Demonstration of CMOS-compatible memristor-based electrochemical biosensor transducer with threshold-sensing functionality

Domain: physics
Published: 2025-12-03
Editorial outcome: minor_revision

Abstract
Many electrochemical biosensors operate based on a threshold-sensing (TS) method, which indicates the presence of a disease when the concentration of a biomarker exceeds a predetermined, disease-specific threshold. The TS in biosensor systems is often implemented using power-hungry signal processing (SP) modules or computers, which increases energy consumption and system complexity. Here, we propose a memristor-based bio-to-electrical transducer with built-in TS functionality, allowing TS to be performed directly within the transducer instead of relying on SP modules and computers. Fabricated resistive random-access memory-based TaO\_x/Ta\_2O\_5 memristors meet the transducer requirements, such as a high on/off ratio greater than 30 while maintaining a long unit pulse width exceeding 10 \u03bcm. The intended operation of the proposed transducer was experimentally confirmed by the immediate change in resistance of the memristor (R\_M) from high resistance state to low resistance state. Using this proposed transducer, a complete electrochemical biosensor system was implemented by integrating a sensor electrode for pH sensing, an SP module, and a display with the proposed transducer. The memristor-based system offers flexible control of the threshold pH point through a simple design, making it well-suited for point-of-care diagnostics, where portability is highly essential.

Introduction
The growing demand for portable bio-healthcare diagnostic devices is driven by the need for high energy efficiency, compact chip design, and efficient computation tailored to the diagnosis of various diseases. This increasing interest is further fueled by an aging population and the rising need for real-time diagnostic capabilities that are not constrained by time or location. Electrochemical biosensor systems, among the most prominent portable diagnostic devices, have been actively researched using various semiconductor devices and nanomaterials to detect serious diseases, such as influenza, diabetes, cancer, cardiovascular conditions, and digestive disorders1\u20135. The biosensor systems generally consist of analytes, transducers, signal processing modules (SPs) like readout integrated circuits (ICs) and digital signal processing (DSP), and displays. These systems operate by converting the biochemical signals from the analytes into electrical signals through transducers, which are then either processed by the SPs within the devices or transmitted wirelessly via Bluetooth to a computer for processing by software programs6,7. The processed signals are compared to unique reference values for each disease, allowing the system to determine whether the disease is present or to assess the level of risk, which is then communicated via the display.

Many electrochemical biosensors operate based on a threshold-sensing (TS) method, which determines the presence of a disease when the concentration or amount of a biomarker in the analyte exceeds a predetermined, disease-specific threshold8\u201310. For example, COVID-19 has key biomarker thresholds, such as lactate dehydrogenase < 365 U/L, lymphocytes > 14.7%, and high-sensitivity C-reactive protein < 41.2 mg/L8. The diagnostic efficiency of acute myocardial infarction is improved when the troponin T concentration is higher than 1 ng/mL9,10. Efficient implementation of the TS function in biosensor systems is of critical importance. Typically, TS is performed in the SP module or an external computer; however, this approach inevitably increases power (or energy) consumption and system complexity due to the reliance on power-hungry ICs, such as analog-to-digital converters, comparators, digital signal processors (DSPs), and computer. If the TS function can be embedded directly into the transducer itself rather than in the SP or computer, a more scalable and efficient biosensor system can be achieved. To date, there have been no reports on bio-to-electrical transducers with the TS function.

A memristor device with a simple structure of metal-insulator-metal (MIM) is a next-generation memory device with non-volatility and variable resistance characteristics, using a mechanism of production and rupture for conductive filaments due to the intrinsic redox reaction11. Owing to the dense cell size of 4F\^2 and low set/reset voltage of less than 1 V of the memristors, they have been used as cells in crossbar arrays of neuromorphic systems and have reduced power consumption and improved energy efficiency of the system12,13. For a neuromorphic system to reach levels comparable to the human brain, which consumes 20 W of power, the memristor devices must ultimately be able to consume less than 10 fJ per synaptic operation and more research is underway to reduce operating current, voltage and latency while having the compatibility with CMOS process, which is essential to be co-integrated with peripheral circuits in the systems14\u201316. Meanwhile, the non-volatility and variable resistance characteristics of the memristor allow it to be used as a bio-to-electrical transducer in the electrochemical biosensor system17\u201319. Ref. 17 exposed an analyte solution to an insulator region of an ITO/TiO\_2/Al MIM memristor and showed a change in the device\u2019s on/off resistance ratio in response to variations in the concentration of the biomarker, nonstructural protein 1 (NS1 protein). When the well diameter in the insulator region exceeded 1.5 mm, a fairly linear relationship between NS1 protein concentration and the on/off resistance ratio characteristics was observed. Ref. 18 exposed a PSA analyte to the Pt metal region of a Pt/Al\_2O\_3/TiO\_2/Pt memristor, where the resistance value of the device itself changed in response to the concentration of the biomarker, although the relationship was not linear. These previous results were iterative implementations for the conventional bio-to-electrical transducers without any TS functionality and revealed the limitations to the reusability of biosensors by directly exposing the memristors built with expensive semiconductor processes to the analyte solutions17\u201319. Furthermore, prior studies have often assumed the availability of precise pulse generation, a requirement that may pose challenges for low-cost home-diagnostic devices employing crystal-less microcontroller units20. Also, the stochastic nature of resistive random-access memory (RRAM) can lead to inaccurate readings and compromised diagnostic results in actual deployments21.

