TW201518722A - Chemical sensors with consistent sensor surface areas - Google Patents

Abstract

In one embodiment, a chemical sensor is described. The chemical sensor includes a chemically-sensitive field effect transistor including a floating gate conductor having an upper surface. A material defines an opening extending to the upper surface of the floating gate conductor, the material comprising a first dielectric underlying a second dielectric. A conductive element contacts the upper surface of the floating gate conductor and extending a distance along a sidewall of the opening.

Description

Chemical sensor with fixed sensor surface area

The present invention relates to a sensor for chemical analysis, and a method of manufacturing the aforementioned sensor.

There are many types of chemical sensors that have been used for the detection of chemical processes. One type is a chemically sensitive field effect transistor (chemFET). The chemically sensitive field effect transistor comprises a source and a drain separated by a channel, and a chemically sensitive region coupled to the channel region. The role of chemically sensitive field effect transistors is based on the regulation of channel conductivity caused by changes in charge in the sensitive region caused by chemical reactions occurring in the vicinity of sensitive regions. The adjustment of the conductivity of the aforementioned channel changes the threshold voltage of the chemically sensitive field effect transistor, which can be measured and used to detect and/or determine the characteristics of the aforementioned chemical reaction. The measurement of the threshold voltage can be performed, for example, by applying appropriate bias voltages to the source and drain electrodes, and then measuring the current generated by the chemically sensitive field effect transistor. For another example, by driving a known current through the chemically sensitive field effect transistor, the voltage generated at the source or drain is then measured.

An ion-sensitive field effect transistor (ISFET) is a type of chemically sensitive field effect transistor that contains an ion sensitive layer in a sensitive region. The presence of ions in the analyte solution changes the surface potential of the interface between the ion sensitive layer and the analyte solution due to the presence of ions in the analyte solution that can cause protonation or deprotonation of the surface charge group. Ion sensitive field The change in surface potential of the sensitive region of the effector crystal affects the threshold voltage of the device, which can be measured to indicate the presence of ions and/or the concentration of ions in the solution. An ion sensitive field effect transistor array can be used to monitor chemical reactions, such as DNA sequencing reactions, depending on the presence, generation, or use of ions during the detection reaction. For example, see Rosberg et al. (Rothberg et al.) U.S. Patent Application No. 12/002,291 (now U.S. Patent No. 7,948,015) filed on Dec. 14, 2009, and which is based on U.S. Provisional Patent Application No. 60/956,324, filed on August 16, 2007, U.S. Provisional Patent Application No. 60/968,748, filed on July 10, 2007, and U.S. Provisional Patent Application, filed on December 14, 2006 Application No. 60/870,073, which is incorporated herein in its entirety by reference. More generally, large arrays of chemically sensitive field effect transistors or other types of chemical sensors can be used to detect and measure the statics of various analytes (eg, hydrogen ions, other ions, compounds, etc.) in various processes and/or Dynamic amount or concentration. The process is, for example, biological or chemical reaction, cell or tissue culture or monitoring of neural activity, nucleic acid sequencing, and the like.

When operating a large-scale array of chemical sensors, there is a problem that the sensor output signal is susceptible to noise. Specifically, the noise affects the correctness of the downstream signal processing, which is used to determine the characteristics of the chemical and/or biological processes detected by the sensor. In addition, the difference in performance of the chemical sensor in the array results in undesirable differences in the sensor output signal, which further complicates the processing of downstream signals. Accordingly, the present invention contemplates providing an apparatus comprising a low noise chemical sensor and a method for fabricating the foregoing apparatus.

An embodiment of the invention discloses a chemical sensor comprising a chemically sensitive field effect transistor comprising a floating gate conductor having an upper surface; a material Defining an opening extending to the upper surface of the floating gate conductor, the material comprising a first dielectric underlying a second dielectric; and a conductive element contacting the floating gate conductor The upper surface and along one of the openings The side walls extend a distance. In an exemplary embodiment, the opening of the chemical sensor includes a lower portion in the first dielectric and an upper portion in the second dielectric. In another embodiment, one of the lower portions of the opening is substantially the same width as one of the upper portions. In another embodiment, the electrically conductive elements together form one of the shapes of the opening. In an embodiment, the conductive element extends to an upper surface of the second dielectric. In an exemplary embodiment, the electrically conductive element includes an inner surface defining a lower portion of one of the reaction regions of the chemical sensor, and the second dielectric includes an inner surface defining an upper portion of the opening. In an exemplary embodiment, the conductive element comprises a conductive material, and an inner surface of the conductive element comprises an oxide of the conductive material. In another embodiment, one of the sensing surfaces of the chemical sensor includes an inner surface of the electrically conductive element. In another embodiment, the chemically sensitive field effect crystal system produces a sensor signal corresponding to a chemical reaction occurring near the conductive element. In one embodiment, the floating gate conductor includes a plurality of conductors electrically connected to each other and separated from each other by a dielectric layer, and the floating gate conduction system is the uppermost layer of the plurality of conductors. conductor.

