High density ion-programmable non-volatile transducer biosensor

Abstract

An apparatus includes a channel, a plurality of reaction sites, and a sensor assembly. The sensor assembly includes at least one gate electrode, one or more source electrodes, one or more drain electrodes, and a plurality of sensing channels. Each source electrode is positioned adjacent to a corresponding reaction site of the plurality of reaction sites. Each drain electrode is positioned adjacent to a corresponding reaction site of the plurality of reaction sites. Each sensing channel of the plurality of sensing channels extends from a corresponding source electrode of the one or more source electrodes to a corresponding drain electrode of the one or more drain electrodes. Each sensing channel is positioned to receive an ion emitted from a corresponding reaction site of the plurality of reaction sites as a voltage is applied to the at least one gate electrode during a sequencing by synthesis process.

Description

HIGH DENSITY ION-PROGRAMMABLE NON-VOLATILE TRANSDUCER BIOSENSORBACKGROUND

[0001] Aspects of the present disclosure relate generally to devices, systems, and methods providing biological or chemical analysis. Various protocols in biological or chemical research involve performing a large number of controlled reactions on local support surfaces or within predefined reaction chambers. The designated reactions may then be observed or detected, and subsequent analysis may help identify or reveal properties of chemicals involved in the reaction. For example, in some multiplex assays, an unknown analyte having an identifiable label (e.g., fluorescent label) may be exposed to thousands of known probes under controlled conditions. Each known probe may be deposited into a corresponding well of a flow cell channel. Observing any chemical reactions that occur between the known probes and the unknown analyte within the wells may help identify or reveal properties of the analyte. Other examples of such protocols include known DNA sequencing processes, such as sequencing-by-synthesis (SBS) or cyclic- array sequencing.

[0002] While a variety of devices, systems, and methods have been made and used to perform biological or chemical analysis, it is believed that no one prior to the inventor(s) has made or used the devices and techniques described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0003] FIG. 1 depicts a schematic view of an example of a system that may be used to provide biological or chemical analysis.

[0004] FIG. 2 depicts a schematic view of an example of a set of components that may cooperate to provide a fluid path in the system of FIG. 1.

[0005] FIG. 3 depicts a schematic view of another example of a system that may be used to provide biological or chemical analysis.

[0006] FIG. 4 depicts a cross-sectional view of an example of a flow cell that may be used in the system of FIG. 1.

[0007] FIG. 5 depicts a cross-sectional view of another example of a flow' cell that may be used in the system of FIG. 1.

[0008] FIG. 6 depicts a top plan view of the flow cell of FIG. 5, with an upper w afer omitted to reveal a low er wafer.

[0009] FIG. 7A depicts a schematic cross-sectional view' of an example of an electrochemicaltransistor in a writing stage of operation.

[0010] FIG. 7B depicts a schematic cross-sectional view of the electrochemical transistor of FIG. 7 A in a reading stage of operation.

[0011] FIG. 7C depicts a schematic cross-sectional view of the electrochemical transistor of FIG. 7A in an erasing stage of operation.

[0012] FIG. 8 depicts set of graphs showing examples of write / erase and read waveforms that may be used to operate the electrochemical transistor of FIG. 7A.

[0013] FIG. 9 depicts a set of graphs showing examples of a sequence of write, read, and erase pulses that may be used during operation of the electrochemical transistor of FIG. 7 A.

[0014] FIG. 10 depicts a schematic top view of an example of a unit memory cell in a resistive random-access memory (RRAM) array that may be used in combination with the electrochemical transistor of FIG. 7 A.

[0015] FIG. 11 depicts a schematic cross-sectional view of an example of a single electrochemical transistor that may be integrated into a flow cell used in a variation of the system of FIG. 1, with a first gate configuration.

[0016] FIG. 12 depicts a schematic cross-sectional view of another example of a single electrochemical transistor that may be integrated into a flow cell used in a variation of the system of FIG. 1, with a second gate configuration.

[0017] FIG. 13 depicts a schematic cross-sectional view of another example of a single electrochemical transistor that may be integrated into a flow cell used in a variation of the system of FIG. 1, with a third gate configuration.

[0018] FIG. 14 depicts a schematic cross-sectional view of a portion of an example of a flow cell that may be used in a vanation of the system of FIG. 1, with an array of wells and respective electrochemical transistors.

[0019] FIG. 15 depicts a schematic cross-sectional view of a portion of another example of a flow cell that may be used in a variation of the system of FIG. 1, with an array of wells and respective electrochemical transistors.

[0020] FIG. 16A depicts a schematic cross-sectional view of the portion of the flow cell of FIG. 15 during a first stage of an example of a manufacturing process.

[0021] FIG. 16B depicts a schematic cross-sectional view of the portion of the flow cell of FIG. 15 during a second stage of an example of a manufacturing process.

[0022] FIG. 16C depicts a schematic cross-sectional view of the portion of the flow cell of FIG. 15 during a third stage of an example of a manufacturing process.

[0023] FIG. 16D depicts a schematic cross-sectional view of the portion of the flow cell of FIG. 15 during a fourth stage of an example of a manufacturing process.

[0024] FIG. 16E depicts a schematic cross-sectional view of the portion of the flow cell of FIG. 15 during a fifth stage of an example of a manufacturing process.

[0025] FIG. 16F depicts a schematic cross-sectional view of the portion of the flow cell of FIG. 15 during a sixth stage of an example of a manufacturing process.

[0026] FIG. 16G depicts a schematic cross-sectional view of the portion of the flow cell of FIG. 15 during a seventh stage of an example of a manufacturing process.

[0027] FIG. 16H depicts a schematic cross-sectional view of the portion of the flow cell of FIG. 15 during an eighth stage of an example of a manufacturing process.

[0028] FIG. 17A depicts a schematic top view of a portion of the flow cell of FIG. 15 during the first stage of FIG. 16A.

[0029] FIG. 17B depicts a schematic top view of a portion of the flow cell of FIG. 15 during the third stage of FIG. 16C.

[0030] FIG. 18 depicts a schematic cross-sectional view of a portion of another example of a flow cell that may be used in a variation of the system of FIG. 1, with an array of wells and respective electrochemical transistors.

[0031] FIG. 19 depicts a schematic exploded view of an example of a tile that may be incorporated into a flow cell that may be used in a variation of the system of FIG. 1.

[0032] FIG. 20 depicts a schematic top view of an example of an arrangement incorporating four of the tiles of FIG. 19, with additional components.

[0033] FIG. 21 depicts a perspective view of another example of a chip assembly that may be incorporated into a flow cell that may be used in a variation of the system of FIG. 1.

[0034] FIG. 22 depicts a schematic cross-sectional view of a portion of an example of a flow cell that may be used in a variation of the system of FIG 1, with the flow cell incorporating the chip assembly of FIG. 21.

[0035] FIG. 23 depicts a schematic cross-sectional view of a portion of another example of a flow cell that may be used in a variation of the system of FIG 1, with the flow cell incorporating the chip assembly of FIG. 21.

[0036] FIG. 24 depicts a set of graphs showing examples of write / erase and read waveforms that may be provided during a nucleotide flush cycle in the event of nucleotide incorporation.

[0037] FIG. 25 depicts a set of graphs showing examples of write / erase and read waveforms that may be provided during a nucleotide flush cycle in the absence of nucleotide incorporation.DETAILED DESCRIPTION

[0038] The following detailed description of certain examples will be better understood when read in conjunction with the appended drawings. To the extent that the figures illustrate diagramsof the functional blocks of various examples, the functional blocks are not necessarily indicative of the division between hardware components. Thus, for example, one or more of the functional blocks (e.g., processors or memories) may be implemented in a single piece of hardware (e.g., a general purpose signal processor or random access memory, hard disk, or the like). Similarly, the programs may be stand-alone programs, may be incorporated as subroutines in an operating system, may be functions in an installed software package, and the like. It should be understood that the various examples are not limited to the arrangements and instrumentality shown in the drawings. It should be appreciated that all combinations of the foregoing aspects and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter and to achieve the benefits and advantages disclosed herein.

[0039] I. Overview of Sy stem for Biological or Chemical Analy sis

[0040] Examples described herein may be used in various biological or chemical processes and systems for academic analysis, commercial analysis, or other analysis. More specifically, examples described herein may be used in various processes and systems where it is desired to detect an event, property, quality, or characteristic that is indicative of a designated reaction. Bioassay systems such as those described herein may be configured to perform a plurality of designated reactions that may be detected individually or collectively. For example, bioassay systems may be used to sequence a dense array of nucleic acid features through iterative cycles of enzymatic manipulation and image acquisition. In some examples, nucleic acids can be attached to a surface and amplified. Examples of such amplification are described in U.S. Pat. No. 7,741,463, entitled “Method of Preparing Libraries of Template Polynucleotides,” issued June 22, 2010, the disclosure of which is incorporated by reference herein, in its entirety; and / or U.S. Pat. No. 7,270,981, entitled “Recombinase Polymerase Amplification,” issued September 18, 2007, the disclosure of which is incorporated by reference herein, in its entirety.

[0041] Components that are used in the bioassay systems may include one or more microfluidic channels that deliver reagents or other reaction components to a reaction site. The reaction sites may be randomly distributed across a substantially planar surface; or may be patterned across a substantially planar surface. Each of the reaction sites may be imaged to detect light from the reaction site. The signals indicating photons emitted from the reaction sites and detected by image sensors may provide illumination values. These illumination values may be combined into an image indicating photons as detected from the reaction sites. These images may be further analyzed to identity7compositions, reactions, conditions, etc., at each reaction site.

[0042] II. Examples of Fluidics Devices and Fluid Flow Paths

[0043] A. Example of System with Higher Volume Throughput

[0044] FIG. 1 illustrates a schematic diagram of an example of a system (100) that may be used to perform an analysis on one or more samples of interest. In some implementations, the sample may include one or more clusters of nucleotides (e.g., DNA) that are linearized to form a single stranded DNA (sstDNA). In the implementation shown, system (100) is configured to receive a flow cell cartridge assembly (102) including a flow cell assembly (103) and a sample cartridge (104). System (100) includes a flow cell receptacle (122) that receives flow cell cartridge assembly (102), a vacuum chuck (124) that supports flow cell assembly (103), and a flow cell interface (126) that is used to establish a fluidic coupling between system (100) and flow cell assembly (103). Flow cell interface (126) may include one or more manifolds. System (100) further includes a sipper manifold assembly (106), a sample loading manifold assembly (108), and a pump manifold assembly (110). System (100) also includes a drive assembly (112), a controller (114), an imaging system (116), and a waste reservoir (118). Controller (114) is electrically and / or communicatively coupled to drive assembly (112) and to imaging system (116); and is configured to cause drive assembly (112) and / or the imaging system (116) to perform various functions as disclosed herein.

[0045] In the present example, flow cell assembly (103) includes a flow cell (128) having a channel (130) and defining a plurality of first openings (132), which are fluidically coupled to the channel (130) and arranged on a first side (134) of the channel (130). Flow cell (128) further includes a plurality of second openings (136) fluidically coupled to the channel (130) and arranged on a second side (138) of the channel (130). Fluid may thus flow through flow cell (128) via channel. While the flow cell (128) is shown including one channel (130), flow cell (128) may include two or more channels (130). Flow cell assembly (103) also includes a flow cell manifold assembly (140) coupled to flow cell (128) and having a first manifold fluidic line (142) and a second manifold fluidic line (144). Flow cell manifold assembly (140) may be in the form of a laminate including a plurality of layers as discussed in more detail below.

[0046] In the implementation shown, first manifold fluidic line (142) has a first fluidic line opening (146) and is fluidically coupled to each of the first openings (132) of flow cell (128); and second manifold fluidic line (144) has a second fluidic line opening (148) and is fluidically coupled to each of the second openings (136). As shown, flow cell assembly (103) includes gaskets (150) coupled to flow cell manifold assembly (140) and fluidically coupled to fluidic line openings (146, 148). In some implementations where flow cell (128) includes a plurality of channels (130), flow cell manifold assembly (140) may include additional fluidic lines (152) that couple first fluidic line openings (146) to a single manifold port (154). In such implementations, a single gasket (150) may be coupled to flow cell manifold assembly (140) that surrounds the manifold port (154) and is in fluidic communication with a plurality of channels (130). Inoperation, flow cell interface (126) engages with corresponding gaskets (150) to establish a fluidic coupling between system (100) and flow cell (128). The engagement between flow cell interface (126) and gaskets (150) reduces or eliminates fluid leakage between flow cell interface (126) and flow cell (128).

[0047] In the implementation shown, first manifold fluidic line (142) has a portion (156) that is substantially parallel to a longitudinal axis (158) of channel (130); and second manifold fluidic line (144) has a portion (160) that is substantially parallel to longitudinal axis (158) of channel (130). Additionally, first manifold fluidic line (142) is shown being at least partially adjacent a first end (162) of flow cell (128) and spaced from a second end (164) of flow cell (128); and second manifold fluidic line (144) is shown being at least partially adjacent second end (164) of flow cell (128) and spaced from first end (162). Other arrangements of manifold fluidic lines (142, 144) may prove suitable, however.

[0048] In the implementation shown, system (100) includes a sample cartridge receptacle (166) that receives sample cartridge (104) that carries one or more samples of interest (e.g., an analyte). System (100) also includes a sample cartridge interface (168) that establishes a fluidic connection with sample cartridge (104). Sample loading manifold assembly (108) includes one or more sample valves (170). Pump manifold assembly (110) includes one or more pumps (172), one or more pump valves (174), and a cache (176). Valves (170, 174) and pumps (172) may take any suitable form. Cache (176) may include a serpentine cache and may temporarily store one or more reaction components during, for example, bypass manipulations of the system (100). While cache (176) is shown being included in pump manifold assembly (110), cache (176) may alternatively be located elsewhere (e.g., in sipper manifold assembly (106) or in another manifold downstream of a bypass fluidic line (178), etc.).

[0049] Sample loading manifold assembly (108) and pump manifold assembly (110) flow" one or more samples of interest from sample cartridge (104) through a fluidic line (180) toward flow' cell cartridge assembly (102). In some implementations, sample loading manifold assembly (108) may individually load or address each channel (130) of flow cell (128) with a respective sample of interest. The process of loading channel (130) with a sample of interest may occur automatically using system (100). As shown in FIG. 1, sample cartridge (104) and sample loading manifold assembly (108) are positioned downstream of flow cell cartridge assembly (102). In the implementation shown, sample loading manifold assembly (108) is coupled between flow cell cartridge assembly (102) and pump manifold assembly (110). To draw a sample of interest from sample cartridge (104) and toward pump manifold assembly (110), sample valves (170), pump valves (174), and / or pumps (172) may be selectively actuated to urge the sample of interest toward pump manifold assembly (110). Sample cartridge (104) may include a plurality of samplereservoirs that are selectively fluidically accessible via the corresponding sample valves (170). To individually flow the sample of interest toward channel (130) of flow cell (128) and away from pump manifold assembly (110), sample valves (170), pump valves (174), and / or pumps (172) may be selectively actuated to urge the sample of interest toward flow cell cartridge assembly (102) and into respective channels (130) of flow cell (128).

[0050] Drive assembly (112) interfaces with sipper manifold assembly (106) and pump manifold assembly (110) to flow one or more reagents that interact with the sample within flow cell (128). In some scenarios, a reversible terminator is attached to the reagent to allow a single nucleotide to be incorporated onto a growing DNA strand. In some such implementations, one or more of the nucleotides has a unique fluorescent label that emits a color when excited. The color (or absence thereol) is used to detect the corresponding nucleotide. In the implementation shown, imaging system (116) excites one or more of the identifiable labels (e.g., a fluorescent label) and thereafter obtains image data for the identifiable labels. The labels may be excited by incident light and / or a laser and the image data may include one or more colors emitted by the respective labels in response to the excitation. The image data (e g., detection data) may be analyzed by system (100). Examples of features and functionalities that may be incorporated into imaging system (116) will be described in greater detail below.

[0051] After the image data is obtained, drive assembly (112) interfaces with sipper manifold assembly (106) and pump manifold assembly (110) to flow another reaction component (e.g., a reagent) through flow cell (128) that is thereafter received by waste reservoir (118) via a primary waste fluidic line (182) and / or otherwise exhausted by system (100). Some reaction components may perform a flushing operation that chemically cleaves the fluorescent label and the reversible terminator from the sstDNA. The sstDNA may then be ready for another cycle.

[0052] The primary waste fluidic line (182) is coupled between pump manifold assembly (110) and w aste reservoir (118). In some implementations, pumps (172) and / or pump valves (174) of pump manifold assembly (110) selectively flow the reaction components from flow cell cartridge assembly (102), through fluidic line (180) and sample loading manifold assembly (108) to primary waste fluidic line (182). Flow cell cartridge assembly (102) is coupled to a central valve (184) via flow7cell interface (126). Central valve (184) is coupled with flow7cell interface (126) via a fluidic line (185). An auxiliary w aste fluidic line (186) is coupled to central valve (184) and to waste reservoir (118). In some implementations, auxiliary waste fluidic line (186) receives excess fluid of a sample of interest from flow cell cartridge assembly (102), via central valve (184), and flows the excess fluid of the sample of interest to w aste reservoir (118) when back loading the sample of interest into flow7cell (128), as described herein.

[0053] Sipper manifold assembly (106) includes a shared line valve (188) and a bypass valve(190). Shared line valve (188) may be referred to as a reagent selector valve. Central valve (184) and the valves (188, 190) of sipper manifold assembly (106) may be selectively actuated to control the flow of fluid through fluidic lines (192, 194, 196). Sipper manifold assembly (106) may be coupled to a corresponding number of reagent reservoirs (198) via reagent sippers (200). Reagent reservoirs (198) may contain fluid (e.g., reagent and / or another reaction component). In some implementations, sipper manifold assembly (106) includes a plurality of ports. Each port of sipper manifold assembly (106) may receive one of the reagent sippers (200). Reagent sippers (200) may be referred to as fluidic lines. Some forms of reagent sippers (200) may include an array of sipper tubes extending downwardly along the z-dimension from ports in the body of sipper manifold assembly (106). Reagent reservoirs (198) may be provided in a cartridge, and the tubes of reagent sippers (200) may be configured to be inserted into corresponding reagent reservoirs (198) in the reagent cartridge so that liquid reagent may be drawn from each reagent reservoir (198) into the sipper manifold assembly (106).

[0054] Shared line valve (188) of sipper manifold assembly (106) is coupled to central valve (184) via shared reagent fluidic line (196). Different reagents may flow through shared reagent fluidic line (196) at different times. In some versions, when performing a flushing operation before changing between one reagent and another, pump manifold assembly (110) may draw wash buffer through shared reagent fluidic line (196). central valve (184), and flow cell cartridge assembly (102).

[0055] Bypass valve (190) of sipper manifold assembly (106) is coupled to central valve (184) via dedicated reagent fluidic lines (194, 196). Each of the dedicated reagent fluidic lines (194, 196) may be associated with a single reagent. The fluids that may flow through dedicated reagent fluidic lines (194, 196) may be used during sequencing operations and may include a cleave reagent, an incorporation reagent, a scan reagent, a cleave wash, and / or a wash buffer.

[0056] Bypass valve (190) is also coupled to cache (176) of pump manifold assembly (110) via bypass fluidic line (178). One or more reagent priming operations, hydration operations, mixing operations, and / or transfer operations may be performed using bypass fluidic line (178). The priming operations, the hydration operations, the mixing operations, and / or the transfer operations may be performed independent of flow cell cartridge assembly (102). Thus, the operations using bypass fluidic line (178) may occur during, for example, incubation of one or more samples of interest within flow cell cartridge assembly (102). That is, shared line valve (188) may be utilized independently of bypass valve (190) such that bypass valve (190) may utilize bypass fluidic line (178) and / or cache (176) to perform one or more operations while shared line valve (188) and / or central valve (184) simultaneously, substantially simultaneously, or offset synchronously perform other operations.

[0057] Drive assembly (112) includes a pump drive assembly (202) and a valve drive assembly (204). Pump drive assembly (202) may be adapted to interface with one or more pumps (172) to pump fluid through flow cell (128) and / or to load one or more samples of interest into flow cell (128). Valve drive assembly (204) may be adapted to interface with one or more of the valves (170, 174, 184. 188, 190) to control the position of the corresponding valves (170, 174, 184, 188, 190).

[0058] FIG. 2 shows an example of a fluidic arrangement (220) that may be incorporated into a variation of system (100). Fluidic arrangement (220) of this example includes a pump manifold assembly (222), which may operate similar to pump manifold assembly (110) described above; a sample loading manifold assembly (228), which may operate similar to sample loading manifold assembly (108) described above; a flow cell interface (240), which may operate similar to flow cell interface (126) described above; a sipper manifold assembly (250), which may operate similar to sipper manifold assembly (106) described above; and a waste reservoir (270), which may operate similar to waste reservoir (118) described above. Pump manifold assembly (222) is coupled with a port assembly (258) of sipper manifold assembly (250) via a fluidic line (224), which may be similar to fluidic line (178); and with sample loading manifold assembly (228) via a fluidic line (226). Sample loading manifold assembly (228) is coupled with flow cell interface (240) via fluidic line (230), which may be similar to fluidic line (180); and with port assembly (258) via fluidic lines (232, 234). Flow cell interface (240) is coupled with sipper manifold assembly (250) via fluidic line (242), which may be similar to fluidic line (185). Sipper manifold assembly (250) includes a manifold body (252) and a common output port (256), which provides fluid communication via fluidic line (185). A valve assembly (254) controls fluid flow through common output port (256) and may operate similar to central valve (184). Port assembly (258) of sipper manifold assembly (250) is coupled with waste reservoir (270) via fluidic line (272), which may be similar to fluidic line (186).

[0059] A plurality of reagent sippers (260) extend from manifold body (252) and are fluidically coupled with valve assembly (254) via respective fluid channels (262) in manifold body (252). Reagent sippers (260) may operate similar to reagent sippers (200). Valve assembly (254) is operable to selectively couple fluid channels (262) with flow cell interface (240) via common output port (256) and fluidic line (230), to thereby selectively provide various reagents to flow cell interface (240). In other words, when each reagent sipper (260) is disposed in a different respective reagent (e.g., in a respective reagent reservoir (198)), a flow cell (e.g., like flow cell (128)) that is coupled with flow cell interface (240) may selectively receive those different reagents based on control of valve assembly (254).

[0060] Port assembly (258) may provide a fluidic interface between pump manifold assembly(222) and sipper manifold assembly (250), thereby allowing sipper manifold assembly (250) to receive pressurized fluid from pump manifold assembly (222). Port assembly (258) may also provide a fluidic interface between sample loading manifold assembly (228) and sipper manifold assembly (250), thereby allowing sipper manifold assembly (250) to receive sample fluid from sample loading manifold assembly (228). In addition, port assembly (258) may provide a fluidic interface between waste reservoir (270) and sipper manifold assembly (250), thereby allowing sipper manifold assembly (250) to communicate waste fluid to waste reservoir (270). Communication of fluids via port assembly (258) may be regulated, at least in part, by valve assembly (254).

