WO2026010872A1 - Reconfigurable cmos chip for dna synthesis and sensing of ph - Google Patents

Abstract

A DNA synthesis and sensing system is proposed for high-throughput DNA synthesis and real-time, full-frame pH sensing. This system includes a CMOS chip with an electrode array fabricated on top and an underlying CMOS control and sensing circuit, along with a microfluidic delivery subsystem for reagent delivery. The method for fabricating the electrode array is detailed. The system operates to synthesize DNA by regulating local pH and sense pH by voltage sensing on an electrode array which contains a plurality of working electrodes arranged in rows and columns and at least one counter electrode. The underlying CMOS circuit is electrically coupled to the working electrodes, controlling DNA synthesis selectively and individually in synthesis mode and sensing pH across the electrode array with a full-frame readout.

Description

RECONFIGURABLE CMOS CHIP FOR DNA SYNTHESIS AND SENSING OF PH

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63/666,441 , filed on July 1 , 2024. The entire disclosure of the above application is incorporated herein by reference.

FIELD

[0002] The present disclosure relates to a reconfigurable CMOS chip for synthesis and sensing of pH.

BACKGROUND

[0003] Scientists seek to understand how genomic, proteomic, and transcriptomic information maps to cellular function. Biology presently lacks a general predictive modeling tool that can map DNA sequence, RNA sequence, protein structure, or small molecule structure to cellular function.

[0004] The present disclosure provides a biotechnology instrument that performs massive parallel experimentation on single cells. The biotechnology instrument would generate massive data to train a machine learning model that takes chemical perturbations as input and returns cellular function as an output.

[0005] The biotechnology instrument such as, for example, a reconfigurable chip for synthesis and sensing of pH may include a CMOS chip that facilitates biochemistry operation, digital logic operation, microcontroller functionality, memory storage, and other functions; an electrode array; a fluid delivery system (e.g., a microfluidic subsystem that facilitates the delivery of reagents to precise locations on the CMOS chip); an integrated circuit and converters (e.g., a FPGA, ADC, and DAC that facilitate communication with the CMOS chip).

[0006] The background description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the present disclosure. SUMMARY

[0007] This section provides a general summary of the disclosure and is not a comprehensive disclosure of its full scope or all of its features.

[0008] In one aspect, a system is presented for DNA synthesis. The system includes: an electrode array, a microfluidic delivery subsystem, and a controller integrated on a substrate. The electrode array is disposed on the substrate and may contain at least one counter electrode and a plurality of working electrodes arranged in rows and columns and. The microfluidic delivery subsystem is fluidly connected to the substrate such that the microfluidic delivery subsystem delivers reagents proximate to the plurality of working electrodes.

[0009] The system may further include a plurality of wells formed in a top surface of a substrate such that a working electrode from the plurality of working electrodes is disposed in each of the plurality of wells.

[0010] The system may also include one or more counter electrode(s) disposed adjacent to the plurality of working electrodes and on the top surface of the substrate. The one or more counter electrode(s) are preferably electrically coupled to ground.

[0011] The system further comprise inwardly facing sidewalls of a given well for each well in the plurality of wells such that the inwardly facing sidewalls increase surface contact between the reagents and a working electrode residing in the given well.

[0012] During operation, the microfluidic system delivers the proper reagent(s) to a specific location on the substrate. During synthesis mode, the controller is operable to apply a voltage selectively and individually to the plurality of working electrodes.

[0013] During sensing mode, the controller is operable to measure voltage at each working electrode of the plurality of working electrodes. The controller in turn determines pH at a given working electrode of the plurality of working electrodes from voltage measured at the given electrode, such that the pH is linearly proportional to the voltage measured at the given working electrode.

[0014] Further areas of applicability will become apparent from the description provided herein. The description and specific examples in this summary are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The present disclosure will become more fully understood from the detailed description and the accompanying drawings, wherein:

[0016] FIG. 1 is a diagram depicting an example architecture of a DNA synthesis system;

[0017] FIG. 2 is a graph showing the linear relationship between an applied voltage and a pH level;

[0018] FIG. 3A is a diagram of an example first step in the DNA synthesis process;

[0019] FIG. 3B is a diagram of an example second step in the DNA synthesis process;

[0020] FIG. 3C is a diagram of an example third step in the DNA synthesis process;

[0021] FIG. 3D is a diagram of an example fourth step in the DNA synthesis process;

[0022] FIG. 3E is a diagram of an example fifth step in the DNA synthesis process;

