Method for measuring thermal resistance between thermal component of instrument and consumable

Abstract

The invention discloses a method for measuring thermal resistance between a thermal component and a consumable of an instrument. The method comprises the following steps: contacting a known consumable with the thermal component to be tested; driving the thermal component using a periodic sine wave input based on a predetermined interrogation frequency; measuring a temperature output from a thermal sensor in response to the periodic sine wave input; multiplying the temperature output by a reference signal in phase with the periodic sine wave input and calculating the resulting DC signal component to determine an in-phase component X; multiplying the plurality of temperature outputs by a 90 DEG phase shifted reference signal and calculating the resulting DC signal component to determine a quadrature out-of-phase component Y; calculating a phase offset in response to the periodic sine wave input based on tan-1 (Y / X) or atan2 (X, Y); and determining a resistance value of the thermal interface using a calibrated resistance phase offset formula and the calculated phase offset.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202080007618.4, application date July 24, 2020, and titled “Method for measuring thermal resistance between thermal components and consumables of an instrument”.

[0002] Related Applications

[0003] This application claims priority to U.S. Provisional Patent Application No. 62 / 887,901, filed on August 16, 2019, entitled “Method for Measuring Thermal Resistance at Interface between Consumable and Thermocycler”, which is incorporated herein by reference in its entirety. This application also claims priority to Netherlands Patent Application No. 2023792, filed on September 6, 2019, entitled “Method for Measuring Thermal Resistance at Interface between Consumable and Thermocycler”, which is incorporated herein by reference in its entirety. Background Art

[0004] Various biochemical schemes involve a large number of controlled reactions on a support surface or in a designated reaction chamber. Controlled reactions can be performed to analyze biological samples or prepare biological samples for subsequent analysis. During or between controlled reactions, the reaction chamber and / or its components can be thermally controlled to perform different reactions and / or improve reaction rates. The analysis can identify or reveal the characteristics of chemicals involved in these reactions. For example, in an array-based cycle sequencing assay (e.g., by sequencing by synthesis (SBS)), a dense array of deoxyribonucleic acid (DNA) features (e.g., template nucleic acids) is sequenced by iterative cycles of enzyme operations. After each cycle, an image can be captured and then analyzed with other images to determine the sequence of the DNA features. In another biochemical assay, an unknown analyte with an identifiable label (e.g., a fluorescent label) can be exposed to an array of known probes with predetermined addresses within the array. Observing the chemical reaction that occurs between the probe and the unknown analyte can help identify or reveal the characteristics of the analyte. Summary of the invention

[0005] The following provides a summary of certain embodiments of the present disclosure. This summary is not an extensive overview and is not intended to identify key or critical aspects or elements of the invention or to delineate the scope thereof.

[0006] Described herein are apparatus, systems, and methods for measuring thermal resistance at an interface between a consumable, such as, for example, a flow cell, and an instrument or thermal component thereof, such as, for example, a thermoelectric cooler (TEC) (e.g., a Peltier driven thermal system). The method described may also be referred to as a transient response test for determining the thermal interface resistance of a consumable flow cell. Specific implementations of the disclosed method use a periodic sinusoidal drive input to a thermal component, such as a TEC, for measuring the thermal response of the thermal component itself. Although some of the examples provided herein may be described with reference to a TEC, such thermal components are merely examples, and the methods described herein may be applicable to other thermal components, such as, for example, resistive heaters and heat blocks. Advantages of the method may include: (i) reducing the thermal stress experienced by the TEC by not changing the power input to the TEC in a stepwise manner; (ii) reducing the time required to acquire multiple data cycles; (iii) allowing phase sensitive detection techniques to achieve very high sensitivity while allowing the excitation level of the test to be relatively low; and (iv) inferring thermal contact with the consumable without the need for a thermal sensor on the consumable. The thermal response of the thermal component to the periodic drive input may be frequency dependent. The specific behavior of a thermal component (such as a TEC) can be modeled in a simulation program with an emphasis on integrated circuits (SPICE) software using an electrical equivalent circuit. The method disclosed in the present invention can be used to identify an incomplete or reduced thermal interface between a component to be thermally controlled (such as a flow cell) and a thermal component (such as a TEC). For example, the method disclosed herein can be used to identify various problems with correctly loading a flow cell with a TEC of an instrument (such as an incompletely engaged spring), which can affect the performance of one or more thermal control reactions. The method disclosed in the present invention can be deployed as an automated field diagnostic and pre-run test to identify dirty or contaminated consumables or instrument thermal components. The method can also be used as a quality control process for testing thermal components, as a quality control process for testing consumables, and / or as a diagnostic process for testing during loading of consumables into an instrument.

[0007] A specific implementation relates to a method for measuring thermal resistance between a thermal component of an instrument and a consumable, comprising: bringing a known consumable into contact with a thermal component of the instrument to be tested; driving the thermal component using a periodic sine wave input based on a predetermined interrogation frequency; measuring a plurality of temperature outputs from a thermal sensor in response to driving the thermal component using the periodic sine wave input; multiplying the plurality of temperature outputs by a reference signal in phase with the periodic sine wave input and calculating the resulting direct current (DC) signal component to determine an in-phase component X; multiplying the plurality of temperature outputs by a 90° phase-shifted reference signal and calculating the resulting DC signal component to determine an orthogonal out-of-phase component Y; and calculating the orthogonal out-of-phase component Y based on tan -1(Y / X) or atan2(X,Y) calculates a phase offset in response to the periodic sine wave input; determines a resistance value of the thermal interface using a calibrated resistance phase offset formula and the calculated phase offset; and compares the determined resistance value with a predetermined resistance threshold. The method can be used as a quality control process for testing thermal components.

[0008] There are variations of any one or more of the above implementations wherein the determined resistance value is above a predetermined resistance threshold, the method further comprising determining that the thermal component has a defect at the thermal interface surface based on the determined resistance value being above the predetermined resistance threshold.

[0009] There may be variations of any one or more of the above implementations wherein the determined resistance value is below a predetermined resistance threshold, the method further comprising determining that the thermal component is acceptable based on the determined resistance value being below the predetermined resistance threshold.

[0010] There are variations on any one or more of the above implementations wherein the thermal component includes a thermoelectric cooler.

[0011] There are variations of any one or more of the above-described embodiments wherein the consumable comprises a flow cell.

[0012] There are variations of any one or more of the above-described implementations wherein the predetermined interrogation frequency is determined based on estimated RC angle values ​​of known consumables and thermal components of the instrument.

[0013] A specific implementation relates to a method for measuring thermal resistance between a thermal component of an instrument and a consumable, comprising: contacting the consumable to be tested with a known thermal component of the instrument; driving the thermal component using a periodic sine wave input based on a predetermined interrogation frequency; measuring multiple temperature outputs from a thermal sensor in response to driving the thermal component using the periodic sine wave input; multiplying the multiple temperature outputs by a reference signal in phase with the periodic sine wave input and calculating the resulting DC signal component to determine an in-phase component X; multiplying the multiple temperature outputs by a 90° phase-shifted reference signal and calculating the resulting DC signal component to determine an orthogonal out-of-phase component Y; and calculating the orthogonal out-of-phase component Y based on tan -1 (Y / X) or atan2(X,Y) calculates the phase offset in response to the periodic sine wave input; determines the resistance value of the thermal interface using a calibrated resistance phase offset formula and the calculated phase offset; and compares the determined resistance value with a predetermined resistance threshold. This method can be used as a quality control process for testing consumables.

[0014] There are variations of any one or more of the above specific implementations, wherein the determined resistance value is higher than a predetermined resistance threshold, and the method also includes determining that the consumable has a defect at the thermal interface surface based on the determined resistance value being higher than the predetermined resistance threshold.

[0015] There are variations of any one or more of the above implementations, wherein the determined resistance value is below a predetermined resistance threshold, the method further comprising determining that the consumable is acceptable based on the determined resistance value being below the predetermined resistance threshold.

[0016] There are variations on any one or more of the above implementations wherein the thermal component includes a thermoelectric cooler.

[0017] There are variations of any one or more of the above-described embodiments wherein the consumable comprises a flow cell.

[0018] There are variations of any one or more of the above-described implementations wherein the predetermined interrogation frequency is determined based on estimated RC angle values ​​of known thermal components of the consumable and the instrument.