To address the above-mentioned constraints, we propose a memristor-based bio-to-electrical transducer with integrated TS functionality, designed to ensure reusability for electrochemical biosensor applications. Here, RRAM-based TaO\_x/Ta\_2O\_5 memristor devices were fabricated using a stable 8-inch Si CMOS process line. By controlling an oxygen reservoir layer of TaO\_x, a memristor species were tailored to meet the proposed transducer requirements, including high on/off ratio and stable operation under long pulse widths. By applying the developed memristor, a complete electrochemical biosensor system was implemented by integrating a sensor electrode, an SP module, and a display with the proposed transducer. The intended TS function of the proposed transducer was experimentally demonstrated by confirming that the resistance of the memristor (R\_M) changed from high resistance state (HRS) to low resistance state (LRS) at a specific value of pH solution (named threshold pH point), and thereby the output voltage changed immediately from low to high values. The threshold pH point (TP) of the system can be tuned to any desired pH level by adjusting the integrated reference voltage (V\_REF), demonstrating that the system is capable of not only diagnosing diseases but also providing prognostic insights. Using this approach, a simplified biosensor system was developed by replacing bulky components with compact ICs. Therefore, the proposed memristor-based electrochemical transducer technology represents a promising candidate for highly portable point-of-care diagnostic devices.

Results
Proposed memristor-based electrochemical biosensor transducer
Figure 1a shows a circuit diagram of the proposed bio-to-electrical transducer with TS functionality. The transducer consists of a sensor electrode, two FETs, a memristor with a resistance of R\_M, and an output resistor with a resistance of R\_O. A gate terminal of an upper FET is extended and connected to the sensor electrode. An analyte solution is dropped onto the extended gate region (i.e., the sensor electrode), not on the memristor, so that the reusability issue of the previous memristor-based transducers is addressed17\u201319. The lower FET provides a variable resistor with a resistance of R\_T by controlling a gate voltage (V\_GS). While previous studies have used memristors with multi-bit characteristics17\u201319, this work utilizes a single-bit memristor with only two resistances: high resistance state (R\_HRS) and low resistance state (R\_LRS), as shown in Fig. 1b, which enables the transducer to exhibit TS functionality. The single-bit memristor is characterized by the change of R\_M from R\_HRS (or R\_LRS) to R\_LRS (or R\_HRS) through the SET (or RESET) process by applying a set voltage (V\_SET) (or reset voltage (V\_RST)), while a forming process with a forming voltage (V\_FORM) is required to initially form conductive filaments of the memristor22\u201324.

The key operation of the proposed transducer with TS functionality is set up with its timing diagram in Fig. 1c, which consists of three stages: initialization, sensing, and reading. In the initialization stage, R\_M is set to R\_HRS by the forming and reset processes of the memristor. When an analyte solution with a biomarker concentration of C is introduced and a reference voltage (V\_REF) is applied, the surface potential of the gate electrode (V\_W) changes due to an intrinsic chemical reaction. At the sensing stage, V\_GS and V\_D are applied. The change in V\_W modulate the drain current (I\_D) according to the current\u2013voltage characteristics of the upper FET. The output voltage (V\_OUT) is formed as the product of I\_D and the equivalent value (R\_EQ) of the bottom three bottom resistors with R\_T, R\_M, and R\_O. Because R\_T is designed to be considerably lower than R\_M and R\_O, V\_OUT is approximately given by I\_D \u00d7 R\_T, and is almost independent of changes in R\_M, as seen in Fig. 1d. When V\_OUT exceeds V\_SET of the memristor, R\_M abruptly changes from R\_HRS to R\_LRS if C exceeds the threshold concentration (C\_TH) (Fig. 1c,d). Here, the turn-on time of V\_D determines the sensing duration and is made as short as possible to minimize stress on the memristor. In the reading stage, V\_GS and V\_D are grounded to turn off the two FETs, and a reading voltage (V\_R) is applied. After turning off the two FETs, a voltage divider circuit is formed by R\_M, R\_O, and V\_R, as shown in Fig. 1e. Based on an inherent equation of V\_OUT = V\_R \u00d7 R\_M / (R\_M + R\_O), V\_OUT exhibits a threshold function of high or low output levels corresponding to R\_LRS and R\_HRS, respectively. Although there is a time interval between the sensing and reading stages, the unique memory function of the memristor allows the R\_M value obtained in the sensing stage to be effectively utilized in the reading stage without any loss of resistance values.

It is paramount to develop a memristor customized for the transducer with TS functionality. The transducer\u2019s TS function is successfully conducted when the high V\_OUT is at least 0.1 V higher than the low V\_OUT. Since we aimed to implement a proof-of-concept transducer prototype that integrates a fabricated memristor through wire bonding and does not include ESD protection techniques, the performance degradation caused by wire bonding and the absence of ESD protection should be considered when defining the memristor specifications22. Accordingly, under the condition that V\_R and R\_O are 0.3 V and 560 \u03a9, respectively, the on/off ratio (i.e., the ratio of R\_HRS and R\_LRS) of the memristor that satisfies the V\_OUT difference of 0.1 V was targeted as 30. In developing the transducer, real-time monitoring of the TS performance is crucial, necessitating the display of values on the V\_OUT node in real-time. To achieve this, a commercial ADC with a sampling rate of 200 kilo samples per second (kS/s) was interfaced between the V\_OUT node and the display. Consequently, voltage pulses with a minimum duration of 10 \u03bcm, corresponding to the sampling rate, were applied to the V\_OUT node, which required a reliable memristor capable of withstanding such extended pulse durations. Moreover, for the envisioned mass production of a self-diagnostic device, although monitoring V\_OUT is not required for data extraction, generating precise short-duration High pulses (<10 \u03bcm) in a cost-effective, crystal-less manner remains a challenge. Thus, our study presents a high-performance memristor device specifically engineered to achieve an on/off ratio surpassing 30, even when subjected to pulse durations exceeding 10 \u03bcm. This optimization renders the device well-suited for deployment in bio-to-electrical transducers, ensuring reliable performance in real-world applications.