[0061] Referring back to FIG. 1, controller (1 14) of the present example includes a user interface (206), a communication interface (208), one or more processors (210), and a memory (212) storing instructions executable by the one or more processors (210) to perform various functions including the disclosed implementations. User interface (206), communication interface (133), and memory (212) are electrically and / or communicatively coupled to the one or more processors (210). User interface (206) may be adapted to receive input from a user and to provide information to the user associated with the operation of system (100) and / or an analysis taking place. User interface (206) may include a touch screen, a display, a keyboard, a speaker(s), a mouse, a track ball, and / or a voice recognition system.

[0062] Communication interface (208) is adapted to enable communication between system (100) and a remote system(s) (e.g., computers) via a network(s) (e.g., the Internet, an intranet, a local-area network (LAN), a wide-area network (WAN), a coaxial-cable network, a wireless network, a wired network, a satellite network, a digital subscriber line (DSL) network, a cellular network, a Bluetooth connection, a near field communication (NFC) connection, etc.). Some of the communications provided to the remote system may be associated with analysis results, imaging data, etc. generated or otherwise obtained by system (100). Some of the communications provided to system (100) may be associated with a fluidics analysis operation, patient records, and / or a protocol(s) to be executed by system (100).

[0063] The one or more processors (210) and / or system (100) may include one or more of a processor-based system(s) or a microprocessor-based system(s). In some implementations, the one or more processors (210) and / or system (100) includes one or more of a programmable processor, a programmable controller, a microprocessor, a microcontroller, a graphics processing unit (GPU), a digital signal processor (DSP), a reduced-instruction set computer (RISC), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA), a field programmable logic device (FPLD), a logic circuit, and / or another logic-based device executing various functions including the ones described herein.

[0064] Memory (212) may include one or more of a semiconductor memory, a magnetically readable memory, an optical memory, a hard disk drive (HDD), an optical storage drive, a solid- state storage device, a solid-state drive (SSD), a flash memory, a read-only memory7(ROM), erasable programmable read-only memory (EPROM), electrically erasable programmable readonly memory (EEPROM), a random-access memory (RAM), a non-volatile RAM (NVRAM) memory, a compact disc (CD), a compact disc read-only memory (CD-ROM), a digital versatile disk (DVD), a Blu-ray disk, a redundant array of independent disks (RAID) system, a cache and / or any other storage device or storage disk in which information is stored for any duration (e.g., permanently, temporarily, for extended periods of time, for buffering, for caching).

[0065] B. Example of System with Lower Volume Throughput

[0066] FIG. 3 illustrates a schematic diagram of another example of a system (300) that may be used to perform an analysis on one or more samples of interest. Except as otherwise described below, system (300) of this example may be configured and operable like system (100) described above with reference to FIG. 1. In some instances, system (100) is used to provide a higher volume throughput; while system (300) is used to provide a lower volume throughput. Alternatively, systems (100, 300) may provide any other suitable amount or degree of throughput. System (300) of the present example receives a reagent cartridge (302) and includes, in part, a gas source (304), a drive assembly (306), a controller (308). an imaging system (310), and a waste reservoir (312). Reagent cartridge (302) may be referred to as a consumable, a reagent reservoir, or a reagent assembly. Controller (308) is electrically and / or communicatively coupled to drive assembly (306) and to imaging system (310) and causes drive assembly (306) and / or imaging system (310) to perform various functions as disclosed herein.

[0067] Reagent cartridge (302) in the implementation shown includes a well assembly (314) having a body (316). Body (316) has a first wall (318) defining a well (320) having a port (322). First wall (318) has a distal end (324) that defines an opening (326) having an opening perimeter (328). A second wall (330) surrounds first wall (318) and has a distal end (332). Distal end (332) may be referred to as an edge or an outer edge. A cover (334) is coupled to distal end (324) of first wall (318) and covers opening (326) along opening perimeter (328) at a connected portion (336); and is uncoupled from distal end (324) of first wall (318) at an unconnected portion (338). Connection portion (336) may be referred to as connection sections or connected segments and unconnected portion (338) may be referred to as unconnected sections or unconnected segments. First wall (318) has a height and second wall (330) has a height that is greater than the height of first wall (318). First well (318) and second well (330) may alternatively be the same or similar heights. An impermeable barrier (340) is coupled to distal end (332) of second wall (330) and covers well (320). Impermeable barrier (340) may be foil, plastic, etc. and may prevent or inhibitmoisture from infiltrating wells (320) of reagent cartridge (302).

[0068] Unconnected portion (338) of cover (334) forms a vent (342) that allows air flow out of well (320). Dried reagent (348) is contained within well (320), and vent (342) is sized to substantially retain dried reagent (348) within the well (320). Body (316) may include a plurality of wells (320) while one well (320) is shown in FIG. 3. Liquid (346) may flow into well (320) via port (322) in practice to rehydrate dried reagent (348). Vent (342) may vent gas from well (320) as liquid (346) flows into well (320); and cover (334) prevents or inhibits reagent (348) and / or liquid (346) from escaping from well (320). Put another way, vents (342) retain reagent (348) and / or liquid (346) within wells (320); and prevent or inhibit reagent (348) and / or liquid (346) from migrating out of wells (320). Vent (342) and cover (334) prevent or inhibit crosscontamination between reagents when reagent cartridge (302) includes more than one well (320). Liquid (346) and dried reagent (348) may be flowed into and out of well (320) to mix liquid (346) from liquid reservoir (362) and dried reagent (348). System (300) and / or reagent cartridge (302) may include a mixing chamber that is used to mix liquid (346) and dried reagent (348) in some implementations. Impermeable barrier (340) may be pierced prior to liquid (346) flowing into well (320).

[0069] Gas source (304) may be used to pressurize liquid reservoir (362) to flow liquid (346) into well (320); and / or a pump (350) may draw liquid (346) from liquid reservoir (362) and flow liquid (346) into well (320) to rehydrate reagent (348). Gas source (304) may be provided by system (300) and / or may be carried by reagent cartridge (302). Gas source (304) may alternatively be omitted. Pump (350) may be implemented by a syringe pump, a peristaltic pump, a diaphragm pump, etc. While pump (350) may be positioned downstream of flow cell (368) as shown, pump (350) may be positioned upstream of flow cell (368) or omitted entirely.

[0070] Reagent cartridge (302) and / or system (300) includes valves (352) that may be selectively actuatable to control the flow of fluid through fluidic lines (356). Such valves (352) may be implemented by a valve manifold, a rotary valve, a selector valve, a pinch valve, a flat valve, a solenoid valve, a check valve, a piezo valve, etc. A regulator (354) may be positioned between gas source (304) and valve (352); and regulate the pressure of the gas provided to valve (352). Regulator (354) may include a valve that controls the flow of the gas from gas source (304).

[0071] Body (316) of well assembly (314) has an edge (364); and impermeable barrier (340) may be hermetically connected to body (316) along edge (364). Impermeable barrier (340) may include foil, plastic, and / or any other suitable material(s). System (300) may pierce impermeable barrier (340), impermeable barrier (340) may be pierced by an individual prior to use, or impermeable barrier (340) may be pierced by some other structure or methodology. System (300) includes an actuator assembly (360) in the implementation shown that interfaces withimpermeable barrier (340) to pierce impermeable barrier (340). System (300) may include a protrusion such as a post having a blunt or sharp end that is movable by actuator assembly (360) to pierce impermeable barrier (340). Impermeable barrier (340) may alternatively be pierced by an operator prior to reagent cartridge (302) being positioned in system (300). System (300) also includes a liquid reservoir (362) containing liquid (346). Liquid (346) may comprise a rehydrating liquid, a wash buffer, and / or any other suitable kind(s) of liquid.

[0072] System (300) further includes a flow cell receptacle (366) that receives a flow cell (368). Flow cell (368) may be configured and operable like flow cell (128). In some variations, flow cell (368) is carried by and / or integrated into reagent cartridge (302). Flow cell (368) may carry the sample of interest. Gas source (304) and / or pump (350) may flow liquid (346) to rehydrate dry reagents (348) and to flow one or more liquid reagents through reagent cartridge (302) that interact with the sample. Imaging system (310) may be configured and operable like imaging system (116). such that imaging system (310) may be used to obtain image data from flow cell (368). After the image data is obtained, drive assembly (306) may interface with reagent cartridge (302) to flow another reaction component (e g., a reagent) through flow cell (368) that is thereafter received by the waste reservoir (312) and / or otherwise exhausted by reagent cartridge (302). In the present example, drive assembly (306) includes a pump drive assembly (370), a valve drive assembly (372), and actuator assembly (360). Pump drive assembly (370) interfaces with pump (350) to pump fluid through reagent cartridge (302) and / or flow cell (368); and valve drive assembly (372) interfaces with valve (352) to control the position of valve (352).

[0073] Controller (308) of this example includes a user interface (374), a communication interface (376), a processor (378), and a memory (380). User interface (374) may be configured and operable like user interface (206) of system (100). Communication interface (376) may be configured and operable like communication interface (208) of system (100). Processor (378) may be configured and operable like processor (210) of system (100). Memory (380) may be configured and operable like memory (212) of system (100).

[0074] Further examples and details of how various features of each system (100. 300) may be configured and operable will be described below. By way of further example only, the various features of system (100, 300) may be configured and operable in accordance with at least some of the teachings of International Pub. No. WO 2023 / 055873, entitled “Flow Cells and Related Flow' Cell Manifold Assemblies and Methods,’" published April 6, 2023. the disclosure of which is incorporated by reference herein, in its entirety; U.S. Pat. No. 9,958,465, entitled “Detection Apparatus having a Microfluorometer, a Fluidic System, and a Flow Cell Latch Clamp Module,” issued May 1, 2018, the disclosure of which is incorporated by reference herein, in its entirety; and / or U.S. Pat. App. No. 63 / 325.462, entitled “Well Assemblies and Related Systems andMethods,” filed March 30, 2022, the disclosure of which is incorporated by reference herein, in its entirety.

[0075] III. Examples of Flow Cell Structures

[0076] As noted above, a system (100, 300) may execute reactions in a flow cell (128, 368) and / or perform analysis on one or more samples of interest in a flow cell (128. 368). The following describes examples of forms that such flow cells (128, 368) may take, it being understood that flow cells (128, 368) may take various other forms and have various other features in addition to or in lieu of the features described below.

[0077] A. Example of Single-Surface Patterned Flow Cell

[0078] FIG. 4 shows an example of a flow cell (400) that includes a patterned substrate (402), which includes depressions (404) separated by interstitial regions (406), and surface chemistry (410, 412) positioned in the depressions (404). Depressions (404) may be in the form of microwells or nanowells. Depressions (404) may be configured to contain nucleic acid strands or other oligonucleotides and thereby provide a reaction site for SBS and / or for other kinds of processes. In some versions, each depression (404) has a cylindraceous configuration, with a generally circular cross-sectional profile. In some other versions, each depression (404) has a polygonal (e.g., hexagonal, octagonal, square, rectangular, elliptical, etc.) cross-sectional profile. Alternatively, depressions (404) may have any other suitable configuration. It should also be understood that depressions (404) may be arranged in any suitable pattern, including but not limited to a grid pattern.

[0079] Surface chemistry (410, 412) of the present example includes functionalized coating layer (410) and primers (412). While not shown, it is to be understood that the depressions (404) may also have surface preparation or treatment chemistry (e.g., silane or a silane denvative) positioned between the substrate (402) and the functionalized coating layer (410). This same surface preparation or treatment chemistry may also be positioned on the interstitial regions (406). In the present example, a hydrogel (440) is applied before lid (420) is bonded to substrate (402). Hydrogel (440) covers surface chemistry (410, 412) in depressions (404). and at least a portion of the patterned substrate (402) (e.g., those interstitial regions (406) that are not also bonding regions (422)). By way of example only, hydrogel (440) may comprise PAZAM, crosslinked polyacrylamide, agarose gel, etc.

[0080] Flow cell (400) of this example further includes a lid (420) bonded to bonding region(s) (422) of patterned substrate (402). In the example show n in FIG. 4, lid (420) includes a top portion (424) that is connected to several sidewalls (426), and these components (424, 426) define a portion of each of the six flow channels (430A, 430B, 430C, 430D, 430E, 430F). The respective sidewalls (426) isolate one flow channel (430A, 430B, 430C, 430D, 430E, 430F) fromeach adjacent flow channel (430A, 430B, 430C, 430D, 430E, 430F). Each flow channel (430A, 430B, 430C, 430D, 430E, 430F) is in selective fluid communication with a respective set of depressions (404).

[0081] Lid (420) may be bonded to bonding region (422) of substrate (402) using any suitable technique, such as laser bonding, diffusion bonding, anodic bonding, eutectic bonding, plasma activation bonding, glass frit bonding, or other methods known in the art. In some versions, a spacer layer (428) may be used to bond lid (420) to bonding region (422). Spacer layer (428) may comprise any material that will seal at least some of interstitial regions (404) (e g., bonding region (422)) of substrate (402) and lid (420) together. While not shown, lid (420) or the patterned substrate (402) may include inlet and outlet ports that are to fluidically engage other ports (not show n), such as those of sample cartridge interface (168), for directing fluid(s) into the respective flow' channels (430A, 430B, 430C, 430D, 430E, 430F) (e.g., from a reagent cartridge or other fluid storage system) and out of the flow channel (e.g., to waste reservoir (118) or another waste removal system). Flow channels (430A. 430B, 430C. 430D, 430E. 430F) may serve to, for example, selectively introduce reaction components or reactants to hydrogel (440) and the underlying surface chemistry' (410, 412) in order initiate designated reactions in / at depressions (404).

[0082] While flow cell (400) includes a pattern of depressions (404) to provide an array of reaction sites, other variations may provide reaction sites on or at various other kinds of structural features, including but not limited to continuously planer surfaces and / or protruding surfaces, etc. By way of further example only, flow cell (400) may be constructed and operable in accordance with at least some of the teachings of U.S. Pat. No. 10,919,033, entitled ‘"Flow Cells with Hydrogel Coating,’’ issued February 16, 2021, the disclosure of which is incorporated by reference herein, in its entirety.

[0083] B. Example of Dual-Surface Patterned Flow Cell

[0084] While FIG. 4 shows an example of a flow cell (400) that has a single surface patterned with reaction sites (i.e., depressions (404) formed in substrate (402)). it may be desirable in some instances to provide a variation of flow' cell (400) that provide tw o surfaces patterned with reaction sites. An example of a dual-surface patterned flow' cell (450) is shown in FIGS. 5-6. In this example, flow cell (450) includes a pair of wafers (452. 454) that are bonded together, with a spacer layer (456) interposed between wafers (452. 454). Each wafer (452, 454) is patterned to provide a respective plurality of depressions (462, 464), such that depressions (462) of wafer (452) align with depressions (464) of wafer (454) when flow- cell (450) is assembled. Depressions (462) are separated from each other by interstitial regions (466); and depressions (464) are separated from each other by interstitial regions (468). Spacer layer (456) does not contact interstitialregions (466, 468) in this example.

[0085] Depressions (462, 464) of flow cell (450) may be configured and operable like depressions (404) of flow cell (400) described above. Each depression (462, 464) of the present example includes a grafted coating (470), which may be similar to functionalized coating layer (410); and primers (472), which may be similar to primers (412) described above. Each depression (462, 464) may further include hydrogel, like hydrogel (440), and / or any other suitable feature(s). As show n in FIGS. 5-6, depressions (462, 464) are provided within a plurality of flow channels (480A, 480B, 480C, 480D). Flow- channels (480A, 480B, 480C, 480D) are separated from each other by walls (458) and ends (459) formed by spacer layer (456). In the example shown in FIG. 6, flow cell (450) provides four flow channels (480A, 480B, 480C, 480D), with each flow? channel (480A, 480B, 480C, 480D) containing several rows and columns of depressions (462, 464). When flow cell (450) is used in system (100, 300), flow channels (480A, 480B, 480C, 480D) may serve to, for example, selectively introduce reaction components or reactants surface chemistry (470, 472) in order initiate designated reactions in / at depressions (462, 464). In some instances, since each wafer (452, 454) has its own set of depressions (462, 464) providing corresponding reaction sites, flow7cell (450) may provide twice as many reactions as a similarly sized flow cell (400) during a given time period.

[0086] The broken lines in FIG. 6 indicate how flow cell (450) may be diced to effectively form smaller flow cells (450A, 450A), with each smaller flow cell (450A, 450A) having its own respective pair of flow7channels (480A, 480B, 480C, 480D). In the present example, however, a single flow cell (450) has more than two flow channels (480A, 480B, 480C, 480D). While flow7cell (450) includes a pattern of depressions (462, 464) to provide an array of reaction sites, other variations may provide reaction sites on or at various other kinds of structural features, including but not limited to continuously planer surfaces and / or protruding surfaces, etc. By w ay of further example only, flow7cell (450) may be constructed and operable in accordance with at least some of the teachings of U.S. Pat. No. 10,955,332, entitled ‘"Flow Cell Package and Method for Making the Same,” issued March 23. 2021, the disclosure of w hich is incorporated by reference herein, in its entirety.

[0087] IV. Examples of Electrochemical Transistor and Memory Configurations

[0088] As noted above, system (100, 300) includes an imaging system (116, 310) that excites one or more identifiable labels (e.g.. a fluorescent label) in samples in reaction sites provided by depressions (404, 462, 464) of a flow cell (128, 368, 400, 450); and thereafter obtains image data for the identifiable labels. This image data is used to identify nucleotides as part of a nucleic acid sequencing process. Alternatively, the image data may be used for various other purposes. While the examples provided above rely on light irradiation and image capture during nucleic acidsequencing processes, some such image-based nucleic acid sequencing systems may provide limitations with respect to density scaling and thus output. For instance, technology limitations and / or cost constraints may effectively restrict the pixel densities that may be achieved for such imaging; and may thereby restrict spatiotemporal fluorescence analysis. In addition, some imaging-based systems may include functionalization of nucleotides (e.g., by adding fluorophores to the nucleotides). In some cases, such functionalization of nucleotides may adversely affect polymerase reaction rates, such that the polymerase reaction rates may be enhanced in the absence of such functionalization of nucleotides.

[0089] In some instances, nucleotides in a flow cell may be identified without using light irradiation and image capture. For instance, some biosensing methods may rely on the direct or indirect measurement of changes in charge, voltage, current, impedance, conductance, electromagnetic field, or other physical measures. Some such methods may employ a transducer element (e.g., electrochemical, optical, or mechanical transducers) in combination with read-out electronics for conditioning (e.g., amplification, filtering, impedance conversion, etc.), processing (e g., multiplexing, digital conversion, etc.) and transmission of the electric signal. Some solid- state electrochemical transducers such as electrodes and field-effect transistors may be particularly suitable for integration in complementary metal-oxide semiconductor (CMOS) based biosensors containing on-chip read-out integrated circuits (ROIC). In some cases, signal amplification circuits in these devices may be located directly underneath the transducers to enable real-time and low-noise amplification of very7small and transient biological signals. Analog circuit elements such as capacitors and resistors used to build these low-noise amplifiers may benefit from a certain amount of physical space that may be difficult to implement in a nanoscale context without degrading signal-to-noise ratio (SNR) performance. Thus, it may be difficult to translate benefits available from scaled logic CMOS technology employed for memory and digital processors to biosensor arrays employing analog circuits.

[0090] Some electronic sensor arrays employing ion-sensitive field-effect transistors (ISFETs) connected to a proton-sensitive layer (e.g.. implemented as an extended or floating gate) may be used to monitor changes in hydrogen ion concentration (pH) during DNA sequencing. In some such instances, pH changes due to nucleotide incorporation may give rise to changes in the surface charge of the proton-sensitive layer, which in return modulates the gate voltage and thus source-drain current of the underlying ISFET. The signal-to-noise performance of an ISFET may depend strongly on the area of the proton-sensitive layer. As the area is scaled down, the ability of the sensor to accurately detect surface charge changes may be compromised. This may be due to a smaller area being able to interact with fewer protons than a larger area, leading to reduced sensitivity and thus decreased SNR. A limit to scaling may also be imposed by fast protondiffusion and proton crosstalk. For instance, an ISFET-based biosensors may contain microwells that constitute different reaction chambers above each individual ISFET transducer. Decreasing the well diameter may allow protons from one well to diffuse out and into neighboring wells at a faster rate, thus requiring a higher sampling frequency, a shorter detection window, and / or lower amplifier / system noise to reliably detect the true signal from each well.

[0091] The examples described below may overcome the scaling challenges and SNR challenges described above by providing ion-programmable, non-volatile, resistive transducers (also referred to as electrochemical transistors, redox transistors, electrochemical ionic synapses, synaptic transistors, or memristors) in a device configuration similar to resistive random-access memory (RRAM). For instance, FIGS. 7A-7C show an example of an electrochemical transistor (500) that includes a substrate (502), a gate electrode (504), a source electrode (512), and a drain electrode (514). A channel layer (508) spans between electrodes (512, 514). Electrodes (512, 514) are supported by substrate (502), with channel layer (508) spanning across substrate (502) between electrodes (512. 514). An electrolyte layer (508) is positioned above channel layer (508); and an ion reservoir (506) is positioned above electrolyte layer (508), with gate electrode (504) being positioned above ion reservoir (506). Electrodes (504, 512, 514) operate by gate voltage- controlled introduction (intercalation) of ions (520) from ion reservoir (506) into channel layer (508), thus modulating the source-drain current. As used herein, the term "‘electrode” shall be understood to include various kinds of electrically conductive leads or terminals that, in cooperation with an electrically conductive channel provided by a channel layer, form an electrochemical transistor. In some versions, the channel layer may be already electrically conductive before ions are intercalated into the channel layer. In some other versions, the channel layer may only become electrically conductive after ions are intercalated into the channel layer.

[0092] Ion reservoir (506) may include an aqueous electrolyte, ionic liquid, polymer electrolyte, solid-state electrolyte, or other ion-storing element in ionic contact with channel layer (510) and either in ionic contact with gate electrode (504) or part thereof. The material of channel layer (510) may include a mixed ionic-electronic conductor that is able to simultaneously conduct ions (520) and compensating electronic charge carriers (e g., electrons and / or holes) through coupled ion-electron transfer redox reactions. These reactions may alter the bulk electronic density of states of channel layer (510), and hence the conductivity of channel layer (510), over a wide dynamic range. In the present example, ion reservoir (506) is electrically isolated from channel layer (510), allowing only ions (520) to flow between ion reservoir (506) and channel layer (510). This ion-conducting but electrically-insulating barrier is provided by electrolyte layer (508). In some versions, electrolyte layer (508) includes a solid material.

