A nanopore array device and a method

Abstract

A nanopore array device comprises a sensor, a detection circuit, one or more resistive heaters, and a temperature control circuit. The sensor comprises an array (9) of nanopore sensor elements (15A, 15B) configured to generate signals which are indicative of interactions between molecular entities and respective nanopores (29A, 29B) supported by each nanopore sensor element (15A, 15B). The detection circuit is configured to process the signals generated by the sensor, and to generate heat which heats the sensor. The one or more resistive heaters (57A, 57B) are configured to generate heat which heat the sensor. The temperature control circuit (49) is configured to control the one or more resistive heaters (57A, 57B) to maintain a temperature of the sensor above a predetermined minimum temperature.

Description

[0001] A NANOPORE ARRAY DEVICE AND A METHOD

[0002] FIELD OF THE APPLICATION

[0003] The present application relates to a nanopore array device and a method.

[0004] BACKGROUND

[0005] Nanopore sensor elements can be used to sense interactions with molecular entities, for example polynucleotides. Nanopore sensor elements may typically employ an electrical signal across a nanopore channel to generate a measurement signal that is interpreted to sense and / or characterise molecular entities as they interact with the nanopore channel. Typically, the electrical signal is applied as a potential difference or current across the nanopore channel that will provide a meaningful measurement signal to be interpreted. The measurement can include, for example, one of ionic current flow, electrical resistance, or voltage. An example of such a device is Oxford Nanopore Technology’s MinlON sequencer, which performs DNA and RNA sequencing. Further details of the structure of such devices may be found in the applicant’s prior applications, such as WO2023222994A1.

[0006] Proper operation of nanopore sensor elements requires them to be maintained within a suitable temperature range. Processing circuity included with the device may generate heat which heats the sensor during use. This may require a cooling, such as with a Peltier cooler, in order to keep the sensor elements within their desired temperature range. An example of such a cooler is described in WO2011067559A1.

[0007] SUMMARY

[0008] A first aspect provides a nanopore array device comprising: a sensor comprising an array of nanopore sensor elements configured to generate signals which are indicative of interactions between molecular entities and respective nanopores supported by each nanopore sensor element of the array of nanopore sensor elements; a detection circuit configured to process the signals generated by the sensor, and to generate heat which heats the sensor; one or more resistive heaters configured to generate heat which heat the sensor; and a temperature control circuit configured to control the one or more resistive heaters to maintain a temperature of the sensor above a predetermined minimum temperature. The performance of the sensor may be sensitive to its operating temperature, which may require the temperature of the sensor to be maintained within a desired operating temperature range to achieve a desired performance. For example, the chemical and biological processes that occur when the nanopore array device is conducting an assay, such as translation of DNA through a nanopore channel, may slow down or stop outside of the operating temperature range.

[0009] On some previous nanopore array devices, the detection circuit generated a large amount of heat when processing the signals. The heat generated by the detection circuit maintained the sensor above the minimum temperature. The main thermal management problem may have instead been maintaining the sensor below a maximum temperature.

[0010] However, there are some circumstances where the heat generated by the detection circuit when processing the signals is insufficient to maintain the temperature of the sensor above the minimum temperature, such as when operating in very cold environments or when using a low power detection circuit. Using the temperature control circuit may solve this problem by controlling the one or more resistive heaters to provide heating to the sensor to maintain the temperature of the sensor above its minimum operating temperature.

[0011] Optionally, the heat generated by the one or more resistive heaters which heats the sensor is supplemental to the heat which heats the sensor generated by the detection circuit.

[0012] As the resistive heaters provide supplemental heat (rather than the heat provided by the resistive heaters being the heat provided by the detection circuit), the temperature of the sensor may be maintained above the predetermined minimum temperature without having to modify (for example, increase) the workload of the detection circuit. As the workload of the detection circuit may naturally be fairly constant during operation, artificially modifying the workload may be difficult to achieve and / or inhibit the ability of the detection circuit to process the signals. Additionally, this may improve the performance of the nanopore array device, especially in examples (discussed below) where the one or more resistive heaters are deactivated when the temperature of the sensor is above a predetermined maximum temperature. This prevents the temperature control circuit having to reduce the workload of the detection circuit to achieve the deactivation. Reduction in the workload of the detection circuit may inhibit the ability of the detection circuit to process the signals effectively.

[0013] Optionally, the detection circuit is a low power detection circuit. Some previous nanopore array devices used high power detection circuits which produced a large amount of heat. This meant the sensor may have required active cooling, e.g. using an external fan, to maintain the temperature of the sensor within its desired operating temperature range. The addition of active cooling may have made the previous nanopore array devices more costly and larger in size.

[0014] Using a low power detection circuit may address this problem by reducing the amount of heat generated by the detection circuit, and thereby transferred from the detection circuit to the sensor. This may reduce the likelihood of the detection circuit heating the sensor to over its desired operating temperature range. This may remove the requirement for additional cooling systems, such as an external fan. This may also help reduce the size and cost of the nanopore array device. The low power detection circuit may include a plurality of detection channels. The maximum power rating of each channel may be 0.2mW. For a detection circuit having 400 channels, the maximum power rating of the whole detection circuit may be 0.08W. In some examples, the maximum power rating of the detection circuit may be 0.1 W. The power rating of the low power detection circuit will depend on the number of channels and the power rating of the individual channels. For example, a 3000-channel device may have a maximum power rating of 0.6W. The power rating of the detection circuit will scale with the size of the nanopore array. As such, while a detection circuit with a greater number of channels will operate at a higher power, the number of nanopores and the size of the nanopore array will increase accordingly.

[0015] Optionally, the nanopore array device comprises an integrated circuit; and the integrated circuit comprises the detection circuit. Optionally, the integrated circuit is an application- specific integrated circuit (ASIC). The use of an ASIC, rather than an off the shelf integrated circuit, may reduce the size and the power consumption of the nanopore array device, and thereby improve the portability of the nanopore array device.

[0016] Optionally, the integrated circuit comprises the one or more resistive heaters. One solution for providing the one or more resistive heaters may be to provide them separately to the integrated circuit. However, by providing the one or more resistive heaters as part of the integrated circuit, a compact and cost-effective solution may be achieved. This may be especially beneficial in nanopore array devices, in which there is a desire to achieve miniaturisation and low cost in order to expand the range of use cases for the nanopore array device.

[0017] Optionally, the integrated circuit comprises power rails; and the one or more resistive heaters are coupled between the power rails.

[0018] Optionally, the integrated circuit is physically coupled to the sensor. As a result, the thermal conductivity, and thereby the heat transfer, between the integrated circuit and the sensor may be greater than if the integrated circuit were physically separate to the sensor. For a given power, the one or more resistive heaters may be able to heat the sensor to the predetermined minimum temperature in a greater range of ambient temperature environments.