Another embodiment of the invention discloses a method for fabricating a chemical sensor, the method comprising: forming a chemically sensitive field effect transistor comprising a floating gate conductor, the floating gate conductor having an upper Forming a material extending to an opening of the upper surface of the floating gate conductor, the material comprising a first dielectric underlying a second dielectric; and forming a conductive element, It contacts the upper surface of the floating gate conductor and extends a distance along a sidewall of the opening. In an exemplary embodiment, the step of forming the material and forming the conductive element includes: forming the first dielectric on the floating gate conductor, wherein the first dielectric system definition extends to the floating gate a recess of the upper surface of the conductor; forming the second dielectric thereon; etching the second dielectric to expose the conductive element, thereby defining an opening; and forming the conductive element in the opening. In another embodiment, the conductive element is formed in the opening The step of: depositing a conductive material in the opening and an upper surface of the first dielectric; and removing at least a portion of the conductive material from the upper surface of the second dielectric. In another embodiment, the step of removing at least a portion of the conductive material includes: depositing a layer of photoresist in the opening; and extracting a portion of the conductive material from the upper surface of the second dielectric together with the photoresist Remove together. In an embodiment, the electrically conductive material comprises titanium. In an exemplary embodiment, the opening is a nanowell. In an exemplary embodiment, the step of forming a conductive element includes conformally depositing a conductive material into the opening. In another embodiment, the electrically conductive element includes an inner surface defining a lower portion of one of the reaction regions of the chemical sensor, and the second dielectric includes an inner surface defining an upper portion of the opening.

The embodiments of the present invention are described in detail in the specification and drawings, and other features, embodiments, and advantages of the present invention are described in the specification, drawings, and claims.

100‧‧‧Integrated circuit device

101‧‧‧ flow cell

102‧‧‧ entrance

103‧‧‧Export

104, 109, 111‧‧‧ channels

105‧‧‧Mobile room

106‧‧‧Waste container

107‧‧‧Microwell array

108‧‧‧ reference electrode

110‧‧‧ washing solution

112‧‧‧Valves

114‧‧‧Reagents

116‧‧‧Valve block

118‧‧‧ Fluid Controller

Lines 120, 122, 126‧‧

124‧‧‧Array controller

127‧‧‧ bus bar

128‧‧‧User Interface

205‧‧‧Sensor array

208‧‧‧reagent flow

301, 302‧‧‧Reaction area

303, 1303‧‧‧ side wall

308, 310, 319, 1503, 2006‧‧‧ dielectric materials

309, 1309, 1630‧‧‧ distance

312‧‧‧ Solid support

Lower part of 314‧‧

315‧‧‧ upper

318‧‧‧Floating gate structure

320‧‧‧Sensor board

321‧‧‧ source area

322‧‧‧Bungee area

323‧‧‧Channel area

324‧‧‧Charge

340‧‧‧Diffusion mechanism

350, 351‧ ‧ chemical sensors

352‧‧‧ gate dielectric layer

354‧‧‧Semiconductor substrate

370‧‧‧Conductive components

371‧‧‧ inner surface

400, 1400, 1500, 1600, 1700, 1800, 1900‧‧‧ structures

600, 602‧‧ ‧ notches

Opening of 1618, 1620‧‧

900, 1704, 1805, 2200‧‧‧ conductive materials

1000, 2300‧‧‧ materials

1 is a block diagram of one of the components of a nucleic acid sequencing system in accordance with an exemplary embodiment.

2 is a partial cross-sectional view of an integrated circuit device and a flow cell in accordance with an exemplary embodiment.

3 is a cross-sectional view of two representative chemical sensors and corresponding reaction regions in accordance with a first embodiment.

4 to 12 are schematic views showing stages of a manufacturing process for forming an array of chemical sensors according to a first embodiment and corresponding reaction regions thereof.

13 to 25 are schematic views of stages in a manufacturing process for forming an array of chemical sensors and corresponding reaction regions according to the first embodiment.

The chemical device of the present invention includes a low noise chemical device such as a chemically sensitive field effect A chemically-sensitive field effect transistor (chemFET) is used to detect a chemical reaction in its surface layer and operatively cooperate with its reaction region. High-density devices can be formed by reducing the planar and top-view areas of individual chemical sensors and overlapping reaction regions. However, as the size of chemical sensors has shrunk, Applicants have discovered that sensors have been correspondingly reduced. The sensing surface area can significantly affect performance, for example, for a chemical sensor having a sensing surface defined at the bottom of the reaction zone, reducing the planar size (eg, width or diameter) of the reaction zone results in a similar reduction in sensing surface area. Case. Applicants have discovered that when the sensing surface area is reduced to the technical limit, the contribution of fluid noise caused by random fluctuations in the charge of the sensing surface to the total change in the sensing surface potential is increasing, which will It will significantly reduce the signal-to-noise ratio (SNR) of the sensor output signal, thus affecting the correctness of downstream signal processing, such as the downstream signal of the program used to determine chemical or biological characteristics after being detected by the sensor. .

The chemical sensor described herein has a plurality of sensing surface regions that are not limited to a two-dimensional region at the bottom of the reaction region; in the embodiments described herein, the sensing surface of the chemical sensor includes a substantially horizontal portion of the lower surface of the reaction zone, and a substantially vertical portion extending along a sidewall of the opening containing the reaction zone, the substantially vertical portion extending along the sidewall being a thickness of the dielectric material forming the lower portion of the opening Defined. The dielectric material can be deposited by a process (such as a thin film deposition process), so that the thickness variation of the entire array is very small; according to the above method, the sensor surface area of the chemical sensor can be well controlled, resulting in The entire array has uniform chemical sensor performance, simplifying downstream signal processing. By extending the sensing surface in a generally vertical direction, the chemical sensor can have the advantage of having a small footprint while still having a sufficiently large sensing surface area to avoid noise associated with the small sensing surface. problem. The footprint of a chemical sensor can depend in part on the width (e.g., diameter) of the reaction zone being covered, and it can be shrunk to allow for the formation of a high density array. In addition, since the sensing surface area can extend to a control distance, which can reach the side wall, the feeling The measured surface area can be relatively large, and as a result, a low-noise chemical sensor can be provided in a high-density array, so that the characteristics of the reaction can be accurately detected.