[0019] A specific implementation relates to a method for measuring thermal resistance between a thermal component of an instrument and a consumable, comprising: bringing the consumable into contact with the thermal component of the instrument; driving the thermal component using a periodic sine wave input based on a predetermined interrogation frequency; measuring a plurality of temperature outputs from a thermal sensor in response to driving the thermal component using the periodic sine wave input; multiplying the plurality of temperature outputs by a reference signal in phase with the periodic sine wave input and calculating the resulting DC signal component to determine an in-phase component X; multiplying the plurality of temperature outputs by a 90° phase-shifted reference signal and calculating the resulting DC signal component to determine an orthogonal out-of-phase component Y; and calculating the orthogonal out-of-phase component Y based on tan -1 (Y / X) or atan2(X,Y) calculates a phase offset in response to the periodic sine wave input; determines a resistance value of the thermal interface using a calibrated resistance phase offset formula and the calculated phase offset; compares the determined resistance value with a first predetermined resistance threshold; compares the determined resistance value with a second predetermined resistance threshold; and determines a characteristic of the thermal interface based on a comparison of the determined resistance value with the first predetermined resistance threshold and the second predetermined resistance threshold. The method can be used as a diagnostic process for testing during loading of consumables into an instrument.

[0020] There may be variations of any one or more of the above implementations wherein the determined resistance value is below a first predetermined resistance threshold, the method further comprising determining that the interface surface is acceptable based on the determined resistance value being below the first predetermined resistance threshold.

[0021] There are variations of any one or more of the above-described specific implementations, wherein the determined resistance value is higher than a second predetermined resistance threshold, and the method also includes determining not to insert the consumable into the instrument based on the determined resistance value being higher than the second predetermined resistance threshold.

[0022] There are variations of any one or more of the above specific implementations, wherein the determined resistance value is below a second predetermined resistance threshold and above a first predetermined resistance threshold, the method further comprising determining that a defect or debris is located at the thermal interface surface based on the determined resistance value being below the second predetermined resistance threshold and above the first predetermined resistance threshold.

[0023] There are variations on any one or more of the above implementations wherein the thermal component includes a thermoelectric cooler.

[0024] There are variations of any one or more of the above-described embodiments wherein the consumable comprises a flow cell for sequencing by synthesis.

[0025] There are variations of any one or more of the above-described implementations wherein the predetermined interrogation frequency is determined based on estimated RC angle values ​​of known thermal components of the consumable and the instrument.

[0026] A specific implementation relates to a computer-readable medium having a computer program stored thereon, the computer program comprising instructions for causing an apparatus to execute a method of any one of the specific implementations described above.

[0027] It should be understood that all combinations of the foregoing concepts and the additional concepts discussed in more detail below (assuming such concepts are not mutually inconsistent) are contemplated as being part of the subject matter disclosed herein. In particular, all combinations of the claimed subject matter appearing at the end of this disclosure are contemplated as being part of the subject matter disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The details of one or more specific implementations are set forth in the accompanying drawings and the following description. Other features, aspects, and advantages will become apparent from the description, drawings, and claims, including:

[0029] Figure 1 Depicting a front perspective view of an assembly showing a positional relationship between a thermal component (e.g., TEC) and a consumable (e.g., flow cell) of an instrument, and methods disclosed herein for establishing and maintaining the quality and integrity of the positional relationship for the assembly;

[0030] Figure 2 Depicted Figure 1 a side view of an assembly of wherein a thermal sensor is visible in the instrument;

[0031] Figure 3 Depicted Figure 2 assemblies where contaminants have disrupted the positional relationship between thermal components and consumables of the instrument;

[0032] Figure 4 A schematic diagram representing an electrical equivalent model of a TEC flow cell system is depicted;

[0033] Figure 5 A Bode plot is depicted that helps identify frequencies that produce a measurable signal that produces a fast measurement and an angular frequency close to R*C, wherein the x-axis represents the periodic excitation frequency and the y-axis represents the magnitude / phase;

[0034] Figure 6 depicts a graph showing a TEC drive signal and a thermal response drive signal used in the method;

[0035] Figure 7 depicts a series of graphs showing the conversion of phase shift to thermal resistance;

[0036] Figure 8 depicts a graph showing response curves specific to the 0.3 Hz excitation frequency used and specific to the specific thermal mass of the components in the tested TEC system;

[0037] Fig. 9 a flow chart depicting the calibration process used with the test method;

[0038] Fig.10 A flow chart depicting the quality control (QC) process for testing hot components;

[0039] Fig.11 A flow chart depicting the QC process for testing consumables;

[0040] Fig.12 a flow chart depicting a diagnostic process for performing a test during loading of consumables into an instrument;

[0041] Fig.13 depicts a table demonstrating the repeatability of measurements using the test method described;

[0042] Fig.14 depicts a table showing instrument variations;

[0043] Fig.15 depicts a table showing consumable variations;

[0044] Fig.16 including a graphical representation of an example fragment depicting an interference thermal interface and a table depicting an increase in thermal resistance (R) greater than 45% due to the interference; and

[0045] Fig.17 A graph showing an example of flow cell ramp-up time based on thermal resistance is depicted. DETAILED DESCRIPTION

[0046] In some cases, the temperature control of consumables (such as flow cells) used in processes such as sequencing by synthesis can rely on the assumption that the consumables reach a known offset relative to the thermal components (such as the thermal block of the TEC) that the consumables contact in the instrument. Initially, the offset can be factory calibrated. However, if the contact between the consumable and the thermal block of the TEC is different from the contact during the factory calibration, such as from intervening debris, this may cause a steady-state temperature error. The magnitude of such an error may be proportional to the temperature of the thermal block of the TEC relative to the ambient temperature. At relatively low temperatures, the steady-state offset error may be within a predetermined error value. However, such an error may represent a large portion of the thermal error budget.

[0047] Differences in thermal resistance at the interface between the thermal components of the instrument and the consumables can also result in differences in the time period for the consumables to reach the desired temperature. In specific implementations where the mass of the thermal block of the TEC is significantly greater than the mass of the consumables of the instrument, the time period to achieve steady state can be determined by the time period involved in heating and cooling the mass of the thermal block of the TEC. In addition, if the time period allowed for thermal operation is long enough, variations in the thermal lag of the consumables behind the thermal block of the TEC can be negligible or unnoticed.

[0048] However, in order to achieve faster thermal ramping (i.e., reduce the time to transition from a first temperature to a second temperature), the mass of the thermal block of the TEC can be reduced so that it is substantially equal to or less than the mass of the consumable. In addition, some thermal engines of the TEC may also have very high heat pumping capabilities. Therefore, such a lower mass thermal block of the TEC can ramp up temperature very quickly, and the rate at which the consumable temperature based on heat transfer will follow will depend on the quality of the thermal interface. In addition, if user error causes the consumable to be loaded incorrectly in the instrument, the thermal block of the TEC can quickly reach a temperature (e.g., within seconds) that can quickly cause damage if the thermal interface quality is not detected. Therefore, described herein are systems and methods for measuring the quality of the thermal interface between a thermal component (such as a TEC) and a thermal control component (such as a flow cell) of an instrument.

[0049] To confirm that the consumable is in contact with the thermal block of the TEC and / or to determine the quality of the thermal interface between the consumable and the thermal block, the thermal block may be heated or cooled. The rate at which the thermal block changes temperature when heat is pumped depends on the thermal resistance between the thermal block and the consumable and the relative thermal capacities of the consumable and the thermal block. Since the relative thermal capacities are known, measurements of the rate at which the thermal block changes temperature when heat is pumped can be used to determine the thermal resistance between the thermal block and the consumable.

[0050] One technique used to characterize such systems is the step response, where the system is excited with a step change and the response is measured in the time domain. The time domain response can be characterized by the time constant tau (τ). Performing such tests on a real Peltier-driven thermal system such as a TEC can be complicated by several factors. For example, the amount of heat pumped by the TEC depends on the temperature difference (ΔT) across the TEC and the resistance of the TEC itself, complicating the application of a known input step height. In addition, due to the non-zero mass of the TEC, the time for the TEC's thermal engine to change the temperature of the TEC's thermal block can be non-zero and can vary with ambient or heat sink temperature, the starting temperature of the thermal block, and the TEC resistance, so a true step function may be difficult to achieve and / or may require recalculation for any changes in ambient conditions. In addition, the stepwise power input to the TEC can produce mechanical, thermal, or electrical stresses on the TEC and can result in a shortened life of the TEC when performed repeatedly.

[0051] Thus, the present disclosure provides a method for measuring thermal resistance at an interface between a consumable and a thermal component of an instrument, which method can reduce mechanical, thermal and / or electrical stress on the thermal component, can acquire several data points within a reduced time period, can achieve high sensitivity detection of resistance at the thermal interface while allowing relatively low excitation levels applied to the TEC, and / or can utilize fewer inputs to determine the resistance at the thermal interface by using a time domain component of the response without the need for calibration or use of an internal thermometer of the thermal component or an external thermal sensor to detect the temperature of the thermal component.

[0052] Various specific implementations of the present invention are now described with reference to the accompanying drawings. Figure numbers are used throughout the specific embodiments to refer to various elements and structures. Although the following specific embodiments contain many details for the purpose of illustration, it will be appreciated by those of ordinary skill in the art that multiple variations and changes of the following details are within the scope of the present invention. Therefore, the following embodiments of the present invention are described without losing the generality of the invention protected by the claims, and without limiting the invention protected by the claims.