[0019] The integrated circuit may be coupled directly to the sensor. Electrical connections, such as solder bumps, may be formed between the integrated circuit and the sensor device. The solder bumps may provide both electrical and mechanical connections between the integrated circuit and the sensor device. As an alternative, an interposer, such as a printed circuit board (PCB) may be formed between the integrated circuit and the sensor device.

[0020] Optionally, the nanopore array device comprises a substrate; the integrated circuit is physically coupled to a first side of the substrate; the array of nanopore sensor elements is located on a second side of the substrate, which is opposite to the first side; and the substrate has a thermal conductivity of no less than 1 OOmW / m.K. As a result, the heat transfer between the integrated circuit and the array of nanopore sensor elements may be greater than if the conductivity were less than lOOmW / m.K. Optionally, the substrate comprises glass.

[0021] Optionally, the substrate comprises a plurality of vias which extend through the substrate. The vias may electrically connect the array of nanopore sensor elements and the integrated circuit.

[0022] Optionally, the integrated circuit comprises a temperature sensor configured to provide an output signal which is indicative of the temperature of the sensor; and the temperature control circuit is configured to process the output signal, and to control the one or more resistive heaters based on the output signal. Providing the temperature sensor as part of the integrated circuit rather than as part of a separate circuit, may provide a cost-effective and compact solution.

[0023] Optionally, the integrated circuit comprises a further temperature sensor configured to provide a further output signal which is indicative of the temperature of the sensor; the further temperature sensor is spaced from the temperature sensor; and the temperature control circuit is configured to process the further output signal and to control the one or more resistive heaters based on the output signal and the further output signal. Providing a second temperature sensor at a different location to the temperature sensor may increase the accuracy of the measurement of the temperature of the sensor and thereby improve the accuracy of the control of the temperature of the sensor.

[0024] Optionally, the integrated circuit comprises the temperature control circuit. Providing the temperature control circuit as part of the integrated circuit rather than as part of a separate circuit, may provide a cost-effective and compact solution.

[0025] Optionally, the one or more resistive heaters are co-located with the detection circuit. The detection circuit may be one of the first parts of a signal chain which processes the signals from the sensor, and thereby may be one of the most physically close parts of the signal chain to the sensor. By co-locating the one or more resistive heaters with the detection circuits, the one or more resistive heaters may be more effective at heating the sensor than if the one or more resistive heaters were co-located with a more downstream part of the signal chain.

[0026] Optionally, the one or more resistive heaters comprises a plurality of resistive heaters. Providing a plurality of resistive heaters may improve the distribution of heat over the nanopore array device, which may reduce the likelihood of areas of the nanopore array being below the predetermined minimum temperature, and thereby those areas of the nanopore array having reduced performance.

[0027] Optionally, each resistive heater of the plurality of resistive heaters corresponds to one nanopore sensor element of the array of nanopore sensor elements. As a result, the likelihood of a nanopore sensor element not being heated to above the predetermined minimum temperature is reduced when compared with, for example, using a single heater to heat the array of nanopore sensor elements.

[0028] Optionally, the predetermined minimum temperature is no less than 36°C. The chemical and biological processes that occur when the nanopore array device is conducting an assay, such as translation of DNA through a nanopore channel, may slow down or stop below a temperature of 36°C. Therefore, maintaining the temperature of the sensor above 36°C may improve the performance of the sensor. Optionally, the predetermined minimum temperature is no less than 37°C.

[0029] Optionally, the temperature control circuit is configured to control the one or more resistive heaters such that the one or more resistive heaters are deactivated when the temperature of the sensor is above a predetermined maximum temperature. The chemical and biological processes that occur when the nanopore array device is conducting an assay may slow down or stop at temperatures above the operating temperature range. Deactivating the one or more resistive heater when the temperature of the sensor is above the predetermined maximum temperature may reduce the likelihood of the nanopore array device exceeding its desired operating temperature range, and thereby the performance of the sensor may be improved. Optionally, the predetermined maximum temperature is no greater than 39°C. The chemical and biological processes that occur when the nanopore array device is conducting an assay, such as translation through a nanopore channel, may slow down or stop above a temperature of 39°C. Therefore, deactivating the one or more resistive heater when the temperature of the sensor is above 39°C may reduce the likelihood of the chemical and biological processes slowing down or stopping and thereby improve the performance of the sensor. Optionally, the predetermined maximum temperature is no greater than 38°C.

[0030] Optionally, the one or more resistive heaters comprises one or more transistors.

[0031] Optionally, the nanopore array device comprises an alert device; the temperature control circuit is configured to send a temperature reached signal to the alert device in response to the temperature of the nanopore array device reaching the predetermined minimum temperature; and the alert device is configured to provide an alert to a user of the nanopore array device in response to receiving the temperature reached signal. This may improve the usability of the nanopore array device by providing with an awareness of when the nanopore array device is ready for use. Providing this alert may not have been a consideration on previous nanopore array devices which required active cooling because the large amount of heat generated by the detection circuit may have heated the sensor to the minimum temperature relatively rapidly, so the sensor not being above the minimum temperature may not have been a regularly occurrence.

[0032] Optionally, a ratio of a maximum heating power of the detection circuit to a total heat capacity of the nanopore array device is no greater than 300pK / s. By providing the ratio of no greater than 300pK / s, the temperature of the sensor may be maintained passively within the operating temperature range (which may be approximately IK between the maximum and the minimum operating temperature) for a typical assay duration (which may be on the order of 1-5 hours) without requiring additional active cooling, such as an external fan. Removing the requirement for active cooling may make the nanopore array device more compact and cost-effective. This may be especially beneficial in nanopore array devices, in which there is a desire to achieve miniaturisation and low cost in order to expand the range of use cases for the nanopore array device. Optionally, the nanopore array device has a total mass of no greater than 200g. As a result, the nanopore array device may be sufficiently light to be transported easily by a user, which may increase the ease of use of the nanopore array device and thereby the range of use cases for the nanopore array device.

[0033] Optionally, as described above, the maximum heating power of each channel the detection circuit is no greater than 0.2mW, which equates to a maximum heating power for a 400- channel detection circuit of 0.08W. In another example, the maximum power per channel may be 0.165mW. For a 3000-channel detection circuit, this equates to a maximum heating power of 0.5W. As a result, the detection circuit may be sufficiently low power to achieve a low nanopore array device mass and the ratio of the maximum heating power of the detection circuit to the total heat capacity of the nanopore array device of no greater than 300pK / s. As described above, the actual heating power of the detection circuit will depend on the heating power of the individual channels and the number of channels.