1 is a block diagram of an element of a nucleic acid sequencing system including a flow cell 101 on an integrated circuit device 100, a reference electrode 108, and a plurality of sequences for sequencing, in accordance with an exemplary embodiment. Reagent 114, a valve block 116, a wash solution 110, a valve 112, a fluid controller 118, a line 120/122/126, a channel 104/109/111, a waste container 106, an array controller 124, and a User interface 128. The integrated circuit device 100 includes a microwell array 107 for covering a sensor array including a chemical device as described herein. The flow cell 101 includes an inlet 102, an outlet 103, and a flow chamber 105 for defining the flow path of the reagent 114 in the microwell array 107. The reference electrode 108 can be of any suitable type or shape, including a concentric cylinder having a fluid passage or a wire inserted into the lumen of the passage 111. The reagent 114 can be driven through the fluid passage, valve, and flow cell 101 using a pump, air pressure, vacuum, or other suitable method, and can be disposed of to the waste container 106 after exiting the outlet 103 of the flow cell 101. Fluid controller 118 may utilize appropriate software to control the driving force of reagent 114 and the operation of valve 112 and valve block 116.

The microwell array 107 includes reaction zones, also referred to herein as microwells, that operatively cooperate with chemical devices in respective sensor arrays. For example, each reaction zone can be coupled to a chemical sensor adapted to detect analytes of interest or reaction characteristics within the reaction zone. The microwell array 107 can be integrated into the integrated circuit device 100 such that the microwell array 107 and the sensor array are part of a single device or wafer. The flow cell 101 can have a variety of configurations for controlling the path and flow rate of the reagent 114 on the microwell array 107. The array controller 124 provides bias and timing control signals to the integrated circuit device 100 for reading the chemical sensors of the sensor array. Array controller 124 also provides a reference bias applied to reference electrode 108 to bias reagent 114 flowing through microwell array 107.

In an experimental example, the array controller 124 collects signals output through the output port of the integrated circuit device 100 and from the chemical sensor of the sensor array through the bus bar 127, and In response to this signal, array controller 124 can be a computer or other computing device. The array controller 124 can include memory for storing data and software applications, a processor for accessing data and executing applications, and components for facilitating communication between components of the system as shown in FIG. . In the present embodiment, the array controller 124 is disposed outside of the integrated circuit device 100; in some embodiments, some or all of the functions performed by the array controller 124 may be controlled by a control on the integrated circuit device 100. Or other data processor to implement. The value of the output signal of the chemical sensor represents one or more physical and/or chemical parameters of the reaction occurring in the reaction zone in the corresponding microwell array 107, for example, in an exemplary embodiment, the output signal The value disclosed in Rearick et al., U.S. Patent Application Serial No. 13/339,846, filed on Dec. U.S. Patent Application Serial No. 61/429,328, filed on Jan. 3, 2011, and the disclosure of the disclosure of U.S. Patent Application Serial No. 13/339,753, filed on Dec. 29, 2011 The processing of the priority of U.S. Patent Application Serial No. 61/428,097, filed on Dec. 29, the entire entire entire entire entire entire entire entire entire entire content The user interface 128 can display output signals received about the flow cell 101 and the chemical sensors in the sensor array of the integrated circuit device 100. The user interface 128 can also display instrument settings and controls and allow The user enters or sets the instrument settings and controls.

The fluid controller 118 can control the delivery of the individual reagents 114 to the flow cell 101 and the integrated circuit device 100, which can be delivered in accordance with a predetermined sequence, a predetermined duration, a predetermined flow rate. Next, the array controller 124 can collect and analyze the output signal of the chemical sensor, which indicates the chemical reaction corresponding to the delivered reagent 114. During the experiment, the system can also monitor and control the integrated circuit. The temperature of the apparatus 100 allows the reaction to be carried out and measured at a known predetermined temperature.

The system can be configured to allow a single fluid or reagent to contact the reference electrode 108 during the entire multi-step reaction process during operation. Valve 112 can be closed to When the reagent 114 flows, it is possible to prevent any of the washing solution 110 from flowing into the passage 109. Although the flow of the wash solution can be stopped, there is still uninterrupted fluid and electrical communication between the reference electrode 108, the channel 109, and the microwell array 107, between the reference electrode 108 and the junction between the channels 109 and 111. The distance can be selected such that little or no reagent flows through the channel 109 and may diffuse into the channel 111 and reach the reference electrode 108. In an exemplary embodiment, the wash solution 110 can be selected to be in continuous contact with the reference electrode 108, a method particularly useful in multi-step reactions using frequent wash steps.

2 is a partial cross-sectional view showing the integrated circuit device 100 and the flow cell 101. The integrated circuit device 100 includes a microwell array 107 of reactive regions that can selectively mate with the sensor array 205. During operation, the flow chamber 105 of the flow cell 101 can define a reagent stream 208 of reagent to be delivered to pass through the open end of the reaction zone in the microwell array 107, the volume, shape, aspect ratio of the reaction zone (eg, The ratio of substrate width to well depth), as well as other dimensional characteristics, can be selected based on the nature of the reaction and the reagents, by-products, or labeling techniques used, if any. The chemical sensor of sensor array 205 corresponds to (and produces an output signal) a chemical reaction within the associated reaction region in microwell array 107 to detect the analyte or reaction characteristic of interest. The chemical sensor of sensor array 205 can be, for example, a chemically sensitive field effect transistor, such as an ion sensitive field effect transistor (ISFET). Examples of chemical devices and array structures that can be used in this embodiment are described in detail in U.S. Patent Application Serial No. 12/785,667, the entire disclosure of U.S. Patent No. 4,546,128, filed on May 24, 2010. U.S. Patent Application Serial No. 12/721,458, to Rotherberg et al., which is hereby incorporated by reference to U.S. Pat. Method and apparatus for measuring analytes, U.S. Patent Application Serial No. 12/475,311 to Rotherberg et al., filed on May 29, 2009, the disclosure of which is incorporated herein by reference. U.S. Patent Application Serial No. 12/474,897, filed on May 29, 2009, the disclosure of which is incorporated herein by reference to U.S. Pat. Application on December 17, the title of a method and apparatus for the measurement of an analyte using a large field effect transistor array, and U.S. Patent Application Serial No. 12/474,897 (now U.S. Patent No. 7,575,865, August 1, 2005) The application, titled Methods for Amplification and Sequencing of Nucleic Acids, each of which is incorporated herein by reference in its entirety.