[0093] FIG. 7A shows a writing stage of operation of electrochemical transistor (500). In thiswriting stage, a voltage source (530) applies a positive voltage to gate electrode (504), while the external circuit between source electrode (512) and drain electrode (514) is open, as represented by open switch (532). During this writing stage, electric charge supplied from voltage source (530) via source electrode (512) may move in and out of channel layer (510) but not into electrolyte layer (508). The positive voltage at gate electrode (504) may provide an electric field with source electrode (512) that energizes ions (520) in ion reservoir (506) and thereby drives ions (520) from ion reservoir (506) into channel layer (510) through intercalation. In addition, the positive voltage at gate electrode (504) may further provide redox reactions that provide a continuous flow of electric charge through the entire circuit and ensure electro-neutrality. In some cases, ions (520) are already present in reservoir (506) before the redox reactions occur. In addition, or in the alternative, the redox reactions may generate at least some of ions (520). These intercalated ions (520) may remain in channel layer (510) until the erasing stage of operation described below. Moreover, the ions (520) intercalated into channel layer (510) change the electrical conductance of channel layer (510) by reducing the electrical resistance of channel layer (510), thereby affecting the electrical current between source electrode (512) and drain electrode (514), as also described below. In some other versions, the ions (520) intercalated into channel layer (510) may increase the electrical resistance of channel layer (510), depending on the material of channel layer (510) and type of intercalated ion (520).

[0094] FIG. 7B shows a reading stage of operation of electrochemical transistor (500). In this reading stage, the external circuit between source electrode (512) and gate electrode (504) is open, as represented by open switch (542), such that gate electrode (504) does not receive voltage at this stage of operation. This may prevent or inhibit further redox reactions at gate electrode (504) and thereby prevent or inhibit further intercalation of additional ions (520) from ion reservoir (506) into channel layer (510). The external circuit between source electrode (512) and drain electrode (514) is closed at the reading stage of operation. A voltage source (540) applies a voltage while an ammeter (544) measures the electrical current in the external circuit between source electrode (512) and drain electrode (514). This measured electrical current may vary based on the number of ions (520) that were intercalated into channel layer (510) during the writing stage of operation (since the intercalated ions (520) change the electrical conductance of channel layer (510) by reducing or increasing the electrical resistance), such that the measured electrical current may represent the number of ions (520) that were intercalated into channel layer (510) during the writing stage of operation. While two voltage sources (530, 540) are provided in the present example, other versions may rely on just one single voltage source (e.g., a voltage source that is always connected with source electrode (512) and switches between gate electrode (504) and drain electrode (514).

[0095] After the electrical cunent is measured via ammeter (544), electrochemical transistor (500) may transition to an erasing stage of operation, as shown in FIG. 7C. In this erasing stage of operation, voltage source (530) applies a negative voltage to gate electrode (504), while the external circuit between source electrode (512) and drain electrode (514) is again open, as represented by open switch (532). During this erasing stage, electric charge supplied from voltage source (530) via source electrode (512) may again move in and out of channel layer (510) but not into electrolyte layer (508). The negative voltage at gate electrode (504) may provide an electric field with source electrode (512) that energizes ions (520) in channel layer (510) and thereby drives ions (520) from channel layer (510) back into ion reservoir (506) through de-intercalation. In addition, the negative voltage at gate electrode (504) may further provide redox reactions that provide a continuous flow of electric charge through the entire circuit and ensure electroneutrality.

[0096] It should be understood from the foregoing that the change in electrical conductance / resi stance of channel layer (510) caused by intercalated ions (520) during the writing stage is non-volatile, as the opening of the circuit between gate electrode (504) and source electrode (512) (as represented by open switch (542)) at the reading stage prevents or inhibits further intercalation / de-intercalation of ions (520) to / from channel layer (510). This non-volatile storage of intercalated ions (520) in channel layer (510) (and the corresponding non-volatile change in electrical conductance / resistance of channel layer (510)) may enable long-term retention of the conductance / resistance state of channel layer (510); may further enable deterministic programming of many discrete conductance / resistance states of channel layer (510); and / or may provide an enhanced SNR. This non-volatile storage characteristic of electrochemical transistor (500) may be advantageous for detection and monitoring of fast, transient biochemical processes and their released ionic products, as described herein. This may provide a benefit over ISFET based sensors that only monitor a real-time, transient pH signal. In other words, electrochemical transistor (500) may store the signal as an analog resistance state, which may be read out by peripheral circuitry (e.g.. ammeter (544)) using longer integration times that help increase the SNR.

[0097] FIG. 8 shows an example of a graph (550) that includes a plot (552) of the voltage (VGS) that may be applied by voltage source (530) to gate electrode (504) over an example of an operational cycle. FIG. 8 also shows a graph (560) that includes a plot (562) of the electrical current (IDS) that may be measured by ammeter (544) during the same operational cycle represented by graph (550). As shown, a process may begin with a first period of time where no voltage (VGS) is applied by voltage source (530) to gate electrode (504), where the electrical current (IDS) between source electrode (512) and drain electrode (514) has a first value. This firstperiod of time corresponds to the reading stage of FIG. 7B. The absence of voltage (VGS) being applied to gate electrode (504) may be regarded as an open-circuit-potential (OCP). The measurement of the electrical current (IDS) between source electrode (512) and drain electrode (514) may be regarded as the high-resistance-state (HRS) of channel layer (510).

[0098] Next, a positive voltage (VGS) pulse is applied by voltage source (530) to gate electrode (504) through a second period of time shown in FIG. 8, with this second period of time corresponding to the writing stage of FIG. 7A. There is no electrical current (IDS) between source electrode (512) and drain electrode (514) through this second period of time. In some instances, the amplitude of this positive voltage (VGS) pulse and / or the duration of this positive voltage (VGS) pulse may be tuned to provide a certain degree of intercalation of ions (520) into channel layer (510), as will be described in greater detail below.

[0099] Next, the positive voltage (VGS) from voltage source (530) to gate electrode (504) ceases through a third period of time shown in FIG. 8, with this third period of time corresponding to the reading stage of FIG. 7B. The electrical cunent (IDS) between source electrode (512) and drain electrode (514) has a second value through this third period of time. As shown, this second value is higher than the first value, due to the change in conductance / resistance of channel layer (510) caused by intercalated ions (520). In other words, the intercalated ions (520) have reduced the electrical resistance of channel layer (510) relative to the HRS, thereby providing greater conductivity in channel layer (510) and a corresponding higher current flow through channel layer (510). With the measurement of the electrical current (IDS) between source electrode (512) and drain electrode (514) being higher when the intercalated ions (520) have reduced the electrical resistance of channel layer (510) relative to the HRS, channel layer (510) may be regarded as being in a low-resistance-state (LRS) at this stage of the process.

[0100] Next, a negative voltage (VGS) is applied by voltage source (530) to gate electrode (504) through a fourth period of time shown in FIG. 8, with this fourth period of time corresponding to the erasing stage of FIG. 7C. There is no electrical current (IDS) between source electrode (512) and drain electrode (514) through this fourth period of time. In the present example, the amplitude of this negative voltage (VGS) pulse and the duration of this negative voltage (VGS) pulse is equal to the amplitude and duration of the positive voltage (VGS) pulse provided during the second period of time as described above, with the only difference being the polarity’ of the voltage (VGS) pulse. In some other versions, the amplitude of the negative voltage (VGS) pulse and / or the duration of the negative voltage (VGS) pulse during the fourth period of time (i.e., an erasing stage) is not equal to the amplitude and / or duration of the positive voltage (VGS) pulse provided during the second period of time (i.e., a writing stage) as described above. Moreover, depending on the material of channel layer (510), the write voltage may be associatedwith a de-intercalation (also leading to a lower conductance), while the erase voltage may be associated with an intercalation of ions (leading to higher conductance).

[0101] Continuing with the present example, the negative voltage (VGS) from voltage source (530) to gate electrode (504) ceases through a fifth period of time shown in FIG. 8, with this fifth period of time corresponding to the reading stage of FIG. 7B. The electrical current (IDS) between source electrode (512) and drain electrode (514) returns to the first value through this fifth period of time, due to the de-intercalation of ions (520) from channel layer (510) during the erasing stage. In other words, the de-intercalation of ions (520) from channel layer (510) has effectively returned channel layer (510) to the HRS, thereby reducing the conductivity in channel layer (510) and the corresponding current flow through channel layer (510).

[0102] FIG. 9 shows an example of a graph (570) that includes a plot (572) of the voltage (VGS) that may be applied by voltage source (530) to gate electrode (504) over another example of an operational cycle. FIG. 9 also shows a graph (580) that includes a plot (582) of the electrical current (IDS) that may be measured by ammeter (544) during the same operational cycle represented by graph (570). As shown in FIG. 9, a series of three positive voltage (VGS) pulses are applied by voltage source (530) to gate electrode (504), thereby providing a series of three separate writing stages. As also shown in FIG. 9, an initial HRS reading stage takes place before the first writing stage; followed by series of three separate reading stages in between each of the three separate writing stages. At each writing stage, more ions (520) are intercalated into channel layer (510), such that the electrical resistance of channel layer (510) is reduced with each writing stage, thereby providing increasing electrical current (IDS) between source electrode (512) and drain electrode (514) at each reading stage.

[0103] As further shown in FIG. 9, after the three writing stages and corresponding reading stages, three negative voltage (VGS) pulses are applied by voltage source (530) to gate electrode (504), thereby providing a series of three separate erasing stages. A series of three separate reading stages is provided between each of the three separate erasing stages. At each erasing stage, more ions (520) are de-intercalated from channel layer (510), such that the electrical resistance of channel layer (510) is increased with each writing stage, thereby providing reduced electrical current (IDS) between source electrode (512) and drain electrode (514) at each reading stage following the erasing stages.

[0104] In the example shown, the positive voltage (VGS) pulses are equal to each other in amplitude and duration; and the negative voltage (VGS) pulses also have equal amplitude and duration (albeit at the negative polarity). While the number of negative voltage (VGS) pulses equals the number of positive voltage (VGS) pulses in this example, there may be scenarios where the number of negative voltage (VGS) pulses may be greater than or less than the number ofpositive voltage (VGS) pulses. In some such cases where the number of negative voltage (VGS) pulses is less than the number of positive voltage (VGS) pulses, the duration of the one or more negative voltage (VGS) pulses may be longer than the duration of the positive voltage (V GS) pulses. If, during each positive voltage (VGS) pulse, equal numbers of ions (520) are intercalated into channel layer (510), the measured electrical current (IDS) will increase by the same increment after each positive voltage (VGS) pulse. If the concentration of ions (520) is not constant over the course of the measurement, each positive voltage (VGS) pulse will lead to increases of measured electrical current (IDS) proportional to the number of intercalated ions (520), which can be used to determine the underlying time-dependent concentration profile of the ions (520).

[0105] It should also be understood that there may be scenarios where the positive voltage (VGS) pulses in a series of positive voltage (VGS) pulses differ (e.g., in duration, amplitude and / or frequency). Similarly, there may be scenarios where the negative voltage (VGS) pulses in a series of negative voltage (VGS) pulses differ (e.g., in duration, amplitude and / or frequency). Such differentiation within a series of voltage (VGS) pulses may be provided dynamically, based on system behaviors, environmental factors, and / or other conditions.

[0106] As noted above, electrochemical transistor (500) may be provided in a resistive random-access memory (RRAM) arrangement (590) shown in FIG. 10, thereby providing high- density storage that might not be otherwise achieved through other biosensor architectures. To the extent that some versions of memory (e.g., NAND flash memory) may be difficult to scale beyond the 16nm node, RRAM may achieve memory cell sizes (598) as small as 4F2, where “F” is the feature size of the technology node and which defines the width of a bit line (594) and word line (592); bit line (594) and word line (592) would correspond to source electrode (512) and drain electrode (514), respectively, of electrochemical transistor (500); and RRAM element (596) would correspond to the channel layer (510). Arranged in a cross-point array, memon cells may be fabricated in the back-end-of-line (BEOL) sandwiched between two or three metal layers, thus leaving the entire region of a substrate (e.g., silicon, etc.) underneath the cross-point array available for peripheral control and read-out circuitry. This arrangement may make the RRAM architecture substantially area-efficient and may enable a high integration density and array size.

[0107] V. Examples of Flow Cells Incorporating Electrochemical Transistors andResistive Random-Access Memory (RRAM) Arrays

[0108] As noted above, imaging based biosensors and ISFET based biosensors may present limitations in sensing density, scaling, and / or throughput. As also noted above, some of these limitations may be overcome through use of electrochemical transistors (e.g., like electrochemical transistor (500)); and through use of a RRAM arrangement (e.g., like RRAM arrangement (590) shown in FIG. 10). In some cases, such features may be particularly beneficial in a nucleic acidsequencing system like systems (100, 300) described above. For instance, biological, biochemical, and electrochemical reactions may be accompanied by the generation of ions such as protons (H+), lithium (Li+), potassium (K+), oxygen (O2) and others. Specifically, during DNA sequencing using SBS, one proton is released during each nucleotide incorporation event. A variation of systems (100. 300) may include a high-density cross-point array of electrochemical transistors that are able to detect these released ions by means of intercalating them into the transistor channel and measuring the resulting non-volatile change in channel conductance. Examples of how such electrochemical transistor arrangements may be configured and used will be described in greater detail below.

[0109] It should be understood that any of the below examples may be incorporated into variation of systems (100, 300) described above, in lieu of including imaging system (116, 310), for use in SBS processes and / or other processes. While the following examples are described in the context of systems (100. 300), it should also be understood that any of the below examples may be incorporated into other kinds of systems that are capable of performing SBS and / or other processes.

[0110] A. Examples of Electrode Arrangements Relative to Single Well of FlowCell

[0111] FIG. 11 shows an example of a flow cell (600) that may be used in a system (100, 300) in lieu of flow cell (128, 368, 400, 450). Except for the differences explicitly described below, flow cell (600) of this example may generally be configured and operable like flow cells (128, 368, 400, 450) described above. Flow cell (600) of this example includes a substrate (602), a gate electrode (604), a source electrode (626), and a drain electrode (628). A channel layer (624) spans between electrodes (626, 628). Electrodes (626, 628) are supported by substrate (602), with channel layer (624) spanning across substrate (602) between electrodes (626, 628). An electrolyte layer (622) is positioned above channel layer (624); and a well (610) is positioned above electrolyte layer (622). with gate electrode (604) being positioned above well (610).

[0112] By way of example only, substrate (602) may comprise silicon, silicon dioxide, and / or any other suitable material(s). By way of further example only, channel layer (624) may comprise tungsten / tungsten trioxide and / or any other suitable material(s). By way of further example only, electrolyte layer (622) may include tantalum oxide and / or any other suitable material(s). By way of further example only, each electrode (626, 628) may comprise platinum, palladium, titanium, copper, silver, and / or any other suitable material(s). By way of further example only, gate electrode (604) may comprise platinum, palladium, titanium, copper, silver, and / or any other suitable material(s).

[0113] In some versions, well (610) is configured and operable like each depression (404) offlow cell (400) described above, such that well (610) may be configured to contain nucleic acid strands or other oligonucleotides and thereby provide a reaction site for SBS and / or for other kinds of processes. As shown in FIG. 11, well ( 10) is laterally bound by walls (620). As also shown in FIG. 11, a space (612) is provided between gate electrode (604) and the upper end of each wall (620). Spaces (612) may provide a channel allowing fluid carrying nucleotides, polymerases, etc., to flow into and out of well (610). During use of flow cell (600), nucleotides or other biomolecules may reside on the top surface of electrolyte layer (622).

[0114] As noted above, spaces (612) allow fluid carrying nucleotides, polymerases, etc., to flow into and out of well (610). Such fluid may further include an aqueous electrolyte. Gate electrode (604) is in contact with the fluid in well (610). Gate electrode (604), source electrode (626), drain electrode (628), and channel layer (624) may be operated like gate electrode (504), source electrode (512), a drain electrode (514), and channel layer (508), respectively. In particular, a positive voltage may be applied to gate electrode (604) to intercalate ions from well (610) to channel layer (614): the corresponding conductance / resistance change may then be measured to determine the number of intercalated ions in channel layer (614); and a negative voltage may be applied to gate electrode (604) to de-intercalate ions from channel layer (614) into well (610). In addition to providing intercalation / de-intercalation of ions to / from channel layer (614), gate electrode (604) may generate an electric field with source electrode (626) over / through well (610) that is large enough to prevent or inhibit diffusion of ions from well (610). For instance, an electric field generated between gate electrode (604) and source electrode (626) may prevent or inhibit ions from escaping well (610) into an adjacent well or other region via spaces (612).

[0115] Like channel layer (510) described above, channel layer (624) of the present example provides a mixed ionic-electronic conductor that is able to simultaneously conduct ions and compensating electronic charge carriers (electrons and / or holes) through coupled ion-electron transfer redox reactions (e.g., when voltage is applied to gate electrode (604)). Mixed ionic- electronic conductors that may change resistance upon cathodic (at reducing voltages at the source electrode) ion intercalation may include tungsten tri oxide, molybdenum trioxide, titanium dioxide, vanadium pentoxide, niobium pentoxide, etc. Materials that may change resistance upon anodic (at oxidizing voltages at the source electrode) ion intercalation may include vanadium pentoxide, chromic oxide, manganese dioxide, iron dioxide, cobalt dioxide, nickel dioxide, rhodium dioxide, and iridium dioxide. Amongst the former group, tungsten trioxide, a CMOS-compatible wide- bandgap semiconductor, has the ability to form a metallic tungsten bronze phase (HxWC ) upon proton intercalation, which gives rise to a change in electrical conductivity. The underlying reversible redox reaction is: WO3+ xH++ xe~ HXWO3. The proton diffusion constant in WO3 / H VO.. may range from 10'11cm2 / s to 2.5xl0‘7cm2 / s and may depend on the materialstructure and deposition method. A high diffusion constant may be beneficial for faster intercalation and hence conductance switching speeds. Similarly, the electrical conductivity of WOs / HxWO-. may range from 10'6S / cm to 102S / cm and may depend on the H+doping level with a substantial increase in conductance at very low H+doping concentration or molar fraction, x. This high sensitivity may be beneficial to detect sparse ions generated during biological or biochemical reactions, such as those provided during SBS or other processes.

[0116] The liquid flowing through well (610) may have a certain ionicity and pH that are suitable for the viability of DNA molecules and polymerases used for nucleotide incorporation. Moreover, proton intercalation from an aqueous electrolyte into a channel layer (624) comprising tungsten trioxide may occur at a lower absolute gate voltage than the voltage for water electrolysis. It should also be understood that the presence of electrolyte layer (622) over channel layer (624) may prevent or inhibit corrosion or oxidation of channel layer (624) that might otherwise occur in the absence of electrolyte layer (622). As noted above in the context of electrolyte layer (508), electrolyte layer (622) may provide electrical insulation while also providing conduction of ions (e.g., protons); while further preventing or inhibiting corrosion or oxidation of channel layer (624). Examples of materials that may be used to form electrolyte layer (622) may include solid electrolytes such as titanium dioxide, hafnium oxide, zirconium dioxide, or tantalum pentoxide. Such an electrolyte layer (622) may provide substantial stability' across a range of pH values; and may also prevent or inhibit O2 present in the electrolyte fluid in well (6100) from oxidizing HxWCh to WO3 in channel layer (624) and thus impacting the retention of the conductance state of channel layer (624).

[0117] While only one well (610) is shown, flow cell (600) may have a plurality of wells (610). In such versions, each well (610) may have a respective underlying source electrode (626), a drain electrode (628), channel layer (624), and electrolyte layer (622). Wells (610) may be scaled as microwells, may be scaled as nanowells, or may have any other suitable scale. In some versions where flow cell (600) has a plurality of wells (610), a single gate electrode (604) may span over two or more wells (610) of a plurality of wells (610). In some other versions where flow cell (600) has a plurality of wells (610), two or more gate electrodes may be provided for a plurality of wells (610) (e.g., as described in greater detail below). In some versions, each well (610) has a cylindraceous configuration, with a generally circular cross-sectional profile. In some other versions, each well (610) has a polygonal (e.g.. hexagonal, octagonal, square, rectangular, elliptical, etc.) cross-sectional profile. Alternatively, each well (610) may have any other suitable configuration. It should also be understood that a plurality of wells (610) may be arranged in any suitable pattern, including but not limited to a grid pattern.

[0118] In some versions, electrolyte layer (622) has a thickness of approximately 10 nm;channel layer (624) has a thickness of approximately 50 nm; and each electrode (626, 628) has a thickness of approximately 50 nm. Alternatively, these components may have any other suitable thicknesses.

[0119] FIG. 12 shows an example of another flow cell (700) that may be used in a system (100. 300) in lieu of flow cell (128, 368, 400, 450). Except for the differences explicitly described below, flow cell (700) of this example may generally be configured and operable like flow cell (600) described above. Flow cell (700) of this example includes a substrate (702), agate electrode (704), a source electrode (726), and a drain electrode (728). A channel layer (724) spans between electrodes (726, 728). Electrodes (726, 728) are supported by substrate (702), with channel layer (724) spanning across substrate (702) between electrodes (726, 728). An electrolyte layer (722) is positioned above channel layer (724); and a well (710) is positioned above electrolyte layer (722).

[0120] By way of example only, substrate (702) may comprise silicon, silicon dioxide, and / or any other suitable material(s). By way of further example only, channel layer (724) may comprise tungsten / tungsten trioxide and / or any other suitable material(s). By way of further example only, electrolyte layer (722) may include tantalum oxide and / or any other suitable material(s). By way of further example only, each electrode (726, 728) may comprise platinum, palladium, titanium, copper, silver, and / or any other suitable material(s). By way of further example only, gate electrode (704) may comprise platinum, palladium, titanium, copper, silver, and / or any other suitable material(s).

[0121] Well (710) is laterally bound by walls (720). Gate electrode (704) is positioned at the top of a respective wall (720). Gate electrode (704) may comprise a single piece of metal positioned atop all walls (720), with an opening formed through the single piece of metal over well (710). A space (712) is provided over well (710). Space (712) may form part of a channel allowing an aqueous electrolyte fluid carrying nucleotides, polymerases, etc., to flow into and out of well (710). Gate electrode (704) is positioned to maintain contact with the fluid in well (710). While not shown in FIG. 12, an upper layer may be positioned over well (710), while still accommodating space (712) to allow the flow of fluid into and out of well (710). As noted above, flow cell (700) may be configured and operable like flow cell (600) described above. The primary difference between flow cell (700) and flow cell (600) is that flow cell (700) provides gate electrode (704) at the tops of walls (720) at the lateral sides of well (710); while flow cell (600) provides gate electrode (604) spaced above the tops of walls (620) and spanning across the width of well (610).

