prepared fluid samples can be delivered to reaction tubes for analysis. Figure 1An exemplary sample cartridge 100 suitable for use with a chip carrier device 200 according to some embodiments is illustrated. Conventionally, such a sample cartridge is associated with a planar reaction tube adapted to analyze a fluid sample processed within the sample cartridge 100. This sample cartridge 100 includes various components, including a main housing having one or more chambers for processing fluid samples, typically included in sample preparation prior to analysis. According to the conventional use of the sample cartridge 100, after the sample cartridge 100 and reaction tube are assembled and a biofluid sample is deposited in the chambers of the sample cartridge, the cartridge is inserted into a cartridge processing module configured for sample preparation and analysis. The cartridge processing module then facilitates the performance of the processing steps required for sample preparation, and the prepared sample is delivered via one of a pair of delivery ports into a fluid conduit of the reaction tube attached to the housing of the sample cartridge 100. The prepared biofluid sample is then delivered to the chamber of the reaction tube via a fluid interface, where it undergoes nucleic acid amplification and testing to indicate the presence or absence of target nucleic acid analytes of interest, such as bacteria, viruses, pathogens, toxins, or other target analytes, for example, by using excitation and optical detection methods. This sample cartridge can also be used to perform analysis with the semiconductor chip described herein using a chip carrier device that can be fluidly coupled to the sample cartridge in the same or similar manner as a conventional reaction tube.

[0057] Exemplary use of a sample cartridge having a planar reaction tube configured for controlled fluid control for a prepared fluid sample is described in commonly assigned U.S. Patent Application No. 6,818,185, filed May 30, 2000, entitled “Sample Cartridge for Performing a Chemical Reaction,” the entire contents of which are incorporated herein by reference for all purposes. Examples of sample cartridges and related modules are also shown and described in U.S. Patent No. 6,374,684, filed August 25, 2000, entitled “Fluid Control and Processing System,” and in U.S. Patent No. 8,048,386, filed February 25, 2002, entitled “Fluid Processing and Control,” the entire contents of which are incorporated herein by reference for all purposes.

[0058] Further understanding can be obtained by referring to U.S. Patent No. 6,374,684. Figure 3The sample cartridge 100 shown in this U.S. patent describes certain aspects of the sample cartridge in more detail. Such a sample cartridge may include a fluid control mechanism, such as a rotary fluid control valve, connected to the chambers of the sample cartridge. Rotation of the rotary fluid control valve establishes fluid communication between the chambers and the valve to control the flow of a biological fluid sample deposited in the cartridge into different chambers, in which various reagents can be dispensed as needed according to a specific protocol to prepare a biological fluid sample for analysis. To operate the rotary valve, the cartridge processing module includes a motor, such as a stepper motor, typically coupled to a drive system that engages with features of the valve in the sample cartridge to control the movement of the valve and the final movement of the fluid sample according to a desired sample preparation protocol. The fluid metering and dispensing functions of the rotary valve can be utilized and controlled to execute specific sample preparation protocols.

[0059] It should be understood that the sample cassette described above is merely one example of a sample processing apparatus suitable for use with a chip carrier device according to the embodiments described herein. While chip carrier configurations that allow the use of such sample cassettes are particularly advantageous because they allow the utilization of existing sample cassettes and sample processing apparatuses, it should be understood that the concepts of chip design described herein can be applied to other sample processing apparatuses, such as the dual-piston rotary valve device described in U.S. Patent 7,032,605, which is incorporated herein by reference. It should also be understood that the chip design described herein can be configured to be compatible with a variety of other chip carrier devices, sample cassette configurations, or other fluid sample processing apparatuses and components, such as any of the apparatuses and components described in U.S. Provisional Application No. 62 / 734,079, filed September 20, 2018, which is incorporated herein by reference.

[0060] D. Instrument Interface

[0061] On the other hand, the module includes an instrument interface for powering and communicating with the chip and for operating thermal components used in thermal cycling. The instrument interface may include a circuit board adapted to engage an electrical interface of the chip device, allowing the module to power, control, and communicate with the chip device. In some embodiments, the instrument interface is located within a common housing of the module to provide a more seamless handling between the sample cartridge and the chip device. The instrument interface may be controlled by the module to coordinate with the transfer of fluid samples from the sample cartridge to the chip.

[0062] In some embodiments, the instrument interface board includes an electrical connector with spring-loaded contacts, and the instrument interface board is mechanically mounted on a pivot when received within a module, the pivot moving toward the chip carrier assembly. The instrument interface board is configured to pivot from an open position before the sample cartridge is loaded to an engaged position when the sample cartridge is loaded. A cam (not shown) positions the interface board such that probes contact the electrical interface of the chip assembly. The probe contacts are typically spring-loaded pins on the instrument interface board that contact corresponding probe contact pads on the electrical interface of the chip assembly to allow the module to control the analysis of fluid samples with the chip. In addition to those components of the chip carrier, the instrument interface board may also accommodate passive and active electronic components as needed for a variety of other tasks. For example, such components may include any components required for signal integrity, amplification, multiplexing, or other such tasks.

[0063] The instrument interface board may also include thermal components that engage with the diagnostic chip within the chip carrier and / or may include thermal components that facilitate operation of the thermal components mounted on the chip carrier device. These components may include air pumps / blowers, servo motors, or any suitable devices that facilitate the operation of the thermal components described herein.

[0064] E. Example System

[0065] Figure 1 The illustration shows a schematic diagram of a system utilizing a conventional sample cartridge 100 fluidly coupled to a chip carrier device 200. The sample cartridge 100 is adapted to be inserted into a compartment of a sample processing module configured to perform one or more processing steps on a fluid sample contained within the cartridge by manipulating the cartridge. An instrument interface 300 of the module is incorporated into the module within the compartment housing the sample cartridge 100, and the instrument interface 300 includes a plate 301 having a receiving opening 302 through which the chip carrier device 200 extends when the cartridge 100 is positioned within the compartment. The instrument interface 300 also includes an instrument board 310, such as a PCB board, extending along the main planar surface of the chip carrier device 200, and includes electrical contacts 312 arranged to electrically connect to corresponding probe contact pads on the main planar surface of the chip device. The instrument interface includes an electrical connector 320, which includes a spring contact 312 and a frame and cam (not shown) for controlling the pivoting movement of the spring contact, thereby engaging the spring contact with a corresponding contact on the chip. The instrument interface also includes a thermal component 330 to facilitate thermal cycling of the sample on the diagnostic chip. In this embodiment, the thermal component 330 includes a heat sink that moves to contact the chip during cooling.

[0066] Figure 2AThe illustration shows an instrument interface board 310 of the module, which includes: a mounting member 314 for a processor, such as a microprocessor; and an electrical connector 320 having spring contacts 312 for engaging with electrical contact pads of a chip device. Typically, the contacts 312 are arranged in a pattern corresponding to the contacts of the chip device, such as a rectangular array. In this embodiment, the contacts 312 are configured as spring pins to deflect when the chip carrier device 200 is inserted through the receiving opening 302, thereby providing a reliable electrical connection between the spring contacts 312 of the spring connector 320 and the corresponding probe contact pads on the instrument interface of the chip device secured within the chip carrier device 200. Figure 2B As shown. Although a rectangular array of spring pins is depicted here, it should be understood that the electrical contacts can be arranged in various other patterns and various other contact structures depending on the corresponding chip carrier device. In some embodiments, the electrical contacts can be configured as one or more edge connectors or other types of multi-pin connector arrangements. It should also be understood that the instrument interface does not need to utilize every contact in order to be compatible with chip carrier devices with different numbers or arrangements of contact pads as needed. In some embodiments, the electrical contacts may include additional adapters to adapt for use with various types of chip carrier devices. In some embodiments, packaging the semiconductor controller as an accessory to the chip carrier device to minimize signal connectivity may be cost-effective. This approach can use any suitable connector device, which may include standard connector types such as USB interfaces (e.g., [+1, -2, sig 3, sig 4]). The thermal component 330 includes a heat sink 331 having a protrusion 332 that is sized and dimensioned to contact the exposed surface of the chip when the chip carrier is inserted into the module. The heat sink is mounted on a movable support 333, and the movement of the heat sink toward the chip is controlled by a servo motor 334.

