Wireless, non-invasive, high-resolution thrill sensor for continuous vascular access monitoring of hemodialysis patients

Domain: chemistry
Published: 2026-03-15
Editorial outcome: major_revision

Abstract
Hemodialysis is the primary life-sustaining therapy for patients with end-stage renal disease (ESRD). Diagnosing and monitoring the health condition of vascular access (VA) for hemodialysis involves the use of ultrasonic imaging and angiography. These infrequent tests cannot, however, identify signs of mild stenosis and sudden onset to facilitate early intervention. Hence, approximately 70% of hemodialysis patients experience VA failure each year, rendering dialysis difficult and posing life-threatening risks. Here, we report wireless, non-invasive thrill sensors incorporating high-resolution accelerometers designed to be conformally placed on VA skin for the continuous monitoring of VA thrill signals, which we tested in multi-platform validation including an in vitro benchtop system, canine models and patients (n=9). Local measurements of VA thrill intensity via continuous wear demonstrated that a decrease in thrill intensity along the entire VA region is indicative of diminished VA function, while an abnormally heightened thrill intensity at a certain location along the VA indicates localized structural lesions. These thrill sensors may aid the early treatment of VA stenosis upon the transition from subjective thrill palpation to quantitative hemodynamic phenotyping.

Introduction
End-stage renal disease (ESRD), the final stage of chronic kidney disease, has an extremely high mortality rate1, 2, 3, 4, and is expected to become the fifth leading cause of shortened life expectancy as the world ages5, 6. Renal replacement therapies, including hemodialysis, are imperative for sustaining life in patients with ESRD7, 8, 9, 10. Current trends indicate that the number of patients undergoing hemodialysis worldwide could reach 5.4 million by 203011, with a projected annual growth rate of 4%12. Hemodialysis requires the special blood circulation for inflow and outflow, achieved through vascular access (VA) — a surgically established direct connection (circulatory short-circuit) between a selected vein and artery in the patient’s forearm or upper arm13, 14, 15, 16 (see Fig. 1a). However, maintaining long-term patency and optimal VA function is challenging17, as repeated punctures during hemodialysis and potential vascular abnormalities from specialized blood flow18 may lead to intimal hyperplasia19. Approximately 70% of patients experience VA failure annually20, primarily due to untreated stenosis. This complication can leave patients unable to undergo hemodialysis, posing a life-threatening risk21, 22. Thus, timely VA monitoring is critical23. Presently, direct assessment of VA blood flow rate using a Doppler ultrasound machine is the most useful indicator of VA stenosis24. Nevertheless, it remains of a clinical nature and possesses limited potential for daily, at-home, rapid and continuous monitoring of VA health conditions25, representing an unmet healthcare need.

In long-term medical practice, clinicians have collated a compendium of empirical methods for evaluating VA health conditions. Due to the distinctiveness of the blood flow inside the VA26, high-frequency vibrations are generated on the skin surface in its vicinity, which are distinctly discernible from the pulsation of arterial blood vessels. This phenomenon is referred to as VA thrill27 and exhibits significant variability among different VA health conditions28 (Fig. 1b-d). Palpation and auscultation of the thrill29 are the most common methods of rapid assessment of VA health conditions and are the only methods that patients can self-assess at home, as outlined in the recommendations for routine maintenance of VA30. Nevertheless, this method is highly subjective31, and the accuracy of the assessment is contingent on the operator's experience. The complex characteristics of VA thrill signals that vary with the degree of stenosis pose significant challenges to its quantitative measurement and corresponding diagnostic strategy. Researchers have sought to develop quantitative methods to monitor VA thrill, including the use of photoplethysmography (PPG) sensors and digital stethoscopes. Specifically, following continuous development32, 33, 34, 35, the PPG sensor has been shown to indirectly assess VA thrill by monitoring changes in arterial pulse along the VA. However, it cannot directly and precisely measure VA thrill and is vulnerable to serious motion artifacts and ambient light interference, resulting in inaccurate assessments. Recent works36, 37, 38, 39 have employed a commercial digital stethoscope for signal acquisition and investigated the screening method of VA stenosis using deep learning signal analysis methods. Nonetheless, the probe of the commercial equipment is large and difficult to wear, making it unsuitable for continuous monitoring of VA health conditions. There is an urgent need for the solution that can expeditiously, objectively and continuously monitor VA health. While arteriovenous fistulas (AVFs) represent the majority of VA cases40, this study focuses on arteriovenous grafts (AVGs) because (1) AVGs exhibit more complex stenosis characteristics than AVFs, occurring at arterial/venous anastomosis, mid-graft, or puncture sites41; (2) AVGs’ variable depth makes thrill assessment via palpation particularly challenging42, creating an unmet need for objective monitoring tools that the KDOQI guidelines (Section 13.2, 13.5, 13.7)30 highlight, which recommends regular physical examination while discouraging routine AVG surveillance by imaging; (3) AVGs become essential and life-sustaining when AVFs fail in long-term hemodialysis patients43; and (4) AVGs’ standardized PTFE material44 facilitates sensor development.

Therefore, to bridge this critical clinical gap, we developed a wireless, non-invasive thrill sensor integrating dual MEMS accelerometers and motion-artifact cancellation methods, which is capable of high-resolution spatial-temporal mapping of VA thrill. Through multi-platform validation, encompassing in vitro benchtop systems, canine models, and human studies, we systematically decode thrill signatures as quantitative biomarkers for VA health conditions and establish two diagnostic signatures: (1) thrill intensity exhibits a persistent positive correlation with blood flow rate in well-functioning VAs, while dysfunctional VAs show an over 20% reduction; (2) pathognomonic focal singularities of heightened intensity precisely localize stenosis sites. These enable a dual-parameter diagnostic strategy: global thrill intensity quantifies VA functional decline, and thrill singularity localizes VA structural lesions. The thrill sensor transforms subjective palpation into objective hemodynamic phenotyping, offering the paradigm for continuous, patient-administered VA surveillance.