3 is a cross-sectional view of two representative chemical sensors and corresponding reaction regions in accordance with an exemplary embodiment. FIG. 3 shows two chemical sensors 350 and 351 that indicate that a small portion of a sensor array can include millions of chemical sensors. Chemical sensor 350 is coupled to respective reaction zone 301 and chemical sensor 351 is coupled to corresponding reaction zone 302. The chemical sensor 350 represents a chemical sensor in the sensor array. In this example, the chemical sensor 350 is a chemically sensitive field effect transistor, more specifically an ion sensitive field effect transistor (ISFET). ). The chemical sensor 350 includes a floating gate structure 318 having a sensor plate 320 coupled to the reaction region 301 by a conductive element 370. As shown in FIG. 3, the sensor plate 320 is the uppermost floating gate conductor in the floating gate structure 318. In this example, the floating gate structure 318 includes a plurality of patterns in the plurality of layers of dielectric material 319. Conductive material of the layer.

The chemical sensor 350 further includes a source region 321 and a drain region 322 in a semiconductor substrate 354. The source region 321 and the drain region 322 comprise a doped semiconductor material, the conductivity type of which is electrically conductive with the substrate 354. Different types, for example, the source region 321 and the drain region 322 may include a P-type doped semiconductor material, and the substrate may include an N-type doped semiconductor material. The channel region 323 separates the source region 321 from the drain region 322. The floating gate structure 318 covers the channel region 323 and is separated from the substrate 354 by a gate dielectric layer 352. The gate dielectric layer 352 can be, for example, Cerium oxide; alternatively, other dielectric materials may be used to form the gate dielectric layer 352.

As shown in FIG. 3, the reaction region 301 is located in an opening having a sidewall 303 extending through the dielectric material 310, 308 and reaching the upper surface of the sensor panel 320. The dielectric materials 310, 308 are respectively different. It may comprise one or more layers of material such as hafnium oxide or tantalum nitride. The The opening includes a lower portion 314 in the dielectric material 308 and adjacent one of the sensor plates 320, the opening further including an upper portion 315 of the dielectric material 310 extending from the lower portion 314 to the dielectric material 310 Upper surface. In the illustrated embodiment, the width of the upper portion 315 of the opening is substantially the same as the width of the lower portion 314 of the opening; however, depending on the material used to form the opening and/or the etching process, the width of the upper portion 315 of the opening may be greater than the opening. The width of the lower portion 314 and vice versa. The opening may, for example, have a circular cross section, and the opening may also be non-circular, for example, the cross section may be square, rectangular, hexagonal or irregular. The size of the opening and its spacing can vary depending on the implementation. In some embodiments, the opening may have a specific diameter defined as 4 times the cross-sectional area (A) of the plan view divided by the square root of π (eg, sqrt(4*A/π)), which is not greater than 5 microns, such as no greater than 3.5 microns, no greater than 2.0 microns, no greater than 1.6 microns, no greater than 1.0 microns, no greater than 0.8 microns, no greater than 0.6 microns, no greater than 0.4 microns, no greater than 0.2 microns, or no greater than 0.1 microns.

The lower portion 314 of the opening includes a conductive element 370 on the sidewall 303 of the dielectric material 310. In the illustrated embodiment, the inner surface 371 of the conductive element 370 defines a lower segment of the reaction region 301, that is, at the conductive member. An intermediate deposition material layer is not disposed between the inner surface 371 of the 370 and the reaction region 301 of the chemical sensor 350. Therefore, the inner surface 371 of the conductive member 370 is conformal to the opening and can serve as the chemical sensor 350. Sensing surface. Those skilled in the art will appreciate that the precise shape and size of conductive element 370, as well as all other materials shown in the figures, are related to the process.

In the illustrated embodiment, the conductive element 370 is a conformal layer of material within the open lower portion 314 such that the conductive element 370 extends over the upper surface of the sensor plate 320; in the illustrated embodiment, the conductive element 370 Extending beyond the lower portion 314 of the opening and into the upper portion 315 of the opening. The inner surface of the dielectric material 310 defines an upper segment of the reaction region 301, which may extend, for example, along at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, or at least 85% of the sidewall 303 Or even along 99% of the side walls 303. The conformal inner surface 371 of the conductive element 370 allows the chemical sensor 350 to have a small plan view area while simultaneously It has a large enough surface area to avoid the noise problems associated with small sensing surfaces. The plan view area of the chemical sensor 350 can be partially judged by the width (or diameter) of the reaction region 301, and can be reduced to allow formation of a high density array. Additionally, since the sensing surface extends over the sidewall 303, the sensing surface area is dependent on the extent of the extension and the perimeter of the reaction zone 301, and it can be relatively large, with the result that it can be provided in a high density array The low noise chemical sensors 350, 351 make it possible to accurately detect the characteristics of the reaction.