[0067] Figure 3 The illustration shows a detailed diagram of a sample cartridge 100 fluidly coupled to a chip carrier device 200 with integrated fluid flow control, according to some embodiments. Typically, the chip carrier device 200 is a planar device including a flow cell chamber and a fluid interface 201. The flow cell chamber is used for contact with active regions of the chip, and the fluid interface 201 is fluidly coupled to a fluid sample container, such as the sample cartridge 100. In this embodiment, the fluid interface 201 is fluidly coupled to the sample cartridge 100 and includes a pair of fluid ports (not visible) coupled to corresponding fluid ports of the sample cartridge. For example, as... Figure 9AAs shown, one side of the planar device is a flow cell chamber. The other side of the planar device may include one or more fluid control features, such as an amplification chamber. The chip carrier device may be formed of a suitable rigid material such that the chip carrier device 200 extends outward from the sample cartridge 100, which provides clearance for various other components, such as instrument interface boards and / or thermal cycling units.

[0068] The chip carrier device 200 includes a fluid interface 201, which may be configured with a fluid port (such as a Luer port) and a flange arrangement identical or similar to that of a typical PCR reaction tube, allowing the fluid sample adapter to be easily connected to existing sample cartridges as described above. However, it should be understood that various other types of fluid ports (e.g., Luer ports, pressure fits, friction fits, snap-fits, locking fits, helical connectors, etc.) may also be used in various other arrangements. Typically, similar to the construction of a conventional PCR reaction tube, the fluid path is confined within a first substrate and sealed by a second substrate, such as a membrane. In some embodiments, the fluid sample adapter also features alignment and assembly protrusions and mechanical snap-fits, allowing the chip carrier component or chip to be easily secured against the flow cell portion of the flow cell. In some embodiments, the chip carrier device includes one or more channels extending between fluid-impermeable connections without any chambers, valves, or ports between the proximal and distal ends. In other embodiments, the device includes one or more valves or ports. In some embodiments, one or more channels may include one or more chambers or zones that can be used to process or analyze fluid samples, for example, chambers or zones that are used for thermal amplification of nucleic acid targets, filtration of samples, chromatographic separation of samples, hybridization, and / or incubation of samples with one or more assay reagents.

[0069] As from Figure 9AAs can be seen in the example, the fluid path leads to the flow cell chamber 953 through a set of flow cell ports 953a, 953b within the flow cell. In this embodiment, the flow cell chamber 953 includes a flow cell inlet port 953a and a flow cell outlet port 953b, which allow controlled fluid to be delivered into the flow cell chamber 953 via a fluid inlet 951a and a fluid outlet 951b through a fluid sample adapter 951. Typically, the flow cell inlet 953a is positioned below the flow cell outlet 953b when the fluid sample adapter 201 is vertically oriented to facilitate controlled fluid flow through the flow cell chamber 953. It should be understood that the use of the terms "inlet" and "outlet" does not limit the function of any fluid inlet or fluid outlet described herein. Fluid can be introduced and discharged from both or either of them. It should be understood that the chip carrier device can be formed as a single unit or assembled from multiple units, and the chip carrier device can incorporate various other features (e.g., valves, filters).

[0070] In some embodiments, the chip carrier device (or at least a portion thereof) is configured to be pre-attached to a sample cartridge, wherein a fluid-impermeable connection is coupled to a corresponding fluid port of the sample cartridge. For example, a sample cartridge pre-connected to a fluid sample adapter 201 may be provided, allowing an end user to insert any chip within the chip carrier device 200 against the flow cell chamber for sample testing.

[0071] The flow cell portion of the chip carrier assembly is constructed with an open chamber that forms a closed flow cell chamber when in contact with the active region of the chip within the chip carrier, facilitating analysis of fluid samples using the chip. The flow cell is shaped and configured to be fluidly coupled to the chip within the chip carrier, which is attached to the fluid sample adapter 201. Typically, the fluid path of the fluid flow portion is fluidly coupled to the flow cell chamber via fluid ports located at the top and bottom of the flow cell chamber. The chamber is formed by raised platforms or ridges that contact the active silicon or glass element used in the detection scheme. The active element is located on the chip carried within the chip carrier and secured to the flow cell by bonding and sealing, which can be accomplished by various means (e.g., using epoxy preforms, dispensed epoxy or other adhesives, gaskets, adhesive-coated gaskets, mechanical features, or various other methods). The purpose of the flow cell adapter is to form a complete flow cell chamber, which is defined on one side by the detection surface and on the remaining sides by the flow cell adapter. The flow cell may include one or more connection features, which are defined as alignment and assembly protrusions and mechanical latches received in corresponding holes to facilitate alignment when the chip is secured inside.

[0072] The chip carrier device may include a contour region sized to accommodate a chip. The contour region includes raised ridges along its periphery for engaging corresponding portions of a flow cell portion and effectively sealing the chip within the chip carrier device. Raised platforms or ridges engage with the active surface of the chip around an open flow cell chamber, thereby forming a closed flow cell chamber. The chip carrier may include windows for providing access to a plurality of probe contacts defined on the chip itself or on an electrical interface of the chip device. Alternatively, the chip carrier device may be sized such that the electrical interface of the chip or chip device extends beyond a distal end of the chip carrier device so that it can be accessed by an instrument interface of the module.

[0073] It should be understood that a chip carrier device with integrated fluid control may include any of the features or structures described herein, or any of the features or structures described in U.S. Provisional Application No. 62 / 734,079, filed September 20, 2018.

[0074] II. Diagnostic chip devices and components

[0075] On one hand, integrated diagnostic chip designs are described that further simplify the basic design of chip devices, thereby reducing manufacturing costs and allowing for further integration and simplification of chip devices.

[0076] The embodiments described in the previous U.S. Provisional Application No. 62 / 734,079 assume the use of a chip design manufactured according to conventional techniques. Current low-cost prior art utilizes a chip-on-board (COB) strategy to eliminate separate semiconductor package components. Typically, COB technology relies on a PCB substrate on which the chip is mounted and performs wire bonding operations and subsequent bond protection operations on the device. The PCB serves to form the mounting surface for the chip and utilizes vias on the PCB to electrically connect the chip to connection points (e.g., probe contact pads) located on the opposite side of the chip. This approach allows a large number of contact pads to be distributed over a relatively large surface area on the opposite side of the chip. Using a separate PCB in this way facilitates semiconductor processing and is the most common and widely accepted method. A significant drawback of this method is its considerable expense, requiring additional material within the PCB (typically as high as the cost of the chip itself) and incurring additional costs in cleaning the chip and the workflow steps required to mount the chip onto the PCB. Therefore, the present invention described herein provides an alternative integrated method for designing and manufacturing diagnostic chips for use within a chip carrier device, leveraging existing sample preparation techniques while further reducing chip manufacturing and workflow costs. These methods outperform conventional COB technology and allow for further simplification without requiring any or only minor modifications to the chip design.

