On-Chip Trace Detection of Heavy Metal Ions in Extreme-Deep Seawater Using CMOS-Integrated Low-Noise Transimpedance Amplifiers

On-Chip Trace Detection of Heavy Metal Ions in Extreme-Deep Seawater Using CMOS-Integrated Low-Noise Transimpedance Amplifiers | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article On-Chip Trace Detection of Heavy Metal Ions in Extreme-Deep Seawater Using CMOS-Integrated Low-Noise Transimpedance Amplifiers Wei Cai, Yiming Yu, Wei Fu, Tao Deng, Chenyu Ma, Yifan Wang, Xi Zhang, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6109364/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Electrochemical techniques are widely employed for detecting trace heavy metal ions in environmental samples by measuring redox reaction currents. While conventional benchtop electrochemical workstations provide high signal fidelity for higher concentrations, their bulky and discrete components face scalability and noise limitations, restricting their ability to detect trace concentration heavy metal ion of deep-sea samples. To address these limitations, we developed a custom-designed, low-noise, multi-channel complementary metal-oxide-semiconductor (CMOS) transimpedance amplifier integrated circuit (IC) with vertically integrated on-chip electrodes. This system achieves an extremely-low noise level of 273.9 fA RMS and reduces the electrochemical reaction (ECR) area to just 1 mm², enabling sensitive detection of heavy metals in the wide range of 0.05–500 µg/L. We validated the system’s performance by detecting Cd²⁺ and Pb²⁺ in real seawater samples collected from a depth of 8,448 meters in the Mariana Trench, achieving concentrations of 0.859 µg/L for Cd²⁺ and 0.921 µg/L for Pb²⁺. Compared to inductively coupled plasma-mass spectrometry (ICP-MS), our system demonstrated excellent agreement for Cd²⁺ (0.10% deviation) and reasonable consistency for Pb²⁺ (28.0% deviation), reflecting its selectivity for free ions. Our work provides a robust, portable, and miniaturized solution for trace heavy metal detection under extreme conditions and complex environmental backgrounds, paving the way for advanced in situ oceanic monitoring technologies. Physical sciences/Engineering/Electrical and electronic engineering Earth and environmental sciences/Environmental sciences/Environmental chemistry/Environmental monitoring Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Heavy metals, such as cadmium (Cd) and lead (Pb), are persistent environmental pollutants with significant adverse effects on human health and ecosystems 1 . These metals interact strongly with biological molecules, leading to high toxicity and irreversible damage 2 – 4 . In extreme environments like the deep sea, heavy metal concentrations are exceedingly low, making their detection highly sensitive to even minor disturbances. While techniques such as inductively coupled plasma-mass spectrometry (ICP-MS) offer unparalleled accuracy for trace-level analysis, their high cost, complex sample preparation, and stringent operational requirements limit their applicability in situ , particularly in remote or extreme conditions 5 , 6 . A compact, scalable solution tailored for such environments is therefore highly desirable. Electrochemical methods provide a cost-effective alternative for heavy metal detection, leveraging redox reactions to quantify metal ion concentrations 7 – 9 . These methods are particularly attractive due to their simplicity, portability, and ability to operate in real-time, making them suitable for field applications such as environmental monitoring and industrial quality control 10 , 11 . However, traditional electrochemical workstations face significant challenges in achieving the sensitivity and detection limits required for ultra-trace analysis. The core limitation lies in the noise performance of transimpedance amplifiers (TIAs), which directly determines the system’s ability to resolve weak current signals in the picoampere (pA) to nanoampere (nA) range. In low-concentration regimes, the current generated by redox reactions can be as low as a few pA, making it critically important to minimize noise contributions from the TIA. Furthermore, the dynamic range of the TIA must be carefully optimized to accommodate both high and low current levels without introducing distortion or saturation, further complicating the design process. Additionally, parasitic capacitance introduced by external wiring and discrete components further degrades signal fidelity, hindering accurate measurements in low-concentration regimes. Parasitic capacitance arises from the physical separation between the working electrode, reference electrode, and counter electrode, as well as from the connections between these components and the TIA. This capacitance creates a low-impedance path for high-frequency noise to couple into the system, reducing the effective bandwidth and increasing the likelihood of signal distortion. Moreover, the use of discrete components in traditional systems introduces additional noise and variability, as each component contributes its own inherent noise characteristics and tolerances. These issues are exacerbated in portable or miniaturized systems, where space constraints limit the ability to mitigate parasitic effects through shielding or filtering. Addressing these limitations requires innovative approaches, such as integrating electrodes and amplifiers onto a single chip to minimize parasitic effects and enhance signal integrity. To address these limitations, we proposed a fully integrated electrochemical detection system based on complementary metal-oxide-semiconductor (CMOS) technology. By vertically integrating on-chip electrodes with low-noise TIAs, parasitic effects were minimized, and unprecedented noise cancellation was achieved. The performance of this design was compared with that of the commercial benchtop system CHI760E. Furthermore, we demonstrated the system’s capability to detect trace heavy metals in real seawater samples collected from a depth of 8,448 m in the Mariana Trench. Our work could offer a robust solution for in situ monitoring in extreme environments, highlighting the potential of our integrated multichannel chip for long-term monitoring of trace heavy metals in extreme marine environments. Design considerations Figure 1 a illustrates the concept of a miniaturized low-noise electrochemical chip for trace heavy metal detection in extreme deep sea, leveraging CMOS technology and vertical integration. The system employs a three-electrode configuration (Titanium working electrode (WE), reference electrode (RE), and counter electrode (CE)) immersed in a solution containing heavy metal ions in Fig. 1 b. A potential difference is applied between the WE and RE, and the generated current between the WE and CE was detected. Heavy metal ions are reduced into amalgams during deposition and re-released during dissolution, enabling quantitative analysis via differential pulse stripping voltammetry (DPSV). Figure 1 c shows the potentiostat principle and the circuit system framework for heavy metal detection. The potentiostat, which connects the WE, RE and CE, is the core component of the three-electrode system, typically composed of two main operational amplifiers and other components. The amplifier at the input allows a specific external signal to be directly transmitted to the RE, forming a fixed potential difference between the RE and WE. The potential of the WE to ground is constant, so controlling the signal applied to the RE enables precise control of the signal applied to the WE without being affected by current-induced voltage drops. This independent performance significantly enhances the precision of experiments, particularly when studying the kinetics and mechanisms of electrochemical reactions, providing more reliable data. Low-noise electrochemical chip encapsulated in epoxy resin on a customized base (Fig. 1 d). The base is installed on a customized PCB and assembled into a heavy metal detection system. The test PCB adopts a main-sub board structure. The sub-board is bonded with the TIA, while the main board consists of the power supply