Results
Thrill Sensor for Continuous Monitoring Vascular Access Health Condition. The proposed thrill sensor can be noninvasively attached to the skin surface above VA, facilitating the wireless, rapid, quantitative monitoring of high-frequency and weak thrill signals. This approach enables the real-time assessment of VA health conditions (Supplementary Fig. 1). In comparison to Doppler ultrasound probes or stethoscopes, our sensor is more compact (30 × 15 × 5 mm3, representing less than 5% of the ultrasound probe's volume) and lighter (~20 g, approximately 4% of the ultrasound probe's weight), with minimal mass and mechanical loading (Supplementary Fig. 2, 3, and 4). The thrill sensor is able to accurately monitor the VA thrill signal, as illustrated in Figure 1e (from a canine's well-functioning VA). This signal is shown to be consistent with the recording and the cardiac cycle synchronously acquired by the electrocardiographic (ECG) monitor and the commercial digital stethoscope (3M™ Littmann® CORE Stethoscope, Eko). Furthermore, the thrill sensor exhibits rapid and sensitive responses to continuous variations in thrill at the patient's VA. As the patient continuously raised the VA arm, the sensor was able to detect an increase in the VA thrill signal (Fig. 1f), thereby demonstrating its excellent dynamic performance. Additionally, comparison between two groups of distinct thrill signals revealed (i) the recovery of the thrill signal after percutaneous transluminal angioplasty (PTA) surgery for venous anastomosis stenosis (Fig. 1g, Supplementary Fig. 5, Supplementary Movies 1 and 2); (ii) the emergence of the pulse signal at venous anastomosis stenosis, whereas this phenomenon did not exist in arterial puncture site stenosis (Fig. 1h and Supplementary Fig. 6); (iii) the change in the thrill signal in a normal VA patient pre/post-hemodialysis (Supplementary Fig. 7); and (iv) the comparison of the thrill measurement results between patient self-attachment and doctor attachment of the thrill sensor (Supplementary Fig. 8 and Supplementary Movie 3). The combination of size, mass and sensitivity achieved with this thrill sensor is unattainable with alternative technologies (Supplementary Fig. 9 and Supplementary Table 1).

The core module of the thrill sensor (see Fig. 2a) consists of a pair of MEMS accelerometers (ADXL355, Analog Devices and LIS2DW12, STMicroelectronics). The former (main, noise density ~25 μg/√Hz) is located in close proximity to the VA surface, facilitating high-precision monitoring of the thrill; the latter (auxiliary, noise density ~85 μg/√Hz) is positioned adjacent to the VA, enabling measurement of limb motion. In addition, powered by a Li-ion battery (UFX351525, 90 mAh, 4.2 V), the thrill sensor's low power consumption (1600 Hz sampling mode and Bluetooth low energy mode) enables 50 minutes of continuous monitoring and wireless data transmission (Supplementary Fig. 10, and see Methods for detailed information on system design and preparation).

Laboratory tests revealed that the thrill sensor is capable of measuring carotid pulse signals in various conditions (sitting, walking), thereby verifying its accuracy in monitoring typical biological vibrations (see Fig. 2b). Further environmental robustness testing under skin temperature variations (36 – 46°C) and sweating conditions confirmed stable pulse detection (see Supplementary Fig. 11). VA thrill is considerably more complex than the arterial pulse generated by the heartbeat. This difference arises because blood flow in arteries is typically laminar45, whereas blood flow within the VA (formed by the direct connection of a vein and an artery) is inherently turbulent46, even when the VA functions well. Figure 2c illustrates the thrill signal of a patient (male, 53 years old) with a well-functioning VA. The thrill sensor recorded both the VA thrill with motion (pink lines, SNR = -26.95 dB) and arm movement (blue lines) simultaneously and then subtracted these to eliminate motion artifacts, obtaining the real VA thrill signal (purple line, SNR = 9.65 dB). According to Supplementary Note 1, a significant 36.6 dB SNR improvement is demonstrated through our dual-accelerometer motion-artifact cancellation method, which establishes a robust foundation for more accurate VA thrill measurement. By extracting a single cardiac cycle of the real VA thrill signal for signal decomposition, it becomes evident that the thrill of a well-functioning VA is composed of two parts: the arterial pulse and the VA high-frequency weak vibration. The arterial pulse contributes to the amplitude of the VA thrill signal, while the VA high-frequency weak vibration, with an amplitude approximately one-third of that of the arterial pulse, contributes to the high-frequency fluctuation (see Fig. 2d). When VA dysfunction occurs, the VA thrill signal becomes more complex and variable because the blood flow becomes more irregular due to abnormal changes in vascular morphology (such as stenosis)47. At present, thrill-based diagnosis relies heavily on the medical experience of clinicians. To this end, we employed VA thrill sensors to systematically and quantitatively characterize VA thrill under varying degrees of stenosis using multi-platform experimental approaches comprising in vitro benchtop systems, animal models, and human studies.

In vitro experiments. A cardiovascular benchtop system containing mimic VA was established for in vitro experiments on the thrill sensor (refer to Fig. 3a and Supplementary Fig. 12). A pulsatile water pump was utilized to emulate cardiac function, with a mimic heart rate ranging from 60 to 150 bpm and a flow rate from 0.1 to 1.9 L/min (the blood flow rate in healthy VAs varies from 0.6 to 1.5 L/min30, 48). The mimic tissue with VA inside was made from silicone (Dragon Skin 00-10), where VA (a direct connection between a selected vein and artery) was simulated by a Y-shaped tubing cavity located 3 mm beneath the surface (for more details, refer to Methods). VA scenarios revealed that the simulated VA thrill signals on the benchtop system, measured by the thrill sensor, exhibited a high degree of consistency with the real VA thrill signals from patients (Supplementary Fig. 13). This demonstrated that the benchtop system had the capacity to simulate VA thrill and can be utilized for subsequent in vitro experiments on the subject.

VA stenosis mainly includes stenosis at VA venous outflow (vein stenosis) and stenosis at VA arterial inflow (artery stenosis), and the majority of VA stenosis is vein stenosis41. As shown in Figure 3b, polytetrafluorethylene (PTFE) cylindrical tubes with varying inner and outer diameter ratios were positioned into the mimic VA in the benchtop system to simulate different degrees of vein stenosis (tiny, blue tube in Fig. 3b) and artery stenosis (tiny, red tube in Fig. 3b), separately. With respect to VA scenarios of mimic vein stenosis, Figure 3c shows the acceleration signals of the simulated VA thrill when the mimic VA was non-stenosis or in 60% stenosis, with a constant simulated heart rate of 60 bpm and a simulated blood flow rate of 600 mL/min. In 60% stenosis, the maximum amplitude of the thrill acceleration time-domain signal was reduced to 1/5 of that when the mimic VA was non-stenosis. The time domain signal is Fourier transformed to obtain the VA thrill acceleration signal spectrogram (Fig. 3d). The characteristic center frequency of the spectrogram was reduced from approximately 200 Hz at full patency to approximately 40 Hz at 60% stenosis, reflecting the intrinsic frequency of the simulated tissues (Supplementary Fig. 14). This showed that in cases of VA stenosis, the low-frequency vibration of the biological tissue due to cardiac activity gradually replaces the high-frequency thrill and dominates. Figure 3e shows the thrill intensity calculated by the simulated VA thrill (Supplementary Fig. 15) when the mimic VA was non-stenosis or in 30%, 60%, and 80% stenosis. The thrill intensity gradually decreased with increasing stenosis level, and stenosis VA exhibited a significant reduction in thrill intensity compared to non-stenotic VA (n = 4, t = 3.598, df = 3.031, p = 0.018 < 0.05, Cohen’s d = 2.544, one-tailed Welch’s t-test, see Methods). Specifically, at early-stage stenosis (< 50%), VA thrill intensity decreased insignificantly, making it difficult to diagnose VA stenosis by palpation or auscultation. However, VA thrill intensity declined rapidly at advanced-stage stenosis (> 50%), certainly leading to a significant change in palpation, but it was too late to undergo minor medical intervention at that time.