[0034] Optionally, the nanopore array device comprises a sample chamber; the sensor is located within the sample chamber; and the sample chamber has a total volume of no less than lOpL. As a result, when an assay is underway, and a sample liquid is located within the sample chamber, the sample liquid may act as a heat sink to reduce the temperature of the sensor. Thereby, by having a total volume of no less than lOpL, the power of the detection circuit may be greater, which may increase the performance of the detection circuit, whilst still maintaining the sensor within the operating temperature range.

[0035] The sensor may further comprise a well support structure, and the array of nanopore sensor elements may comprise an array of wells formed in the well support structure.

[0036] The nanopore array device may further comprise a substrate, and the well support structure may be disposed on or adjacent the substrate. The sensor may further comprise an array of sensor electrodes, each electrode being disposed on the substrate at a base of a respective well. Each well of the array of wells may be configured to support a membrane and each membrane may be configured to have a nanopore inserted therein.

[0037] The signals generated by the array of nanopore sensor elements may be generated by the molecular entities translocating through the nanopores.

[0038] Each well may have a diameter of 200pm or less, and a depth of 200pm or less. In some examples, the wells are cylindrical. The diameter may be from 20pm to 160pm, and in some examples may be from 60pm to 120pm. The wells may be from 50pm to 150pm deep.

[0039] The array of nanopore sensor elements may comprise at least 400 nanopore sensor elements. In some examples, there may be at least 1000 or at least 100,000 nanopore sensor elements. The nanopore sensor elements may be arranged in uniformly arranged rows and columns.

[0040] A second aspect provides a method comprising: generating heat from a detection circuit of a nanopore array device to heat a sensor of the nanopore array device; generating heat, which is supplemental to the heat generated by the detection circuit, from one or more resistive heaters to heat the sensor; and controlling the one or more resistive heaters to maintain a temperature of the sensor above a predetermined minimum temperature.

[0041] Optionally, the method comprises monitoring the temperature of the sensor. When the temperature decreases below the predetermined minimum temperature, the method comprises switching at least one of the one or more resistive heaters on. Optionally, when the temperature increases above a predetermined maximum temperature, the method comprises switching the one or more resistive heaters off.

[0042] Optionally, the method further comprises alerting a user via a user alert interface when the temperature of the sensor is within a predetermined operating range.

[0043] A third aspect provides an integrated circuit for use as part of a nanopore array device, the integrated circuit comprising: a detection circuit configured to process signals generated by a sensor of a nanopore array device, and to generate heat which heats the sensor; and a temperature control circuit configured to control one or more resistive heaters to maintain a temperature of the sensor above a predetermined minimum temperature.

[0044] A third aspect provides a nanopore array device comprising: a sensor comprising an array of nanopore sensor elements configured to generate signals indicative of interactions between molecular entities and respective nanopores supported by each nanopore sensor element of the array of nanopore sensor elements; and a detection circuit for processing the signals generated by the sensor, and to generate heat which heats the sensor, wherein a ratio of a maximum heating power of the detection circuit to a total heat capacity of the nanopore array device is no greater than 300pK / s.

[0045] The performance of the nanopore array device may be sensitive to its operating temperature, which may require the temperature of the nanopore array device to be maintained within a desired operating temperature range (which may be IK between a maximum and a minimum operating temperature) to maintain adequate performance. For example, chemical and biological processes that occur when the nanopore array device is conducting an assay, such as translation of DNA through a nanopore channel, may slow down or stop when the temperature of the sensor is outside of its desired operating temperature range.

[0046] By providing the ratio of no greater than 300pK / s, the temperature of the sensor may be maintained passively within the operating temperature range for a typical assay duration (which may be on the order of 1-5 hours) without requiring additional active cooling, such as an external fan. Removing the requirement for active cooling may make the nanopore array device more compact and cost-effective. This may be especially beneficial in nanopore array devices, in which there is a desire to achieve miniaturisation and low cost in order to expand the range of use cases for the nanopore array device.

[0047] A fourth aspect provides a method of operation of the nanopore array device described in the first aspect. The method comprises monitoring the temperature of the sensor of the nanopore array device, using the temperature control circuit. The method further comprises turning on at least one of the one or more resistive heaters, if the temperature decreases below the predetermined minimum temperature. Optionally, the method further comprises turning off the one or more resistive heaters, if the temperature increases above a predetermined maximum temperature.

[0048] Optional features of aspects may be equally applied to other aspects, where appropriate.

[0049] BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure l is a schematic view of an example nanopore array device;

[0051] Figure 2 is an enlarged view of a portion of the nanopore array device of Figure 1, showing the details of a via formed in a substrate;

[0052] Figure 2 is an enlarged view of a portion of a nanopore array device in an alternative example, showing the details of a via formed in a substrate;

[0053] Figure 4 is a schematic view of a detection circuit of the example nanopore array device;

[0054] Figure 5 is a schematic view of a temperature control system of the example nanopore array device;

[0055] Figure 6 is a further schematic view of the nanopore array device showing the location of components of the temperature control system;

[0056] Figure 7 is a further schematic view of the nanopore array device showing heat generated during operation;

[0057] Figure 8 is a flow chart showing an example method of operation of the nanopore array device; and

[0058] Figure 9 is a flow chart of a further example method.

[0059] DETAILED DESCRIPTION

[0060] Figure 1 shows a nanopore array device 1. The nanopore array device 1 includes a sensor device 3 and an Application Specific Integrated Circuit (ASIC) 5. A top surface of the ASIC 5 is physically coupled to an underside of the sensor device 3. The sensor device 3 includes a substrate 7, which includes a plurality of electrical vias 8, and which supports an array of nanopore sensor elements 9. The array of nanopore sensor elements 9 is configured to detect molecular entities, as will be described in more detail below. The ASIC 5 includes a detection circuit 11 and a temperature control system 13. The detection circuit 11 is electrically coupled to the array of nanopore sensor elements 9 and is configured to process the outputs of the array of nanopore sensor elements 9. The temperature control system 13 is configured to control the temperature of the sensor device 3.

[0061] The plurality of electrical vias 8 is disposed under the array of nanopore sensor elements 9, and is arranged to provide electrical connections between the array of nanopore sensor elements 9 and the ASIC 5.

[0062] The ASIC 5 and the sensor device 3 may be coupled together using semiconductor packaging techniques. Electrical connections are formed between the ASIC 5 and the array of nanopore sensor elements 9. For example, electrical connection points may be provided on an underside of the sensor device 3, and on an upper side of the ASIC 5. These connection points may be coupled together using solder bumps. Each connection point on the underside of the sensor device 3 may be coupled to one of the plurality of electrical vias 8.