module, controlling module and low-noise interfaces. The core of the system is the TIA (Supplementary Fig. 1), which converts the weak current signals from the WE into measurable voltages. To achieve high sensitivity, we adopted a fully differential architecture with a resistive continuous-time feedback design. The feedback resistor (R F = 257 MΩ) was optimized to balance gain, bandwidth, and noise performance. At the transistor level, PMOS inputs were selected for their lower flicker noise 12 , with critical dimensions of W/L = 784 µm/240 nm. Source degeneration resistors further reduced effective transconductance, enhancing noise optimization 13 . The TIA layout fabricated using a 0.18 µm CMOS process, measures 1.255 mm×0.8 mm and integrates four channels with on-chip electrodes (Figs. 2 a and 2 b). Aluminum-coated electrode surfaces were used for durability, and mercury film modification enhanced sensitivity for heavy metal detection. Compared to the state-of-the-art commercial amplifiers like the AD8139, our TIA achieves a noise level of 273.9 fA RMS at 1 kHz low-pass filtering, which is 50× lower than that of AD8139 (Fig. 2 e). This ultra-low noise performance ensures high-fidelity detection of ultra-weak electrochemical signals. Electrical characterization confirmed the system’s accuracy and linearity, with an I-V slope of 1.9868 pA/mV (R 2 = 0.9999) (Figs. 2 c and 2 d). On-chip electrochemical system outperforms standard potentiostats To validate the performance of our on-chip electrochemical system, we compared it with a commercial potentiostat (CHI760E) under identical cyclic voltammetry (CV) conditions. Figures 3 a and 3 b show the recorded voltammograms for both systems using 0.02 µM K 3 [Fe(CN) 6 ]. Our system exhibited a distinct reduction peak near + 0.15 V, indicative of excellent sensitivity, while the CHI760E failed to resolve any peaks across all scan rates. Figure 3 c highlights the linear relationship between the square root of the scan rate and the peak current in our system, confirming its superior detection capability. The detection limit for K 3 [Fe(CN) 6 ] was 1 nM, one order of magnitude lower than the CHI760E (0.02 µM) (Fig. 3 d). This demonstrates the ability of our system to capture redox characteristics at ultra-low concentrations. For heavy metal detection, the electrode surface was modified with a mercury film to enhance sensitivity (Figs. 4 (a–e)). Using differential pulse stripping voltammetry (DPSV), we tested artificial seawater samples containing Cd 2+ and Pb 2+ . Figures 4 f and 4 g show excellent linearity (R 2 > 0.999) across two concentration ranges: 500 µg/L to 5 µg/L and 5 µg/L to 0.05 µg/L. These results confirm the robustness of our system for trace-level detection. Finally, we validated the system’s performance using real seawater samples from the Mariana Trench at a depth of 8,448 m. Our system resolved clear stripping peaks for Cd 2+ and Pb 2+ , achieving concentrations of 0.859 µg/L and 0.921 µg/L, respectively, with standard deviations of 0.10% and 28.0% (Fig. 5 ). While cadmium detection closely matched ICP-MS results (0.858 µg/L), lead values were consistently lower due to the selective nature of our electrochemical system 14 – 16 . Discussion The development of a miniaturized, low-noise electrochemical detection system represents a significant advancement in the field of trace heavy metal analysis, particularly for applications in extreme environments such as the deep sea. By integrating complementary metal-oxide-semiconductor (CMOS) technology with on-chip titanium electrodes, our system achieves unparalleled sensitivity and noise performance, surpassing traditional benchtop electrochemical workstations. Our system addresses the detection limits through several key innovations: (1) the use of source degeneration techniques and non-unity gain buffers in the TIA design, which reduces noise levels to 273.9 fA RMS ; and (2) the vertical integration of on-chip electrodes, which minimizes parasitic capacitance and confines the ECR area to just 1 mm². These advancements enable a detection limit of 0.05 µg/L, two orders of magnitude lower than conventional systems (~ 5 µg/L) at the same condition. To validate the robustness of our system, we conducted experiments using real seawater samples collected from a depth of 8,448 meters in the Mariana Trench. The system successfully detected Cd²⁺ and Pb²⁺ concentrations of 0.859 µg/L and 0.921 µg/L, respectively, without the need for added electrolytes. Compared to inductively coupled plasma-mass spectrometry (ICP-MS), our results showed excellent agreement for Cd²⁺ (0.1% deviation) and reasonable consistency for Pb²⁺ (28.0% deviation). The higher deviation for Pb²⁺ is likely due to the selective nature of our electrochemical system, which primarily detects free ions rather than all chemical forms of heavy metals. This distinction highlights the complementary role of our system alongside analytical techniques like ICP-MS, offering a portable and cost-effective alternative for in situ monitoring. The successful deployment of our system for samples from one of the most extreme environments on Earth - the Mariana Trench - demonstrates its potential for broader applications in environmental monitoring 17 , resource exploration 18 , and ecological research 19 , 20 . For instance, the ability to detect trace heavy metals in situ could provide critical insights into deep-sea ecosystems and anthropogenic pollution pathways 21 , 22 , to name a few. Additionally, the system’s miniaturization and low-power requirements make it suitable for integration into autonomous underwater vehicles (AUVs) or remote sensing platforms 23 . Future work will focus on further optimizing the system’s sensitivity and expanding its applicability to other analytes, such as organic pollutants or biomarkers. In addition, the exploration of advanced surface modification techniques is underway to enhance electrode selectivity and stability. Furthermore, machine learning algorithms are being developed for real-time data analysis and interpretation. These efforts will further solidify the role of integrated electrochemical systems in advancing scientific discovery and environmental stewardship. Conclusion We have developed a CMOS amplifier with on-chip electrodes based on vertical integration technology to push the detection limits of trace heavy metals in deep-sea electrochemical detection. Leveraging the miniaturization advantages of modern CMOS processes, the ECR system was reduced to an area of approximately 1 mm², while the distance between the ECR system and the TIA was shortened to a few hundred micrometers. This design significantly reduces the noise level for multi-channel electrochemical experiments to be reduced to 273.9 fA RMS . In terms of low-concentration signal measurements, our chip extends the detection limit by at least two orders of magnitude compared to traditional electrochemical workstations, achieving a sensitivity of 0.05 µg/L versus the typical 5 µg/L. Furthermore, we validated the ability of the TIA to detect trace heavy metals in real seawater samples collected from a depth of 8,448 m in the Mariana Trench, achieving accurate detection without the need for added electrolytes. These results demonstrate the potential of our system for applications in other fields requiring ultra-low signal detection. Methods Amplifier Chip Fabrication and Packaging. The custom-designed integrated circuit was fabricated using 0.18 µm CMOS process. The chip was directly connected to a custom printed circuit board (PCB) via epoxy resin, serving as a test daughterboard. The daughterboard was interfaced with the main PCB through pin headers. The main PCB included the front-end amplifier, analog-to-digital converter (ADC), and interface circuitry required for the electrochemical detection system. Gold wire bonding under a microscope was used to connect the chip to the PCB, and epoxy resin encapsulation protected the chip and gold wires from corrosion by the solution. A custom-designed DC power supply was implemented to meet the system's requirements, primarily using low-dropout regulators (LDOs) and DC-DC