[0077] Several different approaches are proposed for simplifying the design of diagnostic chips to be used with the sample processing systems and methods described herein. These approaches include: (i) utilizing probe contacts on a separate PCB adjacent to the chip, which allows for additional alternative approaches, including: (ii) replacing the PCB with a cheaper support substrate (e.g., a thinner, lighter, more flexible, etc.) given the reduced size / thickness requirements of any PCB or support substrate for the diagnostic chip; (iii) utilizing flexible PCBs and TAB bonding technology; (iv) using a metal core board as a thermally conductive mounting element to support the chip; and (v) completely removing the substrate and forming probe contact pads within the chip itself.

[0078] A. Probe contacts on a standalone PCB

[0079] In the first aspect, simplified chip design necessitates a significant reduction in PCB size and moving the printed circuit board next to the chip device (e.g., semiconductor / MEMS), while performing wire bonding / wire bonding protection in adjacent areas of the components. In this approach, the diagnostic chip is designed to be electrically connected to probe contacts mounted on a separate PCB. This reduces the size of the PCB or substrate for the chip and also allows probe contacts to be probed from the same side as the chip. In some implementations, this approach typically mounts the PCB and device to a separate surface during the same pick-and-place operation in the semiconductor packaging workflow. This makes the mounting substrate very inexpensive, such as those made of plastics and composites, and also opens up the possibility of using thermally conductive metals or ceramics as support substrates. This strategy is generally preferred to complete the connection to the complete device from the same side as the device. In some implementations, this concept can be used and configured such that the probe contacts still face the opposite direction. The main cost reduction lies in the PCB size and the process flexibility provided by allowing different PCBs and chip devices to be matched without significant redesign. Figures 4A to 4E The illustration shows the sequential steps of assembling a chip device assembly 400, which utilizes a chip having associated probe contact pads disposed on an independent PCB, as described above.

[0080] Figure 4A A support substrate 401 is shown, which can be smaller and thinner than the support substrate typically used when the probe contacts are connected to the back of the PCB through through-holes. Figure 4B The illustration shows a diagnostic chip 410, which is die-cut and mounted on a substrate 400, wherein the active region 411 faces upward and has an array of electrical contacts 412. In some existing chip designs, this array of contacts is much smaller than probe contact pads and is used for testing purposes during chip manufacturing. A PCB 420 is adjacent to the chip 410, the area of ​​the PCB 420 is smaller than the area of ​​the chip, and has probe contact pads disposed on the same side as the chip. Figure 4C An array of electrical contacts is shown, which is connected to probe contacts 422 of PCB 420 via wire bonding portion 430. Figure 4D The addition of a bonding protection layer 440 (e.g., an epoxy resin layer) is shown. Figure 4E An assembly secured within a chip device 450 is shown, the chip device 450 having an integrated flow cell coupled to an active region 411 (not visible). As can be seen, probe contact pads 422 remain accessible for electrical interface probing within a sample processing module to which the device 450 is inserted, as described in the preceding embodiments.

[0081] B. Alternative chip substrate / connection type

[0082] Since the probe contact pads are located on a separate PCB, the chip's support substrate is not only smaller and thinner, but can also utilize a variety of different materials that are cheaper and / or have additional mechanical properties that can provide further advantages. For example, the substrate can be a more economical flexible material, such as a flexible laminate. Furthermore, the reduced area allows for easier substrate mounting; for example, self-adhesive flexible laminate features can be used, as the adhesive provides sufficient bonding strength (compared to conventional PCB components) for the smaller and lighter flexible laminate.

[0083] Figures 5A to 5B An assembly of another chip device assembly 500 is shown. In this example, the assembly includes: a simplified chip 510 having a mechanical chip support 501, which may be part of a flow cell; and a flexible PCB 530 mounted to a substrate 500. Probe contacts are electrically connected to the chip 510 via wire bonding portions 520, on which bonding protection portions 540 are added.

[0084] On the other hand, printed circuit boards with probe contacts can also be flexible PCBs. This makes them suitable for less expensive bonding methods, such as TAB bonding, which are generally cheaper and faster than wire bonding in very high-volume production.

[0085] Figures 5C to 5D An example chip device assembly 500 is shown, which includes a simplified chip 510 and a flexible printed circuit board 530 mounted to a substrate 500, wherein probe contacts are electrically connected to contacts of the chip 510 via a TAB bonding portion 522, and a bonding protection portion 540 is added to the TAB bonding portion 522.

[0086] C. On-chip probe electrical contacts / connections

[0087] On another front, an integrated, simplified chip can be designed using probe contact pads defined within the chip itself. This approach utilizes an additional portion of the chip (on the same side as the active region), thus avoiding wire bonding connections via a PCB. This design avoids the need for separate PCB components for the probe contacts and further eliminates any bonding procedures and various workflow steps. In some embodiments, the chip can be fabricated on an alternative support substrate, such as any of the support substrates described herein. Advantageously, the chip can be fabricated without any separate support substrate, for example, where the silicon wafer defining the chip can act as a support. In such embodiments, the silicon wafer thinning step is unnecessary, thus providing a more cost-effective and simplified fabrication compared to conventionally packaged chip devices. In such embodiments, any available wafer can be used, such as wafers with thicknesses of 925 μm, 775 μm, 725 μm, 675 μm, 625 μm, or 525 μm (thickness typically corresponds to wafer diameter). However, it should be understood that any suitable wafer thickness can be used.

[0088] This approach achieves a more cost-effective solution by completely eliminating a separate PCB and thus any electrical bonding requirements to the chip. By placing the responsibility for electrical connections to the chip entirely on the instrument, the need for a separate PCB, PCB flexible components, wire bonding or TAB bonding sections, and protective sections can be completely eliminated. This allows designs where the chip (e.g., bare silicon / MEMS device) can be directly mounted into an integrated flow cell / chip carrier device. The elimination of steps associated with a separate PCB and related electrical connections saves time and costs roughly equivalent to the cost of the chip itself. Typically, this approach is preferred when the chip (e.g., silicon / MEMS device) has a reasonably low number of connections, allowing sufficient area on the device to be allocated to these connections. This approach may incur some additional cost in terms of the extra silicon area used for contact connections, but for most chip designs, this cost increase is significantly offset by the savings resulting from eliminating a separate PCB and reducing associated workflows.

[0089] Figures 6A to 6C An assembly of an example chip device assembly 600 according to the method described above is shown. Figure 6A A simplified chip 610 is shown, having an active region 611 and a probe contact array 620 formed along one side of the same side. In this embodiment, the chip 610 includes 12 single-row contacts with pads, but it will be understood that it may include fewer or more contact pads. Figure 6B The assembly of chip 610 within a chip carrier device 650 having an integrated flow cell is shown. Figure 6C Chip 610 is shown, which is securely bonded within chip carrier device 650 such that the active region is hermetically bonded to an integrated flow cell (not shown). From Figure 6C As can be seen, the chip device 650 includes a flange 651 and a window 652. The flange 651 can be physically connected to the housing 100, and the probes of the electrical interface of the module into which the chip device 650 is inserted can reach the contact pad array 620 through the window 652. In this embodiment, the contact pads are quite small (e.g., 12 pads with a spacing of 0.8 mm). This design requires a fairly precise and small instrument connection interface design to ensure that the probes consistently and reliably engage the corresponding contact pads.