[0053] The present invention describes an apparatus, system and method for measuring the thermal resistance at the interface between a consumable (such as, for example, a flow cell) and a component of an instrument (such as, for example, a TEC or a heater). The present invention also describes a transient response test for determining the thermal interface resistance of a consumable flow cell.

[0054] With reference to the accompanying drawings, Figures 1 to 3 Various illustrations of a thermal component of an instrument (such as a TEC) and a consumable thermal component 100 are provided. Although only the thermal component of the instrument is depicted, the instrument may include additional components such as a cartridge interface, fluid management components, an analytical computing engine, etc. In the illustration of a TEC with a consumable mounted thereon in a simplified manner, Figure 11, the flow cell 110 can be positioned on top of a carrier plate 112, which can be positioned on top of a TEC 114, which can be positioned on top of a heat sink 120. In some implementations, the carrier plate 112 and flow cell 110 can form part of a flow cell cartridge 122, and the TEC 114 and heat sink 120 can be combined as a TEC assembly 123 within a base instrument. In other implementations, the carrier plate 112, TEC 114, and heat sink 120 can be combined as a TEC assembly 123 within a base instrument. In further implementations, additional carrier plates (not shown) or other intervening components can be provided between one or more of the components depicted herein. For example, a thermally conductive adhesive between the carrier plate 112 and the flow channel 110, between the carrier plate 112 and the TEC 114, and / or between the TEC 114 and the heat sink 120 may be used to adhere one or more of the above-mentioned components together while improving and / or facilitating thermal conduction between the components (e.g., the thermally conductive adhesive may be applied to fill any defects in one or more components that may reduce thermal conduction).

[0055] In some implementations, the thermal sensor (e.g., thermometer) 116 is Figure 2 and Figure 3 114 for detecting the temperature of the TEC 114 during operation. A thermal interface 118 occurs where the carrier plate 112 contacts the upper surface of the TEC 114, and the thermal interface may change each time a new flow cell 110 is mated with the TEC 114. The quality of the thermal interface 118 may affect the thermal control of the flow cell 110. The upper surface of the TEC 114 may not be visible to the user of the consumable thermal component 100. For example, when a cartridge (not shown) carrying the flow cell 110 and / or the flow cell 110 itself is inserted into the base instrument, the flow cell 110 and the TEC assembly 123 with which the flow cell 110 interfaces for thermal control of the flow cell 110 may be located inside the housing of the base instrument and obscured from view. The housing of the base instrument may limit or reduce the impact of contaminants on the process therein. However, ensuring that the surface 113 of the carrier plate 112 is free of debris such as dust, dirt, liquid, etc. may be difficult to perform without disassembling the housing and / or portions of the instrument to visually inspect the surface 113.

[0056] For some specific implementations using consumables used in DNA sequencing (e.g., flow cell 110), and for other purposes used in or with an instrument or components thereof (such as TEC 114 and / or components including thermal components), it is determined whether the flow cell 110 and / or carrier plate 112 of the flow cell cartridge 122 has formed sufficient or acceptable thermal contact with the TEC assembly 123. Figure 2 Depicted Figure 11, showing a flow cell 110 positioned on top of a carrier plate 112, which is located on top of a TEC 114, which is positioned on top of a heat sink 120. In some implementations, a thermometer or other thermal sensor may not be included in the flow cell 110 and / or on the flow cell carrier plate 112. Including a thermal sensor may increase complexity and / or additional technical implementation issues. Furthermore, for single-use consumables, adding a thermal sensor may increase cost, reduce reliability, and / or introduce additional unknown factors to the consumable.

[0057] However, for chemical, medical, and / or biotech consumables that may rely on sensitive temperature control to accommodate desired chemical reactions, determining the quality of the thermal interface with the consumable may be useful to ensure reliable and repeatable reactions within the consumable. In some cases, this thermal interface may not exist at all if the consumable is loaded incorrectly due to user error or instrument loading error.

[0058] In addition to improper insertion of consumables such as flow cell 110 and / or improper installation of the consumable within the instrument, contamination at the thermal interface 118 between the flow cell 110 and / or carrier plate 112 and a thermal component (such as TEC assembly 122), or wear on the TEC assembly side of the interface (such as wear on carrier plate 112) can also disrupt thermal contact and heat transfer between the consumable and the thermal component of the instrument. Figure 3 Depicted Figure 2 , showing a flow tank 110 positioned on top of a carrier plate 112, which is positioned on top of a TEC 114, which is positioned on top of a heat sink 120. Figure 3 In the embodiment of the present invention, contaminants 130 (such as dirt, dust, dehydrated reactants, debris, etc.) have disrupted the thermal interface 118 between the consumable and the instrument. As a result, heat may not be properly transferred between the two items. As described herein, such disruptions can be detected at the response rate of the thermal sensor 116 of the TEC 114 to a carefully controlled drive input.

[0059] The disclosed method uses a thermal sensor (e.g., thermal sensor 116) positioned within or near a component of an instrument (e.g., TEC 114) to detect the rate at which heat flows from the component of the instrument to a consumable (e.g., flow cell cartridge 122) for determining the thermal resistance at an interface (e.g., thermal interface (118)) between the instrument and the consumable. The method does not require any measurement of the temperature of the consumable and can be used to verify the quality of thermal contact before dispensing samples and reagents into the flow cell 110, thereby preventing wasted resources due to contaminated interfaces, improper fit from user error, or hardware failure. The method can also be used to identify interface-related quality issues during factory instrument quality control. Similarly, the method can be used to identify manufacturing defects present in components such as TEC 114, flow cell 122, or other components, where defects in manufacturing can adversely affect the thermal resistance at the thermal interface 118, can add unexpected thermal capacitance to these components, or can create an unfavorable thermal short circuit on the TEC 114.

[0060] In some implementations, the method includes driving the TEC 114 with a periodic sinusoidal input; measuring the periodic thermal response of a thermal sensor 116 within the TEC 114 to the sinusoidal input; isolating a component of the thermal response signal at the frequency of the sinusoidal input and determining its phase shift relative to the drive signal; and using the phase shift (delay) to calculate the thermal resistance of the thermal interface 118 between the TEC 114 and the flow cell cartridge (122). The method can be performed quickly. By way of example only, approximately 10 excitation cycles can be collected at 0.3 Hz in 30 seconds. Alternatively, fewer excitation cycles can be collected in a shorter period of time.

[0061] In some specific implementations of the method, in order to drive the TEC 114 (or another thermal component of the instrument) with a periodic sine wave input, firmware located in the TEC drive electronics initiates a periodic drive signal. When this occurs, the TEC 114 remains stable at room temperature and is driven with low input power (e.g., low amplitude). A suitable drive frequency can be selected by generating a Bode plot based on a SPICE model of the electrical equivalent circuit and analyzing the useful response characteristics of the plot. SPICE is a general open source analog electronic circuit simulator used in integrated circuit and board level design to analyze the integrity of circuit designs and predict circuit behavior. The drive frequency can be based on the RC corner frequency of the thermal system. The RC corner frequency provides the frequency at which the slope or change of the phase shift is the largest for small changes in resistance value. That is, based on small changes in resistance at the thermal interface 118, selecting a frequency at or near the RC corner frequency for the thermal system can provide greater sensitivity.

[0062] Figure 4An electrical schematic 400 is depicted, representing an electrical equivalent model of a TEC flow cell system. In schematic 400, I1 (402) is the alternating amount of heat pumped by the TEC 114. The amplitude of this periodic input is estimated based on the capability of the TEC 114. However, the metric chosen (phase lag) is independent of the drive amplitude. The TEC (404) is the node at which the temperature of the TEC 114 is measured using an integrated thermal sensor 116, which can be placed in very close contact with a heat capacitive TEC ceramic (406) so as to contribute minimal thermal resistance to the thermal circuit. The heat capacitive TEC ceramic (406) is the thermal capacitance of the TEC top ceramic (refer to the disclosed specific implementation), or more generally, all the mass between the consumable and the heat engine (TEC element). The heat capacitive TEC ceramic (406) is calculated from first principles based on the geometry of the component and the thermal capacity of the material. Interface_resistance (408) is the thermal resistance between the TEC 114 and the consumable (e.g., flow cell cartridge 122), which is a value determined by the methods disclosed herein. Interface_resistance (408) is modeled with an estimate based on initial observations and is varied within a range around the initial estimate to determine how the phase lag depends on this value. Consumable (410) is a node representing the temperature of the consumable (e.g., flow cell cartridge 122) and is an output of the model that can be used to validate the performance of the model using consumables equipped with thermal sensors. Thermal_consumable (412) is the thermal capacitance of the consumable (e.g., flow cell cartridge 122) as determined by its geometry and material heat capacity. Consumable_convection / conduction (414) is the thermal resistance of the consumable (e.g., flow cell cartridge 122) to the environment due to convection and conduction losses.