converters to generate ± 1.8 V, ± 0.9 V, and ± 5 V. For example, during noise testing, the TIA was powered by 0/+1.8 V, while during electrochemical experiments, it was powered by -0.9/+0.9 V. Data acquisition (DAQ) was supported by the NI USB-6003 module, which includes four analog input channels and two analog output channels, enabling simultaneous detection across the four TIA channels. Data were transferred to a PC via a USB 2.0 interface. A user-friendly graphical interface was developed in MATLAB 24 , offering scalability and cross-platform operation. Electrode Preparation. The electrode surface of the fabricated CMOS chip consists of titanium and aluminum. To expose the titanium working electrode, the aluminum layer was etched using Type A etching solution (Sigma-Aldrich, China) at room temperature (~ 25℃) for 30 minutes. The etching process was monitored under a magnifier and stopped when the electrode surface transitioned from silver to black 25 . After etching, the electrodes were rinsed three times with deionized water to ensure no residual etchant remained 26 . For cyclic voltammetry (CV) experiments, no mercury plating was required. However, for differential pulse stripping voltammetry (DPSV), the electrode surface was modified with a mercury film. A 0.02 M mercury nitrate solution (Beifangweiye, China) was used for plating. The working electrode was the on-chip titanium electrode, the reference electrode was Ag/AgCl (Gaoss Union, China), and the counter electrode was Pt (Gaoss Union, China). A constant negative potential of − 0.3 V was applied for 15 minutes to form a dense mercury film. Optical microscopy confirmed the silver-gray appearance of the electrode surface, and scanning electron microscopy (Nova NanoSem450, USA) verified the formation of a uniform mercury layer. Noise Measurement of CMOS TIA Chip. Noise measurements were conducted under zero-current input conditions. The system was shielded from external interference using a Faraday cage. The ADC recorded the TIA's voltage output signal over a 10-second interval. The root mean square (RMS) noise of the current signal was calculated, and the power spectral density (PSD) was derived from the recorded data. Cyclic Voltammetry (CV) Measurements. The CV experiments used a mixture of potassium ferricyanide (Macklin, China) and 1 M KCl (Macklin, China). The working electrode was a 0.5 mm-diameter glassy carbon electrode (Gaoss Union, China), the reference electrode was Ag/AgCl (Gaoss Union, China), and the counter electrode was Pt (Gaoss Union, China). A triangular wave input signal was generated using MATLAB and supplied to the PCB. The starting potential was set to -0.1 V, and the ending potential was + 0.5 V, with the slope representing the scan rate. The redox potential of potassium ferricyanide lies between − 0.1 V and + 0.5 V, making this range suitable for CV analysis. Differential Pulse Stripping Voltammetry (DPSV) Measurements. The DPSV experiments were conducted using artificial seawater prepared with a 3.5% NaCl (Macklin, China). Stock solutions of 100 µmol/mL cadmium nitrate and 1000 µmol/mL and lead nitrate (Boer, China) were used to prepare Cd 2+ and Pb 2+ solutions. The working electrode was an on-chip Ti electrode (75 µm × 75 µm), with Ag/AgCl as the reference electrode and Pt as the counter electrode. The input signal, a staircase-shaped square wave, was generated using MATLAB and supplied to the PCB. The experiment consisted of three phases including deposition, resting, and stripping. During the deposition phase, a potential of -1.4 V was applied for 400 s (high concentrations) or 600 s (low concentrations). In the resting phase, a potential of -0.9 V was applied for 10 s. During the stripping phase, a staircase rising square wave was applied from − 0.9 V to -0.3 V. The data acquisition system (DAQ) collected current values during the high and low levels of the stripping phase, generating two I-V curves. The voltammetry curve was obtained by calculating the difference between these two current values. To avoid contamination, measurements were performed in ascending order of concentration. Peak heights were quantified relative to the baseline, which was obtained from DPSV measurements of 3.5% NaCl solution under identical conditions. Each curve was measured repeatedly until two consecutive results were consistent, ensuring accuracy. Seawater Sample Collection and Analysis The seawater sample was collected from a depth of 8,448 m at coordinates 142.15717 ∘ E, 11.5698 ∘ N in the Mariana Trench during the 62nd dive of the manned submersible Fendouzhe , which is employed for deep-sea exploration. The sample was stored at 3℃. During analysis, five consecutive measurements were performed, and the average current was calculated. Inductively coupled plasma-mass spectrometry (Agilent 7700X ICP-MS, USA) was used to validate the results. The seawater sample was diluted twofold, and three measurements were taken to calculate the original concentration. Declarations Data availability Source data is provided with this paper. Competing interests There are no competing interests. Additional information Supplementary information has been provided. Correspondence and requests for materials should be addressed to Wei Cai. Author contributions Y.M.Y., W.F., C.Y.M. and T.D. designed the TIA and device. Y.M.Y., X.Y. and Y.F.W. prepared the TIA and PCB. Y.L., C.Y.M., Y.M.Y. and W.F. completed the architecture of the software. Y.M.Y., C.H.C., X.Z., Y.F.W., W.F. and T.D. prepared the figures. X.Y., T.Y.Z., S.Q.D., D.L. and S.Q.L. designed the experiment. Y.M.Y., W.F., Y.L., Y.G. and W.C. drafted the manuscript. Y.L., Y.G. and W.C. supervised the study. All authors read, revised, and approved the final manuscript. Acknowledgements This work was supported by the National Key Research and Development Program of China (2022YFC3104700 and 2022YFF1203400), National Natural Science Foundation of China (62171211), Zhujiang Program (2021QN02H436), and Science and Technology Innovation Commission of Shenzhen (JCYJ20220814170440001, JCYJ20220818100218039, JCYJ20220530113013030 and JCYJ20230807092459028) as well as NSQKJJ under grant K21799109 and K21799116. References Münzel, T. et al. Soil and water pollution and cardiovascular disease. Nat. Rev. Cardiol. 22, 71–89 (2025). Reid, W. D. K., Cuomo, N. J. & Jamieson, A. J. Geographic and bathymetric comparisons of trace metal concentrations (Cd, Cu, Fe, Mn, and Zn) in deep-sea lysianassoid amphipods from abyssal and hadal depths across the Pacific Ocean. Deep Sea Res. Part Oceanogr. Res. Pap. 138, 11–21 (2018). Paithankar, J. G., Saini, S., Dwivedi, S., Sharma, A. & Chowdhuri, D. K. 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A review on various electrochemical techniques for heavy metal ions detection with different sensing platforms. Biosens. Bioelectron. 94, 443–455 (2017). White, K. A. & Kim, B. N. Quantifying neurotransmitter secretion at single-vesicle resolution using high-density complementary metal–oxide–semiconductor electrode array. Nat. Commun. 12, 431 (2021). Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryInformationOnChipTraceDetectionofHeavyMetalIonsinExtremeDeepSeawaterUsingCMOSIntegratedLowNoiseTransimpedanceAmplifiers.docx On-Chip Trace Detection of Heavy Metal Ions in Extreme-Deep Seawater Using CMOS-Integrated Low-Noise Transimpedance Amplifiers Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6109364","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":424651620,"identity":"26f2bd07-d2d9-43bd-bd6f-e606396237d0","order_by":0,"name":"Wei 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Technology","correspondingAuthor":false,"prefix":"","firstName":"Chenyu","middleName":"","lastName":"Ma","suffix":""},{"id":424651625,"identity":"08f0a46c-c443-449f-b16f-a59e502d7e9d","order_by":5,"name":"Yifan Wang","email":"","orcid":"","institution":"Southern University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Yifan","middleName":"","lastName":"Wang","suffix":""},{"id":424651626,"identity":"6c2f6895-f2cc-4e95-b044-11e4813b5fa5","order_by":6,"name":"Xi Zhang","email":"","orcid":"","institution":"Southern University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Zhang","suffix":""},{"id":424651627,"identity":"b6fa408e-ea20-4b34-b5fc-922e05d88320","order_by":7,"name":"Chenhong Cui","email":"","orcid":"","institution":"Southern University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Chenhong","middleName":"","lastName":"Cui","suffix":""},{"id":424651628,"identity":"565ab8bf-9513-46e0-a4e9-00ef7e98f01b","order_by":8,"name":"Xu Yao","email":"","orcid":"","institution":"Southern University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Xu","middleName":"","lastName":"Yao","suffix":""},{"id":424651629,"identity":"e897abc7-ebe3-4dfe-90d0-1f0c311912d5","order_by":9,"name":"Tingyi Zhang","email":"","orcid":"","institution":"Southern University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Tingyi","middleName":"","lastName":"Zhang","suffix":""},{"id":424651630,"identity":"c29502c4-aa82-47c6-b1f6-d4590321b224","order_by":10,"name":"Shangqi Diao","email":"","orcid":"","institution":"Southern University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Shangqi","middleName":"","lastName":"Diao","suffix":""},{"id":424651631,"identity":"3b801c35-29af-4f91-a36a-ba95b832a6b3","order_by":11,"name":"Dan Li","email":"","orcid":"","institution":"Southern University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Li","suffix":""},{"id":424651632,"identity":"ca4fa55b-1123-458a-9ecc-0f56baf61631","order_by":12,"name":"Songqing Lin","email":"","orcid":"","institution":"Southern University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Songqing","middleName":"","lastName":"Lin","suffix":""},{"id":424651633,"identity":"ba0fa5fa-08e3-43e0-9f2c-2e00c41aba77","order_by":13,"name":"Yuan Gao","email":"","orcid":"","institution":"Southern University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Gao","suffix":""},{"id":424651634,"identity":"ec455a6a-67cc-4cfd-a877-6c0707490be9","order_by":14,"name":"Yi Li","email":"","orcid":"https://orcid.org/0000-0002-6134-3117","institution":"School of Microelectronics, Southern University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-02-26 03:25:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6109364/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6109364/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82708510,"identity":"59511a8c-cb67-4c14-9ea5-4df618705714","added_by":"auto","created_at":"2025-05-14 11:05:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":317508,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSystem Overview and Detection Principle.\u003c/strong\u003e (\u003cstrong\u003ea\u003c/strong\u003e) Schematic illustration of deep-sea operations using a manned submersible for heavy metal detection at depths exceeding 8,000 m in the Mariana Trench. (\u003cstrong\u003eb\u003c/strong\u003e) Detailed view of the electrochemical cell and detection principle. Multiple Ti electrodes are integrated on a multi-channel TIA chip using CMOS technology as WE. Heavy metals form amalgams during deposition and are released during dissolution, enabling reversible detection. (\u003cstrong\u003ec\u003c/strong\u003e) Framework of the heavy metal detection system. The electrochemical cell facilitates redox reactions of heavy metal ions. The three-electrode system consists of the WE, RE, and CE, integrated with the TIA. (\u003cstrong\u003ed\u003c/strong\u003e) Photograph of the TIA and PCB system. TIA is encapsulated in epoxy resin and bonded to a customized base. The PCB is reserved with interfaces for connecting to TIA. The base is installed on a customized PCB and assembled into a heavy metal detection system. The test PCB adopts a main-sub board structure. The sub-board is bonded with the TIA, while the main board consists of the power supply module, controlling module and low-noise interfaces.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-6109364/v1/816e16b83f23c45a0a4579ad.png"},{"id":82708511,"identity":"d70d18cf-445c-4c68-ac01-4acc215415fb","added_by":"auto","created_at":"2025-05-14 11:05:08","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":218083,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTIA Photograph, Layout and Performance Comparison.\u003c/strong\u003e (a) Photograph of the TIA, showing aluminum-coated electrode surfaces. (b) Layout implementation of the TIA, measuring 1.255 mm × 0.8 mm, with four individual channels and integrated on-chip electrodes. (c) Current-time (I-t) curve and (d) Current-voltage (I-V) curve of the TIA, converting pA-level currents to voltage using a 500 MΩ input resistor. (e) Power spectral density (PSD) of our TIA and the state-of-the-art (AD8139). Both are connected to an identical feedback resistance (R\u003csub\u003eF \u003c/sub\u003e= 257 MΩ), shielded in a Faraday cage.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-6109364/v1/662a85ce04359a804ecca212.png"},{"id":82709957,"identity":"30d858ed-686b-471b-81c5-0a85bf4e9bd7","added_by":"auto","created_at":"2025-05-14 11:21:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":185811,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePerformance Validation Using Cyclic Voltammetry (CV).\u003c/strong\u003e (\u003cstrong\u003ea\u003c/strong\u003e) CV measurements of the state-of-the-art commercial instrument CHI760E in 0.02 μM K\u003csub\u003e3\u003c/sub\u003e[Fe(CN)\u003csub\u003e6\u003c/sub\u003e] experiments at varying scan rates. Parameters: initial potential = +0.5 V, high potential = +0.5 V, low potential = -0.1 V, sampling interval = 1 mV. (\u003cstrong\u003eb\u003c/strong\u003e) CV measurements of our system under identical conditions. (\u003cstrong\u003ec\u003c/strong\u003e) Linear relationship between peak current and scan rate for our system, demonstrating excellent linearity. (\u003cstrong\u003ed\u003c/strong\u003e) Detection limits for K\u003csub\u003e3\u003c/sub\u003e[Fe(CN)\u003csub\u003e6\u003c/sub\u003e] at a scan rate of 10 mV/s.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-6109364/v1/c964ef0cf40d02b3992ee3bd.png"},{"id":82708514,"identity":"68247195-680e-408c-a51b-e00329ea283f","added_by":"auto","created_at":"2025-05-14 11:05:08","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":351647,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eElectrode Preparation and Heavy Metal Detection in Artificial Seawater.\u003c/strong\u003e (\u003cstrong\u003ea\u003c/strong\u003e) Photograph of the TIA prepared for electrochemical experiments. TIA is encapsulated with epoxy resin, exposing the aluminum layer on the electrode surface. (\u003cstrong\u003eb\u003c/strong\u003e) TIA has damaged the aluminum layer, exposing the titanium layer and modifying it with a mercury film. The electrodes turned silver-white. (\u003cstrong\u003ec, d, e\u003c/strong\u003e) SME image of exposed Ti electrodes electroplated with a mercury film. (\u003cstrong\u003ef\u003c/strong\u003e, \u003cstrong\u003eg\u003c/strong\u003e) DPSV detection of Cd²⁺ and Pb²⁺ at different concentration gradients in artificial seawater. Parameters: initial potential = −0.9 V, final potential = −0.3 V, increment = 4 mV, amplitude = 0.05 V, pulse width = 0.05 s, sample width = 0.02 s, pulse period = 0.1 s, deposition potential = −1.4 V, deposition time =400 s (high concentrations) or 600 s (low concentrations), quiet time = 10 s. Calibration curves for Cd²⁺ and Pb²⁺. In the high concentration range (5-500 μg/L), R\u003csup\u003e2\u003c/sup\u003e values are 0.999 for Cd²⁺ and 0.997 for Pb²⁺. In the low concentration range (0.05-5 μg/L), R\u003csup\u003e2\u003c/sup\u003e values are 0.999 for both Cd²⁺ and Pb²⁺.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-6109364/v1/ad849c492540f92eb443463d.png"},{"id":82709448,"identity":"2ff07e86-550c-43bb-b1e3-1c361c33e721","added_by":"auto","created_at":"2025-05-14 11:13:08","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":152254,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDemonstration of Mariana Trench Seawater Samples.