[0023] FIG. 4 is diagram of an example control circuit for the DNA synthesis system;

[0024] FIG. 5 is schematic of an example pixel circuit;

[0025] FIG. 6 is a cross-sectional view of the CMOS chip after the first step of the fabrication process;

[0026] FIG. 7 is a cross-sectional view of the CMOS chip after the second step of the fabrication process;

[0027] FIG. 8 is a cross-sectional view of the CMOS chip after the third step of the fabrication process;

[0028] FIG. 9 is a cross-sectional view of the CMOS chip after the fourth step of the fabrication process;

[0029] FIG. 10 is a cross-sectional view of the CMOS chip after the fifth step of the fabrication process;

[0030] FIG. 11 is a cross-sectional view of the CMOS chip after the sixth step of the fabrication process; [0031] FIG. 12 is a cross-sectional view of the CMOS chip after the seventh step of the fabrication process;

[0032] FIG. 13 is a cross-sectional view of the CMOS chip after the eighth step of the fabrication process;

[0033] FIG. 14 is a cross-sectional view of the CMOS chip including the electrical connection to the underlying circuit;

[0034] FIG. 15 is a cross-sectional view of an example embodiment of the CMOS chip with angled sidewalls;

[0035] FIG. 16 is a cross-sectional view of an example embodiment of the CMOS chip with concave sidewalls;

[0036] FIG. 17 is a cross-sectional view of an example embodiment of the CMOS chip with etched sidewalls;

[0037] FIGs. 18A and 18B are a top view and a cross sectional view, respectively, of a particular implementation of the CMOS chip;

[0038] FIG. 19 is a cross sectional of another implementation for the CMOS chip;

[0039] FIG. 20 is a top view of the chip showing that surrounding blocks are a pad frame.

[0040] Corresponding reference numerals indicate corresponding parts throughout the several views of the drawings.

DETAILED DESCRIPTION

[0041] Example embodiments will be described more fully with reference to the accompanying drawings.

[0042] Figure 1 depicts an example architecture for a DNA synthesis system 100. The DNA synthesis system 100 is generally comprised of a microfluidic delivery subsystem 126, a controller (e.g., a Field Programmable Gate Array) 1 12 and/or a control computer 114. The microfluidic delivery subsystem 126 contains a valve 104, a flow cell 106, and a pump 108. The flow cell 106 contains a fluidic inlet 1 16, a chip 120 (e.g. a CMOS chip), a chip holding mechanism 122, a gasket 124, and a fluidic outlet 118. Each of these components are further described below. It is to be understood that only the relevant components of the system are discussed in relation to Figure 1 , but that other components may be needed to control and manage the overall operation of the system. [0043] The valve 104 is fluidly connected to the fluidic inlet 1 16 of the flow cell 106. The fluidic outlet 1 18 of the flow cell 106 is fluidly connected to the pump 108. The control circuit 1 12 and the controller 1 14 controls the valve 104 to selectively deliver reagents 102 and the pump 108 pumps liquid from the flow cell 106 to create waste 110. The reagent(s) 102 are delivered by the microfluidic delivery subsystem 126 through the valve 104 into the fluidic inlet 1 16 of the flow cell 106. The microfluidic delivery subsystem 126 delivers the reagent(s) 102 to precise locations on the chip 120. The reagent(s) 102 exit the flow cell 106 from the fluidic outlet 1 18 and are output as waste 1 10 by the pump 108. The controller 1 14 is reconfigurable to operate in a synthesis mode or a sensing mode. Operation of the controller 1 14 during the synthesis mode and sensing mode will be described below.

[0044] The CMOS chip 120 is comprised of a substrate 200 and an electrode array 198, where the electrode array 198 is disposed on the substrate 200. The electrode array 198 contains at least one counter electrode 208 and a plurality of working electrodes 206. The chip holding mechanism 122 is suitable for holding the chip 120. Although some control components are found off chip, it is important to note that control and sensing circuits for the electrode array are on chip.

[0045] Figure 2 depicts a linear relationship between a detected voltage and a pH level. When a positive voltage is applied to the working electrode 206, like an anode, protons are released and the pH of the solution around the working electrode 206 will be acid. The acid around the working electrode 206 is a local acid area 238. When a negative voltage is applied to a counter electrode 208, like a cathode, protons are released and the pH of the solution around the counter electrode 208 is basic. Therefore, the pH can be sensed by applying positive or negative voltage to the working electrode 206 and the counter electrode 208. The voltage is controlled by the controller 1 14 and applied to the working electrode 206 during synthesis mode.