During the fabrication and/or operation of the device, a thin oxide of material forming the conductive element 370 can be grown, which serves as a sensing material for the chemical sensor 350 (eg, an ion sensitive sensing material), the oxide The formation depends on the conductive material, the process being performed, and the conditions at which the device is operated. For example, in one embodiment, conductive element 370 can be titanium nitride that can be exposed to solution during fabrication or during use to grow on surface 371 of conductive element 370 to form titanium oxide or nitrogen oxides. titanium. In the example, the conductive element 370 is shown as a single layer of material. More generally, the conductive element 370 may include one or more layers of conductive materials, such as metal or ceramic, depending on the actual implementation. The conductive material may be, for example, The metal material or alloy thereof, or may be a ceramic material, or a combination thereof; an exemplary metal material includes aluminum, copper, nickel, titanium, silver, gold, platinum, rhodium, ruthenium, iridium, tungsten, osmium, zirconium, palladium. Or one of the combinations; an exemplary ceramic material comprising one of titanium nitride, titanium aluminum nitride, titanium oxynitride, tantalum nitride, or combinations thereof. In some alternative embodiments, another conformal sensing material (not shown) may be deposited on the conductive element 370 and disposed in the opening, and the sensing material may include one or more different materials to enhance Sensitivity to specific ions, such as tantalum nitride or hafnium oxynitride, and metal oxides such as antimony oxide, aluminum oxide or antimony oxide, generally provide sensitivity to hydrogen ions, while polyvinyl chloride containing valinomycin The sensing material can provide sensitivity to potassium ions. Materials sensitive to other ions such as sodium, silver, iron, bromine, iodine, calcium and nitrate may also be used depending on actual needs.

During operation, reactants, wash solutions, and other reagents can be moved into or out of reaction zone 301 by diffusion mechanism 340, which corresponds to (and produces an associated output signal) charge 324 adjacent to conductive element 370. The amount of charge 324 present in the analyte solution can alter the surface potential at the interface between the analyte solution in reaction zone 301 and conductive element 370. The change in the charge 324 causes a change in the voltage of the floating gate structure 318, which varies sequentially in the threshold voltage of the transistor, and can measure the current in the channel region 323 between the source region 321 and the drain region 322. To measure this change in threshold voltage. The results show that the chemical sensor 350 can be used directly to provide a current based output signal connected to the array line of the source region 321 or the drain region 322, or indirectly to another circuit to provide a voltage based output. Signal. Since the charge 324 can have a higher concentration at the bottom of the reaction zone 301, the distance that the conductive element 370 extends up to the sidewall of the opening 303 requires the amplitude of the expected signal detected by the corresponding charge 324 with the conductive element 370 and the analyte solution. A balance is achieved between the fluid noise caused by random fluctuations in charge; increasing the distance that the conductive element 370 extends up to the sidewall 303 can increase the fluid interface area of the chemical sensor 350, which acts to reduce fluid noise. However, since the charge 324 will diffuse out of the reaction region 301, the concentration of the charge 324 decreases with distance from the bottom of the reaction region 301, with the result that when the upper sidewall segment of the conductive member 370 detects a portion of the signal, it has a lower The charge concentration thus reduces the total amplitude of the desired signal detected by sensor 350. Conversely, when reducing the distance that the conductive element 370 extends up to the sidewall 303, the sensing surface area can be reduced, thereby increasing the total amplitude of the desired signal detected by the sensor 350.

For a very small sensing surface area, Applicants have discovered that changes in fluid noise can be considered as a function of the sensing surface area rather than a function of the amplitude of the desired signal. Since the signal-to-noise ratio (SNR) of the output signal of the sensor is the ratio of the two quantities, there is an optimum distance that the conductive element 370 extends along the sidewall 303, so that the signal-to-noise ratio is maximized. This optimal distance varies according to different embodiments, and it depends on Material properties of conductive element 370 and dielectric material 310, volume, shape, aspect ratio (e.g., ratio of substrate width to well depth), and other dimensional characteristics, nature of reaction, and reagents, by-products used , or the marking technique used (if any). This optimal distance can be determined, for example, based on experience.

The present invention will be described in detail below with reference to FIGS. 4 to 12. The distance that the conductive element 370 extends along the sidewall 303 can be determined, for example, by controlling the etching time of the deposited layer. The dielectric material 310 and the conductive element 370 can be etched, for example, by a time etching process, to selectively form a distance 309 ( For example, the dielectric material 310 extends beyond the distance of the conductive element 370. By using the above method, the sensor surface area of the chemical sensor can be controlled, thereby unifying the performance of the entire array of chemical sensors and simplifying downstream signal processing.

In one embodiment, the reaction carried out in reaction zone 301 can be an analytical reaction used to identify or determine the characteristics or characteristics of the analyte of interest, such reaction can produce direct or indirect by-products that can affect electrical conduction. The amount of charge around element 370; if such by-products produce only a small amount, or rapidly decrease, or react with other components, multiple samples of the same analyte can be simultaneously analyzed using reaction zone 301 to increase the yield The output signal. In one embodiment, a plurality of samples of an analyte may be attached to the solid support 312 (as shown in FIG. 3) before or after deposition in the reaction zone 301, and the solid support 312 may be microparticles. , nano particles, beads, solid or porous colloids. For simplicity and ease of illustration, the solid support 312 is also referred to herein as a particle. For nucleic acid analysis, multiple linked samples can be made by rolling cycle amplification (RCA), exponential RCA, polymerase chain reaction (PCR) or similar techniques to produce amplification products without the need for a solid support. .