[0122] In some versions, electrolyte layer (722) has a thickness of approximately 10 nm; channel layer (724) has a thickness of approximately 50 nm; and each electrode (726, 728) has athickness of approximately 50 nm. Alternatively, these components may have any other suitable thicknesses.

[0123] FIG. 13 shows an example of another flow cell (750) that may be used in a system (100, 300) in lieu of flow cell (128, 368, 400, 450). Except for the differences explicitly described below, flow cell (750) of this example may generally be configured and operable like flow cell (600) described above. Flow cell (750) of this example includes a first substrate (752), a second substrate (754), a gate electrode (756), a source electrode (774), and a drain electrode (776). By way of example only, first substrate (752) may comprise silicon and / or any other suitable material(s) while second substrate (754) may comprise silicon dioxide and / or any other suitable material(s). Source electrode (726) and drain electrode (728) are positioned atop second substrate (754) and are supported by second substrate (754). By way of example only, each electrode (726, 728) may comprise platinum, palladium, titanium, copper, silver, and / or any other suitable material(s).

[0124] An adhesion layer (780) is positioned over a portion of second substrate (754) and over end portions of electrodes (774, 776). A channel layer (782) is positioned over adhesion layer (780), including over the regions of adhesion layer (780) that are over end portions of electrodes (774, 776). An electrolyte layer (784) is positioned above channel layer (782); and a well (760) is positioned above electrolyte layer (784). By way of example only, adhesion layer (780) may include tungsten and / or any other suitable material(s). By way of further example only, channel layer (782) may include tungsten / tungsten trioxide and / or any other suitable material(s). By way of further example only, electrolyte layer (784) may include tantalum oxide and / or any other suitable material(s). A voltage source (790) is operable to apply voltages to gate electrode (756) and source electrode (774) like voltage sources (530, 540) described above, while an ammeter (792) is operable to measure current between electrodes (774, 776) like ammeter (544) described above.

[0125] Well (760) is laterally bound by walls (770). which are supported on bases (772) atop electrodes (774, 778). A space (762) is provided over well (760). Space (762) may form part of a channel allowing an aqueous electrolyte fluid carrying nucleotides, polymerases, etc., to flow into and out of well (760). Gate electrode (756) is positioned within the liquid in well (760). Bases (772) define an opening at the bottom of well (760), through which electrolyte layer (784) is exposed to the fluid within well (760). By way of example only, this opening may have a width of approximately 1 micrometer or any other suitable width. As noted above, flow cell (750) may be configured and operable like flow cell (600) described above. The primary difference between flow cell (750) and flow cell (600) is that flow cell (750) provides a gate electrode (756) that is narrower than the width defined between walls (770) and protrudes into the space defined betweenwalls (770) to reach the fluid in well (710); while flow cell (600) provides gate electrode (604) spaced above the tops of walls (720) and spanning across the width of well (610).

[0126] Another difference between flow cell (750) and flow cell (600) is that flow cell (750) includes adhesion layer (780) between channel layer (782) and electrodes (774, 776); while flow cell (600) does not include adhesion layer. In the present example, adhesion layer (780) provides good mechanical adhesion between channel layer (782) and electrodes (774, 776). Some channel layer (782) materials may tend to not otherwise adhere very well to electrodes (774, 776) electrodes directly. In addition, adhesion layer (780) provides a good electrical contact between channel layer (782) and electrodes (774, 776). Some channel layer (782) materials may tend to not otherwise form good ohmic contacts to the underlying electrodes (774, 776), resulting in high contact resistance. Adhesion layer (782) thus helps in achieving low contact resistances. In some other versions, adhesion layer (780) is not warranted or is otherwise omitted.

[0127] In some versions, electrolyte layer (784) has a thickness of approximately 10 nm; channel layer (782) has a thickness of approximately 0. 1 pm; adhesion layer (780) has a thickness of approximately 10 nm; and each electrode (774, 776) has a thickness of approximately 50 nm. Alternatively, these components may have any other suitable thicknesses.

[0128] B. Examples of Electrode Arrangements Relative to Plurality of Wells

[0129] As noted above, some flow cells may include a plurality of wells where SBS and / or other processes may occur. FIGS. 14, 15, and 18 show examples of flow cells (800, 900, 1000) that each include a plurality of wells (802, 902, 1002). Each flow cell (800, 900, 1000) may be used in a system (100, 300) in lieu of flow cell (128, 368, 400, 450). Except for the differences explicitly described below, each flow cell (800, 900, 1000) may generally be configured and operable like flow cell (600) described above. In some versions, each flow cell (800, 900, 1000) is fabricated using a 22 nm CMOS technology (i.e., such that the CMOS chip may provide a transistor gate length as small as 22 nm) to achieve a high integration density.

[0130] In some versions of each flow cell (800, 900. 1000) described below, the front-end-of- line (FEOL) contains the transistors for the mixed-signal peripheral circuits used for array control, biasing, signal conditioning, and signal processing such as line drivers, sense amplifiers, multiplexers, ADCs, digital-to-analog converters (DACs), decoders, serializes, and other control logic. The BEOL contains metal (e.g., copper) interconnects separated by inter-metal dielectric (e.g., silicon dioxide) and connected through metal (e.g.. copper) vias allowing up to twelve metal layers in 22 nm CMOS. Not all metal layers need to be used in all versions, though some versions may in fact use all metal layers. As described in greater detail below, the two top-most global metal layers (Mx-i, Mx) and vias are used to establish drain and source electrodes of the electrochemical transistors. For instance, a second-from-top global metal layer (Mx-i) line mayconstitute the common drain line of a row of electrochemical transistors; and orthogonal top-most global metal layer (Mx) lines establish the common source lines of columns of electrochemical transistors. Contact between the electrochemical transistor and the drain line is established through a metal (e.g., copper) via. In some versions, the two top-most global metal layers (Mx-i, Mx) global metal interconnects in a 22 nm CMOS process have a pitch of approximately 120 nm. width ranging from approximately 40 nm to approximately 60 nm, and thickness ranging from approximately 20 nm to approximately 30 nm.

[0131] FIG. 14 shows an example of a flow cell (800) that includes a BEOL substrate assembly (810) having a plurality of metal layers (Mi, Mx-i, Mx) and a FEOL substrate assembly (812) under BEOL substrate assembly (810). By way of example only, the two top-most global metal layers (Mx-i, Mx) of BEOL substrate assembly (810) may have a width ranging from approximately 40 nm to approximately 60 nm, and a thickness ranging from approximately 20 nm to approximately 30 nm. By way of further example only, the lower-most local interconnect metal layer (Mi) of BEOL substrate assembly (810) may have a width of approximately 22 nm and a thickness of approximately 11 nm. Alternatively, metal layers (Mi, Mx-i, Mx) of BEOL substrate assembly (810) may have any other suitable widths and / or thicknesses. BEOL substrate assembly (810) may also include silicon dioxide, and / or any other suitable material(s), in which metal layers (Mi, Mx-i, Mx) are disposed.

[0132] FEOL substrate assembly (812) includes a plurality of transistors (870). As noted above, transistors (870) may be provided for mixed-signal peripheral circuits used for array control, biasing, signal conditioning, and signal processing such as line drivers, sense amplifiers, multiplexers. ADCs, DACs, decoders, serializes, and other control logic. FEOL substrate assembly (812) may further include silicon, and or any other suitable material(s), in which transistors (870) are disposed. A plurality of metallic traces (860) in the lower-most local interconnect metal layer (Mi) of BEOL substrate assembly (810) and / or in other layers of BEOL substrate assembly (810) may provide pathways for electrical communication between transistors (870) and other features of flow cell (800).

[0133] A plurality of walls (804) extend upw ardly from BEOL substrate assembly (810) to define a plurality of wells (802). Each wall (804) comprises an electrically resistive material whose resistance is permanent, such that each w all (804) sen es as an electrical insulator. In the example shown, each wall (804) is angled along a vertical plane such that the top end of each well (802) has a width that is greater than the width at the bottom end of each well (802). By way of example only, each wall (804) may have a height of approximately 300 nm; the top end of each well (802) may have a width of approximately 100 nm; and the bottom end of each well (802) may have a width of approximately 50 nm. Alternatively, any of these parameters may have anyother suitable value. Like wells (610, 710, 760) described above, wells (802) of this example are configured to receive a flow of an aqueous electrolyte fluid carrying nucleotides, polymerases, etc. via a fluid channel over wells (802).

[0134] A gate electrode (814) is positioned atop each wall (804) such that gate electrode (814) is positioned to contact the fluid received in wells (804). Gate electrode (814) may comprise a single piece of metal positioned atop all walls (804), with openings formed through the single piece of metal over wells (802). While not shown in FIG. 14, an upper layer may be spaced above wells (804) and gate electrode (814), while still accommodating the flow of fluid into and out of wells (804). By way of example only, gate electrode (814) may comprise platinum, palladium, titanium, copper, silver, and / or any other suitable material(s).

[0135] An electrolyte layer (820) is positioned at the bottom of each well (802) and is slightly wider than the bottom of each well (802). Each well (802) has its own separate, underlying electrolyte layer (820). During use of flow cell (800), nucleotides or other biomolecules may reside on the top surface of each electrolyte layer (820). By way of example only, each electrolyte layer (820) may comprise tantalum oxide and / or any other suitable material(s). By w ay of further example only, each electrode layer (820) may have a thickness on the order of approximately 10 nm; or any other suitable thickness.

[0136] A channel layer (822) is positioned under each electrolyte layer (820), with downwardly projecting end portions (821) of electrolyte layer (820) further encompassing the outer lateral edges of each channel layer (822). During use of flow' cell (800), ions may be intercalated from each well (802) into the underlying channel layer (822) via the intervening electrolyte layer (820). By way of example only, each channel layer (822) may comprise tungsten / tungsten trioxide and / or any other suitable material(s). By way of further example only, each channel layer (822) may have a thickness on the order of approximately 10 nm; or any other suitable thickness. By w ay of further example only, each channel layer (822) may have a width of approximately 50 nm, which may be approximately equal to the width of the bottom of the overlying well (802); or any other suitable width.

[0137] In the present example, an arrangement of wells (802) along one dimension (extending into and out of the page of FIG. 14) share a common source electrode (830) but have different respective drain electrodes (850); while the arrangement of w ells (802) along another dimension (extending left and right along the page of FIG. 14) share a common drain electrode (850) but have different respective source electrodes (830). Each source electrode (830) is positioned in the top-most global metal layer (Mx) of BEOL substrate assembly (810); while the shared drain electrode (850) is positioned in the second-from-top global metal layer (Mx-i) of BEOL substrate assembly (810). A via (840) extends from the top-most global metal layer (Mx) to the second-from-top global metal layer (Mx-i) to provide an electrical path from the region under an associated well (802) to shared drain electrode (850). While vias (840) extend to drain electrodes (850) in this example, some variations may provide vias extending to source electrodes (830); in addition to or as an alternative to vias extending to drain electrodes (850).

[0138] Each source electrode (830) and a corresponding via (840) are positioned to have electrical continuity with a corresponding channel layer (822) under each well (802). In this example, a diffusion barrier (832) is interposed between each source electrode (830) and the overlying channel layer (822). Similarly, a diffusion barrier (842) is interposed between each via (840) and the overlying channel layer (822). Each diffusion barrier (832, 842) is configured to provide good ohmic contact between channel layer (822) and the respective source electrode (830) and via (840). In versions where source electrode (830) and / or via (840) include copper, diffusion barriers (832, 834) may prevent or inhibit the copper from diffusing into channel layer (822). Otherwise, diffusion of copper into channel layer (822) may change the conductivity of channel layer (822), which may adversely affect readings of resistance changes in channel layer (822) caused by intercalation of ions as described herein.

[0139] By way of example only, each source electrode (830) may have a width of approximately 40 nm, approximately 60 nm; or any other suitable width. By way of further example only, each diffusion barrier (832. 842) may have a thickness of approximately 5 nm; or any other suitable thickness. By way of further example only, each diffusion barrier (832, 842) may comprise titanium nitride, titanium nitride / tungsten, tungsten, and / or any other suitable material(s). In some versions, either or both of diffusion barriers (832, 842) is / are omitted, such as in cases where certain metal atoms will not diffuse from source electrode (830) or via (840) into channel layer (822). While copper is noted above as an example of a material that may be used to form source electrode (830) and / or via (840), other versions of source electrode (830) and / or via (840) may include aluminum, platinum, palladium, titanium, silver, and / or any other suitable material(s). Similarly, drain electrode (850) may comprise aluminum, platinum, palladium, titanium, copper, silver, and / or any other suitable material(s).

[0140] During an example of operation of flow cell (800), an initial measurement may be taken of the electrical current (IDS) between each source electrode (830) and the shared drain electrode (850); and this measurement may be regarded as the high-resistance-state (HRS) of the corresponding channel layer (822). Then, aqueous electrolyte fluid carrying nucleotides, polymerases, etc. may be flowed via a channel through wells (802) during an SBS process. During this process, a positive voltage (VGS) pulse may be applied to gate electrode (814); while no electrical current flows between source electrodes (830) and the shared drain electrode (850). While this positive voltage (VGS) is being applied to gate electrode (814), ions may be intercalatedfrom wells (802) into the underlying channel layers (822) via the associated electrolyte layers (820); which may change the conductance / resistance of channel layers (822).

[0141] After the positive voltage (VGS) pulse is no longer being applied to gate electrode (814) (i.e., when positive voltage (VGS) pulse ceases), the electrical current (IDS) between each source electrode (830) and shared drain electrode (850) is measured to evaluate the change in conductance / resistance of channel layers (822). Such change in conductance / resistance of channel layers (822) may indicate the number of ions intercalated from wells (802) into underlying channel layers (822), which may further indicate nucleotide incorporation events as described in greater detail below. Once this reading stage is complete, a negative voltage (VGS) pulse may be applied to gate electrode (814); while no electrical current flows between source electrodes (830) and the shared drain electrode (850). While this negative voltage (VGS) is being applied to gate electrode (814), ions may be de-intercalated from channel layers (822) back into wells (802) via the associated electrolyte layers (820): which may change return the conductance / resistance of channel layers (822) back to the HRS.

[0142] While the foregoing example just describes a single pulse of positive voltage (VGS) is being applied to gate electrode (814) (i.e., a writing pulse), some variations may provide a plurality of writing pulses to gate electrode (814), with an intervening plurality of channel layer (822) conductance / resistance measurements, before a pulse of negative voltage (VGS) is applied to gate electrode (814) (i.e., an erasing pulse). Similarly, while the foregoing example just describes a single erasing pulse to gate electrode (814), some variations may provide a plurality of erasing pulses to gate electrode (814). During the above-described process, transistors (870) may provide the control logic to achieve the driving of voltage (VGS) pulses, the reading of conductance / resistance of channel layers (822), and / or other functionality-.

[0143] FIG. 15 shows an example of another flow cell (900) that includes a BEOL substrate assembly (910) having a plurality of metal lay ers (Mi, Mx-i, Mx) and a FEOL substrate assembly (912) under BEOL substrate assembly (910). By way of example only, the two top-most global metal layers (Mx-i, Mx) of BEOL substrate assembly (910) may have a width ranging from approximately 40 nm to approximately 60 nm, and a thickness ranging from approximately 20 nm to approximately 30 nm. By way of further example only, the lower-most local interconnect metal layer (Mi) of BEOL substrate assembly (910) may have a width of approximately 22 nm and a thickness of approximately 11 nm. Alternatively, metal layers (Mi, Mx-i. Mx) of BEOL substrate assembly (910) may have any other suitable widths and / or thicknesses. BEOL substrate assembly (910) may also include silicon dioxide, and / or any other suitable material(s), in which metal layers (Mi, Mx-i, Mx) are disposed.

[0144] FEOL substrate assembly (912) includes a plurality of transistors (970). As notedabove, transistors (970) may be provided for mixed-signal peripheral circuits used for array control, biasing, signal conditioning, and signal processing such as line drivers, sense amplifiers, multiplexers, ADCs, DACs, decoders, serializes, and other control logic. FEOL substrate assembly (912) may further include silicon, and or any other suitable material(s), in which transistors (970) are disposed. A plurality of metallic traces (960) in the lower-most local interconnect metal layer (Mi) of BEOL substrate assembly (910) and / or in other layers of BEOL substrate assembly (910) may provide pathways for electrical communication between transistors (970) and other features of flow cell (900).

[0145] A plurality of walls (904) extend upwardly relative to BEOL substrate assembly (910) to define a plurality of wells (902). Each wall (904) comprises an electrically resistive material whose resistance is permanent, such that each wall (904) serves as an electrical insulator. In the example shown, each wall (904) is angled along a vertical plane such that the top end of each well (902) has a width that is greater than the width at the bottom end of each well (902). By way of example only, each wall (904) may have a height of approximately 300 nm: the top end of each well (902) may have a width of approximately 100 nm; and the bottom end of each well (902) may have a width of approximately 50 nm. Alternatively, any of these parameters may have any other suitable value. Like wells (610, 710, 760, 802) described above, wells (902) of this example are configured to receive a flow of an aqueous electrolyte fluid carrying nucleotides, polymerases, etc. via a fluid channel over wells (902).

[0146] A gate electrode (914) is positioned atop each wall (904) such that gate electrode (914) is positioned to contact the fluid received in wells (902). Gate electrode (914) may comprise a single piece of metal positioned atop all walls (904), with openings formed through the single piece of metal over wells (902). While not show n in FIG. 15, an upper layer may be spaced above wells (902) and gate electrode (914), while still accommodating the flow- of fluid into and out of wells (902). Gate electrode (914) of this example includes a conductive material that is capable of undergoing reversible redox reactions such as surface oxidation / reduction while not being consumed or corroded by the SBS buffers and chemicals. By way of example only, gate electrode (914) may comprise platinum, palladium, titanium, copper, silver, and / or any other suitable material(s).

[0147] An electrolyte layer (920) is positioned across the entire upper surface (911) of BEOL substrate assembly (910), such that walls (904) are positioned atop electrolyte layer (920) and electrolyte layer (920) spans along the bottom of all of wells (902). During use of flow cell (900), nucleotides or other biomolecules may reside on the top surface of electrolyte layer (920) at the bottom of one or more wells (902). As noted above, electrolyte layer (920) may include a protonconducting but electrically insulating solid electrolyte. By way of example only, electrolyte layer(920) may comprise tantalum oxide, titanium oxide, hafnium oxide, zirconium dioxide, and / or any other suitable material(s). By way of further example only, electrode layer (920) may have a thickness on the order of approximately 10 nm; or any other suitable thickness.

[0148] A plurality of channel layers (922) are positioned under electrolyte layer (920). In this example, each channel layer (922) has lateral outer portions (923) that are also positioned atop portions of the upper surface (911) of BEOL substrate assembly (910). During use of flow cell (900), ions may be intercalated from each well (902) into the underlying channel layer (922) via electrolyte layer (920). By way of example only, each channel layer (922) may comprise tungsten / tungsten trioxide and / or any other suitable material(s). By way of further example only, each channel layer (922) may have a thickness on the order of approximately 10 nm; or any other suitable thickness. By way of further example only, each channel layer (922) may have a width of approximately 50 nm, which may be approximately equal to the width of the bottom of the overlying well (902); or any other suitable width. In some cases, electrolyte layer (920) prevents or inhibits corrosion and oxidation of the material forming channel layer (922).

[0149] In the present example, an arrangement of wells (902) along one dimension (extending into and out of the page of FIG. 15) share a common source electrode (930) but have different respective drain electrodes (950); while wells (902) along another dimension (extending left and right along the page of FIG. 15) share a common drain electrode (950) but have different respective source electrodes (930). Each source electrode (930) is positioned in the top-most global metal layer (Mx) of BEOL substrate assembly (910); while the shared drain electrode (950) is positioned in the second-from-top global metal layer (Mx-i) of BEOL substrate assembly (910). A via (940) extends from the top-most global metal layer (Mx) to the second-from-top global metal layer (Mx.i) to provide an electrical path from the region under an associated well (902) to shared drain electrode (950). While vias (940) extend to drain electrodes (950) in this example, some variations may provide vias extending to source electrodes (930); in addition to or as an alternative to vias extending to drain electrodes (950).

[0150] Each source electrode (930) and a corresponding via (940) are positioned to have electrical continuity with a corresponding channel layer (922) under each well (902). In this example, a diffusion barrier (932) is interposed between each source electrode (930) and the overlying channel layer (922). Similarly, a diffusion barrier (942) is interposed between each via (940) and the overlying channel layer (922). Each diffusion barrier (932, 942) is configured to provide good ohmic contact between channel layer (922) and the respective source electrode (930) and via (940). In versions where source electrode (930) and / or via (940) include copper, diffusion barriers (932, 934) may prevent or inhibit the copper from diffusing into channel layer (922). Otherwise, diffusion of copper into channel layer (922) may change the conductivity of channellayer (922), which may adversely affect readings of resistance changes in channel layer (922) caused by intercalation of ions as described herein.

[0151] By way of example only, each source electrode (930) may have a width of approximately 40 nm; or any other suitable width. By way of further example only, each diffusion barrier (932, 942) may have a thickness of approximately 5 nm; or any other suitable thickness. By way of further example only, each diffusion barrier (932, 942) may comprise titanium nitride, titanium nitride / tungsten, tungsten, and / or any other suitable material(s). In some versions, either or both of diffusion barriers (932, 942) is / are omitted, such as in cases where certain metal atoms will not diffuse from source electrode (930) or via (940) into channel layer (922). While copper is noted above as an example of a material that may be used to form source electrode (930) and / or via (940), other versions of source electrode (930) and / or via (940) may include aluminum, platinum, palladium, titanium, silver, and / or any other suitable material(s). Similarly, drain electrode (950) may comprise aluminum, platinum, palladium, titanium, copper, silver, and / or any other suitable material(s).

[0152] During an example of operation of flow cell (900), an initial measurement may be taken of the electrical current (IDS) between each source electrode (930) and the shared drain electrode (950); and this measurement may be regarded as the high-resistance-state (HRS) of the corresponding channel layer (922). Then, aqueous electrolyte fluid carrying nucleotides, polymerases, etc. may be flowed through wells (902) via a channel during an SBS process. During this process, a positive voltage (VGS) pulse may be applied to gate electrode (914); while no electrical current flows between source electrodes (930) and drain electrodes (950). While this positive voltage (VGS) is being applied to gate electrode (914), ions may be intercalated from wells (902) into the underlying channel layers (922) via electrolyte layer (920); which may change the conductance / resi stance of channel layers (922).