[0063] Consumables_convection / conduction (414) can be estimated based on geometry, airflow assumptions, and temperature assumptions; and the estimate can be verified with measurements designed to approximate the operating conditions of the system. While the estimate maintains a certain level of uncertainty, this value can be varied over the potential operating range to determine the effect on the response of the thermal sensor 116, and the effect is negligible at the interrogation frequency. Ambient (416) represents the ambient temperature. In the electrical equivalent model, this is the thermal ground, and all other temperatures are relative to the ambient. Heat Capacitance_Heat Sink (418) is the thermal capacitance of the heat engine heat sink (e.g., heat sink 120) determined by calculation of the geometry and material heat capacity. Heat Sink_Thermal Resistance (420) is the thermal resistance of the heat sink (e.g., heat sink 120) to the ambient due to convection. Heat Sink_Thermal Resistance (420) is estimated based on known conditions in the system, verified by experiment, and varied in the model to demonstrate negligible effect on the signal of interest at the interrogation frequency.

[0064] Figure 5A Bode plot is depicted to help identify frequencies that produce fast measurements and produce a measurable signal with a corner frequency close to R*C. Figure 5 , a predicted response 500 of the thermal sensor 116 of the TEC 114 is plotted on a graph where the x-axis 502 represents the periodic excitation frequency and where the y-axis 504 represents the magnitude / phase. The solid line 512 represents the magnitude of the response of the thermal sensor 116 of the TEC 114 when driven at various frequencies and measured in dB of attenuation (relative to direct current (DC) excitation). The dashed line 514 represents the phase lag of the thermal sensor 116 behind the drive signal when driven at various frequencies and measured in degrees. The interrogation frequency near the RC corner is shown at 516.

[0065] In some implementations of the method, in order to measure the periodic thermal response of the TEC 114 to a sine wave input using the onboard thermal sensor 116, firmware located in the TEC driver electronics records the thermal response signal. Figure 6 As shown, the thermal response signal is not completely at the driving frequency, but exhibits additional low-frequency components and high-frequency components (eg, thermal drift and electronic noise). Figure 6 Depicted are graphs showing examples of TEC drive signals and thermal response drive signals used in the method. Figure 6 , the drive and thermal response 600 are plotted on a graph where the x-axis 602 represents time, where the left y-axis 604 represents the TEC 114 drive signal level, and the right y-axis 606 represents the signal level of the thermal sensor 116. The drive signal 620 is a time trace of the TEC 114 drive level. The TEC thermal sensor signal 630 is the actual response of the thermal sensor 116 in the TEC 114 when driven with the drive signal 620 shown, while the TEC 114 is in contact with the consumable (e.g., the flow cell cartridge 122). The disclosed method is used to isolate the component of the signal that is at the same frequency as the drive signal and determine its phase shift.

[0066] In some implementations of the method, to isolate the component of the thermal response signal at the frequency of the sine wave input (ω) and determine its phase shift relative to the drive signal, the response signal is multiplied by the reference signal in the time domain. The DC component of the result is the in-phase signal A in The amplitude of . In the time domain, the response signal can also be multiplied by the 90° phase shift reference. The DC component of this result is the orthogonal (out-of-phase) signal A Q The DC component of these signals can be obtained using a least squares fit to the sine wave. The DC component can also be obtained by integrating the signal over a large number of cycles. This integration can be done with analog circuits, such as in a lock-in amplifier, or digitally, such as with a microprocessor. The phase of the response signal is tan -1 (AQ / A in ) or atan2(Ain,Aq). DC component A in and A Q Smaller than the periodic amplitude A.

[0067] Some alternative methods for determining the phase shift of the response of the thermal sensor 116 include using a peak finding algorithm to find the peaks of the drive signal and the response signal and calculating the average delay between the peaks. Some other alternative methods for determining the phase shift of the response of the thermal sensor 116 include fitting a sine wave to the drive signal and the response signal and using the phase of the best fit function to establish the phase shift. Some other alternative methods for determining the phase shift of the response of the thermal sensor 116 include using a lock-in technique to multiply the response signal by in-phase and quadrature reference signals, but finding the DC component of these signals by: (i) using a discrete Fourier transform and a digital low-pass filter; or (ii) averaging the resulting signal over an integer number of cycles.

[0068] In some embodiments of the method, the thermal resistance of the interface 118 between the TEC 114 and the consumable (e.g., the flow cell cartridge 122) can be calculated using a phase shift (delay) by using an electrical equivalent circuit such as Figure 4 The electrical equivalent model shown models the thermal system and generates a curve fit for a range of resistance values ​​at a specific interrogation drive frequency to estimate the thermal resistance. As the resistance (R) changes, the phase of the response also changes. The above model produces a relationship between phase (φ) and resistance (R) at a specific interrogation drive frequency. Figure 4 An example of such a phase (φ) versus resistance (R) relationship over a resistance range of 0.2K / W to 0.5K / W for a thermal system modeled in 3 –0.003708φ 2 –0.2163φ-4.208 curve fitting (see Figure 7 and Figure 8 ). Figure 7 Included is a series of graphs showing the phase shift at specific interrogation drive frequencies as thermal resistance increases. Figure 8 A specific implementation is provided showing the use of a 0.3 Hz excitation frequency and specific Figure 4 Plot of the response curves of the specific thermal masses of the components of the modeled electrical equivalent circuit TEC system.

[0069] exist Figure 7 , graph 700 depicts three Bode plots 710, 720, 730 showing the interface resistance 408 ( Figure 4In Bode plot 710, solid line 712 represents the magnitude of the response of thermal sensor 116 when driven at various frequencies 702 and as measured in dB of attenuation (relative to DC excitation) along y-axis 704; dashed line 714 represents the phase lag of thermal sensor 116 behind the drive signal when driven at various frequencies 702 and measured in degrees along y-axis 706; and point 716 represents the phase lag of dashed line 714 at the interrogation frequency.

[0070] exist Figure 7 In the Bode plot 720 of FIG. 700 , the resistance at the interface 118 (such as the interface_resistance 408) increases. Thus, the solid line 722 represents the magnitude of the response of the thermal sensor 116 when driven at various frequencies 702 and as measured in dB of attenuation (relative to a DC excitation) along the y-axis 704; the dashed line 724 represents the phase lag of the thermal sensor 116 behind the drive signal when driven at various frequencies 702 and measured in degrees along the y-axis 706; and the point 726 represents the phase lag of the dashed line 724 at the interrogation frequency for this increased resistance at the interface 118. As shown, by shifting further toward -90 along the y-axis 708 at the same interrogation frequency, the absolute phase lag (i.e., the y-axis value at which the points 716 and 726 are located) increases as the resistance increases.

[0071] exist Figure 7 In the Bode plot 730 of FIG. 708 , the resistance at the interface (such as interface_resistance 408) further increases. Thus, solid line 732 represents the magnitude of the response of thermal sensor 116 when driven at various frequencies 702 and measured in dB of attenuation (relative to DC excitation) along y-axis 704; dashed line 734 represents the phase lag of thermal sensor 116 behind the drive signal when driven at various frequencies 702 and measured in degrees along y-axis 706; and point 736 represents the phase lag of dashed line 734 at the interrogation frequency for this further increased resistance at interface 118. As shown, by shifting further toward -90 along y-axis 708 at the same interrogation frequency, the absolute phase lag (i.e., the y-axis value at which points 716, 726, and 736 are located) increases as the resistance increases.

[0072] exist Figure 8 , graph 800 depicts the predicted temperature phase lag with varying interface resistance at the interrogation frequency. The thermometer phase lag is predicted by the thermal model for the resistance of various thermal interfaces 118 at the interrogation frequency (black dots 810, 812, 816, 818, 820, 822, 824, 826, and 828), and a third order polynomial fit to these data points (dashed line 830) can be used to estimate the thermal resistance in a similar real-world circuit that exhibits any phase lag in the range of 60° to 90° when driven at the interrogation frequency.

[0073] As described below, in various embodiments, the method may include a calibration process, a quality control (QC) process for testing thermal components (e.g., TEC assembly 123), a QC process for testing consumables (e.g., flow cell cartridge 122), and a diagnostic process for performing tests during loading of consumables into an instrument.

[0074] Fig. 9 A flowchart of a calibration process 900 is depicted, which includes determining a thermal circuit model of a consumable component (e.g., a flow cell cartridge 122) and a thermal component (e.g., a TEC assembly 123) at box 902; estimating an interrogation frequency near an RC corner value based on known thermal capacitances of the consumable component and the thermal component and the thermal circuit model at box 904; generating a plurality of phase offset data points for a plurality of resistance values ​​using the estimated interrogation frequency at box 906; and performing curve fitting of the plurality of phase offsets relative to the plurality of resistance values ​​at box 908.