\u003c/strong\u003e(\u003cstrong\u003ea\u003c/strong\u003e) Schematic diagram of sample collection by the manned submersible \u003cem\u003eFendouzhe\u003c/em\u003e. (\u003cstrong\u003eb\u003c/strong\u003e) Seawater samples collected at 8,448 m in the Mariana Trench. (\u003cstrong\u003ec, d\u003c/strong\u003e) DPSV detection of real seawater samples collected from a depth of 8,448 m in the Mariana Trench using our TIA system. Results of five consecutive measurements of Cd²⁺ and Pb²⁺ concentrations. The dashed lines indicate ICP-MS results of 0.858 μg/L for Cd²⁺ (orange) and 1.28 μg/L for Pb²⁺ (green).\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-6109364/v1/14649a5e537a1a67f6f6452e.png"},{"id":82710769,"identity":"5e46d7d6-06a8-4f81-bf95-c8a70a5fa0ff","added_by":"auto","created_at":"2025-05-14 11:29:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1850866,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6109364/v1/21cf0b03-257d-46ad-95f2-9f5712be97c5.pdf"},{"id":82709451,"identity":"9d3273a9-611c-43ca-b8bc-7aac44e7f72f","added_by":"auto","created_at":"2025-05-14 11:13:08","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":268255,"visible":true,"origin":"","legend":"On-Chip Trace Detection of Heavy Metal Ions in Extreme-Deep Seawater Using CMOS-Integrated Low-Noise Transimpedance Amplifiers","description":"","filename":"SupplementaryInformationOnChipTraceDetectionofHeavyMetalIonsinExtremeDeepSeawaterUsingCMOSIntegratedLowNoiseTransimpedanceAmplifiers.docx","url":"https://assets-eu.researchsquare.com/files/rs-6109364/v1/b37058e09ce33c25a936e68d.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"On-Chip Trace Detection of Heavy Metal Ions in Extreme-Deep Seawater Using CMOS-Integrated Low-Noise Transimpedance Amplifiers","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHeavy metals, such as cadmium (Cd) and lead (Pb), are persistent environmental pollutants with significant adverse effects on human health and ecosystems\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. These metals interact strongly with biological molecules, leading to high toxicity and irreversible damage\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. In extreme environments like the deep sea, heavy metal concentrations are exceedingly low, making their detection highly sensitive to even minor disturbances. While techniques such as inductively coupled plasma-mass spectrometry (ICP-MS) offer unparalleled accuracy for trace-level analysis, their high cost, complex sample preparation, and stringent operational requirements limit their applicability \u003cem\u003ein situ\u003c/em\u003e, particularly in remote or extreme conditions\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. A compact, scalable solution tailored for such environments is therefore highly desirable.\u003c/p\u003e \u003cp\u003eElectrochemical methods provide a cost-effective alternative for heavy metal detection, leveraging redox reactions to quantify metal ion concentrations\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. These methods are particularly attractive due to their simplicity, portability, and ability to operate in real-time, making them suitable for field applications such as environmental monitoring and industrial quality control\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. However, traditional electrochemical workstations face significant challenges in achieving the sensitivity and detection limits required for ultra-trace analysis. The core limitation lies in the noise performance of transimpedance amplifiers (TIAs), which directly determines the system\u0026rsquo;s ability to resolve weak current signals in the picoampere (pA) to nanoampere (nA) range. In low-concentration regimes, the current generated by redox reactions can be as low as a few pA, making it critically important to minimize noise contributions from the TIA. Furthermore, the dynamic range of the TIA must be carefully optimized to accommodate both high and low current levels without introducing distortion or saturation, further complicating the design process.\u003c/p\u003e \u003cp\u003eAdditionally, parasitic capacitance introduced by external wiring and discrete components further degrades signal fidelity, hindering accurate measurements in low-concentration regimes. Parasitic capacitance arises from the physical separation between the working electrode, reference electrode, and counter electrode, as well as from the connections between these components and the TIA. This capacitance creates a low-impedance path for high-frequency noise to couple into the system, reducing the effective bandwidth and increasing the likelihood of signal distortion. Moreover, the use of discrete components in traditional systems introduces additional noise and variability, as each component contributes its own inherent noise characteristics and tolerances. These issues are exacerbated in portable or miniaturized systems, where space constraints limit the ability to mitigate parasitic effects through shielding or filtering. Addressing these limitations requires innovative approaches, such as integrating electrodes and amplifiers onto a single chip to minimize parasitic effects and enhance signal integrity.\u003c/p\u003e \u003cp\u003eTo address these limitations, we proposed a fully integrated electrochemical detection system based on complementary metal-oxide-semiconductor (CMOS) technology. By vertically integrating on-chip electrodes with low-noise TIAs, parasitic effects were minimized, and unprecedented noise cancellation was achieved. The performance of this design was compared with that of the commercial benchtop system CHI760E. Furthermore, we demonstrated the system\u0026rsquo;s capability to detect trace heavy metals in real seawater samples collected from a depth of 8,448 m in the Mariana Trench. Our work could offer a robust solution for in situ monitoring in extreme environments, highlighting the potential of our integrated multichannel chip for long-term monitoring of trace heavy metals in extreme marine environments.\u003c/p\u003e"},{"header":"Design considerations","content":"\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea illustrates the concept of a miniaturized low-noise electrochemical chip for trace heavy metal detection in extreme deep sea, leveraging CMOS technology and vertical integration. The system employs a three-electrode configuration (Titanium working electrode (WE), reference electrode (RE), and counter electrode (CE)) immersed in a solution containing heavy metal ions in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb. A potential difference is applied between the WE and RE, and the generated current between the WE and CE was detected. Heavy metal ions are reduced into amalgams during deposition and re-released during dissolution, enabling quantitative analysis via differential pulse stripping voltammetry (DPSV). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec shows the potentiostat principle and the circuit system framework for heavy metal detection. The potentiostat, which connects the WE, RE and CE, is the core component of the three-electrode system, typically composed of two main operational amplifiers and other components. The amplifier at the input allows a specific external signal to be directly transmitted to the RE, forming a fixed potential difference between the RE and WE. The potential of the WE to ground is constant, so controlling the signal applied to the RE enables precise control of the signal applied to the WE without being affected by current-induced voltage drops. This independent performance significantly enhances the precision of experiments, particularly when studying the kinetics and mechanisms of electrochemical reactions, providing more reliable data. Low-noise electrochemical chip encapsulated in epoxy resin on a customized base (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed). The base is installed on a customized PCB and assembled into a heavy metal detection system. The test PCB adopts a main-sub board structure. The sub-board is bonded with the TIA, while the main board consists of the power supply module, controlling module and low-noise interfaces.\u003c/p\u003e \u003cp\u003eThe core of the system is the TIA (Supplementary Fig.