[0063] In an alternative embodiment, an interposer (not shown in Figure 1), may be included between the ASIC 5 and the sensor device 3. The interposer may provide electrical routing between the connection points on the underside of the sensor device 3, and the connection points on the upper side of the ASIC 5.

[0064] The sensor device 3 may have a detailed construction as disclosed in WO 2009 / 077734 or WO 2014 / 064443, both of which are hereby incorporated by reference in their entirety. The array of nanopore sensor elements 9 shown in Figure 1 includes two nanopore sensor elements 15 A, 15B. For clarity, only two nanopore sensor elements 15 A, 15B are shown in Figure 1, however any number of nanopore sensor elements may be provided. Typically, a large number of nanopore sensor elements may be provided to optimise a data collection rate. For example, 256, 1024, 4396 or more nanopore sensor elements may be included.

[0065] Each of the nanopore sensor elements 15 A, 15B includes a well 17A, 17B. The wells are defined in a top surface 19 of the substrate 7. Each nanopore sensor element 15 A, 15B of the array of nanopore sensor elements 9 has a membrane 21 A, 21B and a sensor electrode 23 A, 23B. The membranes 21 A, 21B are supported across a respective one of the wells 17A, 17B. A nanopore 25A, 25B is inserted in each of the membranes 21 A, 21B. The membranes 21 A, 2 IB may comprise amphiphilic molecules such as a lipid or a polymer.

[0066] In Figure 1 the substrate 7 is shown as a single layer. The substrate 7 may also be a multilayer substrate. For example, the substrate may be formed below each of the wells 17A, 17B, and a well support structure may be formed over the substrate. The wells 17A, 17B may then be formed in the well support structure. An example of a multilayer structure having a substrate, a well support structure may, for example, take the form as described in WO 2014 / 064443 and WO 2021 / 255414, which are herein incorporated by reference in their entireties.

[0067] Each well may have a diameter of 200pm or less, and a depth of 200pm or less. In some examples, the wells are cylindrical. The diameter may be from 20pm to 160pm, and in some examples may be from 60pm to 120pm. The wells may be from 50pm to 150pm deep. The array of nanopore sensor elements may comprise at least 400 nanopore sensor elements. In some examples, there may be at least 1000 or at least 100,000 nanopore sensor elements. The nanopore sensor elements may be arranged in uniformly arranged rows and columns.

[0068] The substrate 7 may be formed silicon. Alternatively, the substrate may be formed from insulating materials, including, for example, ceramic materials (for example alumina oxide, silicon nitride, quartz), amorphous solids or non-crystalline materials. The substrate 7 may also be formed from glass.

[0069] Glass has a number of physical properties that make it a suitable material for this application, for example: a. high electrical resistivity; b. its mechanical properties: good rigidity, flatness, resistance to fracture; c. good thermal conductivity, supporting good thermal communication between the ASIC and the wells, which may be important for controlling the temperature of liquid in the wells; d. a coefficient of thermal expansion that is tolerably well matched to that of interposers (e.g. PCBs) and the (typically) photoresist material used to form the well structure; e. its compatibility with manufacturing processes used to make vias through the structure; f. being manufacturable in volume and at scale; and g. a low potential to introduce chemical or biochemical contamination into the liquid well.

[0070] The sensor device 3 also includes a sample chamber 27. The sample chamber 27 extends across the top surface 19 of the substrate 7, and across the array of nanopore sensor elements 9. Each membrane 21 A, 21B seals a respective well 17A, 17B from the sample chamber 27. The sample chamber 27 is in fluid communication with each nanopore 25 A, 25B. Each nanopore 25 A, 25B defines a nanopore channel 29 A, 29B.

[0071] Each sensor electrode 23 A, 23B is located at the bottom of a respective well 17A, 17B. Each sensor electrode 23 A,23B is therefore located on the opposite side of a respective membrane 21 A, 21B to the sample chamber 27.

[0072] In use, the sample chamber 27 receives a sample containing molecular entities, which interact with the nanopores 25 A, 25B. Each nanopore sensor element 15 A, 15B generates a signal at its sensor electrode 23 A, 23B that is dependent on, and thereby indicative of, the interaction of a molecular entity with the respective nanopore 25 A, 25B. A common electrode 31 is provided in the sample chamber 27 and provides a common reference signal (typically a potential or voltage) to each sensor element 21. The common reference signal may be a fixed reference, such as ground or other fixed potential. Alternatively, the common reference signal may be a variable reference signal. Variation of the reference signal may be by design or because of drift in the reference source. A cover 33 is provided over the top of the sample chamber 27. The common electrode 31 may be disposed adjacent the cover 33. Alternatively, the common electrode 31 may be disposed on the top surface 19 of the substrate 7. The top surface 19 of the substrate 7 forms a lower perimeter of the sample chamber 27. The ASIC 5 is coupled to a lower surface of the substrate 7 and is disposed on the opposite side of the substrate 7 to the sample chamber 27. The common electrode 31 is disposed within the sample chamber 27 on an opposite side of the sample chamber 27 to the array of nanopore sensor elements 9.

[0073] The nanopore channels 29A, 29B are pores, typically having a size of the order of nanometres. The nanopore channels 29A, 29B are of a suitable size to allow the passage of the molecular entities therethrough. In one example, the molecular entities are polymers that interact with the nanopore channels 29A, 29B while translocating through the nanopore channels 29A, 29B. The analyte of interest to be detected by the nanopore 25 A, 25B may be a polynucleotide such as DNA or RNA. The analyte may be a polypeptide or a polysaccharide.

[0074] Molecular entities interact with the nanopores 25A, 25B in the nanopore sensor elements 15 A, 15B causing output of an electrical signal at the sensor electrodes 23 A, 23B that is dependent on that interaction. In one type of sensor device 3, the electrical signal may be the ion current flowing through the nanopores 25 A, 25B. Similarly, electrical properties other than ion current may be measured. Some examples of alternative types of property include without limitation: ionic current, impedance, a tunnelling property, for example tunnelling current (for example as disclosed in Ivanov AP et al., Nano Lett. 2011 Jan 12; 11 (l):279-85 which is herein incorporated by reference in its entirety), and a FET (field effect transistor) voltage (for example as disclosed in WO2005 / 124888 which is hereby incorporated by reference in its entirety). One or more optical properties may be used, optionally combined with electrical properties (Soni GV et al., Rev Sci Instrum. 2010 Jan; Sl(l):014301 which is herein incorporated by reference in its entirety). The property may be a transmembrane current, such as ion current flow through a nanopores 25 A, 25B. The ion current may typically be the DC ion current, although in principle an alternative is to use the AC current flow (i.e. the magnitude of the AC current flowing under application of an AC voltage). The interaction may occur during translocation of the molecular entities with respect to the nanopores 25 A, 25B.