[0153] After the positive voltage (VGS) pulse is no longer being applied to gate electrode (914) (i.e., when positive voltage (VGS) pulse ceases), the electrical current (IDS) between source electrodes (930) and drain electrodes (950) is measured to evaluate the change in conductance / resistance of channel layers (922). Such change in conductance / resistance of channel layers (922) may indicate the number of ions intercalated from wells (902) into underlying channel layers (922), which may further indicate nucleotide incorporation events as described in greater detail below. Once this reading stage is complete, a negative voltage (VGS) pulse may be applied to gate electrode (914); while no electrical current flows between source electrodes (930) and the shared drain electrode (950). While this negative voltage (VGS) is being applied to gate electrode (914), ions may be de-intercalated from channel layers (922) back into wells (902) via electrolyte layer (920); which may change return the conductance / resistance of channel layers (922) back tothe HRS.

[0154] While the foregoing example just describes a single pulse of positive voltage (VGS) is being applied to gate electrode (914) (i.e., a writing pulse), some variations may provide a plurality of writing pulses to gate electrode (914), with an intervening plurality of channel layer (922) conductance / resi stance measurements, before a pulse of negative voltage (VGS) is applied to gate electrode (914) (i.e., an erasing pulse). Similarly, while the foregoing example just describes a single erasing pulse to gate electrode (914), some variations may provide a plurality of erasing pulses to gate electrode (914). During the above-described process, transistors (970) may provide the control logic to achieve the driving of voltage (VGS) pulses, the reading of conductance / resi stance of channel layers (922), and / or other functionality’.

[0155] FIGS. 16A-16G show an example of a process that may be used to form flow cell (900) of FIG. 15, with FIGS. 17A-17B also showing parts of this process. As shown in FIG. 16A, the process may begin with BEOL substrate assembly (910) and FEOL substrate assembly (912) being constructed, and BEOL substrate assembly (910) layered atop FEOL substrate assembly (912) as shown in FIG. 16A, using any suitable techniques. At this stage, the dielectric material (e.g., silicon dioxide, silicon nitride, etc.) of BEOL substrate assembly (910) covers diffusion barriers (932, 942) over source electrodes (930) and vias (940). By way of example only, the region of dielectric material over diffusion barriers (932, 942) may have a thickness of approximately 20 nm; or any other suitable thickness.

[0156] While FIG. 16A shows a cross-sectional side view of this arrangement, FIG. 17A shows a top view of this arrangement, with the dielectric material of BEOL substrate assembly (910) omitted to show the relationships between diffusion barriers (932, 934) that cover source electrode (930) strips and vias (940) and drain electrode (950) strips connected to vias (940). It should be understood that several source electrodes (930) may be formed as exposed regions of the same strip of conductive material; while several drain electrodes (950) may be formed as exposed regions of the same other strip of conductive material. As shown, diffusion barriers (932) that cover source electrode (930) strips are orthogonally positioned relative to drain electrode (950) strips. It should be noted that the orthogonal arrangement of source electrode (930) strips and drain electrode (950) strips may form part of a cross-point array assembly as described above in the context of RRAM arrangement (590) in FIG. 10. As also shown, diffusion barriers (942) are discretely formed with a generally square shape over the vias (940) connecting the drain electrode (950) strips within the spaces defined between diffusion barriers (932) that cover source electrode (930) strips.

[0157] Next, a set of openings (913) are formed through the dielectric material of BEOL substrate assembly (910) over portions of diffusion barriers (932, 942), thereby exposing portionsof diffusion barriers (932, 942), as shown in FIG. 16B. In some versions, each opening (913) has a width of approximately 65 nm; though any other suitable width may be used. Openings (913) may be formed using any suitable techniques. Openings (913) may have a square shape, a circular shape, or any other suitable shape. By way of further example only, openings (913) may be formed via deep-ultraviolet (DUV) lithography and dry etching; and / or using any other suitable technique(s).

[0158] Next, as shown in FIG. 16C, channel layers (922) are patterned over the regions of diffusion barriers (932, 942) that were exposed by openings (913). Channel layers (922) further span across the regions of the dielectric material of BEOL substrate assembly (910) between portions of diffusion barriers (932, 942), such that channel layers (922) are configured to provide electrical continuity between corresponding diffusion barriers (932, 942). As noted above, and as also shown in FIG. 16C, lateral outer portions (923) of channel layers (922) are positioned atop portions of the upper surface (911) of the dielectric material of BEOL substrate assembly (910). In some versions, each channel layer (922) has a width (defined between the outer edges of lateral outer portions (923)) of approximately 85 nm; though any other suitable width may be used. FIG. 17B show s the same arrangement depicted in FIG. 16C, to further illustrate the overlap betw een each channel layer (922) and the corresponding diffusion barriers (932, 942). As shown, the strips of common drain electrodes (950) and the strips of diffusion barriers (932) (and underlying common source electrode (930) strips) together form a grid pattern. As also shown, channel layers (922) (at the bottoms of wells (902), and beneath the reaction sites provided by corresponding regions of electrolyte layer (920)) overlap the intersections of this grid pattern at a slight offset.

[0159] In some versions, each channel layer (922) is in the form of a bilayer assembly where a thinner (e.g., approximately 5 nm thick) layer of tungsten is first directly deposited on diffusion barriers (932, 942); followed by a thicker (e.g., approximately 10 nm thick) layer of tungsten trioxide is directly deposited on the thinner layer of tungsten. In some such cases, the thinner layer of tungsten may provide good ohmic contact and adhesion between diffusion barriers and the thicker layer of tungsten trioxide. Regardless of whether each channel layer (922) is in the form of a bilayer assembly as described above, each channel layer (922) may be deposited using any suitable technique(s), including but not limited to physical vapor deposition (e.g., pulsed DC magnetron sputter deposition, RF magnetron sputter deposition, thermal evaporation, etc.), chemical vapor deposition (e.g.. plasma-enhanced chemical vapor deposition, atomic-layer deposition, etc.), or electrodeposition, etc. While tungsten and tungsten trioxide are described above as examples of materials that may be used to form channel layer (922), other materials may be used, including but not limited to molybdenum trioxide, titanium dioxide, vanadium pentoxide, niobium pentoxide, etc.

[0160] As noted above and as shown in FIG. 16C, lateral outer portions (923) of each channel layer (922) are elevated relative to the central region of channel layer (922), providing each channel layer (922) with a centrally recessed configuration. In some versions, this centrally recessed configuration is provided through a DUV lithography and dry etch process. Alternatively, any other suitable process(es) may be used. In some cases, it may be beneficial to minimize the thickness of each channel layer (922). For instance, minimizing the thickness of each channel layer (922) may minimize the volume of each channel layer (922), which may in turn increase the relative concentration (molar fraction) of intercalated ions (e.g., protons) and resulting change in channel conductance as described herein.

[0161] It should be understood from the foregoing description and from the illustrations provided in FIGS. 17A-17B that flow cell (900) may include wells (902) that are arrayed along two different dimensions (e g., an x-dimension and a y-dimension), such that wells (902) may together form a grid pattern or other two-dimensional pattern. It should be understood from the foregoing description and from the illustrations provided in FIGS. 17A-17B that each drain electrode (950) strip may be shared by a plurality of wells (902) that are arrayed along one dimension (e.g., an x-dimension); while each source electrode (930) strip may be shared by a plurality of wells (902) that are arrayed along another dimension (e g., a y-dimension).

[0162] Next, as shown in FIG. 16D, electrolyte layer (920) is deposited over upper surface (91 1) of the dielectric material of BEOL substrate assembly (910); and over channel layers (922). As shown, electrolyte layer (920) conforms to the varying topography presented by upper surface (911) and channel layers (922), including the recessed central regions of channel layers (922) and the upwardly protruding lateral outer portions (923). In some other versions, electrolyte layer (920) is patterned to only be positioned over channel layers (922), including lateral outer portions (923), such that electrolyte layer (920) need not necessarily span across the entire width of upper surface (911) that is exposed relative to channel layers (922).

[0163] Next, as shown in FIG. 16E, a dielectric material is deposited over electrolyte layer (920) to form a layer (903) that will later form walls (904) as described below. By way of example only, layer (903) may include a CMOS-compatible, permanent photo-imageable resin, silicon nitride, silicon dioxide, tantalum oxide, and / or any other suitable non-conducting material(s). In some versions, dielectric layer (903) may have a thickness of approximately 300 nm; or any other suitable thickness. Dielectric layer (903) may consist of a single monolithic layer or may comprise a plurality of stacked layers. As also shown in FIG. 16E, a metallic layer (915) is deposited over dielectric layer (903), with metallic layer (915) later forming gate electrode (914) as described below'. By way of example only, metallic layer (915) may have a thickness of approximately 50 nm; or any other suitable thickness.

[0164] Next, as shown in FIG. 16F, metallic layer (915) is patterned to form a plurality of openings (917) over dielectric layer (903). By way of example only, openings (917) may be formed using lithography and dry or wet etching; and / or using any other suitable process(es). After openings (917) are formed, dielectric layer (903) is etched (e.g., via anisotropic dry etch, etc.) to form wells (902) under openings (917). as shown in FIG. 16G. It should be understood that the resulting structure shown in FIG. 16G corresponds to the structure shown in FIG. 1 and described above. Metallic layer (915) may act as a hard mask over dielectric layer (903) during this etching process. In addition, electrolyte layer (920) may provide an etch stop layer, such that wells (902) ultimately extend fully from openings (917) to electrolyte layer (920).

[0165] In the present example, the bottom of each well (902) has a width of approximately 85 nm, a depth of approximately 300 nm; though any other suitable width and depth may be used. By way of example only, the width of each well (902) may range from approximately 10 nm to approximately 1,000 nm. By way of further example only, the depth of each well (902) may range from approximately 0 nm to approximately 5.000 nm. In some versions, wells (902) have a pitch (i.e., distance from the center of one well (902) to the center of the next well (902)) of approximately 150 nm; though any other suitable pitch may be used. By way of further example only, the pitch of wells (902) may range from approximately 15 nm to approximately 5,000 nm.

[0166] In some versions, metallic layer (915) is not used as a gate electrode (914) atop each wall (904). In some such versions, metallic layer (915) is still initially deposited (as shown in FIG. 16E) and openings (917) formed (as shown in FIG. 16F), such that the remaining portions of metallic layer (915) still provide a hard mask during the etching of wells (902) (as shown in FIG. 16G). However, after wells (902) are etched, the remaining portions of metallic layer (915) are removed (e.g., via dry etching or wet etching, etc.). The resulting assembly may appear as show n in FIG. 16H. This removal step of FIG. 16H is optional.

[0167] In some versions where the remaining portions of metallic layer (915) are removed after wells (902) are etched, a separate gate electrode is spaced above upper ends of walls (904), similar to the configuration described above with reference to flow cell (600) of FIG. 11; or below with reference to flow cell (1000) of FIG. 18. In some other versions where the remaining portions of metallic layer (915) are removed after wells (902) are etched, a separate gate electrode is inserted into each well (902), similar to the configuration described above with reference to flowcell (750) of FIG. 13. Alternatively, a gate electrode may be provided in any other suitable fashion. In versions where the gate electrode(s) is / are not positioned directly atop each wall (904), a non-metallic material or otherwise dielectric material may be used to provide a hard mask during the process of etching wells (902).

[0168] FIG. 18 shows an example of another flow cell (1000) that is configured and operablesimilarflow cell (900). For instance, flow cell (1000) includes a BEOL substrate assembly (1010) having a plurality of metal layers (Mi, Mx-i, Mx) and a FEOL substrate assembly (1012) under BEOL substrate assembly (1010), with FEOL substrate assembly (1012) including a plurality of transistors (1070). A plurality’ of metallic traces (1060) in the lower-most metal layer (Mi) of BEOL substrate assembly (1010) and / or in other layers of BEOL substrate assembly (1010) may provide pathways for electrical communication between transistors (1070) and other features of flow cell (1000). Flow cell (1000) further includes a plurality of Avails (1004) defining a plurality of wells (1002), with wells (1002) being configured to receive a flow of an aqueous electrolyte fluid carrying nucleotides, polymerases, etc. via a fluid channel over wells (802). Flow cell (1000) further includes an electrolyte layer (1020), a plurality of channel layers (1022) with upwardly positioned lateral outer portions (1023), a plurality of shared source electrode (1030) strips, a plurality’ of vias (1040), a plurality of diffusion barriers (1032, 1042), and a shared drain electrode (1050) strips. Again, the features of flow cell (1000) identified above may be configured and operable similar to the features of the same name in flow cell (900).

[0169] A difference between flow cell (1000) and flow cell (900) is that flow cell (1000) has agate electrode (1014) that is spaced above the top ends of walls (1004) and spanning across wells (1002). By contrast, flow cell (900) has gate electrode (914) that is positioned directly atop the top ends of walls (904). Gate electrode (1014) of flow cell (1000) may nevertheless be operable like gate electrode (914) of flow cell (900). It should also be understood that gate electrode (1014) may be positioned to form part of a channel allowing fluid to flow’ into and out of wells (1002), with gate electrode (1014) still maintaining contact with the fluid flow ing into and out of wells (1002).

[0170] VI. Examples of Chip Assembly Arrangements for Flow Cells with Electrochemical Transistors

[0171] As noted above with reference to FIGS. 10 and 17A-17B, a flow' cell (800, 900, 1000) may include electrochemical transistors where shared source electrode (830, 930, 1030) strips and shared drain electrode (850, 950. 1050) strips are arranged in a cross-point configuration. In some versions, the electrical resistance along each shared source electrode (830, 930, 1030) strip, and along each shared drain electrode (850, 950, 1050) strip, is a small portion (e.g., less than 1%) of the electrical resistance of the corresponding channel layer (822, 922, 1022). This relationship may tend to minimize parasitic voltage drops across these shared electrode (850. 950, 1050, 822, 922, 1022) strips. Conversely, the electrical resistance of each channel layer (822, 922, 1022) may need to be large enough to enable long source and drain lines as needed to operate large arrays.

[0172] In some versions, the HRS resistance of a channel layer (822, 922, 1022) comprising tungsten trioxide with a width of approximately 85 nm, a length of approximately 85 nm, and athickness of approximately 10 mm, may be approximately 29. I 9M The LRS resistance of channel layer (822, 922, 1022) may depend on the number of ions (e.g., protons) intercalated into channel layer (822, 922, 1022) following nucleotide incorporation; which in turn may depend on the number of DNA copy strands present on electrolyte layer (820, 920. 1020) at the bottom of well (802, 902, 1002). The DNA copy strand density may range from few 10s per pm2to 1 million per pm 2.

[0173] By way of example only, in the specific case of 15,000 DNA copy strands per pm2, the surface of an 85 nm x 85 nm channel layer (822, 922, 1022) may be covered by approximately 108 DNA copy strands, each generating one proton during incorporation of a matching nucleotide. Intercalation of all 108 protons into channel layer (822, 922, 1022) may change the molar fraction from x = 0 to x = 8.03 x 10’5in H-WOs. Changes in channel layer (822, 922, 1022) conductivity of 0.66 mS / cm may be possible upon change in molar fraction of Ax = 7.16 x 10‘6. Furthermore, channel layer (822, 922, 1022) conductivity7or resistivity’ of 34.26 mS / cm or 29.19 Qcm, respectively, may be possible for x = 0. The HRS would thus correspond to 29. 19 MQ. Assuming a linear relation between the change in channel layer (822, 922, 1022) conductivity versus change in molar fraction Ax for small Ax, the change in channel layer (822, 922, 1022) conductivity’ for the specific channel layer (822, 922, 1022) implementation may be approximately 11 times larger (i.e., 11 x 0.66 mS / cm). Hence, channel layer (822, 922, 1022) conductivity or resistivity' may be 34.26 mS / cm + 11 x 0.66 mS / cm = 41.52 mS / cm or 24.08 Qcm, respectively, resulting in channel layer (822, 922, 1022) resistance of 24.08M in the LRS, which is approximately 17.5% lower compared to the resistance of channel layer (822, 922, 1022) in the HRS.

[0174] Consequently, in some versions, the interconnect resistance of shared source electrodes (830, 930, 1030) and shared drain electrodes (850, 950, 1050) does not exceed approximately 241 kQ. In some versions of 22nm CMOS, the effective resistance of global metal layers (Mx-i and Mx) may be approximately 3.5 pQcm. This may mean that a 60 nm-wide, and 30 nm-thin wire with a maximum resistance of 241 kQ may have a maximum length of approximately 1.24 cm. In some cases, one such long source line may connect as many as 82.666 electrochemical transistor source electrodes (830, 930, 1030) arranged at a pitch of approximately 150 nm. Similarly, one such long drain line running orthogonal to the source line may’ connect as many as 82,666 electrochemical transistor drain electrodes (850, 950, 1050) arranged at a pitch of approximately 150 nm. The maximum cross-point array size may then be 82,6662= 6.8B, with a sensor density’ of 44 million electrochemical transistors per mm2. Various sensor array sizes and sensor densities are possible in different CMOS nodes employing different interconnect densities and resistances, and with different electrochemical transistor channel layer (822, 922, 1022) sizes and resistances.By way of example only, the density may range between 1,000 to 1,000 million electrochemical transistors per mm2.

[0175] Another constraint to array size may include the parasitic capacitance of the metal interconnects that, together with the interconnect resistance, may introduce considerable resistive- capacitive (RC) delays and signal distortions to high-frequency signals. For instance, an RC delay for a 1-mm global interconnect in 22nm CMOS may be approximately 9 ns. Assuming a 1MHz operating frequency for a reading voltage (VDS) pulse (e.g., from voltage source (540) or the equivalent thereof), with a pulse duration of approximately 1 ps, and allowing the RC delay to be at most 10% of the pulse width (i.e., 100 ns), the longest global interconnect length may be approximately 1.10 cm. Alternatively, the longest global interconnect length may have any other suitable value.

[0176] With the maximum cross-point array size limited to approximately 1.1 cm x 1.1 cm, a chip architecture is conceivable where multiple such arrays, each with its own peripheral and control circuitry, are arranged on a single chip. Examples of such an architecture are shown in FIGS. 19-21. FIG. 19 shows a tile (1100) that may be repeatedly incorporated into a larger arrangement (1200) as show n in FIG. 20: w hile FIG. 21 show s another example of a chip assembly (1300). Tile (1100) of FIG. 19 includes a nanowell assembly (1110), which may correspond to the features of flow cell (800, 900, 1000) that are above BEOL substrate assembly (810, 910, 1010). In the present example, nanowell assembly (1110) includes an array of 6 billion wells (802, 902, 1002), though any other suitable number of w ells may be used. Tile (1100) of FIG. 19 further includes a cross-point array assembly (1120), which may correspond to the features of flow cell (800. 900, 1000) that are contained in BEOL substrate assembly (810, 910. 1010). Tile (1100) of FIG. 19 further includes a peripheral circuit assembly (1130), which may correspond to the features of flow cell (800, 900, 1000) that are contained in FEOL substrate assembly (812, 912, 1012).

[0177] As shown in FIG. 20, chip assembly (1200) of the present example includes four tiles (1100a, 1100b, 1100c, HOOd) and one common circuit assembly (1210). Alternatively, arrangement (1200) may include any other suitable number of tiles (1100a, 1100b, 1100c, 1 lOOd). Each tile (1100a, 1100b, 1100c, HOOd) consists of a cross-point array assembly (1120) and associated peripheral circuit assembly (1130). It should be understood that nanowell assemblies (11 10) are omitted from the view- shown in FIG. 20. As shown, tiles (1100a, 1100b, 1100c, HOOd) are oriented such that the comers of cross-point array assemblies (1120a, 1120b, 1120c, 1120d) meet at an intersection (1220). Common circuit assembly (1210) includes various circuit features such as inputs, outputs, power management circuits, memory buffer, etc., to enable operation of tiles (1100a, 1100b, 1100c, HOOd). In some versions, the inputs and outputs of common circuitassembly (1210) are coupled with controller (114, 308) of system (100, 300). In the example shown, each tile (1100a, 1100b, 1100c, HOOd) has a length of 12 mm and a width of 12 mm; while arrangement (1200) has a length of 32 mm and a width of 24 mm. These dimensions are just examples and may be different in other versions.

[0178] Chip assembly (1300) of FIG. 21 includes a base substrate (1302). a set of four tiles (1310a, 1310b, 1310c, 13 lOd), and a digital interface (1320). It should be understood that any other number of tiles (1310a, 1310b, 1310c, 13 lOd) may be used. Each tile (1310a, 1310b, 1310c, 131 Od) includes a respective set of electrochemical transistors (1312) arranged in a cross-point array assembly (1313), a respective set of peripheral circuits (1314). and a respective control circuit (1316). While only nine electrochemical transistors (1312) are shown in each cross-point array assembly (1313) in FIG. 21, it should be understood that the number of electrochemical transistors (1312) in each cross-point array assembly (1313) may be substantially higher (e.g., on the order of millions or billions). It should also be understood that the electrochemical transistors (1312) shown in FIG. 21 represent the electrochemical transistor components of flow cells (800, 900, 1000), including gate electrodes (814, 914, 1014), source electrodes (830, 930, 1030), and drain electrodes (850, 950, 1050). Moreover, the other components of flow cells (800, 900, 1000) may be integrated in / on each tile (1310a, 1310b, 1310c, 13 lOd) or represent common circuit elements such as the digital interface (1320) shared across all tiles (1310a, 1310b, 1310c. 131 Od).

[0179] By way of example only, peripheral circuit assembly (1314) of each tile (1310a, 1310b, 1310c, 1310d) may include analog and mixed-signal circuits such as sense amplifiers, noise suppression circuitry, filters, decoders, impedance buffers, ADCs, line drivers, level shifters, phase lock loop, switch-mode power supply controller, etc. By way of further example only, control circuit (1316) of each tile (1310a, 1310b, 1310c, 13 lOd) may include row and column controllers. By way of further example only, digital interface (1320) may include serial communication controllers, memory controllers, sampling clocks, counters, timers, pulse-width- modulation controllers, calibration and trim parameter storage, synchronization, mode selection, threshold settings, device ID, temperature sensors, embedded microcontroller core and / or state machine(s), etc. Digital interface (1320) may provide unidirectional or bidirectional communication with controller (114, 308) of system (100, 300) and / or any other suitable external device(s). In some versions of chip assemblies (1200, 1300), the peripheral circuit assembly (1130, 1314) and digital interface (1210, 1320) take up less than half of the total chip area. Assuming a chip area of approximately 26x32 mm2corresponding to the maximum exposure field of a 193 nm DUV lithography system, a chip assembly (1200, 1300) may include at least 18.3 billion electrochemical transistors.