[0090] Figures 7A to 7C A substantially similar chip assembly 700 is shown; however, chip 710 includes an integrated probe contact array 740 defined in a dual-row pad arrangement, which sacrifices some additional area of ​​the chip device to allow for a sufficiently large number of pads, each with enough area to significantly simplify instrument design. In this embodiment, the spacing between the pads and the arrangement of the pads allow for the use of commonly available electrical contact arrangements (e.g., 1.27 mm pitch, dual-row, 16 spring-loaded pins). It should be understood that the probe contact pads can be designed to any desired size, taking into account the available chip area. As in the preceding embodiments, chip 710 is secured within a chip carrier assembly 750 having a fluid interface 751 and a window 752 through which the probe contact array 740 is accessible.

[0091] Figure 8 A shows the instrument interface 860 before the insertion module and... Figures 6A to 7C The chip carrier device 850 described herein is identical to the chip carrier device described above. The instrument interface 860 includes a connector 865 with probes (not visible), which engage with contact pads on the corresponding chip exposed through window 852. The use and operation of the instrument interface and chip are generally related to... Figures 1 to 3 and Figure 8 The concepts discussed in the implementation methods are consistent.

[0092] Figures 9A to 9C It shows the relationship with Figures 6A to 6C A detailed diagram of the chip device assembly 900, which is identical to the chip device assembly described above. Figure 9AA chip carrier device 950 is shown, having an integrated flow cell chamber 953 in fluid communication with a fluid interface 951. The flow cell chamber is disposed within a recess sized to suitably accommodate a chip 910, thereby sealingly engaging the active regions of the chip against the flow cell chamber. The device may include a separate gasket for sealing, or the gasket may be a protrusion defined within the device itself. In some embodiments, the chip carrier device 950 is molded as a single component and may be formed by injection molding or any suitable method. In other embodiments, the chip carrier device may be assembled from multiple components, for example, as in the embodiments previously described. The flow cell is filled with a prepared fluid sample through flow cell inlet ports 953a / outlet ports 953b in fluid communication with inlet ports 951a / outlet ports 951b of the fluid interface 951.

[0093] As from Figure 9B As can be seen in the top view, the size and dimensions of chip 951 correspond to the recesses in chip carrier device 950. Chip carrier device 950 may include various retaining or engaging features to secure chip 951 within, for example, retaining protrusions 955 and snap-fit ​​connections 954, which are sized and arranged to resiliently receive and secure the chip when it is sealed against the flow cell chamber in an active region. Figure 9C As can be seen in the lower view, the integrated flow cell / chip carrier device 950 includes a flow cell inlet channel 930a in fluid communication with a fluid inlet 951a of a fluid interface 951 and a flow cell outlet channel 930b in fluid communication with a fluid interface 951b, enabling the sample cartridge and the module to which the device is attached to precisely control the flow of fluid sample from the fluid sample cartridge through the fluid interface into the flow cell chamber. The chip 910 includes an integrated probe contact pad array 920 on the chip surface, located on the same side as the active region 911, which is positioned accessible through the probe contact window 952 of the integrated flow cell / chip carrier device 950.

[0094] III. Thermal Control Devices and Methods

[0095] Figure 10A An idealized control scheme for thermal cycling between increasing and decreasing temperatures, such as by square wave control, is shown. Ideally, for preparing biological samples for PCR testing, the biological samples are heated to a high temperature T... h With low temperature T c They undergo thermal cycling. Figure 10A The diagram illustrates a T m The melting temperature. Figure 10A Use t m The period of higher temperature was depicted and t was used.f The time period at lower temperatures is depicted. In many conventional systems, the heater or thermoelectric cooler (TEC) is placed near or in contact with the reaction tube or container containing the biological sample, according to the high temperature T. h With low temperature T c The heating rate is controlled by a square wave, typically with the target temperature higher than the sample temperature, to increase the sample heating rate. While this method provides suitable thermal cycling, the overall rate of thermal cycling is limited by the cooling rate, resulting in lower thermal cycling efficiency and longer time consumption. Figure 10B A thermal profile of a semiconductor diagnostic chip using conventional thermal cycling is shown, illustrating the gradual cooling rate of a biological sample from elevated to decreased temperature. This gradual cooling significantly increases the total time of thermal cycling because each thermal cycle must wait for the sample to reach a lower temperature after gradual cooling. Although various cooling methods have been proposed, no method currently provides a reliable solution compatible with existing sample preparation systems. To overcome these challenges, this disclosure provides a thermal component comprising a thermal switch specifically configured to engage the chip and facilitate rapid cooling. Preferably, the thermal switch is integrated into an instrument interface for compatibility with conventional sample preparation cassettes and chip carrier devices carrying semiconductor diagnostic chips.

[0096] Figure 11 A chip carrier and interface assembly 1100 including a thermal switch 1110 according to some embodiments is shown. The thermal switch 1110 of this embodiment includes a heat sink 1111 defined by a copper block, the heat sink 1111 being supported in a cylinder holder 1112 attached to a cylinder 1113. Operation of the cylinder holder 1112 actuates the heat sink 1111 within the holder 1112 to engage a diagnostic chip 1120 during cooling. Optionally, the holder 1112 can be attached to the cylinder 1113 using a leveling O-ring 1114. The cylinder holder 1112 is disposed adjacent to a diagnostic chip holder 1121, in which the semiconductor diagnostic chip 1120 is supported, and the heat sink 1111 extends through a window in the chip holder 1121 to engage the back side of the chip 1120. The other side of the chip 1120, having an active surface, engages with an O-ring 1123 and an O-ring support plate 1122. The instrument interface may also include an electrical interface with a pogo-pin connector, which has a spring pin located on a spring PCB 1132 supported by a spring bracket 1131, such that the spring pin engages a corresponding contact on the active side of the chip 1120 when the chip carrier insertion module is in place.

[0097] Figure 12The diagram shows a comparison between a progressive conventional thermal profile (solid line) of a semiconductor diagnostic chip and an improved thermal profile (dashed line) provided by a thermal switch. As can be seen, the improved thermal profile exhibits a relatively sharp decrease, indicating the advantage of using a thermal switch. Figure 11 The cooling rate is greatly improved by using a thermal switch. In this method, the cooling rate using a thermal switch is increased to 26°C / sec.

[0098] Figure 13 Another embodiment of the assembly 1300 including the thermal switch 1310 is shown. This thermal switch design uses an expandable bladder that allows a thermally conductive sheet to expand against the chip to increase the cooling rate. In this embodiment, the thermally conductive sheet is a pyrolytic highly oriented graphite sheet (PGS), but it is understood that any suitable material (e.g., copper foil) can be used. In this embodiment, the thermal switch is integrated into a chip carrier assembly supporting the diagnostic chip and is operated by an air pump, which may be included within the chip carrier or may be part of an instrument interface. As shown, this embodiment includes a chip carrier having various interface layers supporting the diagnostic chip 1320. The thermal switch includes an air pump 1311 having an air port 1311a extending through the top layer or plate of the chip carrier and sealed by one or more O-rings 1312, allowing airflow into a capsule 1313 to inflate the capsule, thereby engaging one side of the chip with a PGS film 1314 for cooling upon contact with the chip. The assembly may also employ a thermoelectric cooler (TEC) 1316 supported within a TEC support 1315 adjacent to the thermal switch to facilitate a higher heating rate and / or steeper cooling rate for the chip. The assembly may also include an electrical interface comprising a spring-loaded pin assembly 1330 having spring-loaded pins that engage with contacts on the opposite side of the chip 1320 to operate the chip 1320. In this embodiment, the TEC is operated to actively heat the chip 1320, thereby heating the biological sample in the flow cell disposed on the opposite side of the chip 1320 to the target elevation temperature. Afterward, the capsule 1313 expands to rapidly cool the chip 1320 to a reduced temperature. This process is repeated as needed to perform thermal cycling of the sample according to the desired protocol.