CMOS process-compatible TaO\_x/Ta\_2O\_5 memristors for the biosensor transducers
A switching layer (SW) stack of TaO\_x/Ta\_2O\_5 has been largely utilized as memristors23,25\u201327, because of their stable switching operation by means of low Gibbs-energy-based redox reactions28 and excellent CMOS process compatibility23,25\u201327. TaO\_x/Ta\_2O\_5 memristors were fabricated on 8-inch Si wafers, with an SW stack having a reactive sputtered 40 nm-thick TaO\_x layer as an oxygen reservoir and a 4 nm-thick atomic layer deposition (ALD)-deposited Ta\_2O\_5 layer. The top (TE) and bottom (BE) electrodes of the two species were made of TiN metal with a thickness of more than 100 nm, and their device fabrication is detailed in the \u201cMethods\u201d section. The O\_2/Ar gas mixture ratio of the 40 nm-thick TaO\_x layer was varied with 9 (S1), 6 (S2), and 3% (S3), which corresponds to the O\_2/Ar gas amounts with 3/30.3 sccm (S1) to 2/31.3 sccm (S2), and 1/32.3 sccm (S3), respectively. As determined from measured electrical results shown in Fig. 2a\u2013c, the S1, S2, and S3 species exhibited average R\_LRS values of 141, 151, and 158 \u03a9; average R\_HRS values of 1231, 2276, and 3401 \u03a9; and corresponding average on/off ratios of 8.8, 15.1, and 21.6, respectively. As the O\_2/Ar gas mixture ratio in the TaO\_x layer decreased from 9 to 3%, the R\_LRS slightly increased, and the R\_HRS significantly increased, resulting in an increase in the on/off ratio from 8.8 to 21.6. This increase in on/off ratio is attributed to the decrease in the size of the filament, as seen in the proposed current switching mechanism (Table 1). From EDS scan results of fully fabricated memristors (Supplementary Fig. S1), TaO\_x layers of S1 and S3 exhibited O/Ta ratios of 1.04 and 0.39, respectively, while the corresponding Ta\_2O\_5 layers showed 2 and 0.71, which indicate that the TaO\_x/Ta\_2O\_5 SW stack of S3 was more oxygen-deficient than that of S1. As the oxygen-deficient characteristic becomes stronger (i.e., Ta becomes richer), the electrical resistance of the SW stack itself decreases, which lowers the breakdown voltage for filament formation and results in thinner filaments28. The reduction in forming voltage (V\_FORM\_mean) and current (I\_FORM\_mean) of S3 compared to ones of S1 (Supplementary Fig. S2) is a piece of evidence supporting the generation of the thinner filaments. The thin filaments undergo stronger filament rupture than the thick filaments29, assuming that the same number of oxygen anions contribute to filament rupture, as shown in the filament rupture (Reset) column in Table 1. The stronger filament rupture means higher R\_HRS, leading to a higher on/off ratio. As all fabricated memristors exhibited Schottky emission characteristics in voltage ranges from 0.15 to 0.55 V in the HRS, as described by measured logarithmic I\u2013V curves for the conduction mechanism in Supplementary Fig. S3, it can be inferred that the filament rupture initiates near the TaO\_x/Ta\_2O\_5 interface, where a Schottky barrier exists between the two layers.

The TaO\_x thickness was reduced from 40 to 20 nm while maintaining the thickness of Ta\_2O\_5 at 4 nm. The O\_2/Ar gas mixture ratio of TaO\_x was varied at 9 (S4), 6 (S5), and 3% (S6). Measured R\_LRS/R\_HRS values for S4, S5, and S6 were 160/3133, 185/6525, and 224/3364 \u03a9 on average, and their on/off ratio values were 19.7, 35.2, and 15.6 on average, respectively (Supplementary Fig. 3a\u2013c). The on/off ratio values (19.7 and 35.2) obtained at O\_2/Ar gas mixture ratios of 9 and 6% were more than twice those (8.8 and 15.1) of 40 nm-thick TaO\_x-based samples. This on/off ratio increase is also attributed to the decrease in filament size, as shown in the proposed current switching mechanism in Table 2. The electrical resistance of 20 nm-thick TaO\_x layers was smaller compared to the 40 nm-thick species due to their less thickness. For example, in the case of TaO\_x layers with an O\_2/Ar gas mixture ratio of 6%, 20 nm-thick and 40 nm-thick TaO\_x layers showed average resistances of 19 and 36 m\u03a9 (see Supplementary Fig. S4a), respectively, while achieving the same x mole fraction value of TaO\_x of 0.54 (see Supplementary Fig. S4b,c). The reduced resistance results in a smaller soft breakdown voltage in TaO\_x during forming or set operation, leading to thinner filaments, stronger filament ruptures, and higher on/off ratios28,29. The I\_FORM\_mean reduction (from 2.2 to 1.6 mA) and R\_LRS increase (from 151 to 185 \u03a9) of S5 species compared to ones of S2 species (Supplementary Fig. 3d) provide evidence for the formation of thinner filaments.