[0180] FIGS. 22-23 show examples of how chip assembly (1300) may be integrated into aflow cell, though it should be understood that the below teachings may also be applied to arrangement (1200) and / or other variations. FIG. 22 shows an example of a flow cell (1400) where chip assembly (1300) is positioned atop a printed circuit board (PCB) (1402). A lid layer (1410) is positioned over chip assembly (1300) and is secured to chip assembly (1300) by an adhesive (1430). In addition to securing lid layer (1410) to chip assembly (1300). adhesive (1430) spaces lid layer (1410) away from chip assembly (1300) to define a gap (1420) providing a channel through which fluid may flow. Alternatively, any other suitable structures may be used to secure lid layer (1410) relative to chip assembly (1300) and space lid layer (1410) away from chip assembly (1300) to define gap (1420). A set of openings (1412) are formed through lid layer (1410) to reach gap (1420). Fluid may thus be flowed into and out of gap (1420) via openings (1412). Such fluid may include an aqueous electrolyte fluid carrying nucleotides, polymerases, etc., as described above. This fluid flowing through gap (1420) may further reach wells (e.g., wells (802, 902, 1002)) in chip assembly (1300).

[0181] In the example shown in FIG. 22. a gate electrode (1430) is integrated into chip assembly (1300), within gap (1420). While gate electrode (1430) is shown as a continuous layer in FIG. 22, gate electrode (1430) may provide a plurality of pathways for fluid to flow from gap (1420) into wells (e g., wells (802, 902, 1002)) in chip assembly (1300) under gate electrode (1430). Gate electrode (1430) is coupled with PCB (1402) via a wire (1440). One or more other wires (1442) may also extend between PCB (1402) and other electrical components of chip assembly (1300) (e.g., input / output pads connected to digital interface (1320) or peripheral circuit assembly (1130, 1314) via respective traces, etc.). Alternatively, electrical components of PCB (1402) may be coupled with gate electrode (1430) and / or other electrical components of chip assembly (1300) in any other suitable fashion.

[0182] FIG. 23 shows another example of a flow cell (1500) where chip assembly (1300) is positioned atop a printed circuit board (PCB) (1502). A lid layer (1510) is positioned over chip assembly (1300) and is secured to chip assembly (1300) by an adhesive (1530). In addition to securing hd layer (1510) to chip assembly (1300), adhesive (1530) spaces lid layer (1510) away from chip assembly (1300) to define a gap (1520) providing a channel through which fluid may flow. Alternatively, any other suitable structures may be used to secure lid layer (1510) relative to chip assembly (1300) and space lid layer (1510) away from chip assembly (1300) to define gap (1520). A set of openings (1512) are formed through hd layer (1510) to reach gap (1520). Fluid may thus be flowed into and out of gap (1520) via openings (1512). Such fluid may include an aqueous electrolyte fluid carry ing nucleotides, polymerases, etc., as described above. This fluid flowing through gap (1520) may further reach wells (e.g., wells (802, 902, 1002)) in chip assembly (1300).

[0183] In the example shown in FIG. 23, a gate electrode (1530) is inserted into gap (1520) via an opening (1512). Gate electrode (1530) is not directly coupled with PCB (1502) in this example, though gate electrode (1530) may be directly coupled with PCB (1502) (e.g., via a wire) in some other examples. One or more wires (1542) extend between PCB (1502) and other electrical components of chip assembly (1300) (e.g.. input / output pads connected to digital interface (1320) or peripheral circuit assembly (1314) via respective traces, etc.). Alternatively, electrical components of PCB (1502) may be coupled with electrical components of chip assembly (1300) in any other suitable fashion.

[0184] It should be understood that the various flow cells (600, 700, 750, 800, 900. 1000, 1400, 1500) described above may provide an electrochemical random-access memory (ECRAM) sensor assembly that is configured to receive and store ions emitted from the plurality of reaction sites during a process such as, for example, a sequencing by synthesis process. The ECRAM sensor assembly may include a combination of the various electrochemical transistor components described above (e.g., gate electrode (604, 704, 756. 814, 914. 1014. 1430. 1530), source electrode (626, 726, 774, 830, 930, 1030) strips, drain electrode (628, 728, 776, 850, 950, 1050) strips, and channel layer (624, 724, 782, 822, 922, 1022)); and various additional components. Those additional components may (or may not) include at least a portion of one or more of the following: traces (860, 960. 1060), transistors (870, 970, 1070), cross-point array assembly (1120, 1313), peripheral circuit assembly (1 130, 1314), control circuit (1316), digital interface (1210, 1320), and / or PCB (1402, 1502).

[0185] VII. Examples of Methods of Using Electrochemical Transistors in SBS Processes

[0186] As noted above, a flow cell (600, 700, 750, 800. 900, 1000, 1400. 1500) that includes electrochemical transistors arranged in a high-density cross-point array may be used for DNA sequencing (e.g., SBS). Such sequencing may be performed by sequentially flowing four solutions of native nucleotides (i.e., dACTP, dCTP, dGTP, dTTP) through flow cell (600, 700, 750, 800, 900, 1000, 1400, 1500) while applying a global, positive gate voltage (VGS), to all gate electrodes (604. 704, 756, 814, 914, 1014, 1430. 1530) and monitoring for an incorporation signal via changes in the electrical resistance of each channel layer (624, 724, 782, 822, 922, 1022) of each electrochemical transistor. During this process, the upper surfaces of electrolyte layers (622, 722, 784, 820, 920, 1020) within wells (610, 710, 760, 802, 902, 1002) may provide reaction sites where nucleotide strands are anchored. If the nucleotide solution results in a successful incorporation, there will be a burst of ions (e.g., H+) released by the polymerase activity incorporating the matching nucleotide, and a resulting signal from the respective electrochemical transistor. If a solution does not result in incorporation, the respective electrochemical transistor will maintain its initial resistance state (i.e., the HRS).

[0187] FIG. 24 shows a set of graphs (2000, 2010, 2020) representing an example of signals that may be associated with an electrochemical transistor as described above where matching nucleotide incorporation occurs in a well (610, 710, 760, 802, 902, 1002) of a flow cell (600, 700, 750, 800. 900, 1000, 1400, 1500) during a DNA sequencing process. In particular, graph (2000) includes a plot (2002) of ionic concentration in well (610. 710, 760, 802. 902, 1002) over time during the sequencing process; graph (2010) includes a plot (2012) of the voltage (VGS) that may be applied to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530) during the same time period; and graph (2020) includes a plot (2022) of the electrical current (IDS) through channel layer (624. 724, 782. 822, 922, 1022) that may be measured during the same time period.

[0188] As shown in plot (2002), the concentration of ions (H+), which are released by the polymerase activity incorporating the matching nucleotide, increase then decrease along a bell cune during this period.

[0189] As shown in plot (2012), a series of writing pulses of positive voltage (VGS) are applied to gate electrode (604, 704, 756. 814. 914, 1014. 1430, 1530) during the same time period; followed by a series of erasing pulses of negative voltage (VGS) to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530) after the ions (H+) are no longer being released. By way of example only, the amplitude of the writing pulses of positive voltage (VGS) may be less than or equal to approximately 1 V. Alternatively, any other suitable amplitude may be used. By way of further example, each writing pulse of positive voltage (VGS) may have a duration ranging from approximately 1 ps to approximately 100 ms. Alternatively, any other suitable duration may be used. In some versions, the combination of the amplitude and duration of each writing pulse of positive voltage (VGS) is below the threshold for water hydrolysis.

[0190] In the present example, the duration between each writing pulse of positive voltage (VGS) is very short (e.g., approximately 1 ns). In some cases, by minimizing the duration between each writing pulse of positive voltage (VGS) (i.e., the period when positive voltage (VGS) is not being applied to gate electrode (604, 704, 756, 814. 914, 1014, 1430, 1530)), this may minimize a risk of ions (H+) from escaping well (610. 710, 760, 802. 902, 1002) since the positive voltage (VGS) at gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530) may otherwise prevent or inhibit diffusion of ions (H+) from each well (610, 710, 760, 802, 902, 1002). It may be desirable to avoid or at least minimize the escape / diffusion of such ions (H+) because such escaping / diffusing ions (H+) may not be intercalated into channel layer (624. 724, 782, 822, 922, 1022), which may in turn reduce accuracy / reliability of incorporation conclusions drawn from measurements of the current electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) during the reading stages.

[0191] As shown in plot (2022), a series of measurements of the cunent electrical current (IDS)through channel layer (624, 724, 782, 822, 922, 1022) are taken between the pulses of voltage (VGS) that are applied to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530).

[0192] As shown collectively by plots (2002, 2012, 2022) in FIG. 24, the measurement values of the electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) increase as the ions (H+) that are released by the polymerase activity incorporating the matching nucleotide are intercalated into channel layer (624, 724, 782, 822, 922, 1022), thereby increasing the electrical conductivity (i.e., decreasing the electrical resistance) of channel layer (624, 724, 782, 822, 922, 1022). The change in the measurement values of the electrical current (IDS) through channel layer (624, 724, 782, 822. 922, 1022) (i.e., to a LRS value) thus indicate that a matching incorporation event has occurred. As also shown in FIG. 24, and as further described above, the measurement values of the electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) eventually return to the HRS value after a sufficient number of erasing pulses of negative voltage (VGS) are applied to gate electrode (604, 704, 756. 814, 914, 1014, 1430. 1530); as the ions are de-intercalated from channel layer (624, 724. 782, 822. 922, 1022).

[0193] While seven writing pulses of positive voltage (VGS) and two erasing pulses of negative voltage (VGS) are shown in graph (2010), any other suitable number of writing pulses and / or erasing pulses may be used. In some versions, the number of writing pulses and / or erasing pulses is predetermined. In some other versions, the number of writing pulses and / or erasing pulses is automatically adjusted ad hoc, based on real-time feedback.

[0194] For instance, a control logic (e.g., in controller (114, 308) of system (100, 300), in control units (1316) of chip assembly (1300), in digital interface (1320), etc.) may track the measurements of the electrical cunent (IDS) through channel layer (624, 724, 782. 822, 922. 1022) as the writing pulses of positive voltage (VGS) are applied to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530). If the control logic observes an increase in the measurement values of the electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022), the control logic may allow the continued application of writing pulses of positive voltage (VGS) to gate electrode (604. 704, 756, 814, 914. 1014, 1430. 1530) as the measured electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) continues to increase. Once the measured electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) stabilizes at a certain LRS value (e.g., the measured electrical current (IDS) remains substantially the same through application of two or more writing pulses), the control logic may provide a transition to the application of erasing pulses of negative voltage (VGS) to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530).

[0195] In some such cases such as those described above where the number of writing pulses is automatically adjusted ad hoc, based on real-time feedback (e.g., based on values obtainedduring reading stages), the control logic may ensure that gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530) remains in a writing mode (i.e., applying pulses of positive voltage (VGS) to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530)) for the whole duration of nucleotide incorporation to confine the ions (H+) to the reaction site in well (610, 710, 760, 802. 902, 1002); and to minimize signal loss and crosstalk due to diffusion of ions (H+) from one well (610, 710, 760, 802, 902, 1002) to another well (610, 710, 760, 802, 902, 1002). It should be understood that, while gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530) remains in a writing mode (i.e., applying pulses of positive voltage (VGS) to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530)) for the whole duration of nucleotide incorporation, the write voltage on the gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530) may be interrupted after each write pulse to enable reading pulses between source electrode and drain electrode. In other words, the reading and writing pulses may alternate for the whole duration of nucleotide incorporation.

[0196] In versions where the number of erasing pulses is automatically adjusted ad hoc. based on real-time feedback, the control logic may track the measurements of the electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) as the erasing pulses of negative voltage (VGS) are applied to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530). Once the control logic observes that the measurement of the electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) has reached the HRS value, the control logic may cease application of the erasing pulses of negative voltage (VGS) to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530). Once the appropriate number of erasing pulses of negative voltage (VGS) are applied to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530), and channel layer (624, 724, 782, 822, 922, 1022) returns to the HRS, a wash cycle may be applied through flow cell (600, 700, 750, 800, 900, 1000, 1400, 1500) in preparation of another nucleotide flushing and incorporation cycle.

[0197] FIG. 25 shows a set of graphs (2030, 2040, 2050) representing an example of signals that may be associated with an electrochemical transistor as described above where no matching nucleotide incorporation occurs in a well (610, 710, 760, 802, 902, 1002) of a llow cell (600, 700, 750, 800. 900, 1000. 1400, 1500) during a DNA sequencing process. In particular, graph (2030) includes a plot (2032) of ionic concentration in well (610, 710, 760, 802, 902, 1002) over time during the sequencing process; graph (2040) includes a plot (2042) of the voltage (VGS) that may be applied to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530) during the same time period; and graph (2050) includes a plot (2052) of the electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) that may be measured during the same time period.

[0198] As shown in plot (2032), the concentration of ions (H+) does not change during this period, due to the lack of polymerase activity7incorporating a matching nucleotide during this period. As shown in plot (2042), a series of writing pulses of positive voltage (VGS) are appliedto gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530) during the same time period; followed by a series of erasing pulses of negative voltage (VGS) to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530) in accordance with a predetermined duty cycle. As shown in plot (2052), a series of measurements of the current electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) are taken between the pulses of voltage (VGS) that are applied to gate electrode (604, 704, 756, 814, 914, 1014, 1430, 1530). Since no ions (H+) were released due to the lack of nucleotide incorporation, no ions (H+) are intercalated into channel layer (624, 724, 782, 822, 922, 1022). Channel layer (624, 724, 782, 822, 922, 1022) thus remains in the HRS throughout this period, such that the measurements of the current electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) remain consistent throughout this period. The lack of any change in the measured electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) thus indicates that nucleotide incorporation has not occurred.

[0199] In some scenarios, there may be a small number of background ions (H+) that are intercalated into channel layer (624. 724. 782, 822. 922. 1022) even if nucleotide incorporation does not occur. In some such scenarios, however, the effects of such a small number of background ions (H+) being intercalated into channel layer (624, 724, 782, 822, 922, 1022) may be negligible.

[0200] As noted above, a DNA sequencing process (e.g.. SBS) may include a process of sequentially flowing four solutions of native nucleotides (i.e., dACTP, dCTP, dGTP, dTTP) through flow cell (600, 700, 750, 800, 900, 1000, 1400, 1500) while providing the writing / reading / erasing operations through electrochemical transistors of flow' cell (600, 700, 750, 800, 900, 1000, 1400. 1500), to track nucleotide incorporation events. The process described above with respect to FIGS. 24-25 may be carried out for each nucleotide in a sequence, with a washing cycle being performed through flow- cell (600, 700, 750, 800, 900, 1000, 1400, 1500) between stages of flowing different native nucleotides through flow cell (600, 700, 750, 800, 900, 1000, 1400, 1500) to thereby clear any residual nucleotides from flow cell (600, 700, 750, 800, 900, 1000, 1400. 1500) before the next nucleotide is flowed through flow cell (600, 700, 750, 800, 900, 1000, 1400, 1500).

[0201] In the example described above, incorporation of each different kind of nucleotide releases the same or substantially same number of ions (H+) having the same characteristics, such that the reading signal profile of the electrical current (IDS) through channel layer (624, 724, 782, 822, 922, 1022) may be the same or substantially the same regardless of which kind of nucleotide is incorporated during an incorporation event. Thus, in some scenarios, this may involve the above-described sequence where a first nucleotide type is flowed through flow cell (600, 700, 750, 800. 900, 1000, 1400, 1500), followed by a washing cycle through flow cell (600, 700, 750,800, 900, 1000, 1400, 1500), followed by flow of a second nucleotide type through flow cell (600, 700, 750, 800, 900, 1000, 1400, 1500), and so on.

[0202] VIII. Examples of Combinations

[0203] The following examples relate to various non-exhaustive ways in which the teachings herein may be combined or applied. The following examples are not intended to restrict the coverage of any claims that may be presented at any time in this application or in subsequent filings of this application. No disclaimer is intended. The following examples are being provided for nothing more than merely illustrative purposes. It is contemplated that the various teachings herein may be arranged and applied in numerous other ways. It is also contemplated that some variations may omit certain features referred to in the below examples. Therefore, none of the aspects or features referred to below should be deemed critical unless otherwise explicitly indicated as such at a later date by the inventors or by a successor in interest to the inventors. If any claims are presented in this application or in subsequent filings related to this application that include additional features beyond those referred to below, those additional features shall not be presumed to have been added for any reason relating to patentability.

[0204] Example 1

[0205] An apparatus, comprising: a channel configured to receive fluid containing nucleotides; a plurality of reaction sites in the channel, each reaction site of the plurality of reaction sites being configured to anchor a strand of nucleotides; and a sensor assembly, the sensor assembly including: at least one gate electrode, one or more source electrodes, each source electrode of the one or more source electrodes being associated with at least one reaction site of the plurality of reaction sites, one or more drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality of reaction sites, and a plurality of sensing channels, each sensing channel of the plurality of sensing channels extending from a corresponding source electrode of the one or more source electrodes to a corresponding drain electrode of the one or more drain electrodes, each sensing channel being positioned to receive an ion emitted from a corresponding reaction site of the plurality of reaction sites when a voltage is applied to the at least one gate electrode during a sequencing by synthesis process.

[0206] Example 2

[0207] The apparatus of Example 1, the plurality of reaction sites comprising a plurality of wells formed in a floor of the channel.

[0208] Example 3

[0209] The apparatus of Example 2, the plurality of wells comprising a plurality of nanowells.

[0210] Example 4

[0211] The apparatus of any of Examples 1 through 3, the at least one gate electrode comprising a single gate electrode that is configured to apply a voltage to two or more reaction sites of the plurality of reaction sites.

[0212] Example 5

[0213] The apparatus of Example 4, the single gate electrode being configured to apply a voltage to all reaction sites of the plurality of reaction sites.

[0214] Example 6

[0215] The apparatus of any of Examples 1 through 5, the sensor assembly further including a plurality of metallic diffusion barriers, each metallic diffusion barrier being interposed between a corresponding source electrode of the one or more source electrodes and a corresponding sensing channel of the plurality of sensing channels.

[0216] Example 7

[0217] The apparatus of any of Examples 1 through 6, the sensor assembly further including at least one metallic diffusion barrier interposed between a corresponding drain electrode of the one or more drain electrodes and a corresponding sensing channel of the plurality of sensing channels.

[0218] Example 8

[0219] The apparatus of Example 7, further comprising one or more drain electrode vias, each drain electrode via of the one or more drain electrode vias being interposed between the at least one metallic diffusion barrier and the corresponding drain electrode of the one or more drain electrodes.

[0220] Example 9

[0221] The apparatus of any of Examples 1 through 8, further comprising one or more source electrode vias, each source electrode via of the one or more source electrode vias being interposed between a corresponding sensing channel and a corresponding source electrode of the plurality of source electrodes.

[0222] Example 10

[0223] The apparatus of any of Examples 1 through 9, the sensor assembly further including a plurality of sensing channel barriers, each sensing channel barrier of the plurality of sensing channel barriers being interposed between a corresponding sensing channel of the plurality of sensing channels and the corresponding reaction site of the plurality of reaction sites, each sensing channel barrier of the plurality of sensing channel barriers being configured to allow diffusion of ions through the sensing channel barrier.

[0224] Example 11

[0225] The apparatus of Example 10, each sensing channel barrier of the plurality of sensingchannel barriers comprising an electrically insulating material.

[0226] Example 12

[0227] The apparatus of any of Examples 10 through 11, each sensing channel barrier of the plurality of sensing channel barriers comprising tantalum pentoxide.

[0228] Example 13

[0229] The apparatus of any of Examples 1 through 12, the one or more drain electrodes comprising a plurality of drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality of reaction sites.

[0230] Example 14

[0231] The apparatus of any of Examples 1 through 12, the one or more drain electrodes comprising a drain electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

[0232] Example 15

[0233] The apparatus of Example 14, the sensor assembly further including a plurality of conductive drain electrode vias, each conductive drain electrode via of the plurality of conductive drain electrode vias being configured to provide a path for electrical communication between a corresponding sensing channel of the plurality of sensing channels and the drain electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

[0234] Example 16

[0235] The apparatus of any of Examples 1 through 15, the one or more source electrodes comprising a source electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

[0236] Example 17

[0237] The apparatus of Example 16, the sensor assembly further including a plurality of conductive source electrode vias, each conductive source electrode via of the plurality of conductive source electrode vias being configured to provide a path for electrical communication between a corresponding sensing channel of the plurality of sensing channels and the source electrode that is in electrical communication with two or more sensing channels of the plurality' of sensing channels.

[0238] Example 18

[0239] The apparatus of any of Examples 1 through 17, the one or more source electrodes comprising a first source electrode in electrical communication with two or more sensing channels of the plurality of sensing channels.

[0240] Example 19

[0241] The apparatus of Example 18, the one or more drain electrodes comprising a first drain electrode in electrical communication with two or more sensing channels of the plurality of sensing channels.

[0242] Example 20

[0243] The apparatus of Example 19, the first drain electrode being positioned on a line oriented orthogonally relative to a line on which the first source electrode is positioned.

[0244] Example 21

[0245] The apparatus of any of Examples 18 through 20, the first source electrode being in electrical communication with a first sensing channel of the plurality of sensing channels and a second sensing channel of the plurality of sensing channels, the one or more source electrodes further comprising a second source electrode in electrical communication with a second sensing channel of the plurality of sensing channels and a third sensing channel of the plurality of sensing channels.

[0246] Example 22

[0247] The apparatus of Example 21, the first source electrode being oriented parallel to the second source electrode.

[0248] Example 23

[0249] The apparatus of any’ of Examples 21 through 22, the one or more drain electrodes comprising: a first drain electrode in electrical communication with the first sensing channel and the third sensing channel, and a second drain electrode in electrical communication with the second sensing channel and the fourth sensing channel.

[0250] Example 24

[0251] The apparatus of Example 23, the first drain electrode being oriented parallel to the second drain electrode.

[0252] Example 25

[0253] The apparatus of any of Examples 23 through 24, the first source electrode being oriented orthogonally relative to the first drain electrode, the first source electrode further being oriented orthogonally relative to the second drain electrode.

[0254] Example 26

[0255] The apparatus of any of Examples 1 through 25, further comprising a processor, the processor being configured to determine base pairs of nucleotide strands anchored to the plurality of reaction sites, based at least in part on signals from the sensor assembly.

[0256] Example 27

[0257] The apparatus of Example 26, the processor being configured to determine base pairs of nucleotide strands anchored to the plurality of reaction sites, based at least in part on a changein electrical resistance of the plurality of sensing channels.

[0258] Example 28

[0259] The apparatus of any of Examples 1 through 27, further comprising a fluid communication assembly operable to drive fluids through the channel to thereby perform sequencing by synthesis at the plurality of reaction sites.

[0260] Example 29

[0261] An apparatus, comprising: a channel configured to receive fluid containing nucleotides; a plurality of reaction sites in the channel, each reaction site of the plurality of reaction sites being configured to anchor a strand of nucleotides; and an electrochemical random access memory (ECRAM) sensor assembly, the ECRAM sensor assembly being configured to receive and store ions emitted from the plurality of reaction sites during a sequencing by synthesis process.