\u0026nbsp;1), which converts the weak current signals from the WE into measurable voltages. To achieve high sensitivity, we adopted a fully differential architecture with a resistive continuous-time feedback design. The feedback resistor (R\u003csub\u003eF\u003c/sub\u003e = 257 MΩ) was optimized to balance gain, bandwidth, and noise performance. At the transistor level, PMOS inputs were selected for their lower flicker noise\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, with critical dimensions of W/L\u0026thinsp;=\u0026thinsp;784 \u0026micro;m/240 nm. Source degeneration resistors further reduced effective transconductance, enhancing noise optimization\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe TIA layout fabricated using a 0.18 \u0026micro;m CMOS process, measures 1.255 mm\u0026times;0.8 mm and integrates four channels with on-chip electrodes (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Aluminum-coated electrode surfaces were used for durability, and mercury film modification enhanced sensitivity for heavy metal detection. Compared to the state-of-the-art commercial amplifiers like the AD8139, our TIA achieves a noise level of 273.9 fA\u003csub\u003eRMS\u003c/sub\u003e at 1 kHz low-pass filtering, which is 50\u0026times; lower than that of AD8139 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee). This ultra-low noise performance ensures high-fidelity detection of ultra-weak electrochemical signals. Electrical characterization confirmed the system\u0026rsquo;s accuracy and linearity, with an I-V slope of 1.9868 pA/mV (R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.9999) (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eOn-chip electrochemical system outperforms standard potentiostats\u003c/h2\u003e \u003cp\u003eTo validate the performance of our on-chip electrochemical system, we compared it with a commercial potentiostat (CHI760E) under identical cyclic voltammetry (CV) conditions. Figures\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb show the recorded voltammograms for both systems using 0.02 \u0026micro;M K\u003csub\u003e3\u003c/sub\u003e[Fe(CN)\u003csub\u003e6\u003c/sub\u003e]. Our system exhibited a distinct reduction peak near +\u0026thinsp;0.15 V, indicative of excellent sensitivity, while the CHI760E failed to resolve any peaks across all scan rates.\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec highlights the linear relationship between the square root of the scan rate and the peak current in our system, confirming its superior detection capability. The detection limit for K\u003csub\u003e3\u003c/sub\u003e[Fe(CN)\u003csub\u003e6\u003c/sub\u003e] was 1 nM, one order of magnitude lower than the CHI760E (0.02 \u0026micro;M) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed). This demonstrates the ability of our system to capture redox characteristics at ultra-low concentrations.\u003c/p\u003e \u003cp\u003eFor heavy metal detection, the electrode surface was modified with a mercury film to enhance sensitivity (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e(a\u0026ndash;e)). Using differential pulse stripping voltammetry (DPSV), we tested artificial seawater samples containing Cd\u003csup\u003e2+\u003c/sup\u003e and Pb\u003csup\u003e2+\u003c/sup\u003e. Figures\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ef and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eg show excellent linearity (R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.999) across two concentration ranges: 500 \u0026micro;g/L to 5 \u0026micro;g/L and 5 \u0026micro;g/L to 0.05 \u0026micro;g/L. These results confirm the robustness of our system for trace-level detection.\u003c/p\u003e \u003cp\u003eFinally, we validated the system\u0026rsquo;s performance using real seawater samples from the Mariana Trench at a depth of 8,448 m. Our system resolved clear stripping peaks for Cd\u003csup\u003e2+\u003c/sup\u003e and Pb\u003csup\u003e2+\u003c/sup\u003e, achieving concentrations of 0.859 \u0026micro;g/L and 0.921 \u0026micro;g/L, respectively, with standard deviations of 0.10% and 28.0% (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). While cadmium detection closely matched ICP-MS results (0.858 \u0026micro;g/L), lead values were consistently lower due to the selective nature of our electrochemical system\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe development of a miniaturized, low-noise electrochemical detection system represents a significant advancement in the field of trace heavy metal analysis, particularly for applications in extreme environments such as the deep sea. By integrating complementary metal-oxide-semiconductor (CMOS) technology with on-chip titanium electrodes, our system achieves unparalleled sensitivity and noise performance, surpassing traditional benchtop electrochemical workstations. Our system addresses the detection limits through several key innovations: (1) the use of source degeneration techniques and non-unity gain buffers in the TIA design, which reduces noise levels to 273.9 fA\u003csub\u003eRMS\u003c/sub\u003e; and (2) the vertical integration of on-chip electrodes, which minimizes parasitic capacitance and confines the ECR area to just 1 mm\u0026sup2;. These advancements enable a detection limit of 0.05 \u0026micro;g/L, two orders of magnitude lower than conventional systems (~\u0026thinsp;5 \u0026micro;g/L) at the same condition.\u003c/p\u003e \u003cp\u003eTo validate the robustness of our system, we conducted experiments using real seawater samples collected from a depth of 8,448 meters in the Mariana Trench. The system successfully detected Cd\u0026sup2;⁺ and Pb\u0026sup2;⁺ concentrations of 0.859 \u0026micro;g/L and 0.921 \u0026micro;g/L, respectively, without the need for added electrolytes. Compared to inductively coupled plasma-mass spectrometry (ICP-MS), our results showed excellent agreement for Cd\u0026sup2;⁺ (0.1% deviation) and reasonable consistency for Pb\u0026sup2;⁺ (28.0% deviation). The higher deviation for Pb\u0026sup2;⁺ is likely due to the selective nature of our electrochemical system, which primarily detects free ions rather than all chemical forms of heavy metals. This distinction highlights the complementary role of our system alongside analytical techniques like ICP-MS, offering a portable and cost-effective alternative for in situ monitoring.\u003c/p\u003e \u003cp\u003eThe successful deployment of our system for samples from one of the most extreme environments on Earth - the Mariana Trench - demonstrates its potential for broader applications in environmental monitoring\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, resource exploration\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, and ecological research\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. For instance, the ability to detect trace heavy metals \u003cem\u003ein situ\u003c/em\u003e could provide critical insights into deep-sea ecosystems and anthropogenic pollution pathways\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, to name a few. Additionally, the system\u0026rsquo;s miniaturization and low-power requirements make it suitable for integration into autonomous underwater vehicles (AUVs) or remote sensing platforms\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFuture work will focus on further optimizing the system\u0026rsquo;s sensitivity and expanding its applicability to other analytes, such as organic pollutants or biomarkers. In addition, the exploration of advanced surface modification techniques is underway to enhance electrode selectivity and stability. Furthermore, machine learning algorithms are being developed for real-time data analysis and interpretation. These efforts will further solidify the role of integrated electrochemical systems in advancing scientific discovery and environmental stewardship.