In various exemplary embodiments, the methods, systems, and computer readable media may be advantageous for use in processing and/or analyzing data and signals obtained from nucleic acid sequencing of electronic or charged radicals, in electronic or In the sequencing of charged groups (eg, pH-based sequencing), nucleotide incorporation events can be determined by detecting ions (eg, hydrogen ions), which are Performing a naturally occurring by-product of a polymerase-catalyzed nucleotide extension reaction; this can be used to sequence a sample or template nucleic acid, which can be, for example, a fragment of a nucleic acid sequence of interest, and can be directly or as a clonal population Intermittently attached to solid supports such as particles, particles, beads, and the like. The sample or template nucleic acid can be operably associated to a primer and a polymerase and can be subjected to a repetitive cycle or to the addition of a "flow" of deoxynucleoside triphosphates ("dNTPs") (which can be referred to herein as "nucleotides" Streams, which may result in concomitant nucleotides) and washing. The primer can be annealed to the sample or template, so when adding dNTPs that are complementary to the next base in the template, the polymerase can be used to extend the 3' end of the primer. The ionized concentration of each nucleotide stream can then be determined based on the known sequence of nucleotide flows and the measured output signal of the chemical sensor to determine the sample nucleic acid coupled into the reaction zone of the chemical sensor. The type identification, sequence and number of corresponding nucleotides.

4 to 12 are schematic views showing stages of a manufacturing process for forming an array of chemical sensors according to a first embodiment and corresponding reaction regions thereof. 4 shows a structure 400 formed in a first stage that includes a floating gate structure (eg, floating gate structure 318) of chemical sensors 350, 351 that can be deposited by depositing a gate dielectric on semiconductor substrate 354. Material, and depositing a polysilicon layer (or other conductive material) on the gate dielectric material to form the structure 400, and then etching the polysilicon layer and the gate dielectric material layer by using an etch mask to form a gate A dielectric element (eg, gate dielectric layer 352) and a lowermost conductive material element in the floating gate structure. An ion implantation mask is then formed for ion implantation to form a source region and a drain region (eg, source region 321 and drain region 322) of the chemist. The first layer of dielectric material 319 can be deposited over the underlying conductive material component. A conductive post can then be formed in the via formed in the first layer of the etch dielectric material 319 for contacting the lowermost conductive material component of the floating gate structure. A layer of electrically conductive material can then be deposited over the first layer of dielectric material 319 and patterned to form a second electrically conductive material element that is electrically coupled to the electrically conductive pillar. This process can be repeated multiple times to form the completed floating gate structure 318 shown in FIG. In addition, other and / can also be carried out Or another technique to form the structure. The method of forming the structure 400 as shown in FIG. 4 may also include forming other components, such as array lines (such as column lines, row lines, etc.) for accessing the chemical sensor, other doped regions of the substrate 354, And other circuitry for operating the chemical sensor (eg, select switch, access circuit, bias circuit, etc.), depending on the implementation of the components and array configurations in the chemical sensors described herein . In some embodiments, the elements of the structure can be manufactured, for example, using techniques described in the following documents, such as U.S. Patent Application Serial No. 12/785,667 to Sehultz et al. (now U.S. Patent No. 8,546,128, May 2010). U.S. Patent Application Serial No. 12/721,458, issued to Rotherberg et al. Field effect transistor array method and apparatus for measuring analytes, U.S. Patent Application Serial No. 12/475,311, to Rotherberg et al., filed on May 29, 2009, entitled, U.S. Patent Application Serial No. 12/474,897, filed on May 29, 2009, entitled,,,,,,,,,,,,,,,,,,,,,,,,,,,, Application, titled Method and Apparatus for Measuring Analytes Using Large Field Effect Transistor Arrays, and US Patent Application No. 12/474,897 (now U.S. Patent No. 7,575,865, filed on August 1, 2005, titled For amplification and sequencing of nucleic acids, each of which is incorporated herein by reference in its entirety.

Then, a dielectric material 308 having a given thickness is deposited on the structure 400 as shown in FIG. 4 to form a structure as shown in FIG. 5; wherein the dielectric material 308 comprises one or more dielectric layers. The process of depositing the dielectric material 308 can have minimal variations in the thickness of the entire array. For example, the dielectric material 308 can comprise yttrium oxide and can be deposited using a high density plasma (HDP) deposition process, although it can be used. Various techniques for deposition, such as sputtering, reactive sputtering, atomic layer deposition (ALD), low pressure chemical vapor deposition (LPCVD), plasma enhanced chemical vapor deposition (PECVD), metal organic chemical vapor deposition (MOCVD) Wait. Next, the dielectric material 308 of the structure shown in FIG. 5 is etched to form recesses 600, 602 that extend to the upper surface of the floating gate structure of the chemical sensors 350, 351 to form a pattern. The structure shown in FIG. 6 wherein the method of forming the recesses 600, 602 may, for example, use a lithography process to pattern a photoresist layer on the dielectric material 308 to define the locations of the recesses 600, 602 and then utilize The patterned photoresist layer is used as a mask to anisotropically etch the dielectric material 308, and the anisotropic etching of the dielectric material 308 can be performed, for example, by a dry etching process, such as fluorine-based reactive ion etching. (RIE) Process. Next, a layer of conductive material 310 is formed on the structure as shown in FIG. 6, thereby forming a structure as shown in FIG. 7, wherein the conductive material 310 may include one or more layers of a conductive material such as hafnium oxide or tantalum nitride.

Next, the dielectric material 310 is etched to form openings defining the reaction regions 301, 302 that extend to the sensor plate 320 to form a structure as shown in FIG. Wherein, a conformal layer of conductive material 900 is deposited on the structure as shown in FIG. 8 to form a structure as shown in FIG. The electrically conductive material 900 can comprise one or more layers of electrically conductive material. For example, the electrically conductive material 900 can be a titanium nitride layer or a titanium layer. In addition, other and/or additional conductive materials may be used, such as those described with reference to conductive element 370 described above; in addition, more than one layer of conductive material may be deposited. The conductive material 900 can be deposited using various techniques such as sputtering, reactive sputtering, atomic layer deposition (ALD), low pressure chemical vapor deposition (LPCVD), plasma enhanced chemical vapor deposition (PECVD), metal organic chemical vapor phase. Deposition (MOCVD), etc.