As a result, by optimizing the oxygen reservoir layer thickness of TaO\_x and the O\_2/Ar gas mixture ratio, the high on/off ratio of 35.2 with slight current reduction (i.e., R\_LRS/R\_HRS increase to 224/3364 \u03a9) of CMOS process-compatible TaO\_x/Ta\_2O\_5 memristors was achieved for S5 species. While previous reports achieved current reduction in CMOS-incompatible memristors by adjusting only the O\_2/Ar ratio28,30 or only the oxygen reservoir thickness31,32, our study is, to the best of our knowledge, the first to demonstrate both an enhanced on/off ratio and a reduced current in CMOS-compatible memristors by simultaneously tuning the O\_2/Ar ratio and the oxygen reservoir thickness. Meanwhile, the significant reduction in the on/off ratio value of S6 compared to S5 (from 35.2 to 15.6) was due to a dramatic decrease in R\_HRS value from 6525 to 3364 \u03a9 with a slight increase in R\_LRS value from 185 to 224 \u03a9 (Fig. 3b,c). In this study, TaO\_x/Ta\_2O\_5 memristors based on 10 nm-thick and 5 nm-thick TaO\_x layers with various O\_2/Ar gas mixture ratios of 3\u20139% were also fabricated, which showed worse on/off ratio values of 6.4\u201312.8 and 1\u20132, respectively, stemming from R\_HRS degradation. Therefore, it is strongly believed that the on/off ratio reduction of S6 compared to S5 is due to the insufficient oxygen content in TaO\_x to function as an oxygen reservoir.

Pulse measurements were performed for the S5 species, which showed the highest on/off ratio value (Fig. 4a). On a long-pulse program/erase (P/E) cycling measurement with a unit pulse time (T\_PULSE) of 50 \u03bcm, an on/off ratio value remained above 30 until the number of pulses reached 5000 (Fig. 4b), which satisfied the device requirements for the proposed biosensor transducer (i.e., the on/off ratio and pulse duration of more than 30 and 10 \u03bcm, respectively). For reference, a short-pulse P/E cycling measurement with a T\_PULSE of 2 \u03bcm was conducted to check the usability of neuromorphic application, exhibiting a measured on/off ratio value of more than 35 up to several pulses of 30000 (Fig. 4c), which was a good value among the previously reported same CMOS process-compatible memristor stacks of TiN/TaO\_x/Ta\_2O\_5/TiN that did not use noble metals, such as Pt, Au as electrodes23,25,26. Meanwhile, another representative CMOS-compatible memristor stack, TiN/Ti/HfO\_2/TiN22,33,34, labeled S7, was also fabricated (Fig. 4d) and its long-pulse P/E cycling measurement was performed. It should be noted that the S7 was SET stuck after several pulses of more than 4000 (Fig. 4e), which is attributed to the worse TDDB characteristics of HfO\_2 compared to Ta\_2O\_5. For example, a TDDB value of the HfO\_2 layer at an electric field (E-field) of 5 \u00d7 10\^8 V/m was measured to be about 33 times shorter than that of the Ta\_2O\_5 layer at the same E-field (Fig. 4f).

Implementation of the memristor-based electrochemical biosensor transducer and its operation verification in a pH sensor
The memristor-based transducer (Fig. 1a) was practically implemented, as illustrated by the dotted red line in Fig. 5a. Three switches, S/W\_1, S/W\_2, and S/W\_3, were introduced to enable different circuit wiring in the three operational stages: initialization, sensing, and reading. After dropping the analyte solution onto the sensor electrode, it took at least 0.5 to 1 min for the electrochemical reaction to stabilize. Repeated accumulation of this reaction time caused deterioration of the device due to voltage and current stresses on the memristors. Therefore, S/W\_1 was introduced to ensure that these stresses were applied to the memristors only during the sensing stage, which lasts for only a few milliseconds. A parallel two-memristor cell, in which two memristors are connected in parallel, was inserted into the transducer. The variation factor (\u03c3/\u03bc) of resistance of the S5 devices reached approximately 20%, as shown in Figs. 3b; 4c and Supplementary Fig. S5. The parallel memristor cell, previously adopted in memory and logic applications35, was employed to minimize the influence of resistance variation of the transducer, thereby reducing the variation of V\_OUTR, which means a more stable transducer operation (see Supplementary Fig. S6). An electrochemical biosensor system shown in Fig. 5a was designed by integrating a SP block, such as a 12-bit ADC, an MCU, and an organic light-emitting diode (OLED) display with the proposed transducer. ADC monitored the change in V\_OUT, which was processed by the MCU and displayed on the OLED. The MCU not only determined the R\_M value by processing the V\_OUT but also controlled the transducer. The timing diagram and detailed operation of the biosensor are depicted and explained in Fig. 5b, respectively.

