Differential Readout Research Articles

Tuning cohesin trajectories enables differential readout of the Pcdhα cluster across neurons.

Expression of Protocadherin (Pcdh) genes is critical to the generation of neuron identity and wiring of the nervous system. Pcdhα genes are arranged in clusters and exhibit a range of expression profiles, from stochastic to deterministic. Because Pcdhα promoters have high sequence identity and share distal enhancers, how distinct neurons choose which gene to express remains unclear. We show that the interplay between multiple enhancers, epigenetics, and genome folding orchestrates differential readouts of the locus across neurons. The probability of Pcdhα promoter choice depends on enhancer/promoter encounters catalyzed by cohesin, whose extrusion trajectories determine the likelihood that an individual promoter can "escape" heterochromatin-mediated silencing. We propose that tunable locus-specific regulatory elements and cell type-specific cohesin activity underlie the generation of cellular diversity by Pcdh genes.

Dual-Aptamer Drift Canceling Techniques to Improve Long-Term Stability of Real-Time Structure-Switching Aptasensors.

This paper presents a dual-aptamer scheme to mitigate signal drifts caused by structure-switching aptamers during long-term monitoring. Electrochemical aptamer-based (E-AB) biosensors have recently shown great potential for continuous in vivo monitoring. However, the accuracy of detection is often limited by signaling drifts. Traditional approaches rely on kinetic differential measurements (KDM) coupled with square-wave voltammetry to eliminate these drifts. Yet, we have discovered that KDM does not apply universally to all aptamers, as their responses at different SWV frequencies heavily rely on their structure-switching characteristics and the electron transfer (ET) kinetics of the redox reporters. In light of this, we propose a "dual-aptamer" scheme that utilizes two aptamers, each responding differently to the same target molecule to cancel out drift. These paired aptamers are identified through (1) screening from an existing pool of aptamers and (2) engineering the signaling behavior of the redox reporters. We demonstrate the differential signaling of the aptamer pair in the presence of ampicillin and ATP molecules and show that the pair exhibits similar drifts in undiluted goat serum. By implementing drift cancelation, sensor drift is reduced by a factor of 370. Additionally, the differential signaling enables an increased recording throughput by leveraging differential readout electronics. The authors believe that the proposed technique holds significant benefits for long-term in vivo monitoring.

Symmetric Time-Division-Multiplexed SQUID Readout With Two-Layer Switches for Future TES Observatories

Time-division multiplexing (TDM) of transition-edge-sensor (TES) microcalorimeters is being developed as the readout technology for the Athena X-ray integral field unit (X-IFU) and CMB-S4. We present an experimental demonstration of our latest TDM architecture, which has been implemented in a 4-column × 34-row chip that is fully compatible with the X-IFU design specifications. This new “mux21” architecture is designed for differential readout and uses two-layer switches to reduce the number of row-address lines while also incorporating changes that reduce power to roughly 40% and the total number of SQUIDs to half that of TDM chips used in previous publications. With the 160 ns row durations specified for X-IFU, we obtained (2.02 ± 0.03) eV FWHM energy resolution at 5.9 keV in 2-column × 34-row TDM readout of a NASA X-IFU-like TES array, which meets the requirements of X-IFU's energy-resolution budget. Finally, a scaling analysis of our improved TDM readout chain to bolometer applications indicates that multiplexing factors on the scale of several hundred are possible, depending on the readout requirements.

A Low-cost Creatinine Biosensor by Differential Optical Signal Readout for the Whole Blood Analysis.

This study developed a low-cost paper-based biosensor for point-of-care (POC) detection of blood creatinine by using differential optical signal readout. Dual-channel photochemical paper-based test strips were fabricated with stackable multilayer films containing pre-immobilized enzymes and reagents for the identification and conversion of creatinine and creatine. Enzyme-linked reactions generated hydrogen peroxide (H2O2), which formed a blue oxidized condensate with aniline derivatives. The color depth was quantified via the differential optical signal of the two channels and positively correlated with the concentration of the analyte. This method was first proposed to address the issue of endogenous interferences in the enzymatic assay of creatinine, greatly improving the detection accuracy. The proposed biosensor was calibrated with spiked blood samples, and achieved a wide detection range of 31-1483 μmol/L, showing superior detection performance to general enzymatic methods, especially in the low concentration range. Creatine interference testing demonstrated that the biosensor could resist the interference of ≤ 300 μmol/L endogenous creatine. It is believed that the proposed optical differential biosensor for blood creatinine could enable to pave the way for a daily monitoring system for renal diseases.Clinical Relevance- This stackable multilayer paper-based biosensor provides an enzymatic colorimetric assay of creatinine in whole blood, which can be read out by the differential optical signal to exclude interference from endogenous creatine.