[0099] Figure 14 and Figure 15A Side and cross-sectional views of a thermal control assembly 1300 using an expandable bladder-like thermal switch, according to some embodiments, are shown respectively. Figure 14As shown, the spring pin assembly 1330 is disposed on one side to engage with one side of the chip, thereby facilitating the electrical operation of the chip. The opposite side of the chip is disposed against the layers that engage with the TEC 1316 in the TEC holder 1315 and the expandable bladder 1313, which is filled and contracted by the operation of the air pump 1311. Although a particular air pump is shown and described herein, it should be understood that any suitable air pump can be used. Figure 15A A cross-sectional view is shown, illustrating the space between the PGS film 1314 and the chip 1320 before the capsule 1313 expands. Figure 15B It shows Figure 15A Additional detailed diagrams of the components shown illustrate the sample chamber 1329 containing the biological sample, located beneath the active surface of the chip. (See attached diagram.) Figure 15B As depicted in the embodiment, the expandable bladder has a first compression chamber 1350 when the thermal switch is open, and a second compression chamber 1352 when the thermal switch is closed. Figure 15B In the depicted embodiment, chip 1320 can be moved as indicated by arrow 1354.

[0100] Figures 16A to 16D A side view of a variable thermal resistance provided by a variable expansion bladder thermal switch according to some embodiments is shown. By applying different pressures to change the level of expansion, the degree of contact between the thermal material disposed on the bladder can be altered to ensure proportional heating and / or cooling effects. Different pressures allow for proportional deflection of the bladder, thereby providing a proportional contact area between the chip and the flexible conductive material propelled by the bladder. This allows for regulation of the cooling rate and even the heating rate, and helps mitigate thermal overshoot. Furthermore, once full contact is achieved, the thermal resistance of the contact area can be varied by changing the force applied to the chip in this state. Figures 16A to 16D The detailed diagram shows examples of different contact areas provided by different pressures. Figures 16A to 16D This illustrates the chip's relationship to components, such as... Figure 15A The degree of proximity between the bladder-like structures and the thermal material layers within the components.

[0101] Figure 16A The capsule 1313 is shown without any expansion pressure, wherein the capsule 1313 / thermal material 1314 does not contact the chip 1320, thereby providing the highest level of thermal resistance. Figure 16B The low pressure applied to the capsule results in minimal contact between the capsule / thermal material and the chip 1320 (e.g., less than 30% of the exposed chip surface), which provides a moderate level of thermal resistance. Figure 16CThe moderate pressure applied to the capsule results in a moderate amount of contact between the capsule / thermal material and the chip 1320 (e.g., 40% to 60%), which provides low thermal resistance. Figure 16D The diagram illustrates the high pressure applied to the capsule, which results in complete contact between the capsule / thermal material and the chip across essentially the entire exposed chip surface, providing minimal thermal resistance. At this point of complete contact, a further, but less pronounced, reduction in thermal resistance can be achieved by further increasing the capsule pressure, in which state the pressure begins to alter the contact thermal resistance due to the greater force between the chip and the capsule.

[0102] Figure 17 A thermal profile of a semiconductor diagnostic chip utilizing a thermal switch with an expandable capsule, according to some embodiments, is shown. The thermal profile shows a control curve (on the right) without the capsule 1313 enabled (long dashed line), indicating gradual cooling. Conversely, a test curve (on the left) with the capsule 1313 enabled to bring the PGS chip 1314 into contact with the back of the chip 1320 (solid and short dashed line) results in a sharp decrease and a significant increase in the cooling rate.

[0103] Figures 18A to 18C Various views of an example chip carrier device 1800 according to some embodiments are shown. Figure 18A This is a front view. Figure 18B This is the rear view. Figure 18C These are isometric views. These figures depict a chip carrier assembly including a polymer frame 1810, which supports the diagnostic chip 1810 and connects it to a sample cartridge and analytical module, such as... Figure 1 The sample cartridge and analysis module shown are compatible. As shown, the chip carrier 1800 supports the semiconductor diagnostic chip 1810 within it, such that one side of the chip carrier defines a window and a liquid chamber 1804. The window provides access to the electrical contacts of the chip and spring connector, and the liquid chamber 1804 defines a flow cell for biological samples to engage the active regions of the chip (see [link to documentation]). Figure 18B In some embodiments, the carrier may further include an optical cover 1805 disposed on the liquid chamber 1804. (See from...) Figure 18A and Figure 18C As can be seen, the chip carrier frame 1801 is configured such that the back side of the chip (opposite to the active side) is exposed. This configuration allows for the use of thermal switches to improve cooling through heat conduction with the back side.

[0104] In one aspect, the thermal switch is a heat sink that moves to contact the back of the semiconductor diagnostic chip, thereby improving cooling through heat conduction. Figures 19A to 19B An example of this type of heat sink is shown in the image. Figures 19A to 19BA heat sink 1900 with a protrusion 1901 is shown. The heat sink 1900 is spaced apart from the diagnostic chip 1911 in the chip carrier frame 1910 during heating and moves to contact the diagnostic chip 1911 during cooling. Figure 19A The radiator 1900 is shown during heating. Figure 19B A heat sink 1900 is shown during cooling. In this embodiment, the thermally conductive material (heat sink) 1900 contacts the chip 1911, which encloses the liquid chamber containing the sample, to instantaneously remove heat from the sample and surrounding plastic (e.g., optical caps and frames 1910) during thermal cycling. In some embodiments, the semiconductor has a series of resistance heaters that heat the sample to various set points defined by the scheme. When the sample must be cooled, the heaters are turned off and the chip 1911 is momentarily contacted by the heat sink 1900 to conduct heat away.

[0105] Because the heat sink only contacts the semiconductor side of the consumable component and not the optical cover, the temperature of the liquid closer to the semiconductor is lower than the temperature of the liquid closer to the optical cover. This causes a temperature rebound due to heat flowing from the optical side to the semiconductor side (i.e., from the higher side to the lower side). In addition to the temperature difference in the liquid layer mentioned above, the liquid chamber is surrounded by various materials with different thermal conductivities. Plastics tend to conduct heat more slowly than liquids. Therefore, once the contact between the heat sink and the semiconductor is removed, heat from the surrounding plastic flows back into the liquid, causing an increase in liquid temperature. This phenomenon of liquid temperature rise due to the temperature difference between the liquid and the surrounding plastic is called "thermal overshoot" or "thermal rebound." In some embodiments, the thermal component includes additional features to address this overshoot, as described below.