[0075] The electrical signal provides as series of measurements of a property that is associated with an interaction between the molecular entity and the nanopores 25 A, 25B. Such an interaction may occur at a constricted region of the nanopores 25 A, 25B. For example, in the case that the molecular entity is a polymer comprising a series of polymer units which translocate with respect to the nanopores 25A, 25B, the measurements may be of a property that depends on the successive polymer units translocating with respect to the pore.

[0076] Ionic solutions may be provided on either side of the nanopores 25 A, 25B. A sample containing the molecular entities of interest that are polymers may be added to one side of the nanopores 25A, 25B, for example in the sample chamber 27 in the sensor device 3 of Figure 1. The polymers may be allowed to translocate with respect to the nanopores 25 A, 25B, for example under a potential difference or chemical gradient. The electrical signal may be derived during the translocation of the polymer with respect to the pores, for example taken during translocation of the polymer through the nanopores 25 A, 25B. The polymer may partially translocate with respect to the nanopores 25 A, 25B.

[0077] Translocation of the polymer through the nanopores 25A, 25B may occur, either cis to trans or trans to cis, either with or against an applied potential. The translocation may occur under an applied potential which may control the translocation.

[0078] Figure 2 shows an expanded cross-section of a portion of the nanopore array device 1 shown in Figure 1. The substrate 7 comprises a via 8, which provides an electrical connection between the nanopore sensor element 15A and the ASIC 5. The via 8 extends through the substrate 7 between the sensor electrode 23 A and the underside of the substrate 7. The via 8 is located within a respective hole 30 within the substrate 7 and comprises a copper barrel 32 that is filled with an adhesive 34. The copper barrel 32 lines the respective hole 30 and electrically connects the nanopore sensor element 15A to the ASIC 5. The adhesive 34 may aid in the retention of the copper barrel 32 within the hole 30. In this example, the via 8 connects directly to the ASIC 5, and the ASIC 5 has a pattern of contacts (not shown) which align with a corresponding pattern of contacts (not shown) on the underside of the sensor device 3.

[0079] Figure 3 shows an alternative example of a nanopore array device 1, which includes an electrical interposer 36. The electrical interposer 36 may be located between the substrate 7 and the ASIC 5 and used to route electrical signals from the contacts on the ASIC 5 to the contacts on the sensor device 3. The electrical interposer 36 may be a printed circuit board (PCB). The substrate 7 also comprises a via (not shown) for electrically connecting the common electrode 31 to the ASIC 5. The sensor device 3 and the detection circuit 11 will now be described in more detail by way of reference to Figure 4.

[0080] In this example, the sensor device 3 includes four sensor elements, 15 A, 15B, 15C and 15D. Each sensor element includes a respective sensor electrode 23A, 23B, 23C, 23D. The detection circuit 11 has multiple detection channels 37A, 37B, a switching arrangement 39, a data processor 41, and a bias control circuit 43. The switching arrangement 39 is electrically coupled to the sensor electrodes 23 A, 23B, 23C, 23D of each nanopore sensor element 15 A, 15B, 15C, 15D. A function of the detection circuit 11 is to process the electrical signals output from the nanopore sensor elements 15 A, 15B, 15C, 15D. The detection circuit 11 also has the function of controlling the application of bias signals to each nanopore sensor element 15 A, 15B, 15C, 15D.

[0081] The detection circuit 11 is a low power circuit. The maximum power rating of the detection circuit will depend on a number of factors, including at least the maximum power rating of each detection channel and the total number of channels. In one example, the maximum power rating of each channel is 0.2mW. For a detection circuit having 3000 channels, the maximum power rating will be 0.6W. A detection circuit having 500 channels and a maximum power rating of 0.1W is also envisaged. In a further example, each channel may have a maximum power rating of 0.165mW. In use, the detection circuit consumers power in the range of 0.08W to 0.8W.

[0082] Other peripheral circuits may be provided in the nanopore array device, such as control and monitoring circuits, which also consume power and may provide a degree of heating. However, most or all of the power consumption of the device is a result of the detection circuit. The greater the number of channels, the greater the power consumption. By utilising a low power detection circuit, a significant impact is made on the power consumption of the nanopore array device, and on the heating capacity of the device.

[0083] Each detection channel 37 A, 37B receives an electrical signal from a single one of the sensor electrodes 23A, 23B, 23C, 23D and is arranged to amplify that electrical signal. The detection channels 37A, 37B are therefore designed to amplify very small currents with sufficient resolution to detect the characteristic changes caused by the interactions of interest. The detection channels 37A, 37B are also designed with a sufficiently high bandwidth to provide the time resolution needed to detect each such interaction. These constraints require sensitive and therefore expensive components. Each detection channel 37 A, 37B may be similar to standard single channel recording equipment as describe in Stoddart D et al., Proc Natl Acad Sci, 12;106(19):7702-7, Lieberman KR et al, J Am Chem Soc. 2010;132(50): 17961-72, and WO-2000 / 28312. Alternatively, each detection channel 37A, 37B may be arranged as described in detail in WO 2010 / 122293, WO 2011 / 067559 or WO 2016 / 181118.

[0084] The number of nanopore sensor elements in the array of nanopore sensor elements 9 is greater than the number of detection channels 37A, 37B. The nanopore array device 1 is operable to take measurements of a polymer from the nanopore sensor elements 15 A, 15B, 15C, 15D selected in a multiplexed manner. For example, electrical multiplexing may be used. This is achieved by providing the switch arrangement 39 between the sensor electrodes 23 A, 23B, 23C, 23D of the nanopore sensor elements 15A, 15B, 15C, 15D and the detection channels 37A, 37B. For clarity, Figure 4 shows a simplified example with four nanopore sensor elements 15 A, 15B, 15C, 15D and two detection channels 37A, 37B, but the number of elements and channels is typically much greater. For example, for some applications, the sensor device 3 might comprise a total of 4396 nanopore sensor elements and 1024 detection channels. The switch arrangement 39 may be arranged as described in detail in WO 2010 / 122293. For example, the switch arrangement 39 may comprise plural 1-to-N multiplexers each connected from a detection channel 37A, 37B to a group of N nanopore sensor elements 15 A, 15B, 15C, 15D and may include appropriate hardware such as a latch to select the state of the switches. By switching the switch arrangement 39, the nanopore array device 1 may be operated to amplify electrical signals from nanopore sensor elements 15 A, 15B, 15C, 15D selected in an electrically multiplexed manner.