[0046] The controller 1 14 may operate in the sensing mode to measure the voltage at each working electrode 206. The counter electrode 208 is electrically coupled to ground. In an alternative embodiment, there is one global reference electrode instead of the counter electrode 208. Therefore, the measured voltage at the working electrode 206 is the voltage difference between the working electrode 206 and the counter electrode 208. The voltage measured at the working electrode 206 has a linear relationship to the pH level, therefore pH can be determined when measuring the voltage at the working electrode 206. [0047] Figures 3A-3E depict a phosphoramidite method for the DNA synthesis process implemented by the DNA synthesis system 100. In Fig. 3A, the DNA synthesis process begins at Step A where the DNA molecule 250 is fixed onto the working electrode 206. The DNA molecule 250 is protected by an amidite 236. In Step B, the controller 1 14 is operating in synthesis mode which individually and selectively applies positive voltage to the working electrode 206 so that the pH of the solution to be acid which deprotects the DNA molecule 250. The acid around the working electrode 206 is the local acid area 238. The local acid area 238 of one working electrode 206 does not dissipate into another working electrode 206 because of a barrier 240. The barrier 240 ensures that there is no error during sensing mode of the controller 1 14 because each working electrode 206 is separated. In this way, each working electrode 206 is individually and selectively addressable. The barrier 240 can be a physical barrier or a chemical barrier. In Step C, the deprotected DNA molecule 250 couples with new nucleotide. In Step D, the DNA molecule 250 is oxidized to be stabilized for the next DNA synthesis cycle. Steps B, C, and D are repeated multiple times in consecutive order to build the DNA sequence. Lastly, different DNA sequences would be synthesized on the working electrode 206 and the counter electrode 208 as shown in Step E. The sensing mode of the controller 1 14 can operate during any step throughout this process to measure the voltage at each working electrode 206. Sensing mode of the controller 114 is to determine whether the pH level is acid or base as described above in Figure 2.

[0048] Figure 4 is an example for the CMOS control circuit 300 for the DNA synthesis system 100. The control circuit 300 includes a pixel array 198, column-parallel sample buffers 342, ADCs (Analog-to-Digital Converters) 312, and peripheral circuits 328. The pixel array matches with the electrode array where each working electrode is electrically connected to the underlying pixel circuit. The peripheral circuits 328 include a SPI interface (Serial Peripheral Interface) 302, a SRAM (static random access memory) row control 318, a SRAM column control 346, a timing generation block 348, and serializers 350. The SPI interface 302, the SRAM column control 346, the SRAM row control 318 are used for deprotection pattern programming for synthesis mode of the controller 1 14. The sample buffers 342 and the ADCs 312 are per column to realize a full-frame readout for sensing mode of the controller 114. The serializers 350 serialize the digital output from the ADCs 312 and send it off-chip for later processing. The control timing signals for the working electrode 206, the sample buffers 342, and the ADCs 312 are generated by timing generation blocks. The timing generation block 348 generates the proper basis voltages for the working electrodes 206, the sample buffers 342, and the ADCs 312.

[0049] In synthesis mode, the voltage applied to the working electrode 206 can be either generated by off-chip DACs (Digital-to-Analog Converters) 310 or on chip DACs 310 shown in Figure 5. The applied voltage is used to regulate the local pH of the solution at the working electrodes 206 to selectively deprotect the DNA molecule 250 shown in Figure 3B. The deprotection pattern of the electrode array 198 is programmed through the SPI interface 302, the SRAM column control 346, and the SRAM row control 318. In each DNA synthesis cycle, the electrode array 198 is reprogrammed before Step B depicted in Figure 3B to determine the deprotection pattern.

[0050] In sensing mode, the working electrode 206 in one column are time- multiplexed sampled to the column bus by the distributed sampled buffer 342 and converted into digital output by column-parallel ADCs 312 to realize a full-frame pH readout. The ADC 312 outputs are serialized to be sent off-chip.

[0051] Figure 5 is an example of a pixel circuit. Each working electrode is connected to one underlying pixel circuit. The pixel circuit can be reconfigurable between synthesis mode and sensing mode. The pixel circuit includes a SRAM cell 352, a PMOS chip 356, and a switch 326. In synthesis mode, the SRAM cell 352 can be programmed through the method described in Figure 4 to determine whether the DNA deprotection happens on the working electrode 206. The voltage supply, VWE, at the source of the PMOS chip 356 is the desirable voltage to deprotect the DNA molecule 250. While the voltage supply VCE at the source of the NMOS chip 358 is inside the voltage of the counter electrode 208. The counter electrode 208 could be connected to ground. The PMOS chip 356 biases the working electrode 206 to either VWE or VCE based on the control bit stored in the SRAM cell 352. The supply voltage VWE and VCE can be generated by either on- chip or off-chip using DACs 310.