Detection of SARS-CoV-2 RNA with a plasmonic chiral biosensor

The detection of SARS-CoV-2 infection is crucial for effective prevention and surveillance of COVID-19. In this study, we report the development of a novel detection assay named CENSOR that enables sensitive and specific detection of SARS-CoV-2 RNA using a plasmonic chiral biosensor in combination with CRISPR-Cas13a. The chiral biosensor was designed by assembling gold nanorods (AuNR) into three-dimensional plasmonic architectures of controllable chirality on a DNA origami template. This modular assembly mode enhances the flexibility and adaptability of the sensor, thereby improving its universality as a sensing platform. In the presence of SARS-CoV-2 RNA, the CRISPR-Cas13a enzyme triggers collateral cleavage of RNA molecules, resulting in a differential chiral signal readout by the biosensor compared to when there are no RNA targets present. Notably, even subtle variations in the concentration of SARS-CoV-2 RNA can provoke significant changes in chiral signals after preamplification of RNA targets (calculated LOD: 0.133 aM), which establishes the foundation for quantitative detection. Furthermore, CENSOR demonstrated high sensitivity and accuracy in detecting SARS-CoV-2 RNA from clinical samples, suggesting its potential application in clinical settings for viral detection beyond SARS-CoV-2.

Single-Base Resolution Detection of N6-Methyladenosine in RNA by Adenosine Deamination Sequencing.

N6-Methyladenosine (m6A) is one of the most abundant and prevalent natural modifications occurring in diverse RNA species. m6A plays a wide range of roles in physiological and pathological processes. Revealing the functions of m6A relies on the faithful detection of individual m6A sites in RNA. However, developing a simple method for the single-base resolution detection of m6A is still a challenging task. Herein, we report an adenosine deamination sequencing (AD-seq) technique for the facile detection of m6A in RNA at single-base resolution. The AD-seq approach capitalizes on the selective deamination of adenosine, but not m6A, by the evolved tRNA adenosine deaminase (TadA) variant of TadA8e or the dimer protein of TadA-TadA8e. In AD-seq, adenosine is deaminated by TadA8e or TadA-TadA8e to form inosine, which pairs with cytidine and is read as guanosine in sequencing. m6A resists deamination due to the interference of the methyl group at the N6 position of adenosine. Thus, the m6A base pairs with thymine and is still read as adenosine in sequencing. The differential readouts from A and m6A in sequencing can achieve the single-base resolution detection of m6A in RNA. Application of the proposed AD-seq successfully identified individual m6A sites in Escherichia coli 23S rRNA. Taken together, the proposed AD-seq allows simple and cost-effective detection of m6A at single-base resolution in RNA, which provides a valuable tool to decipher the functions of m6A in RNA.

A smartphone-connected point-of-care photochemical biosensor for the determination of whole blood creatinine by differential optical signal readout

The level of creatinine in the human body has clinical implications with regard to a potential association with kidney, muscle, and thyroid dysfunction, hence necessitating fast and accurate detection, especially at the point-of-care (POC) level. This paper presents the design, fabrication, and feasibility of a compact, low-cost and reliable POC photochemical biosensor connected to a smartphone for the determination of whole blood creatinine by differential optical signal readout. Disposable, dual-channel paper-based test strips were fabricated using stackable multilayer films pre-immobilized with enzymes and reagents for the identification and conversion of creatinine and creatine, resulting in dramatic colorimetric signals. A handheld optical reader was integrated with dual-channel differential optical readout to address endogenous interferences in the enzymatic assay of creatinine. We demonstrated this differential concept with spiked blood samples, obtaining a wide detection range of 20–1483 μmol/L and a low detection limit of 0.03 μmol/L. Further interference experiments displayed the differential measuring system's excellent performance against endogenous interference. Furthermore, the sensor's high reliability was confirmed through comparison with the laboratory method, with the results of 43 clinical tests consistent with the bulky automatic biochemical analyzer, with its correlation coefficient R2 = 0.9782. Additionally, the designed optical reader is Bluetooth-enabled and can connect to a cloud-based smartphone to transmit test data, enabling active health management or remote monitoring. We believe the biosensor has the potential to be an alternative to the current creatinine analysis conducted in hospitals and clinical laboratories, and it has promising prospects for contributing to the development of POC devices.