[0262] Example 30

[0263] The apparatus of Example 29. the ECRAM sensor assembly including: at least one gate electrode, one or more source electrodes, each source electrode of the one or more source electrodes being associated with at least one reaction site of the plurality of reaction sites, one or more drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality of reaction sites, and a plurality of sensing channels, each sensing channel of the plurality of sensing channels extending from a corresponding source electrode of the one or more source electrodes to a corresponding drain electrode of the one or more drain electrodes, each sensing channel being positioned to receive an ion emitted from a corresponding reaction site of the plurality of reaction sites during a sequencing by synthesis process.

[0264] Example 31

[0265] A method comprising: flowing a plurality of nucleotides of a first type through a flow channel, the flow channel including a plurality of reaction sites, each reaction site of the plurality of reaction sites including one or more nucleotides anchored to the reaction site, one or more ions being emitted from one or more reaction sites of the plurality of reaction sites while the plurality of nucleotides of the first type are flowed through the flow channel, the one or more ions being emitted when nucleotides of the first type bind to nucleotides anchored to one or more reaction sites to form a first base pair; and sensing the one or more ions emitted when nucleotides of the first type bind to nucleotides anchored to one or more reaction sites to form the first base pair, the one or more emitted ions being sensed by an electrochemical random access memory (ECRAM) sensor assembly.

[0266] Example 32

[0267] The method of Example 31, further comprising: flowing a plurality of nucleotides of asecond type through the flow channel, one or more ions being emitted from one or more reaction sites of the plurality of reaction sites while the plurality of nucleotides of the second type are flowed through the flow channel, the one or more ions being emitted when nucleotides of the second type bind to nucleotides anchored to one or more reaction sites to form a second base pair; and sensing the one or more ions emitted when nucleotides of the second type bind to nucleotides anchored to one or more reaction sites to form the second base pair, the one or more emitted ions being sensed by an electrochemical random access memory' (ECRAM) sensor assembly.

[0268] Example 33

[0269] The method of any of Examples 31 through 32, further comprising: receiving a first signal from the ECRAM sensor assembly; and identifying the formed first base pair based at least in part on the first signal received from the ECRAM sensor assembly.

[0270] Example 34

[0271] The method of Examples 32 and 33, further comprising: receiving a second signal from the ECRAM sensor assembly; and identifying the formed second base pair based at least in part on the second signal received from the ECRAM sensor assembly.

[0272] Example 35

[0273] The method of any of Examples 31 through 34, the ECRAM sensor assembly comprising a plurality of sensing channels, each sensing channel of the plurality of sensing channels having a conductance, the conductance of one or more sensing channels of the plurality of sensing channels changing in response to the one or more ions emitted when nucleotides of the first type bind to nucleotides anchored to one or more reaction sites to form the first base pair.

[0274] Example 36

[0275] The method of Example 35, further comprising applying a voltage to reset the conductance of the one or more sensing channels of the plurality of sensing channels after the conductance of the one or more sensing channels of the plurality of sensing channels changes in response to the one or more ions emitted when nucleotides of the first type bind to nucleotides anchored to one or more reaction sites to form the first base pair.

[0276] Example 37

[0277] The method of Example 36, the act of applying a voltage to reset the conductance of the one or more sensing channels of the plurality of sensing channels resulting in intercalation of the one or more ions emitted when nucleotides of the first type bind to nucleotides anchored to one or more reaction sites to form the first base pair from the one or more sensing channels of the plurality of sensing channels.

[0278] Example 38

[0279] An apparatus, comprising: a channel to receive fluid containing nucleotides; a pluralityof reaction sites in the channel, each reaction site of the plurality of reaction sites to anchor a strand of nucleotides; and a sensor assembly, the sensor assembly including: at least one gate electrode, one or more source electrodes, each source electrode of the one or more source electrodes being associated with at least one reaction site of the plurality of reaction sites, one or more drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality of reaction sites, and a plurality of sensing channels, each sensing channel of the plurality of sensing channels extending from a corresponding source electrode of the one or more source electrodes to a corresponding drain electrode of the one or more drain electrodes, each sensing channel being positioned to receive an ion emitted from a corresponding reaction site of the plurality of reaction sites when a voltage is applied to the at least one gate electrode during a sequencing by synthesis process.

[0280] Example 39

[0281] The apparatus of Example 38, the plurality of reaction sites comprising a plurality of nanowells formed in a floor of the channel.

[0282] Example 40

[0283] The apparatus of Example 39, the plurality of wells comprising a plurality of nanowells.

[0284] Example 41

[0285] The apparatus of any of Examples 38 through 40, the at least one gate electrode comprising a single gate electrode that is to apply a voltage to two or more reaction sites of the plurality7of reaction sites.

[0286] Example 42

[0287] The apparatus of Example 41, the single gate electrode to apply a voltage to all reaction sites of the plurality of reaction sites.

[0288] Example 43

[0289] The apparatus of any of Examples 38 through 42, the sensor assembly further including a plurality of metallic diffusion barriers, each metallic diffusion barrier being interposed between a corresponding source electrode of the one or more source electrodes and a corresponding sensing channel of the plurality7of sensing channels.

[0290] Example 44

[0291] The apparatus of any of Examples 38 through 43. the sensor assembly further including at least one metallic diffusion barrier interposed between a corresponding drain electrode of the one or more drain electrodes and a corresponding sensing channel of the plurality of sensing channels.

[0292] Example 45

[0293] The apparatus of Example 44, further comprising one or more vias, each via of the one or more vias being interposed between the at least one metallic diffusion barrier and the corresponding drain electrode of the one or more drain electrodes.

[0294] Example 46

[0295] The apparatus of any of Examples 38 through 45. the sensor assembly further including a plurality of sensing channel barriers, each sensing channel barrier of the plurality of sensing channel barriers interposed between a corresponding sensing channel of the plurality of sensing channels and the corresponding reaction site of the plurality of reaction sites, each sensing channel barrier of the plurality of sensing channel barriers allows diffusion of ions through the sensing channel barrier.

[0296] Example 47

[0297] The apparatus of Example 46, each sensing channel barrier of the plurality of sensing channel barriers comprising an electrically insulating material.

[0298] Example 48

[0299] The apparatus of any of Examples 46 through 47, each sensing channel barrier of the plurality of sensing channel barriers comprising tantalum pentoxide.

[0300] Example 49

[0301] The apparatus of any of Examples 38 through 48, the one or more drain electrodes comprising a plurality of drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality of reaction sites.

[0302] Example 50

[0303] The apparatus of any of Examples 38 through 48, the one or more drain electrodes comprising a drain electrode that is in electncal communication with two or more sensing channels of the plurality of sensing channels.

[0304] Example 51

[0305] The apparatus of any of Examples 38 through 50, the sensor assembly further including a plurality of conductive drain electrode vias, each conductive drain electrode via of the plurality of conductive drain electrode vias to provide a path for electrical communication between a corresponding sensing channel of the plurality’ of sensing channels and the drain electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

[0306] Example 52

[0307] The apparatus of any of Examples 35 through 51, the one or more source electrodes comprising a source electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

[0308] Example 53

[0309] The apparatus of Example 52, the sensor assembly further including a plurality of conductive source electrode vias, each conductive source electrode via of the plurality7of conductive source electrode vias being configured to provide a path for electrical communication between a corresponding sensing channel of the plurality of sensing channels and the source electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

[0310] Example 54

[0311] The apparatus of any of Examples 38 through 53, the one or more source electrodes comprising a first source electrode in electrical communication with two or more sensing channels of the plurality of sensing channels.

[0312] Example 55

[0313] The apparatus of Example 54, the one or more drain electrodes comprising a first drain electrode in electrical communication with two or more sensing channels of the plurality of sensing channels.

[0314] Example 56

[0315] The apparatus of Example 55, the first drain electrode being positioned on a line oriented orthogonally relative to a line on which the first source electrode is positioned.

[0316] Example 57

[0317] The apparatus of any of Examples 54 through 56, the first source electrode being in electrical communication with a first sensing channel of the plurality of sensing channels and a second sensing channel of the plurality of sensing channels, the one or more source electrodes further comprising a second source electrode in electrical communication with a second sensing channel of the plurality7of sensing channels and a third sensing channel of the plurality of sensing channels.

[0318] Example 58

[0319] The apparatus of Example 57, the first source electrode being oriented parallel to the second source electrode.

[0320] Example 59

[0321] The apparatus of any of Examples 57 through 58, the one or more drain electrodes comprising: a first drain electrode in electrical communication with the first sensing channel and the third sensing channel, and a second drain electrode in electrical communication with the second sensing channel and the fourth sensing channel.

[0322] Example 60

[0323] The apparatus of Example 59, the first drain electrode being oriented parallel to thesecond drain electrode.

[0324] Example 61

[0325] The apparatus of any of Examples 59 through 60. the first source electrode being oriented orthogonally relative to the first drain electrode, the first source electrode further being oriented orthogonally relative to the second drain electrode.

[0326] Example 62

[0327] The apparatus of any of Examples 38 through 61, further comprising a processor, where the processor determines base pairs of nucleotide strands anchored to the plurality of reaction sites, based at least in part on signals from the sensor assembly.

[0328] Example 63

[0329] The apparatus of Example 62, where the processor determines base pairs of nucleotide strands anchored to the plurality of reaction sites, based at least in part on a change in electrical resistance of the plurality of sensing channels.

[0330] Example 64

[0331] The apparatus of any of Examples 38 through 63, further comprising a fluid communication assembly operable to drive fluids through the channel to thereby perform sequencing by synthesis at the plurality of reaction sites.

[0332] Example 65

[0333] An apparatus, comprising: a channel to receive fluid containing nucleotides; a plurality of reaction sites in the channel, each reaction site of the plurality of reaction sites to anchor a strand of nucleotides; and an electrochemical random access memory (ECRAM) sensor assembly, the ECRAM sensor assembly to receive and store ions emitted from the plurality of reaction sites during a sequencing by synthesis process.

[0334] Example 66

[0335] The apparatus of Example 65, the ECRAM sensor assembly including: at least one gate electrode, one or more source electrodes, each source electrode of the one or more source electrodes being associated with at least one reaction site of the plurality of reaction sites, one or more drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality of reaction sites, and a plurality of sensing channels, each sensing channel of the plurality of sensing channels extending from a corresponding source electrode of the one or more source electrodes to a corresponding drain electrode of the one or more drain electrodes, each sensing channel being positioned to receive an ion emitted from a corresponding reaction site of the plurality of reaction sites when a voltage is applied to the at least one gate electrode during a sequencing by synthesis process.

[0336] Example 67

[0337] An apparatus, comprising: a channel configured to receive fluid containing nucleotides; a plurality of reaction sites, each reaction site of the plurality of reaction sites being configured to anchor strands of nucleotides; a plurality of channel layers, each channel layer of the plurality of channel layers being positioned to receive ions released from a corresponding reaction site of the plurality of reaction sites in response to an incorporation event occurring between one or more nucleotides in the fluid of the channel and one or more corresponding nucleotides anchored to the plurality of reaction sites, the channel layer to provide a change in electrical resistance in response to intercalation of the received ions; one or more source electrodes, at least one source electrode of the one or more source electrodes being in electrical communication with one or more channel layer of the plurality of channel layers; and one or more drain electrodes, at least one source electrode of the one or more drain electrodes being in electrical communication with one or more channel layer of the plurality of channel layers.

[0338] Example 68

[0339] The apparatus of Example 67, a first source electrode of the one or more source electrodes and a first drain electrode of the one or more drain electrodes being in electrical communication with a first channel layer of the plurality of channel layers, the apparatus further comprising a circuit to sense an electrical resistance of the first channel layer while current flows between the first source electrode and the first drain electrode.

[0340] Example 69

[0341] The apparatus of any of Examples 67 and 68, further comprising a gate electrode, the gate electrode and the one or more source electrodes to provide an electric field to intercalate ions from the reaction sites into one or more layers of the plurality of channel layers.

[0342] Example 70

[0343] The apparatus of Example 69, the gate electrode to receive a voltage at a first polarity to provide the electric field between the gate electrode and the one or more source electrodes to intercalate ions from the reaction sites into one or more layers of the plurality of channel layers.

[0344] Example 71

[0345] The apparatus of any of Examples 69 through 70, the gate electrode to receive a voltage at a second polarity to provide an electric field between the gate electrode and the one or more source electrodes to de-intercalate ions from the one or more layers of the plurality of channel layers.

[0346] Example 72

[0347] The apparatus of Example 71, the first polarity being positive, the second polarity being negative.

[0348] Example 73

[0349] The apparatus of Example 71, the first polarity being negative, the second polarity being positive.

[0350] Example 74

[0351] The apparatus of any of Examples 67 through 73, further comprising a plurality of wells in fluid communication with the channel, the plurality of reaction sites being positioned within the plurality of wells.

[0352] Example 75

[0353] The apparatus of Example 74, further comprising a plurality of walls defining the plurality of wells, each wall having a top region.

[0354] Example 76

[0355] The apparatus of Example 75, further comprising a gate electrode positioned at a respective top region of the plurality of walls.

[0356] Example 77

[0357] The apparatus of Example 75. further comprising a gate electrode spanning over the plurality of wells, the gate electrode being spaced above and away from the top regions of the plurality of walls.

[0358] Example 78

[0359] The apparatus of any of Examples 67 through 77, further comprising a plurality of electrolyte layers, each electrolyte layer of the plurality of electrolyte layers being positioned atop a respective channel layer of the plurality of channel layers.

[0360] Example 79

[0361] The apparatus of Example 78, at least some reaction sites of the plurality of reaction sites being positioned atop the plurality of electrolyte layers.

[0362] Example 80

[0363] The apparatus of any of Examples 67 through 79, at least one source electrode of the one or more source electrodes comprising a first strip oriented along a first axis, at least one drain electrode of the one or more drain electrodes comprising a second strip oriented along a second axis, the second axis being orthogonal to the first axis.

[0364] Example 81

[0365] The apparatus of any of Examples 67 through 79, the one or more source electrodes comprising a first plurality of strips, each strip of the first plurality of strips being parallel with the other strips of the first plurality of strips along a first dimension, the one or more drain electrodes comprising a second plurality of strips, each strip of the second plurality of strips being parallel with the other strips of the second plurality of strips along a second dimension, the second dimension being orthogonal to the first dimension.

[0366] Example 82

[0367] The apparatus of Example 81, the first plurality of strips and the second plurality of strips together forming a grid pattern with intersections, the plurality of reaction sites having at least some overlap over the intersections of the grid pattern.

[0368] Example 83

[0369] A method comprising: flowing a plurality of nucleotides across a plurality of reaction sites, the flowed nucleotides binding to corresponding nucleotides anchored to the plurality of reaction sites, the binding of flowed nucleotides to corresponding nucleotides anchored to the plurality of reaction sites releasing ions; intercalating the released ions into a channel layer, the intercalation of the released ions causing a change in electrical conductivity of the channel layer; detecting the increase in electrical conductivity of the channel layer; and determining that the flowed nucleotides have bound to the corresponding nucleotides anchored to the plurality of reaction sites, based at least on the detected change in electrical conductivity of the channel layer.

[0370] Example 84

[0371] The method of Example 83, the act of flowing a plurality of nucleotides across a plurality of reaction sites comprising driving a flow' of fluid, the act of intercalating the released ions into a channel layer comprising applying a first electric field to the fluid.

[0372] Example 85

[0373] The method of Example 84, the first electric field being applied to the fluid via a gate electrode.

[0374] Example 86

[0375] The method of any of Examples 84 through 85, the act of applying a first electric field to the fluid comprising applying a series of pulses of voltage to the fluid.

[0376] Example 87

[0377] The method of Example 86, further comprising iteratively detecting the change in electrical conductivity of the channel layer between each pulse of voltage applied to the fluid.

[0378] Example 88

[0379] The method of any of Examples 83 through 87, further comprising de-intercalating the intercalated ions from the channel layer.

[0380] Example 89

[0381] The method of Example 88, further comprising driving a flow of fluid across the plurality of reaction sites, the act of de-intercalating the intercalated ions from the channel layer comprising applying a second electric field to the fluid.

[0382] Example 90

[0383] The method of Example 89, the second electric field being applied to the fluid via agate electrode.

[0384] Example 91

[0385] The method of any of Examples 89 through 90, the act of applying a second electric field to the fluid comprising applying a series of pulses of voltage to the fluid.

[0386] Example 92

[0387] The method of any of Examples 86 through 91, the act of detecting the change in electrical conductivity of the channel layer comprising driving an electrical current through the channel layer via a source electrode and a drain electrode.

[0388] Example 93

[0389] An apparatus, comprising: a fluidic channel; a plurality of nucleic acid sequencing reaction sites in the channel; and an electrochemical random access memory (ECRAM) sensor assembly.

[0390] Example 94

[0391] The apparatus of Example 93. the ECRAM sensor assembly including: at least one gate electrode, one or more source electrodes, each source electrode of the one or more source electrodes being associated with at least one reaction site of the plurality' of nucleic acid sequencing reaction sites, one or more drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality of nucleic acid sequencing reaction sites, and a plurality of sensing channels, each sensing channel of the plurality of sensing channels extending from a corresponding source electrode of the one or more source electrodes to a corresponding drain electrode of the one or more drain electrodes, each sensing channel being positioned to receive an ion emitted from a corresponding reaction site of the plurality of nucleic acid sequencing reaction sites during a sequencing by synthesis process.

[0392] Example 95

[0393] A method comprising: flowing a reagent of a first ty pe through a flow channel, the flow channel including a plurality of reaction sites, each reaction site of the plurality’ of reaction sites including one or more analytes anchored to the reaction site, one or more ions being emitted from one or more reaction sites of the plurality of reaction sites while the reagent is flowed through the floyv channel, the one or more ions being emitted when components of the reagent bind to the one or more analytes anchored to one or more reaction sites; and sensing the one or more ions emitted, the one or more emitted ions being sensed by an electrochemical random access memory’ (ECRAM) sensor assembly.

[0394] Example 96

[0395] The method of Example 95, wherein the reagent comprises a plurality of nucleotides.

[0396] Example 97

[0397] The method of any of Examples 95 through 96, wherein the one or more analytes is one or more nucleotides.

[0398] Example 98

[0399] The method of any of Examples 95 through 97, further comprising: flowing a reagent of a second type through the flow channel, one or more ions being emitted from one or more reaction sites of the plurality of reaction sites while the reagent of the second type are flowed through the flow channel, the one or more ions being emitted when components of the reagent of the second type bind to one or more analytes anchored to one or more reaction sites; and sensing the one or more ions emitted, the one or more emitted ions being sensed by the electrochemical random access memory (ECRAM) sensor assembly.

[0400] Example 99

[0401] A method comprising: providing a plurality of source electrodes and a plurality of drain electrodes within a substrate assembly; providing a plurality of channel layers over the plurality of source electrodes and plurality of drain electrodes, each channel layer of the plurality of channel layers being associated with at least one corresponding source electrode of the plurality of source electrode and with at least one corresponding drain electrode of the plurality of drain electrodes; providing an electrolyte layer over the plurality of channel layers; providing a plurality of reaction sites over the electrolyte layer, each reaction site of the plurality of reaction sites to anchor a strand of nucleotides; and providing a gate electrode, the gate electrode to generate an electric field, the plurality of reaction sites being positioned to receive the electric field generated by the gate electrode.

[0402] Example 100

[0403] The method of Example 99, the act of providing a plurality of source electrodes comprising providing a source electrode strip, the plurality of source electrodes being positioned along the source electrode strip.

[0404] Example 101

[0405] The method of any of Examples 99 through 100. the act of providing a plurality of drain electrodes comprising providing a drain electrode strip, the plurality of drain electrodes being positioned along the drain electrode strip.

[0406] Example 102

[0407] The method of Example 99, the act of providing a plurality of source electrodes comprising providing a source electrode strip, the plurality of source electrodes being positioned along the source electrode strip, the act of providing a plurality of drain electrodes comprising providing a drain electrode strip, the plurality of drain electrodes being positioned along the drain electrode strip, the source electrode strip being oriented orthogonally relative to the drain electrodestrip.

[0408] Example 103

[0409] The method of any of Examples 99 through 102. further comprising providing a plurality of drain electrode vias, each drain electrode via of the plurality of drain electrode vias being interposed between a corresponding channel layer of the plurality of channel layers and a corresponding drain electrode of the one or more drain electrodes.

[0410] Example 104

[0411] The method of any of Examples 99 through 103, further comprising providing a plurality of source electrode vias, each source electrode via of the plurality of source electrode vias being interposed between a corresponding channel layer of the plurality of channel layers and a corresponding source electrode of the plurality of source electrodes.

[0412] Example 105

[0413] The method of any of Examples 99 through 104, further comprising providing a source electrode diffusion barrier between each source electrode of the plurality of source electrodes and the corresponding channel layer of the plurality of channel layers.

[0414] Example 106

[0415] The method of Example 105, each source electrode diffusion barrier comprising a material selected from the group consisting of titanium nitride, titanium nitride / tungsten. and tungsten.

[0416] Example 107

[0417] The method of any of Examples 99 through 106, further comprising providing a drain electrode diffusion barrier between each drain electrode of the plurality of drain electrodes and the corresponding channel layer of the plurality of channel layers.

[0418] Example 106

[0419] The method of Example 107, each drain electrode diffusion barrier comprising a material selected from the group consisting of titanium nitride, titanium nitride / tungsten, tungsten, and combinations thereof.

[0420] Example 107

[0421] The method of any of Examples 99 through 106, further comprising providing a plurality of wells over the electrolyte layer, the plurality of reaction sites being positioned at bottom regions of the plurality of wells.

[0422] Example 108

[0423] The method of Example 107, the wells comprising nanowells.

[0424] Example 109

[0425] The method of any of Examples 107 through 108, further comprising providing a layerof dielectric material over the electrolyte layer, the wells being formed through the layer of dielectric material.

[0426] Example 110

[0427] The method of Example 108, the dielectric material comprising a material selected from the group consisting of permanent photo-imageable resin, silicon nitride, silicon dioxide, tantalum oxide, and combinations thereof.

[0428] Example 111

[0429] The method of any of Examples 109 through 110, the gate electrode being positioned directly atop the layer of dielectric material.

[0430] Example 112

[0431] The method of any of Examples 109 through 111 , the gate electrode being spaced away from the layer of dielectric material.

[0432] Example 113

[0433] The method of any of Examples 99 through 112, the plurality of source electrodes comprising a material selected from the group consisting of aluminum, platinum, palladium, titanium, copper, silver, and combinations thereof.

[0434] Example 114

[0435] The method of any of Examples 99 through 113, the plurality of drain electrodes comprising a material selected from the group consisting of aluminum, platinum, palladium, titanium, copper, silver, and combinations thereof.