[0052] In sensing mode, the working electrode 206 is directly connected to the distributed sample buffer 342. The sample buffer 342 is basically a self-tied source follower that only the input PMOS chip 356 and the select switch PMOS chip 356 inside the working electrode 206 while the current source is shared by the working electrode 206 in one column. The voltage of each working electrode 206 is time-multiplexing sampled to the column bus and sent to the column-parallel ADC 312. The timemultiplexing readout is realized by the control signals Smp_EN generated by the time generation block 348 depicted in Figure 4. The sensing mode could be enabled along with the synthesis mode to check the voltage applied on the working electrode 206 is the desirable one or ensure the accident deprotection does not occur. The sensing mode could also work alone as a pH sensor to study the acid dissipation process.

[0053] Figures 6-13 depict an example fabrication process for the CMOS chip 120. Figure 6 is a cross-sectional view of the chip 120 after the first step of the fabrication process. A substrate 200 and pillars 202 may be any dielectric or semiconductor material 216, for example a fused silica, silicon, a polymer, or any suitable material. The pillars 202 can be formed through an additive process where the substrate 200 is patterned using photolithography or other nanopatterning techniques and then the pillars 202 are deposited in an open patterned area 204. Also, the pillars 202 may be formed through a subtractive process where the deposited material or the substrate 200 is patterned using a nanopatterning technique and the open patterned areas 204 are etched away creating the pillars 202. The pillars 202 will have a depth (d), width (w) and be separated by a pitch (p). The pillars 202 have a length (I) extending outwardly shown in the top view shown in Figure 20. The open patterned area 204 creates channels 210. The dimension of these values can be varied according to implementation of the chip 120.

[0054] Figure 7 is a cross-sectional view of the chip 120 after the second step of the fabrication process. In the second step of the fabrication process of the chip 120, the pillars 202 are patterned with a photoresist 212 across their width (w) through photolithography. The length (I) of each pillar can also be defined with photolithography. Other patterning techniques may be used, such as e-beam lithography, thermal scanning probe lithography, beam pen lithography or any other comparable technique suitable for patterning the top of the pillars 202 with the photoresist 212. Further, glancing angle evaporation may also be used with a sacrificial material to effectively cover the top of the pillar 202.

[0055] Figure 8 is a cross-sectional view of the chip 120 after the third step of the fabrication process. In the third step of the fabrication process of chip 120, the working electrode 206 is deposited via e-beam or thermal evaporation. The evaporation deposition is directional and perpendicular to the substrate 200. The working electrode 206 is deposited on top of the photoresist and in the channels 210. The working electrode 206 may be any material suitable for electrochemical electrodes including but not limited to: Pt (Platinum), Au (Gold), Ir (Iridium), Ru (Ruthenium), and Ag (Silver).

[0056] Figure 9 is a cross-sectional view of the chip 120 after the fourth step of the fabrication process. In the fourth step of the fabrication process of the chip 120, solvent is washed across the substrate 200 dissolving the photoresist 212 and washing away the metal deposited on top the photoresist 212, leaving only the metal deposited in the channels 210.

[0057] Figure 10 is a cross-sectional view of the chip 120 after the fifth step of the fabrication process. In the fifth step of the fabrication process of the chip 120, the working electrode 206 is formed using an angle evaporation technique such as glancing angle evaporation. The evaporation is not perpendicular to the substrate 200 but is tilted at an angle theta. Angle theta is dependent on the evaporator geometry, the pillar 202 depth (d), width (d) and pitch (p). At angle theta, the geometry of the pillars 202 will shadow 214 the opposite side facing the evaporation flux and will not receive any metal deposition.

[0058] Figure 1 1 is a cross-sectional view of the chip 120 after the sixth step of the fabrication process. In the sixth step of the fabrication process of the chip 120, the dielectric material 216 is deposited conformally across the entire substrate. The process can be done by various means, for example, CVD (Chemical Vapor Deposition), PECVD (Plasma enhanced Chemical Vapor Deposition), ALD (Atomic Layer Deposition), sputtering (Physical Vapor Deposition), or another suitable process. The dielectric material 216 may be any material that electrically isolates the working electrode 206 from the counter electrode 208. The thickness of the dielectric material 216 will factor in the area of pH modulation.