Tetraphenylethylene-doped covalent organic frameworks as a highly efficient aggregation-induced electrochemiluminescence emitter for ultrasensitive miRNA-21 analysis

MicroRNAs (miRNAs) as a well-known kind of cancer marker are closely associated with the formation and metastasis of tumors. Here, a novel tetraphenylethylene (TPE)-doped covalent organic frameworks (TPE-COFs) with strong aggregation-induced electrochemiluminescence (AIECL) response was synthesized and introduced to construct an ultrasensitive biosensor for the detection of miRNA-21. The strong aggregation-induced emission (AIE) response was obtained because the molecular motion of TPE was restricted by COFs which had the porosity and highly ordered topological structure. Meanwhile, the porous structure of COFs allowed TPE to react with electrochemiluminescence (ECL) coreactants more effectively. Furthermore, COFs significantly improved the electron transport efficiency of the entire ECL system. All of these endowed the TPE-COFs with superior AIECL performance. Then, a TPE-COFs based ECL resonance energy transfer (ECL-RET) system was constructed for ultrasensitive miRNA-21 biosensing with differential signal readout. The proposed assays exhibited excellent sensitivity with a wide dynamic range from 10 aM to 1 pM and a low detection limit of 2.18 aM. Therefore, these indicated that doping TPE in COFs was a creative way to develop functional COFs and provided an effective way for enhancing AIECL. Furthermore, this work boarded the application of AIECL in analytical chemistry.

Impedance-Matched Differential Superconducting Nanowire Detectors

Superconducting nanowire single-photon detectors (SNSPDs) are the highest-performing photon-counting technology in the near-infrared region. Because of delay-line effects, large-area SNSPDs typically trade off timing resolution and detection efficiency. This unavoidable fundamental constraint might limit their future deployment in demanding scientific applications. Here we introduce a detector design based on transmission-line engineering and differential readout for device-level signal conditioning, enabling a high system detection efficiency and a low detector jitter simultaneously. To make our differential detectors compatible with single-ended time taggers, we also engineer analog differential-to-single-ended readout electronics, with minimal impact on the system timing resolution. Our best niobium nitride differential SNSPD achieves a system detection efficiency of (83.3±4.3)% at 1550nm and (78±5)% at 775nm. The lowest system jitter is 13.0±0.4ps at 1550nm and 9.7±0.4ps at 775nm, limited by intrinsic contributions. These detectors also achieve sub-100-ps timing response at 1/100 of the maximum level, 30.7±0.4ps at 775 nm and 47.6±0.4ps at 1550nm, enabling time-correlated single-photon counting with high-dynamic-range response functions. Furthermore, because of the differential impedance-matched design, our detectors exhibit delay-line imaging capabilities and photon-number resolution. The properties and high-performance metrics achieved by our system make it a versatile photon-detection solution for quantum computing, quantum communication, and many other scientific applications.8 MoreReceived 16 December 2021Revised 7 February 2023Accepted 20 March 2023DOI:https://doi.org/10.1103/PhysRevApplied.19.044093© 2023 American Physical SocietyPhysics Subject Headings (PhySH)Research AreasOptoelectronicsPhysical SystemsLow-temperature superconductorsNanowiresOptical sources & detectorsSuperconducting devicesTechniquesInfrared techniquesPhoton countingSingle-photon detectorsQuantum InformationCondensed Matter, Materials & Applied PhysicsAtomic, Molecular & Optical

A 256 × 256 CMOS image sensor with differential readout and data converter circuits