Figure 3f shows the spectrogram and extracted time-domain signal of simulated VA thrill (Supplementary Fig. 16) in severe vein stenosis (> 80%). A sharp spike in the spectrogram was observed at a frequency ranging from 1 to 2 Hz, which revealed the emergence of an arterial pulse signal. This rule was consistent with the empirical assessment of clinicians during palpation of the VA; that is, severe stenosis at VA venous outflow results in a palpable water-hammer pulse49. In contrast, severe stenosis at VA arterial inflow results in diminished intensity both in VA thrill and pulse50, as illustrated in Figure 3g.

Animal experiments. The animal experiments were performed on 5 canine models to verify the adaptability of the thrill sensor in real scenarios (Fig. 4-6, Supplementary Fig. 17 and 18). Figure 4a illustrates an example of the thrill sensor employed for well-functioning VA (the arteriovenous graft, AVG) thrill monitoring in a labrador. Figure 4b shows the thrill signal on the VA in the left leg and the pulse signal on the superficial femoral artery in the right leg, measured simultaneously. Both the time-domain signal and the time-frequency map can reveal that the VA thrill is the high-frequency vibration of the blood vessel superimposed on the arterial pulse. This is consistent with the signal characteristics of the real patient (refer to Fig. 2c) and can verify the animal model. The spectrogram indicates that the characteristic frequency band of VA thrill is 100-200 Hz. Consequently, the spectral mean value in this band (denoting the energy of the vibration signal, see Methods) was selected to characterize the intensity of the thrill.

Two canines, one designated Canine 1, which had a well-functioning AVG surgically created at least 6 months previously; and another designated Canine 2, which had a repaired AVG after percutaneous transluminal angioplasty (PTA) surgery yesterday, were measured using both the thrill sensor and commercial digital stethoscope for comparison (more experimental details refer to Supplementary Fig. 19). A hemostatic ribbon was employed to induce stenosis in the femoral artery upstream of the AVG (Supplementary Fig. 20). The AVG blood flow rate, as measured by Doppler ultrasound, revealed four distinct stenosis levels (Fig. 4c for Canine 1 and Fig. 4d for Canine 2). Whether Canine 1 had a high initial blood flow rate (984.93 mL/min) or Canine 2 had a low initial blood flow rate (737.41 mL/min), according to the time-domain signals from the thrill sensor and the commercial digital stethoscope, as the flow drop was less than 40%, the measurement results were highly consistent. It also revealed that the thrill attenuation was not significant in mild stenosis, which is consistent with the result of the benchtop system (refer to Fig. 3e). As the flow dropped between 40% and 80%, there was a significant decline in the thrill signal, but the signal measured by the thrill sensor was much stronger than that of the commercial digital stethoscope. Particularly, at 76%, the thrill signal measured by the stethoscope became virtually indistinguishable. When the flow drop was more than 80%, the thrill signal was rendered extremely diminished, thereby limiting both devices to effectively measure such thrill signals. The primary benefit of the thrill sensor stems from the high resolution of the embedded accelerometer, its compact size and small pick-up area, and its compatibility with interference from the surrounding environment.

By applying continuous finger pressure (Supplementary Fig. 21) to the venous side (Fig. 5a) and arterial side (Fig. 5b) of the graft (Canine 1’s VA), the result was an approximately 60% decrease in the blood flow rate within 30 s, as measured by Doppler ultrasound, reaching moderate stenosis. The change in the thrill signal measured by the thrill sensor and the commercial digital stethoscope exhibited a high degree of consistency, following successive stenosis and decreasing continuously. In particular, when the stenosis reached over 50%, the thrill signal measured by the thrill sensor was significantly stronger than that of the stethoscope. This verified the rapid response and continuous measurement capability of the thrill sensor. Furthermore, we performed thrill monitoring and analysis for the graft (Canine 2’s VA) before and after PTA surgery (Fig. 5c and Supplementary Fig. 22). The VA underwent three phases of occlusion (no blood flow detected), half revascularization (blood flow of 402.36 mL/min), and full revascularization (blood flow of 808.07 mL/min), as measured by Doppler ultrasound. The thrill sensor was able to accurately reflect the changing process of the thrill signal. The process began in the occlusion phase (similar to the arterial pulse signal), gradually superimposed the high-frequency vibration with the increase in blood flow rate during thrombolysis and ultimately returned to the normal level. In summary, as shown in Figure 5d, the histogram of thrill intensity variation calculated from the above cases (stenosis or revascularization process of Canine 1 and Canine 2) also demonstrates that, for the same individual, the quantitative thrill intensity measured by the thrill sensor is correlated with the VA blood flow rate, which can reflect the current VA health condition to a certain extent. The abnormal VA exhibited a significant reduction in thrill intensity compared to well-functioning VA (n = 4, t = 7.873, df = 3.258, p = 0.0015 < 0.05, Cohen’s d = 5.567, one-tailed Welch’s t-test, see Methods).

Moreover, based on the thrill sensor, the change of VA thrill in the rapid process of severe stenosis (more than 80% stenosis within 8 s on Canine 3’s well-functioning VA) was analyzed. The thrill intensity decreased from 0.98 to 0.06 during vein-side stenosis and from 0.79 to 0.02 during artery-side stenosis (Fig. 5e). A comparison between the two thrill signals in 7~8 s revealed the emergence of pulse signals at severe vein-side stenosis (blue curve in Fig. 5f), whereas this phenomenon did not exist in severe artery-side stenosis (purple curve in Fig. 5f). These results were consistent with the findings obtained from in vitro experiments via the benchtop system.