A prototype of the fully-integrated biosensor system was implemented, consisting of a sensor electrode, an IC-board, a mem.-board, and an OLED display (Fig. 5c). The sensor electrode was fabricated in a disposable USB form and consisted of a reference electrode and a working electrode, on which patterned Ti/Al metals were formed to function as a potentiometric pH sensor. The mem.-board consisted of a fabricated 5 \u00d7 5 mm\^2 single die with S5 memristors (named as S5 die), which was mounted on a printed circuit board (PCB). The IC-board consisted of the proposed transducer excluding the sensor electrode and memristors, the SP block, and various components, such as operational amplifiers, LDO regulators, capacitors, resistors, switches, and buttons. Several USB ports were provided for interconnection with the sensor electrode, power supply, and UART communication. Two potentiometers were included for controlling V\_REF. All operations were user-controlled via buttons. When the three user buttons of init., sens., and read. were pressed, the display provided information about the device\u2019s R\_M and the IC\u2019s V\_OUT values. The implementation of the biosensor system is described in detail in the \u201cMethods\u201d section.

The functionality of the transducer itself was evaluated by applying an external voltage to the V\_W node, i.e., instead of connecting the sensor electrode to the transducer. With V\_W and V\_GS each fixed to 2 V, the V\_OUT in the sensing stage (V\_OUTS) was measured by applying a pulse train to position 2 of S/W\_1, which consisted of ten consecutive pulses with a T\_PULSE of 20 \u03bcm, exhibiting that the V\_OUTS slightly decreased from 0.69 to 0.62 V up to the eighth pulse (Fig. 6a). This decrease in V\_OUTS indicated successful resistance (R\_MP) transition from HRS to LRS of the parallel memristor cells. The V\_OUTS was given by I\_D \u00d7 R\_EQ, where R\_EQ is R\_T // R\_MP // R\_O, as shown in Fig. 6b. Although R\_T was designed to be small, less than 20 \u03a9, R\_EQ decreased by 10 to 20% with the change in R\_MP from HRS to LRS, resulting in a slight decrease in V\_OUTS. As V\_W was swept from 1.4 to 2.2 V, the changes in V\_OUTS and R\_MP were observed (Fig. 6c). V\_OUTS transitioned linearly at V\_W values from 1.4 to 2 V, following the transfer curve characteristic of the upper FET designed to operate in the linear region (Fig. 6b). When V\_W changed from 2.0 to 2.1 V, R\_MP decreased abruptly from an R\_HRS of about 700 \u03a9 to an R\_LRS of ~80 \u03a9, along with a decrease in V\_OUTS from 0.75 to 0.62 V. When V\_W changed from 2.1 to 2.2 V, R\_MP maintained the R\_LRS. This abrupt R\_MP transition, with a clear transition point at V\_W of 2.1 V, was an experimental result that demonstrated the TS function of the implemented transducer. Although the memristors exhibited device-to-device resistance variation, the resistance parallelization scheme, by employing variation-tolerant R\_EQ instead of directly using R\_MP, effectively suppressed this variation and enabled a stable V\_OUTS response with a clearly defined resistance switching characteristic of the parallel memristor cell (see Supplementary Figs. S5 and S7).

The unique operation of the proposed transducer-based biosensor system was verified in a pH sensor platform by connecting the sensor electrode to the system, i.e., the WE to the V\_W node and the RE to the V\_REF node. With the V\_REF fixed at a value, i.e., 1.9 V, performance parameters of the system, such as V\_W, V\_OUTS, R\_MP, and V\_OUTR at the reading stage (V\_OUTR), were measured in response to the change in pH value (Fig. 6d; Supplementary Fig. S8 and Supplementary Video 1). As the pH decreased from 10 to 2 (i.e., as the acidity increased), the V\_W increased linearly from 1.76 to 2.22 V, exhibiting a close-to-linear behavior with a slope of \u221257 mV/pH, which is within the range of the slope values of previously reported pH sensors36\u201339 and is close to the theoretical Nernst value for the extended-gate FET pH sensor (\u221259.12 to \u221259.16 mV/pH)38,39. R\_MP and V\_OUTR were maintained at HRS (above 600 \u03a9) and low voltage (<140 mV) for pH values from 10 to 6, and at LRS (below 90 \u03a9) and high voltage (above 260 mV) for pH values from 5 to 2. When the pH decreased from 6 to 5, R\_MP transitioned from HRS to LRS, and the corresponding V\_OUTR changed from low to high voltage, experimentally indicating a threshold pH point (TP) for pH sensing was pH 5.

Because V\_W equals the sum of V\_REF and potential difference in V\_W (\u0394V\_W), which are input parameters of the system, is V\_W, where V\_W is linearly proportional to V\_REF (Fig. 6b), V\_REF can serve as an input variable that controls TP. Figure 6e shows pH measurement results of the system with respect to V\_REF, exhibiting that the TP changed from pH 10 to 2 in step of 1 pH unit increments when V\_REF was changed from 2.2 to 1.64 V. A TP versus corresponding V\_REF (called threshold V\_REF) graph showed good linearity with a Pearson\u2019s correlation coefficient of 0.981 (Fig. 6f). The slope deviation of about 6 mV/pH in the graph was attributed to the variation in the sensor electrode utilized. The graph strongly correlated with another graph for \u0394V\_W before and after dropping pH solutions with values between 2 and 10 onto a fabricated sensor electrode (Supplementary Fig. S9). In this study, no surface treatment was performed on the Ti/Au electrodes, and thereby the slope deviation could be significantly reduced through additional surface treatment of the electrode40,41. Furthermore, to substantiate the applicability of the proposed memristor technology towards electrochemical biosensing, we extended its use to the detection of glucose and ascorbic acid with appropriate sample preprocessing (see Supplementary Figs. S10\u2013S12; Supplementary Videos 2 and 3). The memristor device successfully switched its resistance state upon reaching the predefined threshold concentrations of these analytes, further validating the demonstration of the proposed memristor-based biosensor with real biomarkers.