[0075] Determining a thermal circuit model for the consumable components and the thermal components (block 902) may include generating an electrical equivalent circuit having one or more of thermal capacitance and / or thermal resistance components for each component of the thermal system, wherein the resistance component accounts for the thermal resistance at an interface (e.g., thermal interface 118). In the specific implementation described herein, the consumable components and the thermal components are each modeled as having a thermal capacitance, such as Figure 4 As shown. In some implementations, the heat capacity of the consumable component can be determined based on data from the manufacturer or via testing, such as calculating the heat capacity by (material specific heat capacity (in J / gK) x material mass) or by (material volumetric heat capacity (in J / cc-K) x material volume). Similarly, the heat capacity of the consumable component can be determined based on data from the manufacturer or via testing, such as measuring the heat capacity using calorimetric techniques, which generally involve measuring the temperature increase when a known amount of heat is added to a sample. In some implementations, some modeling components can have negligible values ​​when compared to other components, such that they can be considered to be effectively removed from the modeling system.

[0076] Once the electrical equivalent circuit for the thermal system is determined, an estimation of the interrogation frequency around the RC corner value may be performed based on the known thermal capacitances of the consumable components and the thermal components and the thermal circuit model (block 904). That is, all components of the electrical equivalent circuit except the interface resistance may be determined from data from the manufacturer or by conducting tests, and the thermal circuit may be modeled or simulated, such as using SPICE modeling.

[0077] In the specific implementation described in this article, Figure 4 The electrical equivalent circuit used to generate the Figure 5The Bode plot in 512 shows the system response at different drive frequencies (in Hz) and the magnitude of the phase response (in degrees). If the exact drive amplitude is used in the model, the response output magnitude can be shown in °C or K; or it can be dB below the attenuation of the drive amplitude. Figure 5 As shown, the Bode plot of the phase response curve 514 depicts the initial phase drop due to the time constant of the TEC itself (i.e., its thermal capacitance combined with convection losses to the environment), which is a graphical representation of how quickly (or slowly) heat can be transferred to the environment. The interrogation frequency can be estimated based on the Bode plot as the frequency at which the slope is the largest, which corresponds to the RC corner of the electrical equivalent circuit of the thermal system. Figure 5 As shown, the RC angle can be estimated to be approximately 0.3 Hz. In some implementations, the estimation of the interrogation frequency can include iterating the resistance values ​​to optimize or converge the model to determine the RC angle and the corresponding interrogation frequency.

[0078] Once the interrogation frequency is estimated or otherwise determined, a plurality of phase shift data points may be generated for a plurality of resistance values ​​using the estimated interrogation frequency (block 906). That is, a plurality of resistance values ​​of the interface resistance may be input into the model to determine a plurality of corresponding modeled system responses, such as Figure 7 As shown, the phase response at each resistance value increases negatively as the thermal resistance value of the interface increases, as shown by points 716, 726, 736. The plurality of phase offset data points may be plotted relative to the plurality of corresponding resistance values ​​of the model, and a curve fit may be performed for the plurality of phase offsets for the plurality of resistance values ​​(block 908) to generate a phase resistance model formula.

[0079] Although process 900 may be used to generate a phase resistance model of a thermal component (eg, TEC assembly 123), Fig.10 A flow chart is depicted for a specific implementation of testing a thermal component using a phase resistance model of a QC process 1000. The QC process 1000 for testing a thermal component (such as the TEC 114 itself or the TEC assembly 123) may include contacting a known consumable with a thermal component of the instrument to be tested (block 1002). The known consumable may be a pre-tested consumable component such as a flow cell 110, a carrier plate 112, a flow cell assembly 123, or other consumable component with a known acceptable interface resistance.

[0080] The example QC process 1000 also includes driving the thermal component using a periodic sine wave input based on a predetermined interrogation frequency at block 1004. Driving the thermal component using a periodic sine wave input may include using a signal generator to output a sine input at the interrogation frequency estimated during the calibration process 900. In other implementations, other interrogation frequencies may be used.

[0081] The example QC process 1000 also includes measuring a plurality of temperature outputs from a thermal sensor (e.g., thermal sensor 118) in response to driving the thermal component with a periodic sine wave input (block 1006). In some implementations, the temperature outputs may be logged in a log file or data table and / or periodically polled a predetermined number of times during the process 1000.

[0082] The plurality of temperature outputs may be multiplied by a reference signal that is in phase with the periodic sine wave input, and the resulting DC signal component may be calculated to determine the in-phase component X (block 1008). The reference signal may be any signal having the same frequency as the interrogation frequency, including, for example, the periodic sine wave input itself. The resulting DC signal may be calculated based on a sinusoidal fit of the resulting incremented temperature outputs to the reference signal to determine an offset as the in-phase component X. In other specific implementations, the temperature outputs may be averaged over a predetermined period of time to determine the average offset as the in-phase component X.

[0083] The multiple temperature outputs may also be multiplied by a 90° phase shifted reference signal; and the resulting DC signal component may be calculated to determine the quadrature out-of-phase component Y (block 1010). The reference signal may be any signal having the same frequency as the interrogation frequency of the 90° phase shift, including, for example, a 90° phase shifted signal of the periodic sine wave input itself. The resulting DC signal may be calculated based on a sinusoidal fit of the resulting multiplied temperature outputs to the reference signal to determine the offset as the out-of-phase component Y. In other specific implementations, the resulting multiplied temperature outputs and the reference signal may be averaged over a predetermined period of time to determine the average offset as the out-of-phase component Y.

[0084] The phase shift in response to a periodic sine wave input can be based on tan -1 (Y / X) or atan2(X,Y) is calculated (block 1012), where Y is the out-of-phase component and X is the in-phase component. The phase offset can then be used to calculate or determine the corresponding resistance value of the thermal interface using a calibrated resistance phase offset formula (such as the calibrated resistance phase offset formula determined by the calibration process 900) and the calculated phase offset (block 1014). In some implementations, the resistance value determination (block 1014) can be omitted, and the QC process 1000 can directly utilize the phase offset value when comparing with the predetermined phase offset thresholds of blocks 1016, 1018, 1020, which are described in further detail below.

[0085] Using the determined resistance value, the QC process 1000 of the present example also includes comparing the determined resistance value to a predetermined resistance threshold value (block 1016). The predetermined resistance threshold value may be set to a resistance value where insufficient heat transfer occurs between the tested thermal component and a known consumable due to a defect in the thermal component. The predetermined resistance threshold value may be empirically determined based on testing of several thermal components and consumables, such as Fig.14 In some cases, the predetermined resistance threshold may include a margin of error to account for the reference Fig.14 Variations of the thermal components in the particular arrangement described, such as a value of 0.45 K / W. Additionally, in some implementations, determining the corresponding resistance value of the thermal interface using the calibrated resistance phase shift formula and the calculated phase shift can be omitted by using a direct phase shift compared to the phase shift threshold of 1016 (block 1014).

[0086] The example QC process 1000 may also include determining that the thermal component has a defect at a thermal interface surface (e.g., interface surface 118) based on the determined resistance value being above a predetermined resistance threshold (block 1018). The defect at the thermal interface may be any defect, such as dust, dirt, dried reagents, and / or a defect in the thermal component, such as a defect in the TEC 114 itself, a defect in the surface of the TEC 114, or any other defect. In some implementations, the QC process 1000 may also include setting a flag indicating that the thermal component has a defect so that an automated quality control system may move or otherwise mark the thermal component as having a defect. In other implementations, in response to determining that the thermal component has a defect (block 1018), a light may be turned on (e.g., a red light may be illuminated to indicate to a user that the thermal component has a defect), a pop-up indicator may be initiated, and / or another process may be initiated. In some implementations, determining that the thermal component has a defect at the thermal interface surface may be based on the determined resistance value being equal to or above a predetermined resistance threshold (block 1018).

[0087] If the determined resistance value is not above (or equal to) the predetermined resistance threshold, the QC process 1000 of the present example then determines that the thermal component is acceptable based on the determined resistance value being below the predetermined resistance threshold (block 1020). In response to determining that the thermal component is acceptable (block 1020), the QC process 1000 of the present example may also include setting a flag indicating that the thermal component is acceptable so that the automated quality control system may move the thermal component or otherwise mark it as passing the QC process 1000. In other implementations, in response to determining that the thermal component is acceptable (block 1020), a light may be turned on (e.g., a green light may be illuminated to indicate to the user that the thermal component is acceptable), a pop-up indicator may be initiated, and / or another process may be initiated. In some implementations, determining that the thermal component is acceptable may be based on the determined resistance value being equal to or below the predetermined resistance threshold (block 1020).

[0088] Fig.11 A flow chart depicting a specific implementation of testing a consumable 1100 using a phase resistance model of a QC process. The QC process 1100 can be used to test a consumable, such as a flow cell 110, a carrier plate 112, a flow cell assembly 123, or other consumable components having a known acceptable interface resistance. The QC process 1100 can include contacting the consumable to be tested with a known thermal component of the instrument (block 1102). The known thermal component can be a pre-tested thermal component, such as a TEC 114, a TEC assembly 123, or other thermal component having a known acceptable interface resistance.