Having established the efficacy of the thrill sensor for localized, single-point assessment of VA thrill characteristics under varying hemodynamic conditions, we extended our investigation to evaluate the sensor's capability for spatial mapping, that is, the quantitative profiling of thrill distribution along the entire length of the VA arteriovenous graft (AVG). An e-PTFE artificial blood vessel (approximately 20-30 cm in length) is employed in the AVG; in patients undergoing maintenance hemodialysis, stenosis inside the graft is also a prevalent type41. Therefore, quantitative measurement and continuous monitoring of thrill distribution along the AVG are critically important for early stenosis detection. However, current clinical tools face inherent limitations when measuring thrill distribution: ultrasound probes, despite their high-resolution 3D imaging capability, have a large detection footprint (typically ~40 mm in length), which restricts portability and continuous monitoring, while commercial stethoscopes also have bulky auscultation heads (6–8 times the graft diameter, Supplementary Fig. 23). Furthermore, certain existing wearable solutions for VA monitoring may suffer from large-area and long-time attachment, potentially interfering with hemodialysis cannulation and leading to reduced acceptance by patients and nursing staff. In contrast, the design of the thrill sensor incorporates a compact detection area (10×10 mm2) which is capable of confining measurements to a small region. This miniaturized footprint enables flexible placement away from critical cannulation sites, minimizing interference and improving clinical utility and user acceptance with temporary monitoring sessions (e.g., pre-dialysis or interdialytic assessment). Although this resolution cannot pinpoint and image sub-5 mm lesions with ultrasound-level precision, it can detect localized abnormal vibration intensity averaged over the 10×10 mm² area. Such distributed monitoring offers potential for pinpointing the approximate location of stenosis, assessing overall VA health conditions and complementing existing modalities.

The time-domain signals of the thrill via the thrill sensor were obtained from a total of 10 monitoring points on Canine 1’s well-functioning AVG (Fig. 6a-b, Supplementary Fig. 24). Ten points were distributed uniformly along the VA, from the arterial anastomosis (P1) through the U-turn (P6) to the venous anastomosis (P10), as shown in Fig. 6a. Doppler ultrasound measurements (Supplementary Fig. 25 and 26) demonstrated that the AVG depth fluctuated within acceptable limits, except for the anomalous depth of monitoring point P10, and the flow rate was consistently within the normal range. Figure 6c shows the distribution of the thrill intensity, depth and blood flow rate along the AVG of Canine 1. The thrill intensity decreased from 7.87 at the arterial anastomosis (P1), reached a minimum value of 0.42 at the U-turn (P6), and then increased from point to point, reaching 1.13 near the venous anastomosis (P9). Supplementary Figure 27 and 28 show the thrill distribution along the AVG in another two experimental dogs, Canine 3 and Canine 4. In summary, in cases of well-functioning AVGs, the thrill intensity exhibited continuous variation. It underwent a gradual weakening from the arterial anastomosis to the U-turn, followed by a subsequent gradual strengthening from the U-turn to the venous anastomosis, and the greatest intensity was observed at the arterial anastomosis.

In the case of abnormal AVG, as evidenced in Canine 2 (Fig. 6d, Supplementary Fig. 29 and 30), which exhibited 26% residual stenosis at the venous anastomosis (P10) after PTA surgery, the thrill intensity distribution along the AVG was markedly reduced overall. However, the thrill intensity at the venous anastomosis (P10) was abnormally enhanced, which can be considered a singularity on the intensity distribution, and was significantly stronger than the other monitoring points on the entire AVG (Fig. 6e-f). Supplementary Figure 31 presents the results of thrill monitoring in a recently established AVG (Canine 5). As the incision healed, there was an increase in overall blood flow rate. On the 7th day after implantation, the thrill intensity at the same monitoring point on the AVG was up to twice as high as that on the day after implantation. Figure 6g-i summarizes the AVG thrill intensity colormap of 5 experimental dogs. The dogs were divided into three distinct groups: the newly implanted AVG (Canine 5), well-functioning and 6-month mature AVGs (Canine 1, 3, and 4) and the abnormal AVG (Canine 2). The findings reveal that the well-functioning group exhibits a significantly stronger thrill intensity in comparison to the newly implanted and abnormal groups (Supplementary Fig. 32), while the abnormal group shows a unique increase in thrill intensity across the arterial to venous anastomosis.

Human studies. The human study explores the applicability of the thrill sensor in a clinical setting. A total of 9 hemodialysis patients were included in this study. The average age of the patients is 57.5 ± 16.5 years, and 4 (44.4%) are male. The basic patient information and clinical characteristics are summarized in Supplementary Table 2.

First, as shown in Figure 7a, 3 patients with well-functioning VA (arteriovenous graft, AVG, e.g., Patient A: Supplementary Fig. 33, 34, 35) were assessed by the thrill sensor and digital subtraction angiography (DSA) (Patient A and Patient B, whose AVGs returned to normal after repair; Patient C, whose AVG remained healthy for over 6 months). Figure 7b shows the thrill intensity histogram of 10 uniformly distributed monitoring points and thrill signals at key points (P1 and P10: the anastomosis; P6: the U-turn) for each patient. It is evident that the thrill intensity at the arterial anastomosis (P1) is significantly greater than that at the other monitoring points. The thrill intensity exhibits continuous change along the AVG, transitioning from strong (the arterial anastomosis) to weak (the U-turn) and subsequently from weak (the U-turn) to strong (the venous anastomosis). This finding aligns with the typical characteristics of thrill in well-functioning AVGs, as previously found in animal experiments.

Furthermore, 6 patients with abnormal AVG were assessed. Figure 7c shows 3 patients (Patient D, Patient E and Patient F) whose AVG had residual stenosis at the venous anastomosis (P10) after repair (e.g., Patient D: Supplementary Fig. 36, 37, 38). According to Figure 7d, their thill intensity exhibits a reduction of more than 20% in comparison with the well-functioning AVGs (n = 6, t = 2.758, df = 4.222, p = 0.024 < 0.05, Cohen’s d = 1.927, one-tailed Welch’s t-test, see Methods). However, the thrill is abnormally enhanced at the residual stenosis position (P10), which becomes a singularity in the thrill intensity distribution.

Figure 7e shows 3 patients (Patient G: Supplementary Fig. 39, 40, 41, Patient H: Supplementary Fig. 42, 43, 44 and Patient I: Supplementary Fig. 45, 46, 47), whose AVG has an irregular lesion inside (Patient G’s AVG exhibits a morphological 90° turn, Patient H’s AVG has graft ectasia in the vicinity of the arterial puncture point, and Patient I’s AVG undergoes a non-drug-eluting stent implanting near the venous anastomosis). According to Figure 7f, the presence of an irregular lesion in the AVG not only results in an overall weaker thrill intensity compared to the well-functioning AVG but also leads to a singularity of enhanced thrill at the lesion point. Specifically, in Patient G’s AVG, the inside morphological 90° turn is located between the monitoring points P1 and P2, which triggers the Bernoulli effect, resulting in the abnormally enhanced thrill at the downstream position (P2). Additionally, in Patient H’s AVG, the graft ectasia is located between monitoring points P5 and P7, which intensifies turbulent flow, resulting in the abnormally enhanced thrill at the center of the ectasia (P6). In Patient I’s AVG, the stent suppresses the majority of the total energy, but its thrill intensity still experiences tiny enhancement near the stent position (P10).