[0085] The data processor 41 receives the output signals from the detection channels 37A, 37B. The data processor 41 acts as a controller that controls the switch arrangement 39 to connect detection channels 37A, 37B to respective nanopore sensor elements 15 A, 15B, 15C, 15D.

[0086] The bias control circuit 43 performs the function of controlling the application of bias signals to each sensor element 15 A, 15B, 15C, 15D. The bias control circuit 43 is connected to the common electrode 31 and to the sensor electrodes 23 A, 23B, 23C, 23D of each nanopore sensor element 15 A, 15B, 15C, 15D. The bias signals are selected to bias the sensor electrodes 23 A, 23B, 23C, 23D with respect to common electrode 31 to control translocation of the molecular entities with respect to the nanopores 25 A, 25B. In general, it would be possible for a bias signal supplied to a given sensor element 15 A, 15B, 15C, 15D to be a drive bias signal that causes translocation to occur at the sensor element 15 A, 15B, 15C, 15D or an inhibition bias signal that inhibits translocation to occur at the sensor element 15 A, 15B, 15C, 15D. The bias control circuit 43 is controlled by the data processor 41.

[0087] The data processor 41 is connected to the output of the detection channels 37A, 37B and is supplied with the amplified electrical signals therefrom. The data processor 41 stores and analyses the amplified electrical signals. The data processor 41 also controls the other elements of the detection circuit 11, including control of the bias voltage circuit 43 and control of the switch arrangement 39.

[0088] During operation, the data processor 41 is connected to an analysis system 45. The data processor 41 supplies the amplified output signals to the analysis system 45. The analysis system 45 performs further analysis of the amplified electrical signal which is a raw signal representing measurements of the property measured at the sensor device 3. Such an analysis system 45 may for example estimate the identity of the molecular entity in its entirety or in the case that the molecular entity is a polymer may estimate the identity of the polymer units thereof. Thus, the analysis system may be configured as a computer apparatus running an appropriate program. Such a computer apparatus may be connected to the data processor 41 of the nanopore array device 1 directly or via a network, for example within a cloud-based system.

[0089] The temperature control system 13 will now be described in relation to Figures 5 and 6. The temperature control system 13 comprises an array of resistive heaters 47 and a temperature control circuit 49. The temperature control circuit 49 is electrically coupled to the array of resistive heaters 47 and is configured to control the array of resistive heaters 47 to control the temperature of the nanopore array device 1. The array of resistive heaters 47 is coupled between a pair of power rails 51, which supply power to the array of resistive heaters 47. The temperature control system 13 also includes temperature sensors 53 A, 53B and an alert device 55. In this example, the components of the temperature control system 13 are all formed within the ASIC 5. In an alternative example, some or all of the temperature control system 13 may be formed from discrete components, separately from the ASIC 5.

[0090] The array of resistive heaters 47 may include any number of resistive heaters 57A, 57B. In this example, the array of resistive heaters 47 includes a number of resistive heaters that is equal to the number of nanopore sensor elements 15 A, 15B, 15C, 15D in the array of nanopore sensor elements 9. Therefore, the array of resistive heaters 47 has a resistive heater 57A, 57B for each nanopore sensor element 15 A, 15B, 15C, 15D of the array of nanopore sensor elements 13. As shown in Figure 6, each of the resistive heaters 57A, 57B is disposed vertically beneath a corresponding nanopore sensor element 15 A, 15B.

[0091] Each of the resistive heaters 57A, 57B is a transistor and is coupled between the power rails 51. Alternatively, the resistive heaters 57A, 57B may be resistors formed in series with a controllable switch. The resistive heaters 57A, 57B are located adjacent or in close proximity to the detection circuit 11. In an alternative example, the resistive heaters 57A, 57B may be embedded in the substrate 7. Each resistive heater 57A, 57B may be positioned in close proximity to a respective nanopore sensor element. In one example, each nanopore sensor element of the array of elements may include a respective resistive heater element, embedded in the substrate adjacent to or in close proximity to the respective sensor element. Electrical connections may then be made with the control circuitry formed in the ASIC 5.

[0092] The two temperature sensors 53 A, 53B are each in contact with or in close proximity to the substrate 7. They are each thermally connected to the sensor device 3 and electrically connected to the temperature control circuit 49. Each of the temperature sensors 53A, 53B is configured to generate a temperature output signal for the temperature control circuit 49. The temperature output signals are indicative of the temperature of the sensor device 3.

[0093] The temperature control circuit 49 is electrically coupled to the temperature sensors 53A, 53B, the alert device 5, and the array of resistive heaters 47. The temperature control circuit 49 receives the temperature output signals from the temperature sensors 53A, 53B and is configured to control the array of resistive heaters 47 based on the temperature output signals. The alert device 55 is electrically coupled to the temperature control circuit 49. The alert device 55 comprises an LED. Multiple different alert devices are also envisaged, such as a display screen and an audio signal generator, such as a buzzer.

[0094] The performance of the sensor device 3 may be sensitive to its operating temperature. This may require the temperature of the sensor device 3 to be maintained within a desired operating temperature range to achieve a desired performance. For example, the chemical and biological processes that occur when the nanopore array device 1 is conducting an assay, such as translation of DNA through a nanopore channel 29A, 29B, may slow down or stop outside of the operating temperature range.

[0095] As shown in Figure 7, during operation, the detection circuit 11 generates heat 59 as a byproduct of processing the signals generated by the nanopore sensor elements 15 A, 15B. In this example, the substrate 7 is formed from glass and has a thermal conductivity of 1 W / m.K. The substrate 7 may be formed from other materials having a thermal conductivity of no less than lOOmW / m.K.

[0096] The heat 59 generated by the detection circuit 11 is conducted through the substrate 11 and the vias 71 and heats the sensor device 3. Additionally, some heat 61 is conducted away from the sensor device 3 into the liquid contained in the sample chamber 27, which cools the sensor device 3. The sample chamber 27 has a volume of 25pL, which may enable the liquid in the sample chamber 27 to act as a heat sink. The sample chamber 27 having a volume of no less than lOpL is also envisaged.

[0097] There is a maximum heating power that the detection circuit 11 can provide to the sensor device 3. The detection circuit 11 has a maximum heating power, which is the maximum amount of heat 59 generated by the detection circuit 11. The maximum heating power will depend on the maximum power rating of the detection circuit 11 (which is discussed above). The maximum heating power will generally be less than the maximum power rating, because not all of the power consumed by the detection circuit will be converted into heat. As described above, the maximum heating power will depend on the power rating of the individual detection channels, and the number of channels. The nanopore array device 1 has a mass of 200g when empty (i.e., without any liquids inserted) and is predominantly formed from cyclic olefin copolymer (COC) (i.e., greater than 50% of a mass of the nanopore array device). As a result, the nanopore array device 1 has a total heat capacity, when empty, of 220J / k. The maximum heating power of the detection circuit 11 is such that the ratio of the maximum heating power to the total heat capacity of the nanopore array device 1 is no greater than 300pK / s. The maximum heating power is lower than the power rating of the detection circuit, as not all of the power consumed by the detection circuit is converted to heat. Therefore, if the ambient environment in which the nanopore array device 1 is operating is too cold, the heat 59 generated by the detection circuit 11 may either be insufficient to heat the sensor device 3 up to above a predetermined minimum temperature or may take an unacceptably long time to do so. This problem may be addressed by the operation of the array of resistive heaters 47, as will now be described in connection with Figure 8.