[0089] The QC process 1100 of the present example includes driving the thermal component using a periodic sine wave input based on a predetermined interrogation frequency (block 1104). Driving the thermal component using a periodic sine wave input may include using a signal generator to output a sine input at the interrogation frequency estimated during the calibration process 900. In other implementations, other interrogation frequencies may be used.

[0090] The QC process 1100 of this example also includes measuring a plurality of temperature outputs from a thermal sensor (e.g., thermal sensor 118) in response to driving the thermal component with a periodic sine wave input (block 1106). In some implementations, the temperature outputs may be logged in a log file or data table and / or periodically polled a predetermined number of times during the process 1100. The plurality of temperature outputs may be multiplied by a reference signal that is in phase with the periodic sine wave input, and the resulting DC signal component may be calculated to determine the in-phase component X (block 1108). The reference signal may be any signal having the same frequency as the interrogation frequency, including, for example, the periodic sine wave input itself. The resulting DC signal may be calculated based on a sinusoidal fit of the resulting augmented temperature outputs to the reference signal to determine an offset as the in-phase component X. In other implementations, the temperature outputs may be averaged over a predetermined period of time to determine the average offset as the in-phase component X.

[0091] The multiple temperature outputs may also be multiplied by a 90° phase shifted reference signal; and the resulting DC signal component may be calculated to determine the quadrature out-of-phase component Y (block 1110). The reference signal may be any signal having the same frequency as the interrogation frequency of the 90° phase shift, including, for example, a 90° phase shifted signal of the periodic sine wave input itself. The resulting DC signal may be calculated based on a sinusoidal fit of the resulting multiplied temperature outputs to the reference signal to determine the offset as the out-of-phase component Y. In other specific implementations, the resulting multiplied temperature outputs and the reference signal may be averaged over a predetermined period of time to determine the average offset as the out-of-phase component Y.

[0092] The phase shift in response to a periodic sine wave input can be based on tan -1 (Y / X) or atan2(X,Y) is calculated (block 1112), where Y is the out-of-phase component and X is the in-phase component. The phase offset can then be used to calculate or determine a corresponding resistance value of a thermal interface (e.g., thermal interface 118) using a calibrated resistance phase offset formula (such as the calibrated resistance phase offset formula determined by calibration process 900) and the calculated phase offset (block 1114). In some implementations, the resistance value determination (block 1114) can be omitted, and the QC process 1100 can directly utilize the phase offset value when comparing with the predetermined phase offset thresholds of blocks 1116, 1118, 1120, which are described in further detail below.

[0093] Using the determined resistance value, the example QC process 1100 also includes comparing the determined resistance value to a predetermined resistance threshold (block 1116). The predetermined resistance threshold may be set to a resistance value where insufficient heat transfer occurs between the tested consumable and a known thermal component due to a defect in the consumable. The predetermined resistance threshold may be empirically determined based on testing of several thermal components and consumables, such as Fig.15 In some cases, the predetermined resistance threshold may include a margin of error to account for the reference Fig.15 Variations of the thermal components in the particular consumable arrangements described, such as values ​​of 0.45 K / W or 0.375 K / W.

[0094] The QC process 1100 of this example may also include determining that the consumable has a defect at a thermal interface surface (e.g., interface surface 118) based on the determined resistance value being higher than a predetermined resistance threshold (box 1118). The defect at the thermal interface may be any defect, such as dust, dirt, dry reagents, and / or defects in the consumable itself, such as defects in the substrate of the consumable, defects in the adhesive bonding of the consumable, or any other defect. In some specific implementations, the QC process 1100 may also include setting a mark indicating that the consumable has a defect, so that the automated quality control system can move the consumable or otherwise mark it as having a defect. In other specific implementations, in response to determining that the consumable has a defect (box 1118), a light may be turned on (e.g., a red light may be illuminated to indicate to the user that the consumable has a defect), a pop-up indicator may be activated, and / or another process may be activated. In some implementations, determining that the consumable has a defect at the thermal interface surface in response to the determined resistance value being above a predetermined resistance threshold can be based on the determined resistance value being equal to or above the predetermined resistance threshold (block 1118 ).

[0095] If the determined resistance value is not higher than (or equal to) a predetermined resistance threshold, the QC process 1100 of the present example then determines that the consumable is acceptable based on the determined resistance value being lower than the predetermined resistance threshold (box 1120). In response to determining that the consumable is acceptable, the process 1100 may also include setting a mark indicating that the consumable is acceptable so that the automated quality control system can move the consumable or otherwise mark it as passing the QC process 1100. In other specific implementations, in response to determining that the consumable is acceptable (box 1120), a light may be turned on (e.g., a green light may be illuminated to indicate to the user that the consumable is acceptable), a pop-up indicator may be activated, and / or another process may be activated. In some specific implementations, determining that the consumable is acceptable may be based on the determined resistance value being equal to or lower than the predetermined resistance threshold (box 1120).

[0096] Fig.12A flow chart is depicted for testing a diagnostic process for loading consumables into an instrument 1200 for QC purposes. In some specific implementations, such an instrument may include a housing or other components that may obscure a visual inspection of a thermal interface (e.g., thermal interface 118) between the consumable and the thermal component of the instrument. For example, the upper surface of TEC 114 or TEC assembly 123 may not be visible to the user of the instrument. When consumables such as flow cell cartridge 122 and / or flow cell 110 itself are inserted into the instrument, the consumables and corresponding thermal components such as TEC 112 or TEC 123 components that interface with the consumables for thermal control may be located inside the housing of the instrument and obscure and invisible. The housing of the instrument may generally limit or reduce the impact of contaminants on the process therein. However, ensuring that the thermal interface between the consumable and the thermal component is free of debris such as dust, dirt, liquid, etc. may be difficult to perform without disassembling the housing and / or portions of the instrument to visually inspect the surface of the thermal interface. Thus, the example diagnostic process 1200 may be implemented by the instrument as part of a pre-run quality control check to determine that the consumable is loaded into the instrument and that the thermal interface between the consumable and the instrument has an acceptably low thermal resistance such that adequate thermal control of the consumable can be achieved through the thermal components.

[0097] In some implementations, the diagnostic process 1200 may include first contacting the consumable with a thermal component of the instrument (block 1202). As described above, the thermal component may be a pre-tested thermal component, such as TEC 114, TEC assembly 123, or other thermal component with a known acceptable interface resistance when the instrument is manufactured. In some implementations, contacting the consumable with the thermal component may include a user inserting the flow cell cartridge 123 and / or the flow cell 1120 into the instrument, and the instrument running an automated process to engage the flow cell cartridge 123 and / or the flow cell 110 with the thermal component.

[0098] The diagnostic process 1200 of the present example also includes driving the thermal component using a periodic sine wave input based on a predetermined interrogation frequency (block 1204). Driving the thermal component using a periodic sine wave input may include using a signal generator to output a sine input at the interrogation frequency estimated during the calibration process 900. In other implementations, other interrogation frequencies may be used. In some implementations, data of the periodic sine wave input may be stored in a memory or storage device of the instrument.

[0099] The diagnostic process 1200 of this example also includes measuring a plurality of temperature outputs from a thermal sensor (e.g., thermal sensor 118) in response to driving the thermal component with a periodic sine wave input (block 1206). In some implementations, the temperature outputs may be logged in a log file or data table and / or periodically polled a predetermined number of times during the process 1200. The plurality of temperature outputs may be multiplied by a reference signal that is in phase with the periodic sine wave input, and the resulting DC signal component may be calculated to determine the in-phase component X (block 1208). The reference signal may be any signal having the same frequency as the interrogation frequency, including, for example, the periodic sine wave input itself. The resulting DC signal may be calculated based on a sinusoidal fit of the resulting augmented temperature outputs to the reference signal to determine an offset as the in-phase component X. In other implementations, the temperature outputs may be averaged over a predetermined period of time to determine the average offset as the in-phase component X.

[0100] The multiple temperature outputs may also be multiplied by a 90° phase shifted reference signal; and the resulting DC signal component may be calculated to determine the quadrature out-of-phase component Y (block 1210). The reference signal may be any signal having the same frequency as the interrogation frequency of the 90° phase shift, including, for example, a 90° phase shifted signal of the periodic sine wave input itself. The resulting DC signal may be calculated based on a sinusoidal fit of the resulting multiplied temperature outputs to the reference signal to determine the offset as the out-of-phase component Y. In other specific implementations, the resulting multiplied temperature outputs and the reference signal may be averaged over a predetermined period of time to determine the average offset as the out-of-phase component Y.