Next, a material 1000 is formed on the structure as shown in FIG. 9 to form a structure as shown in FIG. 10; the material 1000 may comprise one or more layers of deposited dielectric material such as hafnium oxide or tantalum nitride; The material 1000 can include a photoresist. In an embodiment, when the material 1000 can include a photoresist, local etching of the material 1000 and the conductive material 900 can be performed to define a distance 309 of the dielectric material 310, that is, to expose the sidewall. A distance 309 of 303, which in turn forms a structure as shown in FIG. Material 1000 and conductive depending on the process and/or materials used The material 900 may be etched simultaneously or separately, for example, by local etching using one of oxygen photoresist etching, argon sputtering breakthrough etching, or titanium hydrogen bromide etching. Next, material 1000 is etched to form openings defining reaction regions 301, 302 that extend to conductive elements 370, 900 to form a structure as shown in FIG. In one embodiment, the residual photoresist must be removed from the opening, which can be performed using techniques well known in the art, such as oxygen plasma ash.

Figure 13 is a cross-sectional view of two representative chemical sensors and corresponding reaction regions in accordance with a second embodiment. The two representative chemical sensors shown in FIG. 13 are different from the two representative chemical sensors shown in FIG. 3, the differences being shown in FIG. 13 including passing through the sensor plate 320. The through hole is provided with a microwell/nano well above, and therefore the manufacturing method of the structure shown in FIG. 3 is different from the manufacturing method of the structure shown in FIG. 13, and the details are as follows.

14 through 25 are schematic diagrams of various stages of a fabrication process for forming an array of chemical sensors and their corresponding well structures in accordance with an exemplary embodiment. One of the structures 1400 shown in FIG. 14 includes a plurality of floating gate structures (eg, floating gate structures 318) of chemical devices 350, 351. The method of forming structure 1400 can form a method that refers to structure 400 as shown in FIG. As shown in FIG. 15, a dielectric material 1503 can be formed on the sensor plate 320 of the field effect transistor of the chemical device 350. Next, as shown in FIG. 16, the structure shown in FIG. A dielectric material 1503 of 1500 is etched to form openings 1618, 1620 (as vias) that extend to the upper surface of the plurality of floating gate structures of chemical devices 350, 351 to form structure 1600 as shown in FIG. The method of forming the openings 1618, 1620 may, for example, use a lithography process to pattern a layer of photoresist on the dielectric material 1503 to define the locations of the openings 1618, 1620, and then utilize the patterned photoresist layer. As a mask, the dielectric material 1503 is anisotropically etched. The anisotropic etch of dielectric material 1503 can be performed, for example, using a dry etch process, such as a fluorine based reactive ion etch (RIE) process. In the present embodiment, the openings 1618, 1620 are separated by a distance 1630, and the openings 1618, 1620 The appropriate size is applied as a via, for example, the separation distance 1630 can be the minimum feature size of the process used to form the openings 1618, 1620 (eg, lithography); wherein the distance 1630 can be much larger than the width 1620. Next, a layer of conductive material 1704 is deposited over structure 1600 as shown in FIG. 16 to form structure 1700 as shown in FIG. 17, wherein conductive material 1704 can also be referred to as a conductive pad; conductive material 1704 can include one or more layers. The electrically conductive material, for example, the electrically conductive material 1704 can be a titanium nitride layer or a titanium layer. In addition, other and/or additional conductive materials may be used, such as those described with reference to the conductive elements described above; in addition, more than one layer of conductive material may be deposited. Conductive material 1704 can be deposited using a variety of techniques such as sputtering, reactive sputtering, atomic layer deposition (ALD), low pressure chemical vapor deposition (LPCVD), plasma enhanced chemical vapor deposition (PECVD), metal organic chemical vapor phase. Deposition (MOCVD), etc.

Next, a layer of conductive material 1805 (e.g., tungsten) can be deposited, for example, on structure 1700 as shown in FIG. 17, thereby forming structure 1800 of FIG. Among them, conductive material 1805 can be deposited using various techniques such as sputtering, reactive sputtering, atomic layer deposition (ALD), low pressure chemical vapor deposition (LPCVD), plasma enhanced chemical vapor deposition (PECVD), metal organic chemistry. Vapor deposition (MOCVD), etc., or any other suitable technique. Conductive material 1704 and conductive material 1805 can then be planarized using, for example, a chemical mechanical polishing (CMP) process to form structure 1900 as shown in FIG. An additional step may be optionally performed to form a via barrier liner (not shown) on the planarized conductive material 1704 and the conductive material 1805. For example, the material of the via barrier liner may comprise titanium nitride. .

Next, a dielectric material 2006 is formed on the structure as shown in FIG. 19, thereby forming a structure as shown in FIG. The dielectric material 2006 can comprise one or more layers of deposited dielectric material such as hafnium oxide or tantalum nitride. Dielectric material 2006 is then etched to form openings that extend to dielectric material 1503 and planarized conductive material 1704 and conductive material 1805, thereby forming a structure as shown in FIG. After the opening is formed, the dielectric material 1503 can be locally etched, as shown in this embodiment, so that the conductive material 1704 and the conductive material 1805 are high. The dielectric material 1503 is protruded into the opening. Next, a conformal layer of conductive material 2200 is deposited on the structure shown in FIG. 21 to form a structure as shown in FIG. The conductive material 2200 may comprise one or more layers of conductive material. For example, the conductive material 2200 may be a titanium nitride layer or a titanium layer. In addition, other and/or additional conductive materials may be used, such as those described with reference to conductive element 370 described above; in addition, more than one layer of conductive material may be deposited. Conductive material 2200 can be deposited using various techniques such as sputtering, reactive sputtering, atomic layer deposition (ALD), low pressure chemical vapor deposition (LPCVD), plasma enhanced chemical vapor deposition (PECVD), metal organic chemical vapor phase. Deposition (MOCVD), etc.