[0106] Figures 19A to 19BA heat sink 1900 is shown that is spaced apart from the diagnostic chip 1911 during heating and moves to contact the diagnostic chip 1911 during cooling. As shown, the heat sink 1900 includes a protruding portion 1901 having a planar portion that is sized and shaped to contact the exposed portion 1911 of the semiconductor diagnostic chip 1911. The heat sink can be mounted on a movable support that is movable by: a servo motor, an improved servo motor acting as a DC motor, a voice coil actuator, or any suitable device. In some embodiments, the heat sink material includes aluminum (e.g., a cooling effect of about 110°C / s), black anodized aluminum (e.g., a cooling effect of about 40°C / s), or a combination thereof. In some embodiments, the thermal switch is configured to contact the semiconductor chip with a suitable force (e.g., 0.1N or greater, about 6N) to ensure sufficient contact, thereby promoting heat conduction to improve the cooling effect. In some embodiments, to prevent thermal overshoot (thermal bounce), the heat sinks are spaced apart but remain close to the semiconductor chip (e.g., within a range of 10 mm or less, within a range of 5 mm or less, or about 3 mm). In some embodiments, the heat sinks contact the semiconductor during cooling (i.e., at 0 mm).

[0107] It should be understood that various features or combinations of features can be used to address thermal overshoot. In some implementations, the thermal overshoot feature may include one or more fans that blow air onto the semiconductor chip immediately after cooling to suppress thermal overshoot. Figures 20A to 20B An example of this method is shown, wherein the heat sink 2000 includes an air outlet 2002 located in a protrusion 2001 that contacts a semiconductor chip (not shown). After contacting the chip and cooling it to a reduced target temperature, the heat sink is spaced apart from the chip and a fan operates to suppress thermal overshoot. Figure 20B As shown, the heat sink may include a fan 2006 on the rear side adjacent to the cooling fins 2005, with the air outlet located on the opposite side facing the chip.

[0108] In other embodiments, thermal overshoot characteristics may include positioning the heat sink itself close to, but spaced apart from, the semiconductor chip. By maintaining a heat sink proximity (e.g., less than 3 mm, less than 2 mm, less than 1 mm, between mm0 and 0.5 mm), studies have determined that the heat sink can absorb heat while in contact with the semiconductor and while very close to it. The cooling capacity of the heat sink decreases as the heat sink moves away from the semiconductor. This very close proximity is used to eliminate overshoot. In this case, the heat sink absorbs heat through convection and radiation heat transfer. In some embodiments, the heat sink is designed to run PCR tests continuously without any active cooling mechanism (i.e., an external fan that cools the heat sink to prevent it from being affected by heat absorbed from the semiconductor) to cool the heat sink (i.e., the heat sink does not receive enough heat to reduce the cooling rate or does not meet engineering specifications).

[0109] Figure 21 The diagram shows a thermal profile of a semiconductor chip cooled using the two features described above to suppress thermal overshoot. As shown, the cooling fan method (dashed line) reduces thermal overshoot, but the temperature increase is still significant, and this method requires modification of the heatsink and additional fan components. The second method, which keeps the heatsink close to the chip, offers a significant improvement in further reducing the incidence of thermal overshoot. Furthermore, the second method relies on the heatsink itself and does not require additional modifications or components.

[0110] Figure 22 A chip 2500 within a carrier and interface assembly 2502 according to some embodiments is shown. The carrier and interface assembly 2502 includes a thermal control component with a thermal switch 2600. In some embodiments, the thermal switch 2600 can perform thermal control operations, such as cooling operations, on the chip 2500. According to this embodiment, the thermal switch 2600 may include a heat sink 2504, which is movable relative to a voice coil actuator 2700. In some embodiments, the heat sink 2504 is movable within a maximum distance of 5 mm from the chip 2500. In other embodiments, the heat sink 2504 is movable within a range of approximately 0 mm to 1 mm from the chip 2500, or within a range of approximately 0 mm to 2 mm from the chip 2500, or within another distance range from the chip 2500 adapted to the configuration of the instrument and other components. In the depicted embodiment, the voice coil actuator 2700 includes a coil wound within the magnetic field of a magnet 2508 around a cylindrical coil frame, such as a spool (coil) 2506, the magnet 2508 being oriented within a housing 2510 and an iron housing 2512 such that the magnetic field is selectively contained therein. Figure 22As shown in the embodiment, the voice coil actuator may further include a spring 2514 and a guide pin 2516, such that when current is applied, the spring 2514 will push the magnet 2508 away from the coil 2506 and will move the heat sink 2504 toward the chip 2500 during cooling, and when no current is applied, the spring 2514 will move the heat sink 2504 away from the chip 2500. The thermal switch 2600 may be controlled by a controller or control unit, such as a processor 2800 or other control components. In the embodiment, under the control of the processor 2800, a motor driver may signal the voice coil actuator 2700 to induce movement. Preferably, the thermal switch 2600 may be compatible with conventional sample preparation cassettes and chip carrier devices that carry semiconductor diagnostic chips. Although Figure 22 An implementation using a voice coil actuator 2700 as the drive mechanism is depicted, but other drive mechanisms such as servo motors or DC motors can be used with the heat sink 2504. Using a voice coil is simple, helps reduce power consumption, and provides a proportional heating or cooling effect based on the position of the heat sink 2504 relative to the chip 2500.

[0111] In this embodiment, the heat sink 2504 may engage the chip 2500 during cooling, or the heat sink 2504 may stop and vibrate at a location immediately adjacent to the chip 2500. In other embodiments, the heat sink 2504 may engage the chip 2500 during a portion of the cooling process, and the heat sink 2504 may stop and vibrate at a location immediately adjacent to the chip 2500 during a portion of the cooling process. Repeatedly engaging and disengaging the chip 2500 from the heat sink 2504 allows the chip 2500 to be cooled with a high degree of temperature precision. This is advantageous because PCR cycles require precise temperature control to obtain better results. Since the cooling rate is inversely proportional to the distance between the surface of the chip 2500 and the surface of the conductive material, it may be beneficial to vibrate the conductive material adjacent to the chip 2500, such as the heat sink 2504. Additionally, vibrating the conductive material results in convective cooling, which can counteract the heat received by the convective material by cooling the chip 2500.

[0112] Utilizing the principle of the Lorentz force, the heat sink 2504 can be moved precisely. Cooling of the chip 2500 can occur within a certain threshold distance between the chip 2500 and the heat sink 2504. For example, the threshold distance for cooling can be within approximately 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, or some other distance defined by specific properties of the chip 2500, the heat sink 2504, the instrument, and other factors. As used herein, the threshold distance for cooling is defined as the "thermal boundary." In one embodiment, the thermal boundary can be determined by positioning the heat sink 2504 at different distances from the chip 2500 and monitoring the power consumption caused by heat sources on the chip 2500 to maintain the increased temperature. For example, the temperature of the chip 2500 can be kept constant, and the power consumption caused by heat sources on the chip can be monitored such that when the power consumption caused by the heat sources needs to increase to maintain the temperature of the chip 2500, the thermal boundary has been located due to the proximity of the heat sink 2504. In some implementations, similar to the process described above for suppressing overshoot, the control unit determines the number of "adjacent locations" to optimize the cooling rate with respect to a threshold distance for cooling. These "adjacent locations" have different levels of cooling rates; for example, locations closer to the chip have a higher level of cooling capacity, and the cooling capacity decreases as the thermally conductive material moves away from the chip 2500. The advantage of the control unit is that it uses these "adjacent locations" to cool the chip 2500, cool the heatsink 2504, and also suppress thermal overshoot.