[0101] The phase shift in response to a periodic sine wave input can be based on tan -1 (Y / X) or atan2(X,Y) to calculate (block 1212), where Y is the out-of-phase component and X is the in-phase component. The phase offset can then be used to calculate or determine the corresponding resistance value of the thermal interface (e.g., thermal interface 118) using a calibrated resistance phase offset formula (such as the calibrated resistance phase offset formula determined by the calibration process 900) and the calculated phase offset (block 1214). The calibrated resistance phase offset formula can be a single formula for a group of instruments stored in a memory or storage device of the instrument. In other specific implementations, the calibrated resistance phase offset formula may be specific to the instrument and calculated during the manufacture and / or final calibration of the instrument. In some specific implementations, the resistance value determination (block 1214) can be omitted, and the diagnostic process 1200 can directly utilize the phase offset value when comparing with the predetermined phase offset thresholds of blocks 1216, 1218, 1220, 1222, which are described in further detail below.

[0102] Using the determined resistance value, the diagnostic process 1200 of the example also includes comparing the determined resistance value to a first predetermined resistance threshold and a second predetermined resistance threshold (block 1216). The first predetermined resistance threshold may be set to a resistance value where insufficient heat transfer occurs between the consumable and the thermal component of the instrument due to defects or debris at the thermal interface between the consumable and the thermal component. The first predetermined resistance threshold may be empirically determined based on testing of several thermal components and consumables, such as Figures 13 to 16 The values ​​shown.

[0103] In some cases, the first predetermined resistance threshold utilized in the diagnostic process 1200 may include a margin of error to account for variations in the thermal component and / or the consumable. The second predetermined resistance threshold may be set to a sufficiently high resistance value such that minimal or no heat transfer occurs between the thermal component and the consumable because the consumable is not loaded into the instrument or the thermal interface between the thermal component and the consumable has a high resistance. The second predetermined resistance threshold may be determined empirically based on testing of several instruments, such as Fig.13 The values ​​shown, where no consumable is loaded, and the resistance value is, for example, 1.313K / W compared to an average value of 0.359454 with the consumable loaded, and an acceptable thermal interface for the particular instrument tested. In some cases, the second predetermined resistance threshold may include a margin of error to account for variations in the thermal components and / or consumables.

[0104] Based on a comparison of the determined resistance value with a first predetermined resistance threshold and a second predetermined resistance threshold, the diagnostic process 1200 in this specific implementation proceeds to determine whether the consumable is not properly inserted into the instrument (box 1218); if defects or debris at the thermal interface will affect the operation of the instrument, proceed to box 1220; or, if the resistance at the thermal interface is acceptable, proceed to further processing of the instrument (box 1222).

[0105] The diagnostic process 1200 may determine that the consumable is not correctly inserted into the instrument based on the determined resistance value being higher than a second predetermined resistance threshold (block 1218). If the diagnostic process 1200 determines that the consumable is not correctly inserted into the instrument (block 1218), the diagnostic process 1200 may also include setting a flag indicating that the consumable is not loaded to suspend operation of the instrument and / or otherwise indicate to the user that the consumable is not correctly loaded. In other specific implementations, in response to determining that the consumable is not correctly loaded (block 1218), a light may be turned on (e.g., a red light may be illuminated to indicate to the user that the consumable is not correctly loaded), a pop-up indicator may be activated, and / or another process may be activated. In some specific implementations, determining that the consumable is not correctly inserted into the instrument may be based on the determined resistance value being equal to or higher than the second predetermined resistance threshold (block 1218).

[0106] The diagnostic process 1200 may determine that a defect or debris at the thermal interface will affect the operation of the instrument based on the determined resistance value being below the second predetermined resistance threshold and above the first predetermined resistance threshold (block 1220). The defect or debris at the thermal interface may be any defect, such as dust, dirt, dried reagents, and / or defects in the consumable, such as defects in the substrate of the consumable, defects in the adhesive bond of the consumable, or any other defect, and / or defects in the thermal component itself, such as defects in the TEC 114 itself, defects in the surface of the TEC 114, or any other defect.

[0107] If the diagnostic process 1200 determines that a defect or debris at the thermal interface will affect the operation of the instrument (box 1220), the diagnostic process 1200 can set a flag indicating the presence of debris or defects at the thermal interface to suspend the operation of the instrument and / or otherwise indicate to the user that the thermal interface between the consumable and the thermal component of the instrument is blocked. In other specific implementations, in response to determining that there are defects and debris at the thermal interface (box 1220), a light can be turned on (e.g., a red light or a yellow light can be illuminated to indicate to the user that the thermal interface has debris or defects), a pop-up indicator can be initiated, and / or another process can be initiated. In some specific implementations, the diagnostic process 1200 can initiate an ejection operation to eject the consumable so that the user can clean the consumable, maintain the thermal component, and / or reinsert the consumable if it is improperly inserted or misaligned. In some specific implementations, determining that there are defects or debris at the thermal interface will affect the operation of the instrument can be based on the determined resistance value being equal to or above a first predetermined resistance threshold (box 1220).

[0108] If the determined resistance value is not above the first predetermined resistance threshold, the diagnostic process 1200 may determine that the thermal interface is acceptable (block 1222). Based on determining that the thermal interface is acceptable, the diagnostic process 1200 may also include setting a flag indicating that the thermal interface is acceptable so that the instrument can continue to operate; or otherwise marking the thermal interface as passing the diagnostic process. In other specific implementations, in response to determining that the thermal interface is acceptable (block 1222), a light may be turned on (e.g., a green light may be illuminated to indicate to the user that the thermal interface is acceptable), a pop-up indicator may be initiated, and / or another process may be initiated. In some specific implementations, determining that the thermal interface is acceptable may be based on the determined resistance value being equal to or below the first predetermined resistance threshold (block 1222).

[0109] Fig.13A table showing an example of repeated measurements using the described technique to demonstrate measurement repeatability is depicted. The data indicates that if the specification range is narrow to about +20% / -0% of the expected measurement, the measurement will easily resolve variations of only a few percent in interface resistance and can therefore have acceptable accuracy to distinguish good from bad interfaces. The table also lists an example of the measurement results when no consumable is installed. This measurement is 3.6 times higher, indicating that missing consumables can be easily detected with this measurement.

[0110] Fig.14 Depicted is a table showing how the measurements produced different results on several prototype instruments using two different instances of the same consumable. The instrument variation is significantly higher than the measurement repeatability, indicating that actual part-to-part variation is being measured.

[0111] Fig.15 A table showing how the measurement can produce different results on several consumables in the same instrument is depicted. Consumable variation is only slightly higher than measurement repeatability

[0112] Fig.16 Shown is a cardboard contaminant (circled) that could theoretically be present in the interface between the TEC 114 and the flow cell carrier plate 112. The described measurement technique can measure a 45% increase in interface resistance for the contaminant, demonstrating that real-world contamination can produce measurement results that are significantly larger than measurement repeatability and larger than instrument and consumable variations.

[0113] Fig.17 A graph 1300 is depicted showing an example of ramp-up time of a flow cell 122 based on thermal resistance with various defects at the thermal interface 118. Such defects may result from the presence of contaminants 130 (e.g., dirt, dust, dehydrated reactants, debris, etc.) at the thermal interface 118, from the flow cell cartridge 112 being improperly loaded onto the TEC assembly 123, from manufacturing defects in components of the flow cell cartridge 112 or the TEC assembly 123, or from some other condition. However, in this example, various data points 1332, 1334, 1336 represent conditions where contaminants 130 are located at the thermal interface 118; whereas data point 1330 represents a condition where contaminants 130 are not present at the thermal interface 118.

[0114] In the graph 1300, the y-axis 1302 represents the ramp-up time of the flow cell 122 in seconds, while the x-axis 1304 represents the thermal resistance at the thermal interface 118 in K / W as determined by the methods described herein. As used herein, "ramp-up time" is the time it takes for a thermal sensor (not shown) placed within the flow cell 110 to change from a specified starting temperature to a specified target temperature when driven by the TEC 114.

[0115] exist Fig.17, horizontal line 1310 represents an example of a threshold ramp time value, wherein the ramp time of the flow cell 122 is expected to be lower than the threshold represented by the horizontal line 1310. In other words, a ramp time value that exceeds the threshold represented by the horizontal line 1310 may be considered unacceptable. In this example, the threshold ramp time value is approximately 12 seconds. Alternatively, the threshold ramp time value may be in the range of approximately 9 seconds to approximately 30 seconds. Vertical line 1320 represents an example of a threshold thermal resistance value, wherein the thermal resistance at the thermal interface 118 is expected to be lower than the threshold represented by the vertical line 1320. In other words, a thermal resistance value that exceeds the threshold represented by the vertical line 1320 may be considered unacceptable. In this example, the threshold thermal resistance value is approximately 0.66K / W. Alternatively, the threshold thermal resistance value may be in the range of approximately 0.36K / W to approximately 0.91K / W.