In addition, we implemented a simplified version of the biosensor by replacing the bulky components of the ADC and display with a comparator, hold circuit, and LED (Supplementary Fig. S13a). The comparator detected and compared the V\_OUTR to a 0.2 V reference voltage during the read stage. When the user pressed the button for a read operation, if V\_OUTR was less than 0.2 V, the memristor went into the HRS; otherwise, V\_OUTR went high, and a hold circuit maintained this voltage for approximately 1 s, causing the LED to turn on (Supplementary Fig. S13b). The user could easily check the status of the memristor repeatedly by pressing the button for the read stage. The TP value of the pH sensor was successfully detected at intervals of 1 pH unit by checking the LED turning on and off while varying the change in V\_REF (Supplementary Fig. S13c). The simplified system achieved approximately a 4-fold reduction in IC board size and a 12.4-fold reduction in power consumption, relative to the fully-integrated version (Supplementary Table S1).

Our sensor technology is compared with previously reported semiconductor-based sensors (see Supplementary Table S2). To the best of our knowledge, the sensors developed in this work are the first demonstration of a semiconductor device-based electrochemical biosensor that exhibits TS functionality at the transducer level together with complete system-level integration. Unlike prior transducing devices, our memristor device also offers full CMOS compatibility, which is readily extendable to monolithic integration with SP blocks and thereby facilitating the realization of miniaturized sensor systems. Moreover, our transducer is the only one that simultaneously exhibits intrinsic TS functionality and long-term non-volatility (Supplementary Fig. S14), which is potentially valuable for miniaturized sensors with self-diagnosis capability requiring data retention.

Owing to its simplicity, scalability, and functionality, the proposed memristor-based technology shows promise for future integration into portable sensing platforms, including point-of-care and health-monitoring systems. Furthermore, in miniaturized electronic devices, such as ingestible capsule prototypes, this approach could offer advantages, such as miniaturization, non-volatile memory, scalability, and ultra-low power consumption, potentially contributing to future efforts aimed at monitoring internal physiological environments in a safe and minimally invasive manner (Supplementary Fig. S15).

Although this study was conducted as a proof-of-concept for the proposed biosensor transducer, effective control of V\_SET variation of the memristors is critical for ensuring reliable biosensor operation. Possible mitigation strategies at the device, circuit, and system levels are summarized in Supplementary Fig. S16 and Supplementary Note 1.

Furthermore, further efforts are required to validate the sensing functionality under realistic biochemical conditions. The proposed memristor-based transducer was evaluated for biosensing applications using pH, glucose and ascorbic acid, as representative analytes. Among these, glucose detection currently operates effectively only under strong alkaline conditions, indicating the need for further material and interface optimization. Future studies should therefore assess device performance in complex biofluid environments to understand the influence of factors such as biofouling, signal drift, and cross-sensitivity. Ultimately, comprehensive validation with clinically relevant samples under real-world operating conditions will be essential to establish the broader translational potential of this technology.

Methods
Device fabrication
A 100 nm SiO\_2 layer on 8-inch Si wafers was thermally oxidized in a furnace. A BE stack of Ti/Al/Ti/TiN with a thickness of 10/450/10/120 nm was sputtered on the SiO\_2 layer. A 4 nm-thick Ta\_2O\_5 layer was deposited on the sputtered TiN BE by thermal ALD at 200 \u00b0C using a tantalum precursor, TBTDET. The TaO\_x layers with varying thicknesses of 5, 10, 20, and 40 nm and O\_2/Ar gas mixture ratios of 3, 6, and 9% were deposited on the Ta\_2O\_5 layer using a reactive sputtering system at 400 \u00b0C. A 12 nm TiN TE layer was sputtered on the TaO\_x layer. The active region (4 \u03bcm\^2) was defined by dry etching with Cl\_2 and BCl\_3 gases. Subsequent processes followed the standard back-end-of-line procedure, as shown in Fig. S1c. An 800 nm-thick inter-metal dielectric layer of SiO\_2 was formed by high-density plasma chemical vapor deposition with a process temperature at 350 \u00b0C, plasma-enhanced CVD at 400 \u00b0C, and chemical mechanical polishing. Metal vias and plugs were sequentially formed by dry etching with CF\_x gases and tungsten-based molecular organic CVD at 300 \u00b0C. Finally, the metal interconnection (M1) of the Ti/Al/Ti/TiN stack was patterned to form TE and BE pads for contacting microprobes during electrical measurements.