[0098] When the nanopore array device 1 is first switched on, the temperature control system 13 is also switched on (step 200). The temperature control circuit 49 monitors the outputs of the temperature sensors 53A, 53B to determine whether the sensor device 3 is above or below the predetermined minimum temperature (step 202). In this example, the predetermined minimum temperature is 37°C. In most circumstances, because the nanopore array device 1 will be at room temperature (for example 21 °C), and because the detection circuit 11 will not have been operational (or not operational for long), at switch-on, the sensor device 3 will be below the predetermined minimum temperature.

[0099] In response to receiving the temperature output signals from the two temperature sensors 53A, 53B which indicate that the temperature of the sensor device 3 is below the predetermined minimum temperature, the temperature control circuit 49 activates the array of resistive heaters 47 (step 204). The heat 63 generated by the array of resistive heaters 47 is conducted through the substrate 7 and the vias 8 to the array of nanopore sensor elements 9, which increases the temperature of the sensor device 3. As shown in Figure 7, the heat 63 provided by the array of resistive heaters 47 is supplemental to (i.e., in addition to) the heat 59 provided by the detection circuit 11 (step 206).

[0100] In the alternative, if the sensor device 3 is already above the predetermined minimum temperature at step 202, the temperature control circuit 49 does not switch on the array of resistive heaters 47 (step 208). The temperature control circuit 49 then continues to monitor the temperature of the sensor device 3 (step 202). This may occur if the nanopore array device is located in an environment where the ambient temperature is already above 37°C. Following step 206, the temperature control circuit 49 continues to monitor the outputs of the temperature sensors 53 A, 53B to determine whether the sensor device 3 goes above the predetermined minimum temperature (step 210). In response to the temperature of the sensor device 3 increasing above the predetermined minimum temperature, the temperature control circuit 49 sends a temperature reached signal to the alert device 55 (step 212). The alert device 55 responds by illuminating the LED to provide an alert to the user that the sensor device 3 has reached its predetermined minimum temperature and is thereby ready for use (step 214). In other examples, the temperature control circuit 49 sends the temperature reached signal to the analysis system 45, which in turn displays an alert to the user.

[0101] The temperature control circuit 49 continues to monitor the outputs of the temperature sensors 53A, 53B to determine whether the sensor device 3 reaches the predetermined maximum temperature (step 216). In this example, the predetermined maximum temperature is 38°C. In response to the temperature of the sensor device 3 increasing to greater than the predetermined maximum temperature, the temperature control circuit 49 deactivates the array of resistive heaters 47 (step 218). This cycle of activation and deactivation is repeated to maintain the temperature of the sensor device 3 between the predetermined maximum temperature and predetermined minimum temperature. The use of other control schemes which maintain the temperature of the sensor device 3 above the predetermined minimum temperature and below the predetermined maximum temperature is also envisaged. For example, proportional-integral-derivative control could be used to maintain the temperature of the sensor device 3 at a predetermined target temperature which is between the predetermined minimum temperature and the predetermined maximum temperature.

[0102] The predetermined maximum temperature and the predetermined minimum temperature are specified based on the desired operating temperature range of the nanopore array device 1. This is influenced by characteristics of the chemical and biological processes that occur when the nanopore array device 1 is conducting an assay. In this example, the predetermined minimum temperature is 37°C, and the predetermined maximum temperature is 38°C. The predetermined minimum temperature being no less than 36°C and / or no greater than 39°C is also envisaged.

[0103] Figure 9 shows a flow chart which details an alternative method 300. Firstly, heat is generated (step 301) from the detection circuit 11 of the nanopore array device 1 to heat a sensor device 3 of the nanopore array device 1. Secondly, heat, which is supplemental to the heat generated by the detection circuit, is generated (step 303) by the resistive heaters 57A, 57B to heat the sensor device 3. Thirdly, the resistive heaters 57A, 57B are controlled (step 305) to maintain a temperature of the sensor device above a predetermined minimum temperature.

[0104] The temperature of the sensor device 3 is determined by three primary heat sources. These are a) the ambient temperature of the environment in which the nanopore array device 1 is disposed; b) the heat generated by the detection circuit 11; and c) the heat generated by the array of resistive heaters 47. The ambient temperature and the heat generated by the detection circuit are not generally controllable. However, a user may choose to place the nanopore array device 1 in a location with a particular temperature. Additionally, although not described above, the detection circuit 11 may be controllable to operate in different modes which consume different amounts of power. Therefore, the detection circuit 11 may generate different levels of heat. In contrast to the ambient temperate and the heat generated by the detection circuit 11, the heat generated by array of resistive heaters 47 is controllable.

[0105] The manner in which the array of resistive heaters 47 is controlled by the temperate control circuit 49 will depend upon the ambient temperature and the heat generated by the detection circuit 11. For example, when the nanopore array device 1 is first turned on, the detection circuit 11 will not be generating much heat. If the ambient temperature around the nanopore array device 1 is room temperature (for example 21 °C), then the temperature control system 13 may be required to keep the array of resistive heaters 47 on for a long period, until the sensor device 3 achieves operational temperature. In contrast, once the detection circuit 11 is fully operational, and / or if the nanopore array device 1 is in a hotter environment, the temperature control system 13 may be required to keep the array of resistive heaters 47 on for a shorter period, or they may not be used at all.

[0106] In the above example, the ASIC 5 comprises the temperature control system 13. However, other examples are envisaged in which the temperature control system 13 is provided separately to the ASIC 5. For example, the resistive heaters 57A, 57B and temperature control circuit 49 could be provided in a separate ASIC to the ASIC 5 which has the detection circuit 11. In further examples, the components of the ASIC 5, such as the resistive heaters 57A, 57B, could be provided in their own packing and located separately to the ASIC 5, such as on the opposite side of the substate 7 to the ASIC 5. In this respect, the temperature control system 13 may be a retrofit device. The temperature control system 13 could be configured to be attached to a legacy nanopore array device that did not originally include temperature control. In the above examples, the temperature control system 13 is described as having binary operation. That is, it is either off, and not heating, or on, and heating. In an alternative example, the temperature control system 13 may be able to control the heating power of the array of resistive heaters 47. For example, the heating power may be set based on the amount of temperature increase required to achieve the operating temperature. Whilst particular examples have been described, it should be understood that these are illustrative examples only and that various modifications may be made without departing from the scope of the invention as defined by the claims.