[0059] Figure 12 is a cross-sectional view of the chip 120 after the seventh step of the fabrication process. In the seventh step of the fabrication process of the chip 120, the counter electrode 208 is deposited via another angled evaporation deposition. The angled evaporation deposition in the seventh step of the fabrication process of the chip 120 is also an angled deposition so the evaporated flux will only partially coat one side of the pillar 202 due to shadowing.

[0060] Figure 13 is a cross-sectional view of the chip 120 after the eighth step of the fabrication process. In the eighth step of the fabrication process of the chip 120, the dielectric material 216 is etched back. The etching is through wet or dry etching processes. The etching process is chosen to be selective to the dielectric material 216 and not etch the working electrode 206, the counter electrode 208, or the substrate 200. The counter electrode 208 will mask and protect the dielectric material 216 covered by the counter electrode 208 from the etching process. [0061] Figure 14 is a cross-sectional view of the chip 120 including the electrical connection to the underlying circuit. The chip substrate 200 will have electrical leads 218 patterned into it that will connect the working electrode 206 to the control and sensing circuit. Alternative fabrication techniques are available such as the pillar 202 shape being retrograded similar to a negative photolithography liftoff process. The pillars 202 have sidewalls 224 that can take different shapes to increase surface contact between the reagents 102 and the working electrode 206. If the pillars 202 are Si[100], the sidewalls 224 can be angled via KOH wet etching. A subsequent SiOx layer can be conformally grown or deposited over the features. The sidewalls 224 could also be fabricated via a tailored RIE or applicable dry etch process.

[0062] Figure 15 is a cross-sectional view of an alternative embodiment of the chip 120 with angled sidewalls. In this example, the sidewalls 224 of the pillars 202 are outwardly angled from the top surface of the substrate 200 to the counter electrode 208. This shape can be fabricated with an isotropic wet or dry etch process.

[0063] Figure 16 is a cross-sectional view of another embodiment of the chip 120 with concave sidewalls. In this example, the sidewalls 224 of the pillars 202 are concave. This shape can be fabricated with an undercut to the pillars 202 defining an electrode gap.

[0064] Figure 17 is a cross-sectional view of yet another embodiment of the chip 120 with etched walls. In this example, the sidewalls 224 of the pillars 202 are partially etched. The bottom portion of the sidewalls 224 proximate to the working electrode 206 is etched such that the bottom portion of the sidewalls 224 have a larger distance between them than the upper portion of the sidewalls 224 proximate to the counter electrode 208.

[0065] Figures 18A and 18B further depicts a particular implementation for the CMOS chip 120. In this implementation, the working electrode 206 is depicted at the base of each well 230. Each well 230 encompasses numerous pH modulation sites, known as synthesis sites 228. High voltage may be applied between the working electrode 206 and the counter electrode 208 in each well 230 that is concealed/encapsulated. Each well 230 is encapsulated so that the DNA synthesis system 100 can electroporate cells selectively. The photoresist utilized for a membrane 232 formation and anchoring may be dimensionally arranged such that electroporation events are isolated. The membrane 232 is generally formed from SU-8/PI/modified for hydrophobicity encompassing several synthesis sites 228. The membrane 232 is to ensure the local acid area 238 does not dissipate to an unselected working electrode 206 because each working electrode 206 must be individually addressable. Therefore, the membrane 232 ensures that the local acid area 238 stays within the given well 230 during the synthesis mode.

[0066] Figure 19 depicts another implementation for the CMOS chip 120. In this implementation, the reagents 102 stay in the open area of the given well 230 because the membrane 232 encapsulates them. Temperature control rings 234 regulate temperature of the CMOS chip. The temperature control rings 234 are controlled by the control circuit.

[0067] Figure 20 is a top view of the chip 120. The electrode array is fabricated exactly above the pixel array. The surrounding blocks 380 are the pad frame of the chip 120.

[0068] The foregoing description of the embodiments has been provided for purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosure. Individual elements or features of a particular embodiment are generally not limited to that particular embodiment, but, where applicable, are interchangeable and can be used in a selected embodiment, even if not specifically shown or described. The same may also be varied in many ways. Such variations are not to be regarded as a departure from the disclosure, and all such modifications are intended to be included within the scope of the disclosure.