Next, the material 2300 is formed on the structure as shown in FIG. 22 to form a structure as shown in FIG. 23; the material 2300 may comprise one or more layers of deposited dielectric material such as hafnium oxide or tantalum nitride; The material 2300 can include a photoresist. In an embodiment, when the material 2300 can include a photoresist, local etching of the material 2300 and the conductive material 2200 can be performed to define a distance 1309 of the dielectric material 310, that is, to expose the sidewall. A distance 309 of 1303, which in turn forms a structure as shown in FIG. Depending on the process and/or materials used, the material 2300 and the conductive material 2200 may be etched simultaneously or separately, for example, by one of oxygen photoresist etching, argon sputtering breakthrough etching, or titanium hydrogen bromide etching. Etching. Next, material 2300 is etched to form openings defining reaction regions 301, 302 that extend to conductive elements 370, 2200 to form a structure as shown in FIG. In one embodiment, the residual photoresist must be removed from the opening, which can be performed using techniques well known in the art, such as oxygen plasma ash.

While the present invention has been described with reference to the preferred embodiments and examples, It is contemplated that those skilled in the art can implement and make appropriate modifications and combinations, which are still within the spirit of the invention and the scope of the following claims.

301, 302‧‧‧Reaction area

303‧‧‧ side wall

308, 310, 319‧‧‧ dielectric materials

309‧‧‧ distance

312‧‧‧ Solid support

Lower part of 314‧‧

315‧‧‧ upper

318‧‧‧Floating gate structure

320‧‧‧Sensor board

321‧‧‧ source area

322‧‧‧Bungee area

323‧‧‧Channel area

340‧‧‧Diffusion mechanism

350, 351‧ ‧ chemical sensors

352‧‧‧ gate dielectric layer

354‧‧‧Semiconductor substrate

370‧‧‧Conductive components

371‧‧‧ inner surface

Claims (19)

A chemical sensor comprising: a chemically sensitive field effect transistor comprising a floating gate conductor having an upper surface; a material extending to the upper surface of the floating gate conductor An opening, the material comprising a first dielectric underlying a second dielectric; and a conductive element contacting the upper surface of the floating gate conductor and along one of the openings The side walls extend a distance. The chemical sensor of claim 1, wherein the opening comprises a lower portion in the first dielectric and an upper portion in the second dielectric. A chemical sensor according to claim 2, wherein one of the lower portions of the opening has a width substantially the same as a width of one of the upper portions. The chemical sensor of claim 2, wherein the conductive elements collectively form one of the openings. The chemical sensor of claim 1, wherein the conductive element extends to an upper surface of the second dielectric. The chemical sensor of claim 1, wherein the conductive element comprises an inner surface defining a lower portion of one of the reaction regions of the chemical sensor, and the second dielectric comprises an inner portion defining an upper portion of the opening surface. The chemical sensor of claim 1, wherein the conductive element comprises a conductive material, and an inner surface of the conductive element comprises an oxide of the conductive material. A chemical sensor according to claim 1, wherein one of the sensing surfaces of the chemical sensor comprises an inner surface of the conductive element. The chemical sensor of claim 1, wherein the chemically sensitive field effect crystal system generates a sensor signal corresponding to a chemical reaction occurring near the conductive element. The chemical sensor of claim 1, wherein the floating gate conductor comprises a plurality of conductors electrically connected to each other and separated from each other by a dielectric layer, and the floating gate conducting system is among the plurality of conductors The uppermost layer of the conductor. A method for fabricating a chemical sensor, the method comprising: forming a chemically sensitive field effect transistor comprising a floating gate conductor having an upper surface; forming a material defining an extension Opening to one of the upper surfaces of the floating gate conductor, the material comprising a first dielectric underlying a second dielectric; and forming a conductive element contacting the floating gate conductor The upper surface extends a distance along a side wall of the opening. The method of claim 11, wherein the forming the material and forming the conductive element comprises: forming the first dielectric on the floating gate conductor, wherein the first dielectric system definition extends to the floating gate a recess of the upper surface of the conductor; forming the second dielectric thereon; etching the second dielectric to expose the conductive element, thereby defining an opening; and forming the conductive element in the opening. The method of claim 12, wherein the step of forming the conductive element in the opening comprises: depositing a conductive material in the opening and on an upper surface of the first dielectric; and from the second dielectric The upper surface removes at least a portion of the electrically conductive material. The method of claim 13, wherein the removing at least a portion of the electrically conductive material comprises: depositing a layer of photoresist in the opening; and extracting a portion of the electrically conductive material from the upper surface of the second dielectric together with the light The resistance is removed together. The method of claim 14, further comprising removing the residual photoresist. The method of claim 11, wherein the electrically conductive material comprises titanium. The method of claim 11, wherein the opening is a nanowell. The method of claim 11, wherein the step of forming a conductive element comprises conformally depositing a conductive material in the opening. The method of claim 11, wherein the conductive element comprises an inner surface defining a lower portion of one of the reaction regions of the chemical sensor, and the second dielectric comprises an inner surface defining an upper portion of the opening.