Biosensor implementation
The memristor-based biosensor system consists of a USB-type sensor electrode, a mem.-board, an IC-board, and a display as shown in Fig. 5c. For the USB-type sensor electrode, an 800 nm-thick SiO\_2 layer was thermally oxidized on an 8-inch Si substrate, 20 nm-thick Ti and 200 nm-thick Au layers were patterned using an evaporator, optical lithography, and dry etching processes. The wafer with the patterned Ti/Au metals was then diced into 5 \u00d7 5 mm\^2 chip including electrodes. Each chip was installed on a PCB substrate using wire bonding and epoxy passivation in a USB-A form factor. For the mem.-board, an 8-inch wafer with S5 memristors was diced into 5 \u00d7 5 mm\^2 (named as S5 die), and Au electrodes were formed on a 30 \u00d7 30 mm\^2 PCB. TE and BE electrodes of the S5 die and the Au electrodes of the PCB were connected through Au wire bonding. Two memristors used in the parallel two-memristor cell configuration were interconnected on the S5 die through a standard metal formation process involving sequential photolithography and metal deposition steps, in which two TEs and two BEs were connected to each other. Electrical components on the IC board include nMOS transistors (ALD212902SAL, Advanced Linear Devices) for forming I\_D and R\_T of the transducer and an MCU (nRF52832, Nordic Semiconductor) for SP, operational amplifiers (LMP7721MA, Texas Instruments), linear voltage regulators (LTC3025, Analog Devices), diodes, resistors, capacitors, buttons, switches, and various connectors. The IC board was assembled on a 2-layer FR4 PCB, with each component placed using a soldering iron (FX-951, Hakko) and a heat gun (861DW, Quick). To implement a prototype of the biosensor, the mem.-board and the IC-board were connected with alligator clips (JM-013), a commercial OLED display (SSD1306, Solomon Systech), and a 5 V charger were used. The firmware was developed in Segger Embedded Studio and uploaded to the MCU for portability.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "This paper proposes a novel bioelectrical signal transducer with threshold-sensing (TS) functionality, enabling electrochemical biosensing applications by utilizing a memristor with single-bit memory characteristics. To meet device requirements for the transducer (achieving a high on/off ratio exceeding 30 while maintaining a long pulse width exceeding 10 milliseconds), a CMOS-compatible TaOX/Ta₂O₅ memristor was developed through process optimization – specifically, setting the oxygen-storage TaOX layer with an O₂/Ar gas mixture ratio of 6% and a thickness of 20 nm. Subsequently, a complete electrochemical biosensor system was constructed by integrating sensing electrodes, signal processing modules, and displays based on the optimized memristor. Experimental verification confirmed the TS functionality: by adjusting VREF from 1.64 V to 2.2 V, the threshold pH point (TP) could be precisely tuned across the pH 1-10 range in 1-pH increments, demonstrating excellent linearity between TP and pH values (Pearson correlation coefficient = 0.981). Furthermore, a more streamlined biosensor version was implemented by replacing bulky ADC and display components with a comparator, hold circuit, and LED. The proposed memristor-based system technology holds some application potential in portable point-of-care diagnostics. Before recommend it for publication, there some questions that need to be addressed.\nQ1: Should the reference to 'Fig. S1' in line 201 on page 10 be corrected to 'Fig. S2'? This is because the forming voltage and forming current mentioned in line 200 are actually presented in Fig. S2.\nQ2: Regarding the caption of Fig. 5 on page 14, which mentions the use of 'only ten consecutive pulses with a unit pulse time (TPULSE) of 20 μs to minimize voltage stress to the memristors' during the sensing stage – how were the three parameters (20 μs pulse width, 10 pulses, and 80 μs duration in the reading stage) experimentally determined? Why is 10 pulses considered the optimal solution for stress minimization?\nQ3: In the schematic diagram in the first half of Fig. 5(c) on page 14, the IC board is shown connected to the four terminals (BE1, TE1, BE2, TE2) of the memristor chip via serial ports. However, in the photograph in the latter half, only two alligator clips are used to establish the connection. What explains this discrepancy in connection methods?\nQ4: Regarding lines 264-265 on page 15 stating 'To minimize the influence of the resistance variation on the transducer, the parallel memristor cell was chosen, which has been utilized in the memory and logic fields' - what specific advantages does this dual-memristor configuration offer compared to the previously mentioned single-memristor structure? How does this architectural improvement enhance the performance of your system?\nQ5: Line 387 on page 18 mentions that 'the simplified biosensor version using a comparator, hold circuit, and LED to replace bulky ADC and display components could still accurately detect threshold points at pH 1 intervals.' However, the more complex version with ADC and MCU also achieved threshold detection at pH 1 intervals. Could the complex version potentially achieve higher detection precision? What are the advantages of the simplified version over the complex one? What is the performance gap between these two versions? We recommend adding comparative experiments.\nQ6: Could you please supplement an experiment to demonstrate the real-time detection capability of the complex version (with ADC and MCU)?\nQ7: Is the memristor strictly necessary for this work? Could other devices potentially replace the memristor's functionality, given that memristor chip fabrication is relatively complex?", "reviewer_2": "In this paper, authors report the CMOS-compatible memristor-based electrochemical biosensor transducer with threshold-sensing functionality. The revision suggestions are as follows:\n(1) The application of sensing effect based on memristor has been reported in previous studies, and the author should highlight the innovation of this work by comparing it with the results reported previously.\n(2) The production and quality of figures need to be further improved.\n(3) The formation of conductive filaments requires relevant experimental evidence, such as in situ TEM images.\n(4) What are the important and unique applications of this work compared to other related reports (such as: Nature Communications, 2023, 14, 8489)? The author should clarify in the main text.