SummaryIn this paper, a 256 × 256 CMOS image sensor is introduced in which the pixel signals are read and converted into digital data in a completely differential mode. This technique helps to obtain pixel signals with higher linearity and accuracy compared with conventional methods. Improving the linearity and accuracy of the image sensor has a direct impact on increasing the quality of the generated images. The simulation results of the proposed pixel readout circuit show that the THD, SINAD, SNR, and SFDR are 0.45%, 47 dB, 66 dB, and 46 dB, respectively. The voltage gain of the proposed readout circuit is about 1, causing it to read the photodetector signals more accurately than the conventional methods. A full differential single‐slope ADC with a working frequency of 50 Mhz has the task of converting the pixel signal to 10 bits of digital data. The total power consumption of a column of sensors is about 80 μW. All the circuits are designed and implemented using 0.18‐μm CMOS technology in Virtuoso and simulated by the SPECTRE.

ISFET Pixel Array With Selectable Sensitivity and Bulk-Based Offset-Drift Nullification Capability for Reduction of Non-Ideality Effects

This article presents a monolithic, cost-effective, label free, low power, robust <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$3\times2$ </tex-math></inline-formula> fully differential ion-sensitive field-effect transistor (ISFET) pixel array aimed at pH sensing. Each pixel is based on a differential readout architecture which eliminates need for additional non-ideality compensation circuitry. Additionally, the design offers the capability to correct for residual drift and trapped charge offset through substrate-based voltage adjustment during calibration. The design also provides a unique ability for selecting pH sensitivity according to the desired mode of operation which has not been demonstrated previously. We present experimental results obtained from the pixel array fabricated in an unmodified AMS <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$0.35~\mu \text{m}$ </tex-math></inline-formula> CMOS process using a 3.3 V power supply. Each pixel demonstrates a differential sensitivity of 61 mV/pH when operated in high sensitivity mode and 25 mV/pH when operated in high non-ideality rejection mode over the entire pH range, with the ability to remove the already small drift of 0.3 mV/min and any offset mismatch by adjusting the substrate voltage.

An Analog SiPM Based Receiver With On-Chip Wideband Amplifier Module for Direct ToF LiDAR Applications

An analog silicon photomultiplier (SiPM) based receiver with wideband transimpedance amplifier (TIA) is proposed for direct ToF LiDAR applications. The analog SiPM comprises a <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$16\times 32$ </tex-math></inline-formula> single photon avalanche diodes (SPADs) array with a 25% fill factor. A fully differential pixel readout circuit is proposed within the pixel cell to facilitate the monolithic integration with the subsequent TIA and reduce the output capacitance of the analog SiPM. The TIA with the multipath feedforward compensation technique is proposed to improve the stability and achieve a wider −3-dB bandwidth. The adder array is used in this design to output the intensity information for the walk error compensation and the target identification. The proposed receiver, which is fabricated in <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$0.18~\mu \text{m}$ </tex-math></inline-formula> HV-CMOS technology, achieves a −3-dB bandwidth of 420 MHz. A maximum detection range of 65 m is obtained with 20 W laser peak power, <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$1.8^{\circ }\times 1.8^{\circ }$ </tex-math></inline-formula> field of view, and 40 mm aperture. A ranging accuracy of ±0.4 cm and precision of 4.5 cm are attained under a condition of 5 klux ambient light based on 1000 measurement results.

A CMOS Double-Demodulation Lock-In Amplifier for Stimulated Raman Scattering Signal Detection

In typical stimulated Raman scattering (SRS) signal extraction, the photodetector and lock-in amplifier are often based on separate platforms, rendering the system cumbersome and non-scalable. This paper proposes an SRS double-demodulation lock-in amplifier implemented with a complementary metal-oxide semiconductor (CMOS) image sensor technology that integrates two-stage 1/f noise and offset reduction circuits with a high-speed lateral electric field modulation (LEFM) photo-demodulator. A weak SRS signal is buried in a large offset with a ratio of 10−4 to 10−6; boosting such signals in a CMOS device requires an extremely high offset and noise reduction capability. The double-modulation two-stage lock-in amplifier demodulates at 40 MHz with a sampling frequency of 20 MHz, can suppress the laser and circuit’s 1/f noise to achieve higher detection sensitivity. A prototype chip fabricated using 0.11 μm CMOS image sensor technology is evaluated. Both simulation and measurement results are presented to verify the functionality and show that the differential readout structure can successfully reject laser common mode components while emphasizing its differences. The measurement results show that the double-modulation lock-in amplifier effectively suppresses the circuit’s 1/f noise by a factor of nearly two decades.