Claims

CLAIMS What is claimed is:

1 . A system for DNA synthesis comprising: a substrate; an electrode array disposed on the substrate, wherein the electrode array has at least one counter electrode and a plurality of working electrodes arranged in rows and columns; a microfluidic delivery subsystem configured to deliver reagents proximate to the plurality of working electrodes; and a controller electrically coupled to each of the plurality of working electrodes; wherein, during a synthesis mode, the controller is operable to apply a voltage selectively and individually to the plurality of working electrodes; wherein, during a sensing mode, the controller is operable to measure voltage at each working electrode of the plurality of working electrodes.

2. The system of claim 1 wherein, during the synthesis mode, the controller operates to apply voltage to a given working electrode of the plurality of working electrodes, such that a DNA molecule at the working electrode couples to a nucleotide and builds a DNA sequence.

3. The system of claim 1 wherein, during the sensing mode, the controller operates to determine pH at a given working electrode of the plurality of working electrodes from voltage measured at the given working electrode, such that the pH is linearly proportional to the voltage measured at the given working electrode.

4. The system of claim 1 further comprises a plurality of wells formed in a top surface of the substrate, such that a working electrode from the plurality of working electrodes is disposed in each of the plurality of wells.

5. The system of claim 4 wherein the at least one counter electrode is disposed adjacent to the plurality of working electrodes and on the top surface of the substrate.

6. The system of claim 5 wherein, for each well in the plurality of wells, inwardly facing sidewalls of a given well are configured to increase surface contact between the reagents and a working electrode residing in the given well.

7. The system of claim 6 wherein the inwardly facing sidewalls of the given well are angled outward from the top surface of the substrate towards bottom of the given well.

8. The system of claim 6 wherein the inwardly facing sidewalls of the given well are concave.

9. The system of claim 1 wherein the at least one counter electrode is electrically coupled to ground.

10. A system for DNA synthesis comprising: a substrate; an electrode array disposed on the substrate, wherein the electrode array has at least one counter electrode and a plurality of working electrodes arranged in rows and columns; a microfluidic delivery subsystem configured to deliver reagents proximate to the plurality of working electrodes; and a control circuit fabricated on the substrate and disposed between the substrate and the electrode array, where the control circuit is electrically coupled to each of the plurality of working electrodes; wherein, during a synthesis mode, the control circuit operates to apply a voltage selectively and individually to the plurality of working electrodes; wherein, during a sensing mode, the control circuit operates to measure voltage at each working electrode of the plurality of working electrodes.

1 1 . The system of claim 10 wherein, during the synthesis mode, the control circuit operates to apply voltage to a given working electrode of the plurality of working electrodes, such that a DNA molecule at the working electrode couples to a nucleotide and builds a DNA sequence.

12. The system of claim 11 wherein, during the sensing mode, the control circuit operates to determine pH at a given working electrode of the plurality of working electrodes from voltage measured at the given working electrode, such that the pH is linearly proportional to the voltage measured at the given working electrode.

13. The system of claim 12 further comprises a plurality of wells formed in a top surface of the substrate, such that a working electrode from the plurality of working electrodes is disposed in each of the plurality of wells.

14. The system of claim 13 wherein the at least one counter electrode is disposed adjacent to the plurality of working electrodes and on the top surface of the substrate.

15. The system of claim 14 wherein the at least one counter electrode is electrically coupled to ground.

16. A system for DNA synthesis comprising: a substrate; an electrode array disposed on the substrate, wherein the electrode array has at least one counter electrode and a plurality of working electrodes arranged in rows and columns; a control circuit fabricated on the substrate and disposed between the substrate and the electrode array, where the control circuit is electrically coupled to each of the plurality of working electrodes; and a plurality of wells formed in a top surface of the substrate, such that a working electrode from the plurality of working electrodes is disposed in each of the plurality of wells; wherein, during a synthesis mode, the control circuit operates to apply a voltage selectively and individually to the plurality of working electrodes; wherein, during a sensing mode, the control circuit operates to measure voltage at each working electrode of the plurality of working electrodes.

17. The system of claim 16 wherein, during the synthesis mode, the control circuit operates to apply voltage to a given working electrode of the plurality of working electrodes, such that a DNA molecule at the working electrode couples to a nucleotide and builds a DNA sequence.

18. The system of claim 17 wherein, during the sensing mode, the control circuit operates to determine pH at a given working electrode of the plurality of working electrodes from voltage measured at the given working electrode, such that the pH is linearly proportional to the voltage measured at the given working electrode.

19. The system of claim 18 wherein the at least one counter electrode is disposed adjacent to the plurality of working electrodes and on the top surface of the substrate.

20. The system of claim 19 wherein the at least one counter electrode is electrically coupled to ground.