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe have developed a CMOS amplifier with on-chip electrodes based on vertical integration technology to push the detection limits of trace heavy metals in deep-sea electrochemical detection. Leveraging the miniaturization advantages of modern CMOS processes, the ECR system was reduced to an area of approximately 1 mm\u0026sup2;, while the distance between the ECR system and the TIA was shortened to a few hundred micrometers. This design significantly reduces the noise level for multi-channel electrochemical experiments to be reduced to 273.9 fA\u003csub\u003eRMS\u003c/sub\u003e. In terms of low-concentration signal measurements, our chip extends the detection limit by at least two orders of magnitude compared to traditional electrochemical workstations, achieving a sensitivity of 0.05 \u0026micro;g/L versus the typical 5 \u0026micro;g/L. Furthermore, we validated the ability of the TIA to detect trace heavy metals in real seawater samples collected from a depth of 8,448 m in the Mariana Trench, achieving accurate detection without the need for added electrolytes. These results demonstrate the potential of our system for applications in other fields requiring ultra-low signal detection.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cem\u003eAmplifier Chip Fabrication and Packaging.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe custom-designed integrated circuit was fabricated using 0.18 \u0026micro;m CMOS process. The chip was directly connected to a custom printed circuit board (PCB) via epoxy resin, serving as a test daughterboard. The daughterboard was interfaced with the main PCB through pin headers. The main PCB included the front-end amplifier, analog-to-digital converter (ADC), and interface circuitry required for the electrochemical detection system. Gold wire bonding under a microscope was used to connect the chip to the PCB, and epoxy resin encapsulation protected the chip and gold wires from corrosion by the solution.\u003c/p\u003e \u003cp\u003eA custom-designed DC power supply was implemented to meet the system's requirements, primarily using low-dropout regulators (LDOs) and DC-DC converters to generate\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8 V, \u0026plusmn;\u0026thinsp;0.9 V, and \u0026plusmn;\u0026thinsp;5 V. For example, during noise testing, the TIA was powered by 0/+1.8 V, while during electrochemical experiments, it was powered by -0.9/+0.9 V. Data acquisition (DAQ) was supported by the NI USB-6003 module, which includes four analog input channels and two analog output channels, enabling simultaneous detection across the four TIA channels. Data were transferred to a PC via a USB 2.0 interface. A user-friendly graphical interface was developed in MATLAB\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, offering scalability and cross-platform operation.\u003c/p\u003e \u003cp\u003e \u003cem\u003eElectrode Preparation.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe electrode surface of the fabricated CMOS chip consists of titanium and aluminum. To expose the titanium working electrode, the aluminum layer was etched using Type A etching solution (Sigma-Aldrich, China) at room temperature (~\u0026thinsp;25℃) for 30 minutes. The etching process was monitored under a magnifier and stopped when the electrode surface transitioned from silver to black\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. After etching, the electrodes were rinsed three times with deionized water to ensure no residual etchant remained\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFor cyclic voltammetry (CV) experiments, no mercury plating was required. However, for differential pulse stripping voltammetry (DPSV), the electrode surface was modified with a mercury film. A 0.02 M mercury nitrate solution (Beifangweiye, China) was used for plating. The working electrode was the on-chip titanium electrode, the reference electrode was Ag/AgCl (Gaoss Union, China), and the counter electrode was Pt (Gaoss Union, China). A constant negative potential of \u0026minus;\u0026thinsp;0.3 V was applied for 15 minutes to form a dense mercury film. Optical microscopy confirmed the silver-gray appearance of the electrode surface, and scanning electron microscopy (Nova NanoSem450, USA) verified the formation of a uniform mercury layer.\u003c/p\u003e \u003cp\u003e \u003cem\u003eNoise Measurement of CMOS TIA Chip.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eNoise measurements were conducted under zero-current input conditions. The system was shielded from external interference using a Faraday cage. The ADC recorded the TIA's voltage output signal over a 10-second interval. The root mean square (RMS) noise of the current signal was calculated, and the power spectral density (PSD) was derived from the recorded data.\u003c/p\u003e \u003cp\u003e \u003cem\u003eCyclic Voltammetry (CV) Measurements.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe CV experiments used a mixture of potassium ferricyanide (Macklin, China) and 1 M KCl (Macklin, China). The working electrode was a 0.5 mm-diameter glassy carbon electrode (Gaoss Union, China), the reference electrode was Ag/AgCl (Gaoss Union, China), and the counter electrode was Pt (Gaoss Union, China). A triangular wave input signal was generated using MATLAB and supplied to the PCB. The starting potential was set to -0.1 V, and the ending potential was +\u0026thinsp;0.5 V, with the slope representing the scan rate. The redox potential of potassium ferricyanide lies between \u0026minus;\u0026thinsp;0.1 V and +\u0026thinsp;0.5 V, making this range suitable for CV analysis.\u003c/p\u003e \u003cp\u003e \u003cem\u003eDifferential Pulse Stripping Voltammetry (DPSV) Measurements.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe DPSV experiments were conducted using artificial seawater prepared with a 3.5% NaCl (Macklin, China). Stock solutions of 100 \u0026micro;mol/mL cadmium nitrate and 1000 \u0026micro;mol/mL and lead nitrate (Boer, China) were used to prepare Cd\u003csup\u003e2+\u003c/sup\u003e and Pb\u003csup\u003e2+\u003c/sup\u003e solutions. The working electrode was an on-chip Ti electrode (75 \u0026micro;m \u0026times; 75 \u0026micro;m), with Ag/AgCl as the reference electrode and Pt as the counter electrode. The input signal, a staircase-shaped square wave, was generated using MATLAB and supplied to the PCB.\u003c/p\u003e \u003cp\u003eThe experiment consisted of three phases including deposition, resting, and stripping. During the deposition phase, a potential of -1.4 V was applied for 400 s (high concentrations) or 600 s (low concentrations). In the resting phase, a potential of -0.9 V was applied for 10 s. During the stripping phase, a staircase rising square wave was applied from \u0026minus;\u0026thinsp;0.9 V to -0.3 V. The data acquisition system (DAQ) collected current values during the high and low levels of the stripping phase, generating two I-V curves. The voltammetry curve was obtained by calculating the difference between these two current values.\u003c/p\u003e \u003cp\u003eTo avoid contamination, measurements were performed in ascending order of concentration. Peak heights were quantified relative to the baseline, which was obtained from DPSV measurements of 3.5% NaCl solution under identical conditions. Each curve was measured repeatedly until two consecutive results were consistent, ensuring accuracy.\u003c/p\u003e\n\u003ch3\u003eSeawater Sample Collection and Analysis\u003c/h3\u003e\n\u003cp\u003eThe seawater sample was collected from a depth of 8,448 m at coordinates 142.15717\u003csup\u003e∘\u003c/sup\u003eE, 11.5698\u003csup\u003e∘\u003c/sup\u003eN in the Mariana Trench during the 62nd dive of the manned submersible \u003cem\u003eFendouzhe\u003c/em\u003e, which is employed for deep-sea exploration. The sample was stored at 3℃. During analysis, five consecutive measurements were performed, and the average current was calculated.\u003c/p\u003e \u003cp\u003eInductively coupled plasma-mass spectrometry (Agilent 7700X ICP-MS, USA) was used to validate the results. The seawater sample was diluted twofold, and three measurements were taken to calculate the original concentration.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eSource data is provided with this paper.\u003c/p\u003e \u003c/div\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThere are no competing interests.\u003c/p\u003e\u003ch2\u003eAdditional information\u003c/h2\u003e \u003cp\u003eSupplementary information has been provided.