Consequently, in instances where the AVG is abnormal, the predominant feature of thrill is characterized by a diminished overall intensity, with a distinct singularity of thrill intensity observed at the lesion point. This finding also aligns with the characteristics of thrill along the abnormal AVG in animal experiments.

According to Supplementary Figure 48, the Bland‒Altman plots demonstrate the comparability between normalized thrill intensity and dimensionless blood flow rate. Based on clinical assessments using the thrill sensor, the human studies revealed two defining characteristics of the thrill related to vascular access health conditions: (1) thrill intensity exhibits a persistent positive correlation with blood flow rate in well-functioning AVGs (Patient A-C), and abnormal AVGs (Patient D-I) face over 20% reduction in global thrill intensity compared to well-functioning AVGs (see Fig. 7g); (2) focal singularities of heightened thrill intensity precisely localized at the lesion point in abnormal AVGs (see Fig. 7h).

Methods
Fabrication of the thrill sensor. A laminate composite film of copper/polyimide/copper (18 μm/12.5 μm/18 μm, Shenzhen JLC Technology Group Co., Ltd.) served as the substrate for the thrill sensor. The copper layer is processed through the wet etching process to pattern the traces and bond pads. The substrate is drilled by micro twist drill bits and electroplated by graphite conductive adhesive (Ausbond A528). Successive cleaning with stainless steel liquid flux (Worthington Inc.) and deionized water prepared the resulting flexible printed circuit board (f-PCB) for electronic components by removing surface oxides. The surface mount components on the f-PCB are soldered with low-temperature lead-free solder paste (LF999, KELLYSHUN) by a reflow oven (T937, Tai’an Puhui Electric Technology Co., Ltd.) to establish electrical contact between the components and the copper pads.

Design of the wireless electronic system. A pair of MEMS accelerometers (ADXL355, Analog Devices and LIS2DW12, STMicroelectronics) collect the thrill and motion artifact signals, and transmit the data to the BLE/Wi-Fi dual-mode SoC (ESP32C3-FH4, Espressif Systems) through the SPI communication protocol (written by Arduino IDE 1.8.19, Arduino). The signal is transmitted to the user’s mobile device (PyCharm on the laptop computer side and BLE Assist on the smartphone side) or the MQTT server (Local server) through a 2.4 GHz ceramic antenna (2450AT18A100E, JOHANSON). The system is powered by a Li-ion battery (UFX351525, 90 mAh, 4.2 V, Guangdong Ufine New Energy Co., Ltd.), and a linear voltage regulator LP5912-3.3DRVR (Texas Instruments) steadily reduces the voltage to 3.3 V for use by the electronic system.

Data acquisition and instrumentation. Simultaneous data acquisition for several thrill sensors occurs through Bluetooth low energy (BLE) with a host laptop (Legion Y9000X, Lenovo). The data are recorded via a custom interface (PyCharm 2023.1.2, JetBrains) and processed with custom algorithms (MATLAB R2022b, MathWorks). Vibration samples are acquired at a sampling frequency of 1600 Hz.

Signal filtering and data analysis. A second order Butterworth bandpass filter with a lower cut-off frequency of 100 Hz and a higher cut-off frequency of 200 Hz was applied to the raw thrill signals to extract the characteristic signal of VA thrill, which was quite distinct from the normal physical vibration including arterial pulse and limb motion. The filtered signals were then processed to quantify the thrill intensity through spectral energy analysis. They were segmented into 2-second epochs (50% overlap), multiplied by a Hamming window, and transformed to the frequency domain via fast Fourier transform (FFT). Power spectral density (PSD) was computed, and the thrill intensity (I_thrill) was quantified as the mean PSD (the spectral mean value) over the 100-200 Hz band, I_thrill = \int_{f1}^{f2} PSD(f) df / (f2 - f1), where f2 = 200 Hz, f1 = 100 Hz.

Benchtop vascular access model. The model is a simulated vascular access system with a modulus of elasticity close to human skin. First, a mold with a cuboid cavity is designed for a specific vascular access depth and diameter. Then, a 3D printed polyvinyl alcohol (PVA, water-soluble) tube, shaped like the vascular access, is placed into the mold. Next, a uniform mixture of the two components of Dragon Skin 00-10 (Smooth-On, Inc., mass of A: mass of B = 1:1) was poured, and the model was left at room temperature (25°C) for 5 h. Finally, the cured cuboid model was removed from the mold and immersed in hot water (90°C) for 24 h to dissolve the PVA tube, and the benchtop vascular access model was obtained.

The flow through vascular access model is controlled with a high-precision pulsatile pump (PLPTXG003, Shanghai Preclinic Medtech Co., Ltd.) at a representative blood flow rate (Q = 0.1 to 1.9 L/min) and simulated heart rate (60 to 150 bpm). A recirculating water bath (3 L) maintained at 36 °C simulated the artificial blood temperature. The thrill sensor is mounted on the benchtop vascular access model surface along the path of flow for vibration sensing.

Benchtop model stenosis. Different degrees of stenosis are simulated through PTFE cylindrical tubes (2 mm length) with different wall thicknesses (inner / outer diameter ratio = 3/16, 1/2, 13/16) placed into the benchtop vascular access model. The position of the PTFE cylindrical tubes was adjusted to create different types of stenosis.

Animal experiment protocol. Animal experiments were approved by the Laboratory Animal Welfare and Ethics Committee of Pudong Hospital, Fudan University (No. 20240329-002). Three 4-year-old male Labrador dogs (Canine 1: 4 years/28 kg, Canine 3: 4 years/29 kg, Canine 4: 4 years/27 kg) from Sunnatech Shanghai Co., Ltd. were used for experiments of well-functioning VA. A 4-year-old male Labrador dog (Canine 2: 4 years/27 kg) from Sunnatech Shanghai Co., Ltd. was used for experiments of abnormal VA (with PTA surgery). A 4-year-old male Labrador dog (Canine 5: 4 years/26 kg) from Weifang Shengnuo Experimental Animal Breeding Co., Ltd. was used for newly implanted VA experiments. This breed of dog is usually used in preclinical large animal studies of vascular access. They were premedicated using intramuscular injection of 2 mg/kg tiletamine-zolazepam (Zoletil 50) followed by endotracheal intubation. Animals were placed in a supine position, and anesthesia was maintained using inhalation of 1–3% isoflurane (RWD R510) at a 1 L/min flow rate of 100% O2. Throughout the procedure, electrocardiogram, transcutaneous oxyhemoglobin saturation (SpO2), and inspired oxygen fraction were continuously monitored. After the experiment, inject butorphanol 0.05 mg/kg subcutaneously and use a thermal blanket to keep the dogs warm. Clean stainless-steel cages were used for breeding. After all appropriate measurements were obtained, surgically remove the implanted VA vessel, continue to raise the dog and seek adoption.