[0113] Figure 23 The following is illustrated according to some embodiments of the use of Figure 22 The thermal profile of the semiconductor diagnostic chip of the thermal switch in the embodiment of the thermal switch 2600 depicted is shown. The thermal profile illustrates one method of using the thermal switch 2600 in combination with regions A 3000, B 3002, and C 3004 (not shown) in three different ways. In region A 3000, the heat sink 2504 engages the chip 2500 for a short time and then disconnects from the chip 2500 for a short time. The engagement and disconnection times can vary; for example, the engagement time can be at least 50 ms, and the disconnection time can be 75 ms. The engagement time can be equal to or different from the disconnection time. This continuous engagement and disconnection (step) can be repeated multiple times, such as at least three, at least five, at least ten, at least 50, or at least 100 times. Figure 23In the embodiment described herein, region A 3000 may have eight bonding and disconnection steps. In this embodiment, the bonding step may be 100 ms, and the disconnection step may be 100 ms. Furthermore, the duty cycle may be variable for the bonding time, disconnection time, and the number of times chip 2500 is bonded and disconnected in region A 2000. Figure 23 In the implementation described herein, region A 3000 may have a duty cycle of 78.4%, such that heatsink 2504 is within the thermal boundary of chip 2500 for 78.4% of the total duration of region A and outside the thermal boundary of chip 2500 for 21.6% of the total duration of region A. In this implementation, the duty cycle operates according to pulse width modulation (PWM) principles. In other implementations, the duty cycle may be between 0% and 100%. The system may be linear, allowing the controller to control the amount of power applied to voice coil actuator 2700, thereby determining the position of heatsink 2504 relative to chip 2500. The chip 2500 engagement time, chip 2500 disengagement time, the number of times chip 2500 is engaged and disengaged by heatsink 2504, and the duty cycle may be adjustable variables, such as those adjustable based on test and environmental conditions.

[0114] In one embodiment, the entire cooling process may include the steps of engaging and disengaging the heat sink 2504 from the chip 2500. In other embodiments, the cooling process may also include the step of keeping the heat sink 2504 in close contact with the surface of the chip 2500. For example, according to Figure 23 In the embodiment depicted, after the steps in region A 3000 are completed, the cooling process continues to regions B 3002 and C 3004. In the depicted embodiment, regions B 3002 and C 3004 can be similar to region A 3000, but in region A 3000, the heat sink 2504 is bonded to the chip 2500, while in regions B 3002 and C 3004, the heat sink 2504 remains in close proximity to the surface of the chip 2500 during the bonding period in region A. Figure 23 In the depicted implementation, zone B 3002 may have fifteen adjacent steps and non-adjacent steps. In this implementation, the adjacent steps of zone B 3002 may be 100 ms, and the non-adjacent steps may also be 100 ms. Figure 23 In the implementation described herein, zone B 3002 can have a duty cycle of 52.9%. According to... Figure 23 In the embodiment depicted, region C 3004 (not shown) may have fifteen adjacent steps and non-adjacent steps. In this embodiment, the adjacent steps of region C 3004 may be 100 ms, and the non-adjacent steps may also be 100 ms. Figure 23In the embodiments described herein, zone C 3004 may have a duty cycle of 39.2%. In some embodiments, the thermal switch 2600 may be used with different methods. In other embodiments, the thermal switch 2600 may be used with any number of zones (as described herein), such as one zone, two zones, five zones, etc.

[0115] If passed Figure 23 As illustrated, compared to keeping the heat sink 2504 in close proximity to the chip 2500, the contact between the heat sink 2504 and the chip 2500 directly results in a sharp drop in the temperature of the chip 2500 and an increased cooling rate. The combination of regions A 3000, B 3002, and C 3004 can utilize both conductive and convection cooling, wherein, during the convection cooling phase, vibrations of the heat sink 2504 cool both the chip 2500 and the heat sink 2504 itself. In some embodiments, the cooling process may only include the step of keeping the heat sink 2504 in close proximity to the surface of the chip 2500. Using... Figure 23 Similar methods to those described in the paper can help cool chips in a more controlled and precise manner, with a faster cooling rate in the range of 30°C / s to 80°C / s.

[0116] Figure 24 Utilization according to some embodiments is shown Figure 22 The thermal switch described in the embodiment 2600 and the reference thermal switch Figure 23 The described method includes a thermal profile of a semiconductor diagnostic chip. For example... Figure 23 The curve graph depicts multiple runs, as shown in the diagram. (Refer to...) Figure 23 The described methods demonstrate consistent results in precise temperature control. The aforementioned features are advantageous for improving thermal cycling for several reasons. First, the disclosed concepts described herein provide faster time to result (TTR). Second, these concepts allow for thermal cycling over a wider temperature range, and moderately dusty environments allow customers to use the instrument in such environments. This use is increasing in developing countries where hospitals or testing centers are difficult to access, and in mobile hospitals assisting medical teams in making home visits to patients. Therefore, the methods described herein provide faster cooling and the ability to reach the setpoint temperature with minimal deviation. Although the above features are described in relation to the thermal cycling of semiconductor diagnostic chips, it should be understood that these concepts can be applied to improve cooling during thermal cycling of any vessel or container for biological fluid samples, particularly vessels made of metal or any thermally conductive material.

[0117] In the foregoing description, the invention has been described with reference to specific embodiments thereof, but those skilled in the art will recognize that the invention is not limited thereto. Various features, embodiments, and aspects of the invention described above can be used alone or in combination. Furthermore, the invention can be used in any number of environments and applications beyond those described herein without departing from the broader spirit and scope of this specification. Therefore, the specification and drawings should be considered illustrative rather than restrictive. It will be appreciated that the terms “comprising,” “including,” and “having” as used herein are specifically intended to be understood as open-ended terms in the art.

[0118] The various embodiments described above are provided by way of illustration only and should not be construed as limiting the claims appended herein. Those skilled in the art will readily recognize that various modifications and variations can be made without following the exemplary embodiments and applications illustrated and described herein and without departing from the full scope of the appended claims.

Claims

1. A thermal control unit, comprising: A block-shaped component, said block-shaped component being made of thermally conductive metal; A support that supports the block-shaped member made of a thermally conductive material so that the block-shaped member can move within the support, the support having a distal portion that is engaged adjacent to and / or a chip carrier device supporting the semiconductor diagnostic chip; as well as A cylinder, connected to the bracket and having an air passage, through which pressurized air is transmitted to move the block in a distal direction, such that the block moves within the bracket and contacts the surface of the diagnostic chip to cool the diagnostic chip by thermal conduction.

2. The thermal control unit according to claim 1, wherein, The block-shaped component is a mass made of metal, which has protruding portions that are shaped and sized to contact the surface of the diagnostic chip.

3. The thermal control unit according to claim 1, wherein, The thermally conductive material includes metals.

4. The thermal control unit according to claim 3, wherein, The thermally conductive material includes copper.

5. The thermal control unit according to claim 1, further comprising: A control unit configured to selectively apply pressurized air via the cylinder during one or more cooling sections of a thermal cycle to selectively move the diagnostic chip and engage the diagnostic chip with the block.

6. The thermal control unit according to claim 1, further comprising: A heater, positioned adjacent to the diagnostic chip and configured to selectively heat the diagnostic chip during a heating portion of a thermal cycle.

7. A thermal control unit, comprising: A chip carrier device having one or more layers therein for supporting a semiconductor chip; A thermally conductive layer is disposed adjacent to the diagnostic chip and is movable between a first position spaced apart from the diagnostic chip and a second position in contact with the diagnostic chip; as well as An expandable capsule is disposed adjacent to the diagnostic chip, wherein the thermally conductive layer is disposed between the expandable capsule and the diagnostic chip. The component is configured such that when the expandable bladder expands, the thermally conductive material contacts the back surface of the diagnostic chip at the second position, and when the expandable bladder contracts, the thermally conductive material is disposed at the first position spaced apart from the back surface of the diagnostic chip.