\u003c/p\u003e \u003cp\u003eCorrespondence and requests for materials should be addressed to Wei Cai.\u003c/p\u003e \u003ch2\u003eAuthor contributions\u003c/h2\u003e \u003cp\u003eY.M.Y., W.F., C.Y.M. and T.D. designed the TIA and device. Y.M.Y., X.Y. and Y.F.W. prepared the TIA and PCB. Y.L., C.Y.M., Y.M.Y. and W.F. completed the architecture of the software. Y.M.Y., C.H.C., X.Z., Y.F.W., W.F. and T.D. prepared the figures. X.Y., T.Y.Z., S.Q.D., D.L. and S.Q.L. designed the experiment. Y.M.Y., W.F., Y.L., Y.G. and W.C. drafted the manuscript. Y.L., Y.G. and W.C. supervised the study. All authors read, revised, and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThis work was supported by the National Key Research and Development Program of China (2022YFC3104700 and 2022YFF1203400), National Natural Science Foundation of China (62171211), Zhujiang Program (2021QN02H436), and Science and Technology Innovation Commission of Shenzhen (JCYJ20220814170440001, JCYJ20220818100218039, JCYJ20220530113013030 and JCYJ20230807092459028) as well as NSQKJJ under grant K21799109 and K21799116.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eM\u0026uuml;nzel, T. \u003cem\u003eet al.\u003c/em\u003e Soil and water pollution and cardiovascular disease. Nat. Rev. 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Actuators B Chem. 310, 127809 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJunlin Zhou, Cheng, M. \u0026amp; Forbes, L. SPICE models for flicker noise in p-MOSFETs in the saturation region. IEEE Trans. Comput.-Aided Des. Integr. Circuits Syst. 20, 763\u0026ndash;767 (2001).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonsurro, P., Pennisi, S., Scotti, G. \u0026amp; Trifiletti, A. Linearization Technique for Source-Degenerated CMOS Differential Transconductors. IEEE Trans. Circuits Syst. II Express Briefs 54, 848\u0026ndash;852 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFighera, M., Van Der Wal, P. D., Tercier-Waeber, M.-L. \u0026amp; Shea, H. Three-Electrode on-Chip Sensors for Voltammetric Detection of Trace Metals in Natural Waters. ECS Trans. 75, 303\u0026ndash;314 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRehacek, V., Hotovy, I. \u0026amp; Vojs, M. Bismuth-coated diamond-like carbon microelectrodes for heavy metals determination. Sens. Actuators B Chem. 127, 193\u0026ndash;197 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBahinting, S. E. D. \u003cem\u003eet al.\u003c/em\u003e Bismuth Film-Coated Gold Ultramicroelectrode Array for Simultaneous Quantification of Pb(II) and Cd(II) by Square Wave Anodic Stripping Voltammetry. Sensors 21, 1811 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiao, C., Wang, Y. \u0026amp; Tian, J. Formation of marine barite in the deep-sea environment: Evidence from sinking particles in the challenger deep, Mariana Trench. Reg. Stud. Mar. Sci. 50, 102159 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, G. \u003cem\u003eet al.\u003c/em\u003e Self-powered soft robot in the Mariana Trench. Nature 591, 66\u0026ndash;71 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJamieson, A. J., Malkocs, T., Piertney, S. B., Fujii, T. \u0026amp; Zhang, Z. Bioaccumulation of persistent organic pollutants in the deepest ocean fauna. Nat. Ecol. Evol. 1, 0051 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu, J. \u003cem\u003eet al.\u003c/em\u003e A unique subseafloor microbiosphere in the Mariana Trench driven by episodic sedimentation. Mar. Life Sci. Technol. 6, 168\u0026ndash;181 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePinheiro, M. \u003cem\u003eet al.\u003c/em\u003e Stressors of emerging concern in deep-sea environments: microplastics, pharmaceuticals, personal care products and deep-sea mining. Sci. Total Environ. 876, 162557 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou, L. \u003cem\u003eet al.\u003c/em\u003e Toxicology assessment of deep-sea mining impacts on Gigantidas platifrons: A comparative in situ and laboratory metal exposure study. Sci. Total Environ. 933, 173184 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChang, H.-C. \u003cem\u003eet al.\u003c/em\u003e Autonomous Water Quality Monitoring and Water Surface Cleaning for Unmanned Surface Vehicle. Sensors 21, 1102 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFleming S J. Probing nanopore-DNA interactions with MspA. PhD thesis, Harvard University, 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBansod, B., Kumar, T., Thakur, R., Rana, S. \u0026amp; Singh, I. A review on various electrochemical techniques for heavy metal ions detection with different sensing platforms. Biosens. Bioelectron. 94, 443\u0026ndash;455 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhite, K. A. \u0026amp; Kim, B. N. Quantifying neurotransmitter secretion at single-vesicle resolution using high-density complementary metal\u0026ndash;oxide\u0026ndash;semiconductor electrode array. Nat. Commun. 12, 431 (2021).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6109364/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6109364/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eElectrochemical techniques are widely employed for detecting trace heavy metal ions in environmental samples by measuring redox reaction currents. While conventional benchtop electrochemical workstations provide high signal fidelity for higher concentrations, their bulky and discrete components face scalability and noise limitations, restricting their ability to detect trace concentration heavy metal ion of deep-sea samples. To address these limitations, we developed a custom-designed, low-noise, multi-channel complementary metal-oxide-semiconductor (CMOS) transimpedance amplifier integrated circuit (IC) with vertically integrated on-chip electrodes. This system achieves an extremely-low noise level of 273.9 fA\u003csub\u003eRMS\u003c/sub\u003e and reduces the electrochemical reaction (ECR) area to just 1 mm\u0026sup2;, enabling sensitive detection of heavy metals in the wide range of 0.05\u0026ndash;500 \u0026micro;g/L. We validated the system\u0026rsquo;s performance by detecting Cd\u0026sup2;⁺ and Pb\u0026sup2;⁺ in real seawater samples collected from a depth of 8,448 meters in the Mariana Trench, achieving concentrations of 0.859 \u0026micro;g/L for Cd\u0026sup2;⁺ and 0.921 \u0026micro;g/L for Pb\u0026sup2;⁺. Compared to inductively coupled plasma-mass spectrometry (ICP-MS), our system demonstrated excellent agreement for Cd\u0026sup2;⁺ (0.10% deviation) and reasonable consistency for Pb\u0026sup2;⁺ (28.0% deviation), reflecting its selectivity for free ions. Our work provides a robust, portable, and miniaturized solution for trace heavy metal detection under extreme conditions and complex environmental backgrounds, paving the way for advanced \u003cem\u003ein situ\u003c/em\u003e oceanic monitoring technologies.\u003c/p\u003e","manuscriptTitle":"On-Chip Trace Detection of Heavy Metal Ions in Extreme-Deep Seawater Using CMOS-Integrated Low-Noise Transimpedance Amplifiers","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-14 11:05:03","doi":"10.21203/rs.3.rs-6109364/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-engineering","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commseng","sideBox":"Learn more about [Communications Engineering](http://link.springer.com/journal/44172)","snPcode":"44172","submissionUrl":"https://mts-commseng.nature.com/cgi-bin/main.plex","title":"Communications Engineering","twitterHandle":"@commseng","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4269fb26-99e1-40a4-829a-52bcbdffb0d0","owner":[],"postedDate":"May 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":45254471,"name":"Physical sciences/Engineering/Electrical and electronic engineering"},{"id":45254472,"name":"Earth and environmental sciences/Environmental sciences/Environmental chemistry/Environmental monitoring"}],"tags":[],"updatedAt":"2025-05-14T11:05:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-14 11:05:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6109364","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6109364","identity":"rs-6109364","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}