When measuring VA thrill, the thrill sensor was mounted on the surface of the canine’s body, directly above the vascular access, using ultrathin medical adhesive tape (3M™ 1524). A commercial digital stethoscope (3M™ Littmann® CORE Stethoscope, Eko) was placed near the thrill sensor to simultaneously measure VA thrill sounds. Standard Doppler ultrasound imaging of the VA was performed with a 4D cardiovascular ultrasound system (Vivid E95, GE HealthCare) by applying the probe directly onto the skin over the VA region to measure the blood flow rate and blood vessel depth. The standard device operation protocol consisted of the synchronized thrill sensing and stethoscope auscultating step (10 - 30 s), and ultrasound step (300 s). The measurement of a single monitoring point was repeated 3 times.

Thrill assessment in changing situations of canine’s VA. In the first situation, a hemostatic ribbon was employed to induce stenosis in the femoral artery upstream of the VA. The femoral artery and vein bundles were identified and traced on Doppler ultrasound. A 5 cm longitudinal superficial skin incision in the groin cranial to this point was made using electrocautery, and the subcutaneous tissues were dissected down using blunt-tip scissors. The femoral artery was exposed using blunt dissection, and a hemostatic ribbon was wrapped around the artery so the blood vessel was tightened to a certain ratio as needed to control the blood flow rate. The thrill sensor and the digital stethoscope were placed 1 cm proximal to the arterial anastomosis. The device operation protocol consisted of the synchronized thrill sensing and stethoscope auscultating step (10 s), and ultrasound step (300 s).

In the second situation, continuous stenosis was introduced by applying continuous finger pressure to the venous side and arterial side of the VA. The point of compression was 1 cm proximal to the arterial anastomosis. The thrill sensor and the digital stethoscope were placed 3 cm proximal to the arterial anastomosis. The device operation protocol consisted of the synchronized thrill sensing and stethoscope auscultating step (30 s), and ultrasound step (at the beginning and end of the continuous compression process).

In the third situation, PTA surgery was performed to repair a blocked VA. Over a 0.035-inch guidewire, a 6-8 millimeter mustang balloon dilatation catheter (Boston Scientific) was coaxially delivered to the VA vessel under fluoroscopic guidance. The thrill sensor was placed 3 cm proximal to the arterial anastomosis. The device operation protocol consisted of the thrill sensing step (10 s) and ultrasound step (300 s) at occlusion, half revascularization and full revascularization.

Thrill distribution mapping of canine’s VA. Each experiment to map the thrill distribution of canine’s VA was carried out at 10 monitoring points. Ten points were distributed uniformly along the VA, from the arterial anastomosis to the venous anastomosis. Each monitoring point is repeated 3 times to form a single measurement. At each monitoring point, the device operation protocol consisted of the thrill sensing step (10 s) and ultrasound step (300 s).

Inclusion and exclusion criteria in the human studies. The human studies were approved by the Institutional Review Board of Huashan Hospital (HIRB), Fudan University (No. 2025-1099). We performed the human study at Huashan Hospital, Fudan University between December 2024 and June 2025. All patients undergoing hemodialysis with arteriovenous graft (AVG) were eligible for the study. The only exclusion criterion was lack of informed consent. The following information was collected from 9 enrolled participants: age, self-reported gender, chief complaint and past history. Written informed consent was obtained from all participants, which included authorization for the publication of identifiable personal information. All participants received extra physical examination for free.

Thrill distribution mapping of the patient’s AVG. The thrill sensor and the digital stethoscope were epidermally adhered at 10 selected monitoring points over the patient’s AVG, and 10 points were distributed uniformly along the looped graft, from the arterial anastomosis to the venous anastomosis. Each monitoring point is repeated 3 times to form a single measurement. At each monitoring point, the device operation protocol consisted of the synchronized thrill sensing and stethoscope auscultating step (10 s), and ultrasound step (300 s).

Statistics and reproducibility. No statistical method was used to predetermine the sample size. No data were excluded from the analysis. There was no blinding in this study. This study employed three calibrated devices used interchangeably across each experiment without bias. Animal studies involved five canines, and human studies included nine patients.

Statistical validation. In vitro experiments, according to Fig. 3e, our claim is that abnormal VAs exhibit a significant reduction in thrill intensity compared to well-functioning VAs. The Welch’s t-test comparing the two groups’ thrill intensity (well-functioning VA: n = 4, μ = 2.365, σ = 0.035; abnormal VA: n = 4, μ = 1.490, σ = 0.485) was performed by SPSS software, with the null hypothesis (H₀): the abnormal VA’s mean had no significant reduction of the well-functioning VA. The result yields a significant difference (p = 0.018 < 0.05), thus rejecting H₀ and supporting our claim. In animal experiments, according to Fig. 5d, our claim is that abnormal VA (Canine 2) exhibits a significant reduction in thrill intensity compared to well-functioning VA (Canine 1). The Welch’s t-test comparing the two groups’ thrill intensity (well-functioning VA: n = 4, μ = 4.5958, σ = 1.070; abnormal VA: n = 4, μ = 0.2946, σ = 0.222) was performed, with the null hypothesis (H₀): the abnormal VA’s mean had no significant reduction of the well-functioning VA. The result yields a significant difference (p = 0.0015 < 0.05), thus rejecting H₀ and supporting our claim. In human studies, according to Fig. 7d, our claim is that dysfunctional VAs exhibit a >20% reduction in thrill intensity compared to well-functioning VAs. The Welch’s t-test comparing the two groups’ thrill intensity (well-functioning VA: n = 3, μ = 5.022, σ = 1.560; abnormal VA: n = 6, μ = 1.556, σ = 1.289) is performed, with the null hypothesis (H₀): the abnormal VA’s mean was ≥80% of the well-functioning group. The result yields a significant difference (p = 0.024 < 0.05), thus rejecting H₀ and supporting our claim.