[0436] Example 115

[0437] The method of any of Examples 99 through 114, the plurality of channel layers comprising tungsten / tungsten trioxide.

[0438] Example 116

[0439] The method of any of Examples 99 through 115, the electrolyte layer comprising a tantalum oxide.

[0440] Example 117

[0441] A method comprising: providing a fluidic channel; providing a plurality of nucleic acid sequencing reaction sites in the channel; and providing an electrochemical random access memory (ECRAM) sensor assembly, the ECRAM sensor assembly to sense ions released during nucleotide incorporation events occurring at the plurality of nucleic acid sequencing reaction sites.

[0442] Example 118

[0443] The method of Example 117, the ECRAM sensor assembly including: at least one gate electrode, one or more source electrodes, each source electrode of the one or more source electrodes being associated with at least one reaction site of the plurality’ of nucleic acidsequencing reaction sites, one or more drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality of nucleic acid sequencing reaction sites, and a plurality of sensing channels, each sensing channel of the plurality' of sensing channels extending from a corresponding source electrode of the one or more source electrodes to a corresponding drain electrode of the one or more drain electrodes, each sensing channel being positioned to receive an ion emitted from a corresponding reaction site of the plurality of nucleic acid sequencing reaction sites during a sequencing by synthesis process.

[0444] Example 119

[0445] The method of any of Examples 117 through 118, the act of providing a plurality of nucleic acid sequencing reaction sites in the channel comprising providing a plurality of wells in the fluidic channel, the plurality of reaction sites being positioned at bottom regions of the plurality of wells.

[0446] Example 120

[0447] The method of any of Examples 117 through 119, the act of providing an ECRAM sensor assembly comprising depositing a plurality of layers, the plurality of nucleic acid sequencing reaction sites being positioned above the plurality of layers.

[0448] IX. Miscellaneous

[0449] While the foregoing examples are provided in the context of a system (100) that maybe used in nucleotide sequencing processes, the teachings herein may also be readily applied in other contexts, including in systems that perform other processes (i.e., other than nucleotide sequencing procedures). The teachings herein are thus not necessarily limited to systems that are used to perform nucleotide sequencing processes.

[0450] It is to be understood that the subject matter described herein is not limited in its application to the details of construction and the arrangement of components set forth in the description herein or illustrated in the drawings hereof. The subject matter described herein is capable of other implementations and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. As used herein, an element or step recited in the singular and proceeded with the word “a” or “an” should be understood as not excluding plural of said elements or steps, unless such exclusion is explicitly stated. Furthermore, references to “one example” are not intended to be interpreted as excluding the existence of additional examples that also incorporate the recited features. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

[0451] When used in the claims, the term “set” should be understood as one or more thingswhich are grouped together. Similarly, when used in the claims “based on” should be understood as indicating that one thing is determined at least in part by what it is specified as being “based on.” Where one thing is required to be exclusively determined by another thing, then that thing will be referred to as being “exclusively based on” that which it is determined by.

[0452] Unless specified or limited otherwise, the terms “mounted.” “connected.” “supported,” and “coupled” and variations thereof are used broadly and encompass both direct and indirect mountings, connections, supports, and couplings. Further, “connected” and “coupled” are not restricted to physical or mechanical connections or couplings. Also, it is to be understood that phraseology and terminology used herein with reference to device or element orientation (such as, for example, terms like “above,” “below,” “front,” “rear,” “distal,” “proximal,” and the like) are only used to simplify description of one or more examples described herein, and do not alone indicate or imply that the device or element referred to must have a particular orientation. In addition, terms such as “outer” and “inner” are used herein for purposes of description and are not intended to indicate or imply relative importance or significance.

[0453] It is to be understood that the above description is intended to be illustrative, and not restrictive. For example, the above-described examples (and / or aspects thereof) may be used in combination with each other. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the presently described subject matter without departing from its scope. While the dimensions, types of materials and coatings described herein are intended to define the parameters of the disclosed subject matter, they are by no means limiting and instead illustrations. Many further examples will be apparent to those of skill in the art upon reviewing the above description. The scope of the disclosed subject matter should, therefore, be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. In the appended claims, the terms “including” and “in which” are used as the plain-English equivalents of the respective terms “comprising” and “wherein.” Moreover, in the following claims, the terms “first,” “second,” and “third,” etc. are used merely as labels, and are not intended to impose numerical requirements on their objects. Further, the limitations of the following claims are not written in means — plus-function format and are not intended to be interpreted based on 35 U.S.C. §112(f) paragraph, unless and until such claim limitations expressly use the phrase “means for” followed by a statement of function void of further structure.

[0454] The following claims recite aspects of certain examples of the disclosed subj ect matter and are considered to be part of the above disclosure. These aspects may be combined with one another.

Claims

What is claimed is:

1. An apparatus, comprising: a channel configured to receive fluid containing nucleotides; a plurality of reaction sites in the channel, each reaction site of the plurality of reaction sites being configured to anchor a strand of nucleotides; and a sensor assembly, the sensor assembly including: at least one gate electrode, one or more source electrodes, each source electrode of the one or more source electrodes being associated with at least one reaction site of the plurality of reaction sites, one or more drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality of reaction sites, and a plurality' of sensing channels, each sensing channel of the plurality' of sensing channels extending from a corresponding source electrode of the one or more source electrodes to a corresponding drain electrode of the one or more drain electrodes, each sensing channel being positioned to receive an ion emitted from a corresponding reaction site of the plurality of reaction sites when a voltage is applied to the at least one gate electrode during a sequencing by synthesis process.

2. The apparatus of claim 1, the plurality of reaction sites comprising a plurality of wells formed in a floor of the channel.

3. The apparatus of any of claims 1 through 2, the at least one gate electrode comprising a single gate electrode that is configured to apply a voltage to two or more reaction sites of the plurality of reaction sites.

4. The apparatus of claim 3, the single gate electrode being configured to apply a voltage to all reaction sites of the plurality of reaction sites.

5. The apparatus of any of claims 1 through 4, the sensor assembly further including a plurality of metallic diffusion barriers, each metallic diffusion barrier being interposedbetween a corresponding source electrode of the one or more source electrodes and a corresponding sensing channel of the plurality of sensing channels.

6. The apparatus of any of claims 1 through 5, the sensor assembly further including at least one metallic diffusion barrier interposed between a corresponding drain electrode of the one or more drain electrodes and a corresponding sensing channel of the plurality of sensing channels.

7. The apparatus of claim 6. further comprising one or more drain electrode vias, each drain electrode via of the one or more drain electrode vias being interposed between the at least one metallic diffusion barrier and the corresponding drain electrode of the one or more drain electrodes.

8. The apparatus of any of claims 1 through 7, further comprising one or more source electrode vias, each source electrode via of the one or more source electrode vias being interposed between a corresponding sensing channel and a corresponding source electrode of the plurality of source electrodes.

9. The apparatus of any of claims 1 through 8, the sensor assembly further including a plurality of sensing channel barriers, each sensing channel barrier of the plurality of sensing channel barriers being interposed between a corresponding sensing channel of the plurality of sensing channels and the corresponding reaction site of the plurality of reaction sites, each sensing channel barrier of the plurality of sensing channel barriers being configured to allow diffusion of ions through the sensing channel barrier.

10. The apparatus of claim 9, each sensing channel barrier of the plurality of sensing channel barriers comprising an electrically insulating material.

11. The apparatus of any of claims 9 through 10, each sensing channel barrier of the plurality of sensing channel barriers comprising tantalum pentoxide.

12. The apparatus of any of claims 1 through 11, the one or more drain electrodes comprising a plurality of drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality7of reaction sites.

13. The apparatus of any of claims 1 through 11, the one or more drain electrodes comprising a drain electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

14. The apparatus of claim 13, the sensor assembly further including a plurality of conductive drain electrode vias, each conductive drain electrode via of the plurality of conductive drain electrode vias being configured to provide a path for electrical communication between a corresponding sensing channel of the plurality of sensing channels and the drain electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

15. The apparatus of any of claims 1 through 14, the one or more source electrodes comprising a source electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

16. The apparatus of claim 15, the sensor assembly further including a plurality of conductive source electrode vias, each conductive source electrode via of the plurality of conductive source electrode vias being configured to provide a path for electrical communication between a corresponding sensing channel of the plurality of sensing channels and the source electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

17. The apparatus of any of claims 1 through 16, the one or more source electrodes comprising a first source electrode in electrical communication with two or more sensing channels of the plurality of sensing channels.

18. The apparatus of claim 17, the one or more drain electrodes comprising a first drain electrode in electrical communication with two or more sensing channels of the plurality of sensing channels.

19. The apparatus of claim 18, the first drain electrode being positioned on a line oriented orthogonally relative to a line on which the first source electrode is positioned.

20. The apparatus of any of claims 1 through 19, further comprising a processor, the processor being configured to determine base pairs of nucleotide strands anchored to the plurality7of reaction sites, based at least in part on signals from the sensor assembly.

21. The apparatus of claim 20, the processor being configured to determine base pairs of nucleotide strands anchored to the plurality of reaction sites, based at least in part on a change in electrical resistance of the plurality of sensing channels.

22. An apparatus, comprising: a channel configured to receive fluid containing nucleotides; a plurality7of reaction sites in the channel, each reaction site of the plurality of reaction sites being configured to anchor a strand of nucleotides; and an electrochemical random access memory (ECRAM) sensor assembly, the ECRAM sensor assembly being configured to receive and store ions emitted from the plurality7of reaction sites during a sequencing by synthesis process.

23. The apparatus of claim 22, the ECRAM sensor assembly including: at least one gate electrode, one or more source electrodes, each source electrode of the one or more source electrodes being associated with at least one reaction site of the plurality of reaction sites, one or more drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality of reaction sites, and a plurality of sensing channels, each sensing channel of the plurality of sensing channels extending from a corresponding source electrode of the one or more source electrodes to a corresponding drain electrode of the one or more drain electrodes, each sensing channel being positioned to receive an ion emitted from a corresponding reaction site of the plurality of reaction sites during a sequencing by synthesis process.

24. A method comprising:flowing a plurality of nucleotides of a first type through a flow channel, the flow channel including a plurality of reaction sites, each reaction site of the plurality of reaction sites including one or more nucleotides anchored to the reaction site, one or more ions being emitted from one or more reaction sites of the plurality of reaction sites while the plurality of nucleotides of the first type are flowed through the flow channel, the one or more ions being emitted when nucleotides of the first ty pe bind to nucleotides anchored to one or more reaction sites to form a first base pair; and sensing the one or more ions emitted when nucleotides of the first type bind to nucleotides anchored to one or more reaction sites to form the first base pair, the one or more emitted ions being sensed by an electrochemical random access memory (ECRAM) sensor assembly.

25. The method of claim 24, further comprising: flowing a plurality of nucleotides of a second type through the flow7channel, one or more ions being emitted from one or more reaction sites of the plurality7of reaction sites while the plurality of nucleotides of the second type are flowed through the flow channel, the one or more ions being emitted when nucleotides of the second type bind to nucleotides anchored to one or more reaction sites to form a second base pair; and sensing the one or more ions emitted when nucleotides of the second type bind to nucleotides anchored to one or more reaction sites to form the second base pair, the one or more emitted ions being sensed by an electrochemical random access memory (ECRAM) sensor assembly.

26. The method of any of claims 24 through 25, further comprising: receiving a first signal from the ECRAM sensor assembly; and identifying the formed first base pair based at least in part on the first signal received from the ECRAM sensor assembly.

27. The method of claims 25 and 26, further comprising: receiving a second signal from the ECRAM sensor assembly; and identifying the formed second base pair based at least in part on the second signal received from the ECRAM sensor assembly.

28. The method of any of claims 24 through 27, the ECRAM sensor assembly comprising a plurality7of sensing channels, each sensing channel of the plurality7of sensing channels having a conductance, the conductance of one or more sensing channels of the plurality7of sensing channels changing in response to the one or more ions emitted when nucleotides of the first type bind to nucleotides anchored to one or more reaction sites to form the first base pair.

29. The method of claim 28, further comprising applying a voltage to reset the conductance of the one or more sensing channels of the plurality of sensing channels after the conductance of the one or more sensing channels of the plurality of sensing channels changes in response to the one or more ions emitted when nucleotides of the first ty pe bind to nucleotides anchored to one or more reaction sites to form the first base pair.

30. The method of claim 29, the act of applying a voltage to reset the conductance of the one or more sensing channels of the plurality' of sensing channels resulting in intercalation of the one or more ions emitted when nucleotides of the first ty pe bind to nucleotides anchored to one or more reaction sites to form the first base pair from the one or more sensing channels of the plurality of sensing channels.

31. An apparatus, comprising: a channel to receive fluid containing nucleotides; a plurality7of reaction sites in the channel, each reaction site of the plurality of reaction sites to anchor a strand of nucleotides; and a sensor assembly, the sensor assembly including: at least one gate electrode, one or more source electrodes, each source electrode of the one or more source electrodes being associated with at least one reaction site of the plurality7of reaction sites, one or more drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality of reaction sites, and a plurality7of sensing channels, each sensing channel of the plurality7of sensing channels extending from a corresponding source electrode of the one or more source electrodes to a corresponding drainelectrode of the one or more drain electrodes, each sensing channel being positioned to receive an ion emitted from a corresponding reaction site of the plurality of reaction sites when a voltage is applied to the at least one gate electrode during a sequencing by synthesis process.

32. The apparatus of claim 31, the plurality of reaction sites comprising a plurality of nanowells formed in a floor of the channel.

33. The apparatus of any of claims 31 through 32, the at least one gate electrode comprising a single gate electrode that is to apply a voltage to two or more reaction sites of the plurality of reaction sites.

34. The apparatus of any of claims 31 through 33. the sensor assembly further including a plurality of metallic diffusion barriers, each metallic diffusion barrier being interposed between a corresponding source electrode of the one or more source electrodes and a corresponding sensing channel of the plurality of sensing channels.

35. The apparatus of any of claims 31 through 34, the sensor assembly further including at least one metallic diffusion barrier interposed between a corresponding drain electrode of the one or more drain electrodes and a corresponding sensing channel of the plurality of sensing channels.

36. The apparatus of any of claims 31 through 35, the sensor assembly further including a plurality of sensing channel barriers, each sensing channel barrier of the plurality of sensing channel barriers interposed between a corresponding sensing channel of the plurality of sensing channels and the corresponding reaction site of the plurality of reaction sites, each sensing channel barrier of the plurality of sensing channel barriers allows diffusion of ions through the sensing channel barrier.

37. The apparatus of claim 36, each sensing channel barrier of the plurality of sensing channel barriers comprising tantalum pentoxide.

38. The apparatus of any of claims 31 through 37, the one or more drain electrodes comprising a plurality of drain electrodes, each drain electrode of the one or more drain electrodes being associated with at least one reaction site of the plurality7of reaction sites.

39. The apparatus of any of claims 31 through 37. the one or more drain electrodes comprising a drain electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

40. The apparatus of any of claims 31 through 39, the one or more source electrodes comprising a source electrode that is in electrical communication with two or more sensing channels of the plurality of sensing channels.

41. The apparatus of any of claims 31 through 40, the one or more source electrodes comprising a first source electrode in electrical communication with two or more sensing channels of the plurality of sensing channels.

42. The apparatus of claim 41, the one or more drain electrodes comprising a first drain electrode in electrical communication with two or more sensing channels of the plurality of sensing channels.

43. The apparatus of any of claims 41 through 42, the first source electrode being in electrical communication with a first sensing channel of the plurality of sensing channels and a second sensing channel of the plurality of sensing channels, the one or more source electrodes further comprising a second source electrode in electrical communication with a second sensing channel of the plurality7of sensing channels and a third sensing channel of the plurality of sensing channels.

44. The apparatus of any of claims 31 through 43, further comprising a processor, where the processor determines base pairs of nucleotide strands anchored to the plurality7of reaction sites, based at least in part on signals from the sensor assembly .

45. The apparatus of claim 44, where the processor determines base pairs of nucleotide strands anchored to the plurality of reaction sites, based at least in part on a change in electrical resistance of the plurality7of sensing channels.

46. The apparatus of any of claims 31 through 45, further comprising a fluid communication assembly operable to drive fluids through the channel to thereby perform sequencing by synthesis at the plurality of reaction sites.

47. An apparatus, comprising: a channel configured to receive fluid containing nucleotides: a plurality of reaction sites, each reaction site of the plurality of reaction sites being configured to anchor strands of nucleotides; a plurality of channel layers, each channel layer of the plurality of channel layers being positioned to receive ions released from a corresponding reaction site of the plurality of reaction sites in response to an incorporation event occurring between one or more nucleotides in the fluid of the channel and one or more corresponding nucleotides anchored to the plurality of reaction sites, the channel layer to provide a change in electrical resistance in response to intercalation of the received ions; one or more source electrodes, at least one source electrode of the one or more source electrodes being in electrical communication with one or more channel layer of the plurality of channel layers; and one or more drain electrodes, at least one source electrode of the one or more drain electrodes being in electrical communication with one or more channel layer of the plurality of channel layers.

48. The apparatus of claim 47, a first source electrode of the one or more source electrodes and a first drain electrode of the one or more drain electrodes being in electrical communication with a first channel layer of the plurality of channel layers, the apparatus further comprising a circuit to sense an electrical resistance of the first channel layer while current flows between the first source electrode and the first drain electrode.

49. The apparatus claim 47, further comprising a gate electrode, the gate electrode and the one or more source electrodes to provide an electric field to intercalate ions from the reaction sites into one or more layers of the plurality of channel layers.

50. The apparatus of claim 49, the gate electrode to receive a voltage at a first polarity to provide the electric field between the gate electrode and the one or more sourceelectrodes to intercalate ions from the reaction sites into one or more layers of the plurality of channel layers.

51. The apparatus of any of claims 49 through 50, the gate electrode to receive a voltage at a second polarity to provide an electric field between the gate electrode and the one or more source electrodes to de-intercalate ions from the one or more layers of the plurality of channel layers.

52. The apparatus of claim 47, further comprising a plurality of wells in fluid communication with the channel, the plurality of reaction sites being positioned within the plurality of wells.

53. The apparatus of claim 52, further comprising a plurality of walls defining the plurality of wells, each wall having a top region.

54. The apparatus of claim 53, further comprising a gate electrode positioned at a respective top region of the plurality of walls.

55. The apparatus of claim 53, further comprising a gate electrode spanning over the plurality of wells, the gate electrode being spaced above and away from the top regions of the plurality7of walls.

56. The apparatus of claim 47, further comprising a plurality of electrolyte layers, each electrolyte layer of the plurality7of electrolyte layers being positioned atop a respective channel layer of the plurality of channel layers.

57. The apparatus of claim 56, at least some reaction sites of the plurality of reaction sites being positioned atop the plurality of electrolyte layers.

58. The apparatus of any of claims 47 through 57, the one or more source electrodes comprising a first plurality of strips, each strip of the first plurality of strips being parallel with the other strips of the first plurality of strips along a first dimension, the one or more drain electrodes comprising a second plurality of strips, each strip of the second plurality7of strips being parallel with the other strips of the second plurality of strips along a second dimension, the second dimension being orthogonal to the first dimension.

59. A method comprising: flowing a plurality of nucleotides across a plurality of reaction sites, the flowed nucleotides binding to corresponding nucleotides anchored to the plurality of reaction sites, the binding of flowed nucleotides to corresponding nucleotides anchored to the plurality of reaction sites releasing ions; intercalating the released ions into a channel layer, the intercalation of the released ions causing a change in electrical conductivity of the channel layer; detecting the increase in electrical conductivity of the channel layer; and determining that the flowed nucleotides have bound to the corresponding nucleotides anchored to the plurality of reaction sites, based at least on the detected change in electrical conductivity of the channel layer.

60. The method of claim 59, the act of flowing a plurality of nucleotides across a plurality of reaction sites comprising driving a flow7of fluid, the act of intercalating the released ions into a channel layer comprising applying a first electric field to the fluid. the first electric field being applied to the fluid via a gate electrode.

61. The method of claim 60, the act of applying a first electric field to the fluid comprising applying a series of pulses of voltage to the fluid.

62. The method of claim 61, further comprising iteratively detecting the change in electrical conductivity7of the channel layer between each pulse of voltage applied to the fluid.

63. The method of any of claims 59 through 62, further comprising de-intercalating the intercalated ions from the channel layer.

64. The method of claim 63, further comprising driving a flow7of fluid across the plurality of reaction sites, the act of de-intercalating the intercalated ions from the channel layer comprising applying a second electric field to the fluid, the second electric field being applied to the fluid via a gate electrode.-SO-65. The method of claim 64, the act of applying a second electric field to the fluid comprising applying a series of pulses of voltage to the fluid.

66. The method of any of claims 61 through 65, the act of detecting the change in electrical conductivity of the channel layer comprising driving an electrical current through the channel layer via a source electrode and a drain electrode.

67. An apparatus, comprising: a fluidic channel; a plurality of nucleic acid sequencing reaction sites in the channel; and an electrochemical random access memory (ECRAM) sensor assembly.

68. A method comprising: flowing a reagent of a first type through a flow channel, the flow channel including a plurality of reaction sites, each reaction site of the plurality of reaction sites including one or more analytes anchored to the reaction site, one or more ions being emitted from one or more reaction sites of the plurality’ of reaction sites while the reagent is flowed through the flow channel, the one or more ions being emitted when components of the reagent bind to the one or more analytes anchored to one or more reaction sites; and sensing the one or more ions emitted, the one or more emitted ions being sensed by an electrochemical random access memory (ECRAM) sensor assembly.

69. The method of claim 68, wherein the reagent comprises a plurality’ of nucleotides.

70. The method of claim 68, wherein the one or more analytes is one or more nucleotides.

71. The method of any of claims 68 through 70, further comprising: flowing a reagent of a second type through the flow channel, one or more ions being emitted from one or more reaction sites of the plurality of reaction sites while the reagent of the second type are flowed through the flow channel, the one or more ions being emitted when components of thereagent of the second type bind to one or more analytes anchored to one or more reaction sites; and sensing the one or more ions emitted, the one or more emitted ions being sensed by the electrochemical random access memory (ECRAM) sensor assembly.

72. A method comprising: providing a plurality of source electrodes and a plurality of drain electrodes within a substrate assembly; providing a plurality of channel layers over the plurality of source electrodes and plurality of drain electrodes, each channel layer of the plurality of channel layers being associated with at least one corresponding source electrode of the plurality of source electrode and with at least one corresponding drain electrode of the plurality of drain electrodes; providing an electrolyte layer over the plurality of channel layers; providing a plurality of reaction sites over the electrolyte layer, each reaction site of the plurality of reaction sites to anchor a strand of nucleotides; and providing a gate electrode, the gate electrode to generate an electric field, the plurality' of reaction sites being positioned to receive the electric field generated by the gate electrode.

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