8. The thermal control unit according to claim 7, wherein, The capsule can expand to one or more intermediate positions to achieve a proportional contact area between the thermally conductive layer and the chip, thereby achieving a proportional cooling and / or heating effect.

9. The thermal control unit according to claim 7, wherein, When the bladder can expand to provide full-area contact with the chip, and the pressure can be further varied to change the thermal resistance of the contact between the thermally conductive layer and the chip, an auxiliary mode with proportional cooling and / or heating effects can be achieved.

10. The thermal control unit according to claim 7, further comprising: An air pump, which is connected to the inflatable bladder.

11. The thermal control unit according to claim 7, wherein, The air pump is located in the instrument of the module connected to the chip carrier device, and the air pump is removably connected to the inflatable bladder through one or more conduits or openings passing through one or more layers of the chip carrier device.

12. The thermal control unit according to claim 7, wherein, The thermally conductive material includes a PGS film.

13. The thermal control unit according to claim 10, further comprising: A control unit, operatively connected to the air pump and configured to selectively expand the expandable bladder during the cooling portion of a thermal cycle to achieve cooling.

14. The thermal control unit according to claim 10, wherein, The control unit is also configured to contract the expandable bladder after cooling during the thermal cycling process to facilitate heating during the heating portion of the thermal cycle.

15. The thermal control unit according to claim 10, further comprising: A heater, positioned adjacent to the diagnostic chip, is provided to provide heating during the thermal cycling process.

16. The thermal control unit according to claim 13, wherein, The controller is also configured to selectively heat the heater for heating and selectively expand the expandable sac for cooling, so as to cycle between heating and cooling during thermal cycling of the biological sample in contact with the diagnostic chip.

17. The thermal control unit according to claim 13, wherein, The heater includes a thermoelectric cooler.

18. The thermal control unit according to claim 15, wherein, The thermoelectric cooler is thermally connected to the thermally conductive material to distribute heat on the back side of the diagnostic chip.

19. A thermal control unit, comprising: A heat sink, the heat sink comprising a mass made of a thermally conductive material, wherein the heat sink includes a protrusion portion that is sized and dimensioned to engage the surface of a diagnostic chip; A movable support member supports the heat sink and is configured to allow the heat sink to move between multiple positions; and A controller configured to move the movable support between a plurality of positions, including a first position spaced apart from the diagnostic chip for heating and a second position in which the protrusion contacts the surface of the diagnostic chip for cooling.

20. The thermal control unit according to claim 19, wherein, The thermally conductive material is a metal.

21. The thermal control unit according to claim 19, wherein, The thermally conductive material includes aluminum.

22. The thermal control unit according to claim 19, wherein, The thermally conductive material includes any one of the following: aluminum, black anodized aluminum; or a combination of aluminum and black anodized aluminum; or any thermally conductive material.

23. The thermal control unit according to claim 19, wherein, The heat sink includes: One or more features used to suppress thermal overshoot.

24. The thermal control unit according to claim 21, wherein, The one or more thermal overshoot features include: A blower that directs air to the surface of the diagnostic chip after cooling in order to suppress thermal overshoot after the heat sink is removed from the surface of the diagnostic chip.

25. The thermal control unit according to claim 22, wherein, The blower includes a fan that directs air through an air outlet located in the protrusion of the heat sink and directly to the surface of the diagnostic chip.

26. The thermal control unit according to claim 19, wherein, The one or more thermal overshoot features include: One or more adjacent locations of the heat sink, wherein the heat sink remains in close proximity to the surface of the diagnostic chip after cooling to suppress thermal overshoot.

27. The thermal control unit according to claim 26, wherein, The one or more adjacent locations include multiple adjacent locations with different cooling rates.

28. The thermal control unit according to claim 26, wherein, The one or more adjacent locations include an adjacent distance of 3 mm or less from the surface of the diagnostic chip.

29. The thermal control unit according to claim 26, wherein, The one or more adjacent locations include distances between 0 mm and 0.5 mm from the surface of the diagnostic chip.

30. The thermal control unit according to claim 26, wherein, The thermal control unit is entirely mounted on the instrument of the module connected to the chip carrier device that supports the diagnostic chip, and the chip carrier device is attached to the sample cassette inserted into the module.

31. A method for cooling a diagnostic chip, the method comprising the following steps: (a) The surface of the diagnostic chip is brought into contact with a heat sink, the heat sink including a mass made of a thermally conductive material, wherein the heat sink includes a protrusion portion that is sized and dimensioned to engage the surface of the diagnostic chip; (b) Terminating the contact between the surface of the diagnostic chip and the heat sink; and (c) Repeat steps (a) and (b) at least once more.

32. The method according to claim 31, wherein, Step (a) lasts for at least 10 milliseconds.

33. The method according to claim 31, wherein, Step (b) lasts for at least 10 milliseconds.

34. A method for cooling a diagnostic chip, the method comprising the following steps: (a) Vibrating a heat sink comprising a mass element made of thermally conductive material, wherein the heat sink includes a protrusion portion that is sized and dimensioned to engage the surface of the diagnostic chip within the thermal boundary of the diagnostic chip; (b) Increasing the distance between the diagnostic chip and the heat sink so that the heat sink does not vibrate within the thermal boundary of the diagnostic chip; and (c) Repeat steps (a) and (b) at least once more.

35. The method according to claim 34, wherein, Step (a) lasts for at least 10 milliseconds.

36. The method according to claim 34, wherein, Step (b) lasts for at least 10 milliseconds.

37. The method of claim 34, wherein, During step (b), the vibration of the heat sink cools itself to avoid the effects of the thermally conductive material that cooled the diagnostic chip in step (a).

38. The method according to claim 34, wherein, During step (a), the cooling rate of the diagnostic chip is inversely proportional to the distance between the heat sink and the surface of the diagnostic chip.

39. The method according to claim 31, wherein, The method according to claim 31 is followed by the method according to claim 34.

40. A method for performing thermal control operations on a diagnostic chip, the method comprising: Move the heat sink toward the surface of the diagnostic chip; Keep the heat sink within the thermal boundary of the diagnostic chip; Remove the heat sink from the surface of the diagnostic chip; Keep the heat sink outside the thermal boundary of the diagnostic chip; as well as Repeat the following steps at least once more: move the heat sink toward the surface of the diagnostic chip, keep the heat sink within the thermal boundary of the diagnostic chip, move the heat sink away from the surface of the diagnostic chip, and keep the heat sink outside the thermal boundary of the diagnostic chip; and The heat sink includes a mass made of thermally conductive material and a protrusion portion, the protrusion portion being sized and dimensioned to engage the surface of the diagnostic chip, and wherein the heat sink cools the diagnostic chip when it is located within the thermal boundary of the diagnostic chip.

41. The method according to claim 40, wherein, Removing the heat sink from the surface of the diagnostic chip results in the heat sink being moved outside the thermal boundary of the diagnostic chip.

42. The method according to claim 40, wherein, The controller controls the movement of the heat sink to keep the temperature of the diagnostic chip at a predetermined temperature or temperature range.

43. The method according to claim 40, wherein, The duty cycle can be in the range of 0% to 100%.

44. The method of claim 40, wherein, Move the heat sink toward the surface of the diagnostic chip and keep the heat sink within the thermal boundary of the diagnostic chip for a total of at least 10 milliseconds.

45. The method according to claim 40, wherein, The heat sink is removed from the surface of the diagnostic chip and held outside the thermal boundary of the diagnostic chip for a total of at least 10 milliseconds.

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