Ethics. Every experiment involving animals, human participants, or clinical samples have been carried out following a protocol approved by an ethical commission. Each participant gave informed written consent. The first author, Y.W., consent to the publication of his photo (Fig. 1a) as an illustrative schematic diagram of the device placed on the arm.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "This manuscript presents a wireless, non-invasive thrill sensor for continuous vascular access (VA) monitoring in hemodialysis patients, addressing a significant clinical need for early detection of stenosis and VA failure. The study is well-structured, incorporating multi-platform validation (in vitro, canine models, and human trials) to demonstrate the sensor’s capability for high-resolution spatiotemporal mapping of VA thrill signals. The technology shows potential for transforming subjective palpation into objective hemodynamic phenotyping, aligning with Nature Communications’ scope for innovative, translational research with broad impact. However, the manuscript requires major revisions to enhance methodological clarity, statistical rigor, and clinical contextualization to meet the journal’s high standards.\n1.The dual-accelerometer design for motion-artifact cancellation is a key innovation, but the methodology lacks detail. Provide a quantitative analysis of motion-artifact suppression (e.g., signal-to-noise ratio comparisons with and without cancellation) and clarify how the auxiliary accelerometer’s data are processed to isolate thrill-specific signals.\n2.The study lacks statistical validation for key claims (e.g., thrill intensity reduction >20% in dysfunctional VA). Include statistical tests (e.g., t-tests, ANOVA) for comparisons between well-functioning and abnormal VA groups across all platforms (in vitro, canine, human). Specify sample sizes, p-values, and effect sizes to support reproducibility.\n3.While Doppler ultrasound is used as a reference, the manuscript does not quantitatively compare the sensor’s accuracy against clinical gold standards (e.g., sensitivity/specificity for stenosis detection). Add a receiver operating characteristic (ROC) analysis or Bland-Altman plots to validate diagnostic accuracy in human trials.\n4.The sensor’s performance over extended periods (e.g., hours/days) is not assessed. Include data on long-term stability, battery life under continuous operation, and robustness to environmental factors (e.g., temperature changes, sweat) to strengthen translational feasibility.\n5.Although spatial thrill mapping is demonstrated, the resolution (10×10 mm²) is not compared against clinical alternatives (e.g., ultrasound probe footprint). Quantify the spatial resolution’s impact on stenosis localization accuracy and discuss limitations for detecting small (<5 mm) lesions.\n6.The sensor distinguishes venous vs. arterial stenosis in vitro and in canines, but human data focus primarily on venous stenosis. Include examples of arterial stenosis in human trials and analyze whether thrill signatures differ significantly between stenosis types.\n7.The manuscript would benefit from a discussion of how the sensor would be integrated into existing clinical workflows (e.g., data interpretation protocols, alignment with current guidelines such as KDOQI) and cost-effectiveness compared to ultrasound.", "reviewer_2": "What are the noteworthy results? --> The study reveals an interesting method to non-invasively detect and quantify Vascular Access problems.\nWill the work be of significance to the field and related fields? --> YES.\nHow does it compare to the established literature? --> The work is original and well-documented in 3 stages: in-vitro lab bench model, in-vivo animal model and in-vivo human tests (n=9).\nIf the work is not original, please provide relevant references. --> NA.\nDoes the work support the conclusions and claims, or is additional evidence needed? --> Sufficient evidence.\nAre there any flaws in the data analysis, interpretation and conclusions? Only one minor thing: Please add \"(n=9)\" in the abstract, so that the extent of in-human data is clear. Do these prohibit publication or require revision? --> Adding the n=9 would suffice for me.\nIs the methodology sound? --> YES.\nDoes the work meet the expected standards in your field? --> YES.\nIs there enough detail provided in the methods for the work to be reproduced? --> YES.\nIt is very rare that I review such a well-written manuscript with only one minor text revision. BRAVO!", "reviewer_3": "The manuscript „Wireless, Non-invasive, High-resolution Thrill Sensor for Continuous Vascular Access Monitoring of Hemodialysis Patients“ describes a new technique dedicated for the surveillance of hemodialysis vascular access. It is based on a combination of high resolution accelerometers. The Authors present results of in vitro experiments, then in 2 dogs and in several patients on chronic hemodialysis.\nKey results\nThis is an interesting device that could bring new possibilities for adiagnoising vascular access stenoses and flow decline, especially for tele-diagnosis.\nHowever, this manuscript describes rather a case series, with no clear statistical comparison of already used methods, such as Doppler ultrasonography. The blood velocity waves change with the distance from anastomosis or with the shape of vein/graft. The flow depends not only on the anatomy, but also on the hydration status, heart failure etc.\n2 biomodels (dogs!) and a small group of patients are not sufficient for the validation of the new non-invasive device\nValidity\nThe device is adequately described, but only graphical comparison with other methods (ultrasound, stethoscope) is presented.\nAs this is a new non-invasive device, I would expect a detailed comparison in at least in dozens of patients, including the information of their stenosis (angiography, ultrasound) and flow.\nSignificance\nThe device could be clinically very useful, but this manuscript does not confirm it,\nData and methodology\nThe manuscript is extremely long, with many figures that show either the similar anatomy (dogs) or widely known facts of flow changes along a graft/vein.\nSome figures are complicatedb and their description is in the main text instead of a legend.\nAnalytical approach\nSee above.\nSuggested improvements\nI would recomment examining a group of patients with the new device and an established method in various scenarios: 1. pre- and post hemodialysis; 2. Known stenosis vs. normal fistula/graft; 3. Rest/movement of the patient; 4. Self attachment of the device by the patients.\nClarity and context\nThe manuscript is too long and complicated but it does not support the use of the new device adequately.\nReferences\nThe list of references is rather short when one looks at the length of the manuscript.", "reviewer_4": "Wireless, Non-invasive, High-resolution Thrill Sensor for Continuous Vascular 1 Access Monitoring of Hemodialysis Patients\nThe authors present a new innovation in the field of vascular access and monitoring of hemodialysis patients. The article is original and clearly articulates the pressing need for new technologies to improve outcomes for CDK-ESRD patients. The article presents a new type of wearable thrill detector to replace standard auscultation of auditory signals with a stethoscope, invented by Rene Laennec in 1816. The article compares standard techniques compared to the proposed wearable thrill detection in normal and failing AV access. The device compensates for everyday artefacts such as movement and shivering and was tested on the bench using a mock vascular circuit using various degrees of occlusion. Validation then turned to a preclinical model that paralleled existing technologies such as a digital stethoscope and could be compared with ultrasound doppler. However, despite showing that changes could be detected across the graft length there were less convincing elements when results were spatially mapped. The article manages to cover the gamut from bench testing, preclinical and then to include human studies which should be congratulated. They work confirms the relationship between thrill intensity and flow which is diminished on stenosis or ectasia. However, care should be taken as previous attempts at wearable detectors, despite achieving commercial success are less well tolerated by the end users, both clinician, nursing team and patient which surely limits their impact and future success.