Claims

CLAIMS1. A nanopore array device comprising: a sensor comprising an array of nanopore sensor elements configured to generate signals which are indicative of interactions between molecular entities and respective nanopores supported by each nanopore sensor element of the array of nanopore sensor elements; a detection circuit configured to process the signals generated by the sensor, and to generate heat which heats the sensor; one or more resistive heaters configured to generate heat which heat the sensor; and a temperature control circuit configured to control the one or more resistive heaters to maintain a temperature of the sensor above a predetermined minimum temperature.

2. A nanopore array device as claimed in claim 1, wherein the heat generated by the one or more resistive heaters which heats the sensor is supplemental to the heat which heats the sensor generated by the detection circuit.

3. A nanopore array device as claimed in any one of claims 1 or 2, wherein the detection circuit is a low power detection circuit.

4. A nanopore array device as claimed in any one of the preceding claims, wherein: the nanopore array device comprises an integrated circuit; and the integrated circuit comprises the detection circuit.

5. A nanopore array device as claimed in claim 4, wherein the integrated circuit comprises the one or more resistive heaters.

6. A nanopore array device as claimed in claim 5, wherein: the integrated circuit is physically coupled to the sensor.

7. A nanopore array device as claimed in claim 6, wherein: the nanopore array device comprises a substrate;the integrated circuit is physically coupled to a first side of the substrate; the array of nanopore sensor elements is located on a second side of the substrate, which is opposite to the first side; and the substrate has a thermal conductivity of no less than lOOmW / m.K.

8. A nanopore array device as claimed in any one of claims 4 to 7, wherein: the integrated circuit comprises a temperature sensor configured to provide an output signal which is indicative of the temperature of the sensor; and the temperature control circuit is configured: to process the output signal, and to control the one or more resistive heaters based on the output signal.

9. A nanopore array device as claimed in any one of claims 4 to 8, wherein the integrated circuit comprises the temperature control circuit.

10. A nanopore array device as claimed in any one of the preceding claims, wherein the one or more resistive heaters are co-located with the detection circuit.

11. A nanopore array device as claimed in any one of the preceding claims, wherein the one or more resistive heaters comprises a plurality of resistive heaters.

12. A nanopore array device as claimed in claim 14, wherein each resistive heater of the plurality of resistive heaters corresponds to one nanopore sensor element of the array of nanopore sensor elements.

13. A nanopore array device as claimed in any one of the preceding claims, wherein the predetermined minimum temperature is no less than 36°C.

14. A nanopore array device as claimed in any one of the preceding claims, wherein the temperature control circuit is configured to control the one or more resistive heaters such that the one or more resistive heaters are deactivated when the temperature of the sensor is above a predetermined maximum temperature.

15. A nanopore array device as claimed in claim 14, wherein the predetermined maximum temperature is no greater than 39°C.

16. A nanopore array device as claimed in any one of the preceding claims, wherein the one or more resistive heaters comprises one or more transistors.

17. A nanopore array device as claimed in any one of the preceding claims, wherein: the nanopore array device comprises an alert device; the temperature control circuit is configured to send a temperature reached signal to the alert device in response to the temperature of the nanopore array device reaching the predetermined minimum temperature; and the alert device is configured to provide an alert to a user of the nanopore array device in response to receiving the temperature reached signal.

18. A nanopore array device as claimed in any one of the preceding claims, wherein a ratio of a maximum heating power of the detection circuit to a total heat capacity of the nanopore array device is no greater than 300pK / s.

19. A nanopore array device according to any one of the preceding claims, wherein the sensor further comprises a well support structure, and the array of nanopore sensor elements comprise an array of wells formed in the well support structure.

20. A nanopore array device according to claim 19, further comprising a substrate, wherein the well support structure is disposed on or adjacent the substrate; and wherein the sensor further comprises an array of sensor electrodes, each electrode being disposed on the substrate at a base of a respective well.

21. A nanopore array device according to claims 19 or 20, wherein each well of the array of wells is configured to support a membrane and each membrane is configured to have a nanopore inserted therein.

22. A nanopore array device according to claims 21, wherein the signals generated by the array of nanopore sensor elements are generated by the molecular entities translocating through the nanopores.

23. A nanopore array device according to any one of claims 19 to 22, wherein each well has a diameter of 200pm or less, and a depth of 200pm or less.

24. A nanopore array device according to any one of the preceding claims, wherein the array of nanopore sensor elements comprises at least 400 nanopore sensor elements.

25. A method comprising: generating heat from a detection circuit of a nanopore array device to heat a sensor of the nanopore array device; generating heat, which is supplemental to the heat generated by the detection circuit, from one or more resistive heaters to heat the sensor; and controlling the one or more resistive heaters to maintain a temperature of the sensor above a predetermined minimum temperature.

26. A method according to claim 25, further comprising: monitoring the temperature of the sensor, and when the temperature decreases below the predetermined minimum temperature, switching at least one of the one or more resistive heaters on.

27. A method according to claims 25 or 26, further comprising: monitoring the temperature of the sensor, and when the temperature increases above a predetermined maximum temperature, switching the one or more resistive heaters off.

28. A method according to any of claims 25 to 27, further comprising: alerting a user via a user alert interface when the temperature of the sensor is within a predetermined operating range.

29. An integrated circuit for use as part of a nanopore array device, the integrated circuit comprising: a detection circuit configured to process signals generated by a sensor of a nanopore array device, and to generate heat which heats the sensor; and a temperature control circuit configured to control one or more resistive heaters to maintain a temperature of the sensor above a predetermined minimum temperature.

30. A nanopore array device, comprising: a sensor comprising an array of nanopore sensor elements configured to generate signals indicative of interactions between molecular entities and respective nanopores supported by each nanopore sensor element of the array of nanopore sensor elements; and a detection circuit for processing the signals generated by the sensor, and to generate heat which heats the sensor, wherein a ratio of a maximum heating power of the detection circuit to a total heat capacity of the nanopore array device is no greater than 300pK / s.

31. A method of operation of the nanopore array device of any of claims 1 to 24, comprising: monitoring the temperature of the sensor of the nanopore array device, using the temperature control circuit; turning on at least one of the one or more resistive heaters, if the temperature decreases below the predetermined minimum temperature; and turning off the one or more resistive heaters, if the temperature increases above a predetermined maximum temperature.

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