[0116] Fig.17 1330, 1332 in the data points 1330, 1332 illustrate acceptable conditions for the thermal interface 118 such that the ramp-up time of the flow cell 122 is below the threshold represented by the horizontal line 1310; and such that the thermal resistance value is below the threshold represented by the vertical line 1320. As described above, the data point 1330 represents a condition where no contaminant 130 is present at the thermal interface 118. The data point 1332 represents a condition where the contaminant 130 is present at the thermal interface 118; however, such contaminant 130 is not sufficient to affect the thermal interface 118 to increase the ramp-up time of the flow cell 122 to exceed the threshold represented by the horizontal line 1310 or to increase the thermal resistance to exceed the value represented by the vertical line 1320.

[0117] Data point 1334 shows a condition where the thermal interface 118 is unacceptable (or at least acceptable but undesirable) due to an interface defect. Under the condition represented by data point 1334, the ramp-up time of the flow cell 122 unacceptably (or undesirably) exceeds the threshold represented by horizontal line 1310, even though the thermal resistance at the thermal interface 118 is acceptably below the threshold represented by vertical line 1320. In some cases, the condition represented by data point 1334 may be considered unacceptable in the context of factory quality control; but may be considered acceptable (although undesirable) in the context of field use quality control. In other words, a thermal interface 118 presenting a condition associated with data point 1334 in the factory may be rejected; while a thermal interface 118 presenting a condition associated with data point 1334 in the field (i.e., operation by an end user) may be considered acceptable (although undesirable).

[0118] Data point 1336 illustrates a condition where the thermal interface 118 is unacceptable due to an interface defect, which causes the ramp-up time of the flow channel 122 to be unacceptably high, and therefore the thermal resistance value of the thermal interface 118 to be unacceptably high.

[0119] The above description is provided to enable those skilled in the art to practice the various configurations described herein. Although the subject technology has been described in detail with reference to various drawings and configurations, it should be understood that these drawings and configurations are only for illustrative purposes and should not be considered to limit the scope of the subject technology.

[0120] As used herein, an element or step recited in the singular and preceded by the word "a" or "an" should be understood as not excluding a plurality of said elements or steps, unless such exclusion is explicitly stated. Furthermore, reference to "one implementation" is not intended to be interpreted as excluding the existence of additional implementations that also include the recited features. Furthermore, unless explicitly stated to the contrary, an implementation that "comprises" or "has" one or more elements having a particular property may include additional elements, whether or not they have that property.

[0121] The terms "substantially" and "approximately" used throughout this specification are used to describe and illustrate small fluctuations, such as small fluctuations due to variations in processing. For example, they may refer to less than or equal to ±5%, such as less than or equal to ±2%, such as less than or equal to ±1%, such as less than or equal to ±0.5%, such as less than or equal to ±0.2%, such as less than or equal to ±0.1%, such as less than or equal to ±0.05% and / or 0%.

[0122] There may be many other ways to realize the subject technology. Without departing from the scope of the subject technology, the various functions and elements described herein may be divided differently from those shown and elements. Various modifications to these specific implementations may be apparent to those skilled in the art, and the general principles defined herein may be applied to other specific implementations. Therefore, without departing from the scope of the subject technology, those of ordinary skill in the art may make many changes and modifications to the subject technology. For example, different numbers of given modules or units may be adopted, one or more different types of given modules or units may be adopted, given modules or units may be added or given modules or units may be omitted.

[0123] Underlined and / or italicized headings and subheadings are used for convenience only, do not limit the subject technology, and are not referenced in conjunction with the explanation of the description of the subject technology. All structural and functional equivalents of the elements of the various specific implementations described throughout this disclosure that are known or will later be known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be covered by the subject technology. In addition, nothing disclosed herein is intended to be dedicated to the public, regardless of whether such disclosure is explicitly recited in the above description.

[0124] It should be understood that all combinations of the foregoing concepts and the additional concepts discussed in more detail below (assuming such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein. In particular, all combinations of the claimed subject matter appearing at the end of this disclosure are contemplated as being part of the inventive subject matter disclosed herein.

Claims

1. An apparatus comprising: shell; a thermal component located within the housing and configured to receive a consumable, the consumable and the thermal component forming a thermal interface when the consumable is received on the thermal component, wherein the consumable is configured to receive a sample and a reagent; a temperature sensor configured to detect a temperature of the thermal component; as well as A computer readable medium storing a computer program, the computer program including instructions for causing the instrument to determine whether there is a defect associated with the thermal component by performing at least the following operations: Using a wave input to drive the thermal component, measuring a thermal response signal using the temperature sensor of the instrument in response to driving the thermal component using the wave input, determining an offset between the thermal response signal and the wave input, calculating a thermal resistance value of the thermal interface using a calibrated resistance offset formula and the determined offset, and The calculated thermal resistance value is compared to a predetermined resistance threshold, the comparison between the calculated thermal resistance value and the predetermined resistance threshold indicating whether a defect associated with the thermal component is present.

2. The apparatus of claim 1, wherein the thermal component comprises a thermoelectric cooler.

3. An instrument according to claim 1, wherein the consumable comprises a flow cell.

4. The instrument of claim 1 , wherein the computer readable medium storing the computer program further comprises instructions for causing the instrument to set a flag indicating suspension of operation of the instrument in response to the comparison between the calculated thermal resistance value and the predetermined resistance threshold.

5. An instrument according to claim 1, wherein the computer-readable medium storing the computer program also includes the following instructions, the instructions are used to initiate an ejection operation to eject the consumable from the instrument in response to a comparison between the calculated thermal resistance value and the predetermined resistance threshold.

6. The apparatus of claim 1, the wave input comprising a periodic sine wave input.

7. The apparatus of claim 6, the offset between the thermal response signal and the periodic sine wave input comprising a phase offset.

8. The instrument of claim 7, the calibrated resistance offset formula comprising a calibrated resistance phase offset formula.

9. A method for detecting defects associated with a thermal component of an instrument, the method comprising: contacting a consumable with the thermal component of the instrument to form a thermal interface; driving the thermal component using a wave input; measuring a thermal response signal using a temperature sensor of the instrument in response to driving the thermal component using the wave input; determining an offset of the thermal response signal in response to the wave input; calculating a thermal resistance value of the thermal interface using a calibrated resistance offset formula and the determined offset; as well as The calculated thermal resistance value is compared to a predetermined resistance threshold to determine if a defect associated with the thermal component exists.

10. The method of claim 9, wherein comparing the calculated thermal resistance value to a predetermined resistance threshold to determine whether a defect associated with the thermal component exists comprises: It is determined whether the thermal component is defective.

11. The method of claim 9, wherein comparing the calculated thermal resistance value to a predetermined resistance threshold to determine whether a defect associated with the thermal component exists comprises: It is determined whether a defect exists at the thermal interface.

12. The method of claim 9, wherein comparing the calculated thermal resistance value to a predetermined resistance threshold to determine whether a defect associated with the thermal component exists comprises: Determine if the consumable is defective.

13. The method of claim 9, wherein the operation of driving the thermal component using a wave input comprises: The thermal component is driven using a periodic sine wave input.

14. The method of claim 9, wherein the operation of driving the thermal component using a wave input comprises: The thermal component is driven using a wave input based on a predetermined determined interrogation frequency.

15. The method of claim 9, the operation of determining a shift of the thermal response signal in response to the wave input comprising: determining a phase shift of the thermal response signal in response to the wave input; and The operation of calculating the thermal resistance value of the thermal interface using a calibrated resistance offset formula and the determined offset includes calculating the thermal resistance value of the thermal interface using a calibrated resistance phase offset formula and the determined phase offset.

16. The method of claim 9, wherein comparing the calculated thermal resistance value to a predetermined resistance threshold to determine if a defect associated with the thermal component is present is performed during a pre-operational quality control check of the instrument.

17. The method according to claim 9, further comprising: In response to the calculated thermal resistance value being below the predetermined resistance threshold, it is determined that there is no defect associated with the thermal component.

18. The method according to claim 9, further comprising: In response to the calculated thermal resistance value exceeding the predetermined resistance threshold, it is determined that the defect associated with the thermal component is present.

19. The method according to claim 18, further comprising: In response to determining that the defect associated with the thermal component exists, performing one or both of the following actions: setting a flag indicating that operation of the instrument is suspended, or An ejection operation is initiated to eject the consumable from the instrument.

20. A method for detecting defects associated with a thermal component of an instrument, the method comprising: driving the thermal component of the instrument using a periodic sine wave input based on a predetermined interrogation frequency; measuring a thermal response signal using a temperature sensor of the instrument in response to driving the thermal component using the periodic sine wave input; determining a phase shift of the thermal response signal in response to the periodic sine wave input; calculating a thermal resistance value of the thermal interface using a calibrated resistance phase shift formula and the determined phase shift; comparing the calculated thermal resistance value with a predetermined resistance threshold; and One of the following: In response to the calculated thermal resistance value exceeding the predetermined resistance threshold, determining that there is a defect associated with the thermal component, or In response to the calculated thermal resistance value being lower than the predetermined resistance threshold, It is determined that there are no defects associated with the thermal component.

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