Bisulfite-Free and Single-Base Resolution Detection of Epigenetic DNA Modification of 5-Methylcytosine by Methyltransferase-Directed Labeling with APOBEC3A Deamination Sequencing.

DNA methylation (5-methylcytosine, 5mC) is the most prevalent epigenetic modification that is predominantly found in CG dinucleotides in mammalian genomes. In-depth investigation of the functions of 5mC heavily relies on the quantitative measurement of 5mC at single-base resolution in genomes. Here, we proposed a methyltransferase-directed labeling with APOBEC3A (A3A) deamination sequencing (MLAD-seq) method for the single-base resolution and quantitative detection of 5mC in DNA. In MLAD-seq, a mutant of DNA methyltransferase, M.MpeI-N374K, is utilized to selectively transfer a carboxymethyl group to the 5 position of cytosine in the CG dinucleotide to form 5-carboxymethylcytosine (5camC) using carboxy-S-adenosyl-l-methionine (caSAM) as the cofactor. After A3A treatment, 5camC is resistant to the deamination and base pairs with guanine. Thus, the cytosines in CG sites are read as C in sequencing. On the contrary, the methyl group in 5mC inhibits its carboxymethylcytosine by M.MpeI-N374K and therefore is readily deaminated by A3A to produce thymine that pairs with adenine and is read as T in sequencing. The differential readouts from C and 5mC in the MLAD-seq enable the single-base resolution mapping of 5mC in CG sites in DNA. With the developed MLAD-seq method, we observed the hypermethylation in the promoter region of retinoic acid receptor β (RARB) gene from human nonsmall cell lung tumor tissue. Compared to harsh reaction conditions in bisulfite sequencing that could lead to significant degradation of DNA, the whole procedure of MLAD-seq is carried out under mild conditions, which will avoid DNA damage. Thus, MLAD-seq is more suitable in the scenario where only limited input DNA is available. Taken together, the MLAD-seq offers a valuable tool for bisulfite-free, single-base resolution and quantitative detection of 5mC in limited DNA.

Integrated optical waveguide atomic force microscopy system with a differential splitter readout

There is an urgent need for high-speed atomic force microscopy (AFM) systems, and chip-AFM on an integrated optical waveguide provides a perfect solution. A differential splitter of double waveguides is introduced as a readout method of an integrated optical waveguide AFM to overcome the non-linear response of a conventional optical waveguide AFM. Results show that an optical waveguide AFM with a 190 nm width and 1 μm height nano-tip shows a good monotonic dependence on the cantilever deflection within a range of ± 0.4 μm using a differential splitter readout method.

A low-power differential readout interface for capacitive accelerometer-based SHM applications

A low-power differential readout interface for capacitive accelerometer-based SHM applications

Proteomic Correlates of Enhanced Daptomycin Activity following β-Lactam Preconditioning in Daptomycin-Resistant, Methicillin-Resistant Staphylococcus aureus.

Clinical treatment options for daptomycin (DAP)-resistant (DAP-R), methicillin-resistant Staphylococcus aureus (MRSA) infections are relatively limited. Current therapeutic strategies often take advantage of potential synergistic activity of DAP plus β-lactams; however, the mechanisms underlying their combinatorial efficacy are likely complex and remain incompletely understood. We recently showed that in vitro β-lactam passaging can resensitize DAP-R strains to a DAP-susceptible (DAP-S) phenotype. To further investigate the implications of selected β-lactam pretreatments on DAP plus β-lactam combination efficacy, we utilized DAP-R strain D712. We studied six such combinations, featuring β-lactams with a broad range of penicillin-binding protein-targeting profiles (PBP-1 to -4), using DAP-R strain D712. Of note, preconditioning with each β-lactam antibiotic (sequential exposures), followed by DAP exposure, yielded significantly enhanced in vitro activity compared to either DAP treatment alone or simultaneous exposures to both antibiotics. To explore the underpinnings of these outcomes, proteomic analyses were performed, with or without β-lactam preconditioning. Relative proteomic quantitation comparing β-lactam pretreatments (versus untreated controls) identified differential modulation of several well-known metabolic, cellular, and biosynthetic processes, i.e., the autolytic and riboflavin biosynthetic pathways. Moreover, these differential proteomic readouts with β-lactam preconditioning were not PBP target specific. Taken together, these studies suggest that the cellular response to β-lactam preconditioning in DAP-R MRSA leads to distinct and complex changes in the proteome that appear to resensitize such strains to DAP-mediated killing.