\n(5) English grammar and writing errors require careful correction by the author.", "reviewer_3": "This paper reports on a TaOx/Ta2O5 memristor device designed for biomarker threshold-sensing applications. The authors conducted extensive research on memristor performance and demonstrated the concept by integrating a sensor electrode for pH sensing, a signal processing (SP) module, and a display with the proposed transducer. However, the pH demonstration falls short of illustrating the biomarker detection capabilities mentioned in the introduction, such as C-reactive protein detection, which presents significantly greater technical challenges for accurate measurement. The authors' contributions primarily focus on memristor characterization. Given that TaOx/Ta2O5 materials have been widely applied in memristors and numerous reports on biomarker threshold detection already exist (Nature Electronics, 2023, 6, 765–770; Nature Electronics, 2024, 7, 1176–1185; Nature Communications, 2025, 16, 4334, among others), the novelty presented in this paper is insufficient for publication in Nature Communications. The following suggestions are provided to improve the manuscript:\n1. It is suggested that the authors propose a specific application scenario that is well-suited to pH threshold-biosensing capabilities.\n2. Using only pH sensing as proof-of-concept fails to demonstrate relevance to actual diagnostic applications. Real biomarkers (glucose, troponin, etc.) in complex biological matrices are essential for meaningful validation.\n3. Device variability maybe the critical obstacle to practical applications. The stochastic nature of RRAM could lead to false positive result. Device-to-device variability characterization is insufficiently addressed in your work. Additionally, what quality control measures do you implement to ensure acceptable device-to-device consistency for reliable biosensor operation?\n4. Clinical samples contain numerous potential interferents that could compromise specificity. Interference testing is needed.\n5. Error bars are missing in Fig 6. Were these measurements obtained from a single device, or do they represent averaged data from multiple independent devices?\n6. Will temperature and humidity affect the stability of the sensor? What environmental compensation strategies will you implement?", "reviewer_4": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts."}, "author_response": "Response Letter to Reviewers’ Comments\nWe sincerely appreciate the reviewers’ time and effort in evaluating our manuscript and for providing\nconstructive comments and suggestions that have helped improve the quality of our work. In response\nto the reviewers’ evaluations, we have made a point-by-point response to the reviewers’ comments and\nincluded additional experimental and simulation results. We have also revised the manuscript to\nimprove the clarity of the manuscript to present our findings more effectively. Based on the responses\nbelow, we have updated 2 figures in the revised manuscript, added 10 supplementary figures, 2\nsupplementary tables, 1 supplementary note, and 3 supplementary videos in the revised Supplementary\nInformation. All modifications and additions in the revised manuscript and Supplementary Information\nare highlighted in red. Our detailed point-by-point responses to the reviewers’ comments are as\nfollows.\nReviewer #1\nThis paper proposes a novel bioelectrical signal transducer with threshold-sensing (TS)\nfunctionality, enabling electrochemical biosensing applications by utilizing a memristor\nwith single-bit memory characteristics. To meet device requirements for the transducer\n(achieving a high on/off ratio exceeding 30 while maintaining a long pulse width\nexceeding 10 milliseconds), a CMOS-compatible TaO /Ta O memristor was developed\nX 2 5\nthrough process optimization – specifically, setting the oxygen-storage TaO layer with\nX\nan O /Ar gas mixture ratio of 6% and a thickness of 20 nm. Subsequently, a complete\n2\nelectrochemical biosensor system was constructed by integrating sensing electrodes,\nsignal processing modules, and displays based on the optimized memristor.\nExperimental verification confirmed the TS functionality: by adjusting V from 1.64\nREF\nV to 2.2 V, the threshold pH point (TP) could be precisely tuned across the pH 1-10\nrange in 1-pH increments, demonstrating excellent linearity between TP and pH values\n(Pearson correlation coefficient = 0.981). Furthermore, a more streamlined biosensor\nversion was implemented by replacing bulky ADC and display components with a\ncomparator, hold circuit, and LED. The proposed memristor-based system technology\nholds some application potential in portable point-of-care diagnostics. Before\nrecommend it for publication, there some questions that need to be addressed.\nResponse: We sincerely appreciate the reviewer’s constructive comments on our work and\nvaluable suggestions for enhancing the quality of the study.\nComment #1: ... [truncated for brevity, full text in source] ...\n(See full response in source document)"}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have answered all my comments. I can recommend it for publication in Nature Communications.", "reviewer_2": "This revised manuscript can be accepted for publication.", "reviewer_3": "The authors have addressed most of my comments. The revised manuscript is much clearer in its novelty. Just a minor point: Although this work was conducted as a proof-of-concept study for the proposed biosensor transducer, detecting glucose and AA in a strong alkaline environment is not suitable for physiological conditions.", "reviewer_4": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts."}, "author_response": "Response Letter to Reviewers’ Comments\nWe sincerely appreciate the reviewers’ time and effort in evaluating our manuscript and for providing\nadditional comments and suggestions that have helped improve the quality of our work. In response to\nthe reviewers’ evaluations, we have made a point-by-point response to the reviewers’ comments. All\nmodifications and additions in the revised manuscript are highlighted in red. Our detailed point-by-\npoint responses to the reviewers’ comments are as follows.\nReviewer #3\nThe authors have addressed most of my comments. The revised manuscript is much\nclearer in its novelty. Just a minor point: Although this work was conducted as a proof-\nof-concept study for the proposed biosensor transducer, detecting glucose and AA in a\nstrong alkaline environment is not suitable for physiological conditions.\nResponse: We sincerely appreciate the reviewer’s constructive comments on our work and\nvaluable suggestions for enhancing the quality of the study. To address the reviewer’s\ncomment, we have appended the revised manuscript and revised Supplementary Information\nas follows:\nPage 12, line 310: ... [truncated for brevity, full text in source]"}]

Decision letter