Superconducting nanowire single photon detector under AC-bias with self-differential readout

Superconducting nanowire single photon detector (SNSPD) has been widely used in many fields such as quantum computing, quantum key distribution and laser radar, due to its high detection efficiency, low dark count rate, high counting rate, and low timing jitter. In most cases, the SNSPD works under the DC-bias mode that can detect single photons arrived at any time. In some cases such as satellite laser ranging and single-photon laser radar where the light pulses arrive regularly, the AC-bias mode enables the SNSPD to work with higher counting rates and lower background dark counts, which however requires complicated readout due to the low signal-to-noise ratio of the photon response. In this work, we report on an AC-biased SNSPD system with a self-differential readout circuit. The system includes a 2-pixel SNSPD consisting of two parallel nanowires, which are biased with 100 MHz sinusoidal current. The output signals of these two nanowires are amplified and combined for the differential readout of the photon response. The resulting response pulse possesses a signal-to-noise ratio ten times higher than that extracted before self-differential readout. In addition, the dark counts are reduced by a factor of 4, and the count rates are increased by a factor of 1.5, in comparison with those under the DC-bias mode. This work provides a specific method to read out the AC-biased SNSPD.

Improving Transungual Permeation Study Design by Increased Bovine Hoof Membrane Thickness and Subsequent Infection.

Ungual formulations are regularly tested using human nails or animal surrogates in Franz diffusion cell experiments. Membranes sometimes less than 100 µm thick are used, disregarding the higher physiological thickness of human nails and possible fungal infection. In this study, bovine hoof membranes, healthy or infected with Trichophyton rubrum, underwent different imaging techniques highlighting that continuous pores traversed the entire membrane and infection resulted in fungal growth, both superficial, as well as in the membrane’s matrix. These membrane characteristics resulted in substantial differences in the permeation of the antifungal model substance bifonazole, depending on the dosage forms. Increasing the thickness of healthy membranes from 100 µm to 400 µm disproportionally reduced the permeated amount of bifonazole from the liquid and semisolid forms and allowed for a more pronounced assessment of the effects by excipients, such as urea as the permeation enhancer. Similarly, an infection of 400-µm membranes drastically increased the permeated amount. Therefore, the thickness and infection statuses of the membranes in the permeation experiments were essential for a differential readout, and standardized formulation-dependent experimental setups would be highly beneficial.

A High-Performance 9.5% Scandium-Doped Aluminum Nitride Piezoelectric MEMS Hydrophone With Honeycomb Structure

This letter presents a high-performance scandium-doped aluminum nitride (Sc <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><i>x</i></sub> Al <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1-<i>x</i></sub> N, x = 9.5%) piezoelectric MEMS hydrophone. The doping of Sc increases the piezoelectric constants of the piezoelectric sensing layer and hence results in better receive sensitivity for the ScAlN-based piezoelectric MEMS hydrophone. The sensing cells of the MEMS hydrophone sensor are designed in a bioinspired honeycomb structure for achieving high fill-factor and thus a large receive sensitivity. The top electrodes of the sensing cells are split into the inner and outer sections with optimized size ratios for differential readout, which further enhances the sensor’s sensitivity. The receive sensitivity is improved even further by reducing the top oxide thickness on the sensing diaphragm. The best measured receive sensitivity of the reported MEMS hydrophone with differential readout is −164.5 dB (re: 1 V/ <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\mu $ </tex-math></inline-formula> Pa). An equivalent noise density as low as 44 dB (re: <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$1 ~\mu $ </tex-math></inline-formula> Pa/ <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\surd $ </tex-math></inline-formula> Hz) at 1kHz is achieved. These metrics are much better than those of state-of-the-art bulk piezoceramic hydrophones as well as other reported piezoelectric MEMS hydrophones.