\nMajor concerns\n1. 80% of VA is in the form of fistulas and yet the authors direct their technology to 10-15% of AVGs without explanation – this needs to be addressed please and put in context of the VA field.\n2. Fig 6 – I am unsure how the thrill detection can be deconvoluted successfully between well functioning AVGs and abnormal VA data from the animal model. This data show a wide variation in the intensity drops across the in and outflow. Specifically, across the arterial to venous segments which show a 95% , 57%, 24% increases in normal grafts but a 70% increase, 60% decrease and 38% decrease in the abnormal AVGs. These changes, not withstanding that Canine 5 was measured at two different time points, Day 1 and Day 7 needs further explanation. Please expand on this apparent vsariation and include when were the other measures made for consistency please ?\nMinor\n• Pg 9 Ln72 “type stenosis 36” I assume is a non superscripted reference for correction.\n• Note. Other wearable devices have been attempted (see Alio) but gained less traction than expected. When used in practice they get in the way of the delivery of vascular access and are not favoured by patients or nursing staff – this should be considered."}, "author_response": "We sincerely thank the reviewer for the positive comments. Regarding the concern about the methodological clarity, statistical rigor, and clinical contextualization, we have included more comprehensive details in the point-by-point response below.\n1. The dual-accelerometer design for motion-artifact cancellation is a key innovation, but the methodology lacks detail. Provide a quantitative analysis of motion-artifact suppression (e.g., signal-to-noise ratio comparisons with and without cancellation) and clarify how the auxiliary accelerometer’s data are processed to isolate thrill-specific signals.\nResponse:\nWe sincerely thank the reviewer for this insightful comment. As suggested, a quantitative analysis of motion-artifact suppression (signal-to-noise ratio comparisons with and without cancellation) has been added in the revision. In details, the signal-to-noise ratio (SNR) of signal without our motion-artifact cancellation approach is -26.95 dB, while the SNR of signal with cancellation is increased to 9.65 dB. It demonstrates a significant 36.6 dB SNR improvement through our dual-accelerometer motion-artifact cancellation method.\nWe have included the comprehensive quantitative analysis of SNR in the revised manuscript and Supplementary Information.\nRevision:\n(Line 138~143, Results)\nThe thrill sensor recorded both the VA thrill with motion (pink lines, SNR = -26.95 dB) and arm movement (blue lines) simultaneously, and then subtracted these to eliminate motion artifacts, obtaining the real VA thrill signal (purple line, SNR = 9.65 dB). According to Supplementary Note 1, it demonstrates a significant 36.6 dB SNR improvement through our dual-accelerometer motion-artifact cancellation method, which establishes a robust foundation for more accurate VA thrill measurement.\n(Page 2, Supplementary Information)\nSupplementary Note 1 | Quantitative analysis of motion-artifact suppression.\nSignal 1 (S1: the thrill signal + motion artifacts) is the raw composite signal, Signal 2 (S2: motion artifacts) is the raw noise signal, and Signal 3 (S3: the thrill signal + residual noise) is the subtraction of Signal 2 from Signal 1.\nRaw signal of the thrill and motion artifacts\nNo. Time/s Signal 1 Signal 2 Signal 3\n1 25 0.94151 0.92570 0.01581\n2 25.001 0.95166 0.92570 0.02596\n3 25.002 0.89551 0.92072 -0.02521\n… … … … …\n15000 39.999 0.87991 0.87492 0.00499\n15001 40 0.90564 0.86695 0.03869\nMean Value 0.90422 0.90661 -0.00239\nMean Square Value 0.82000 0.82267 0.00185\nThis analysis is based on three key assumptions: (1) the thrill signal (S) and motion artifacts (N) are statistically independent (Cov(S,N)=0); (2) mean of the thrill signal is approximately zero (μ_S≈0), supported by S3's small mean (-0.00239); (3) residual noise primarily reflects imperfect motion subtraction rather than new noise sources.\nFor Signal 1, the total signal power as the variance:\nVar(S1) = Mean Square Value(S1) - Mean(S1)² = 0.82000 - (0.90422)² ≈ 0.00239 (1)\nSimilarly, the motion artifact power is derived from Signal 2:\nVar(S2) = 0.82267 – (0.90661)² ≈ 0.00073 (2)\nThe estimated thrill signal power is then obtained by subtraction under the independence assumption:\nVar(thrill) ≈ Var(S1) – Var(S2) ≈ 0.00166 (3)\nTherefore, the signal-to-noise ratio without cancellation (SNR1) is calculated by this formula:\nSNR1=10*log(thrill signal power/motion artifact power)=10*log(0.00166/0.82267)≈-26.95 dB (4)\nAfter motion cancellation (Signal 3 = Signal 1 – Signal 2), the signal power of Signal 3 is:\nVar(S3) = 0.00185 - (-0.00239)² ≈ 0.00184 (5)\nThe estimated residual noise power is:\nVar(residual noise) = Var(S3) – Var(thrill) ≈ 0.00018 (6)\nTherefore, the signal-to-noise ratio with cancellation (SNR3) is calculated by this formula:\nSNR3 = 10*log(thrill signal power/residual noise power) = 10*log(0.00166/0.00018)≈9.65 dB (7)\nThus, it demonstrates a significant 36.6 dB SNR improvement through our dual-accelerometer cancellation method.\nThe auxiliary accelerometer data (Signal 2) was processed through: (1) temporal synchronization with the primary sensor using cross-correlation; (2) amplitude scaling and direct subtraction (S3=S1-S2). The residual noise primarily arises from minor nonlinearities in motion artifact transfer between sensors and slight timing misalignments.\n2. The study lacks statistical validation for key claims (e.g., thrill intensity reduction >20% in dysfunctional VA). Include statistical tests (e.g., t-tests, ANOVA) for comparisons between well-functioning and abnormal VA groups across all platforms (in vitro, canine, human). Specify sample sizes, p-values, and effect sizes to support reproducibility.\nResponse:\nWe sincerely thank the reviewer for the valuable feedback. As suggested, statistical t-tests for comparisons between well-functioning and abnormal VA groups across all platforms (in vitro, canine, human) have been added in the revision.\nIn vitro experiments, according to Fig. 3e, our claim is that abnormal VA exhibit a significant reduction in thrill intensity compared to well-functioning VA. We perform a Welch’s t-test comparing the two groups’ thrill intensity (well-functioning VA: n=4, μ=2.365, σ=0.035; abnormal VA: n=4, μ=1.490, σ=0.485), with the null hypothesis (H₀): the abnormal VA’s mean has no significant reduction of the well-functioning VA’s. The result from SPSS software yields a significant difference (t = 3.598, df = 3.031, p = 0.018 < 0.05, one-tailed) with large effect size (Cohen’s d = 2.544), thus rejecting H₀ and supporting our claim.\nIn animal experiments, according to Fig. 5d, our claim is that abnormal VA (Canine 2) exhibit a significant reduction in thrill intensity compared to well-functioning VA (Canine 1). We perform a Welch’s t-test comparing the two groups’ thrill intensity (well-functioning VA: n=4, μ=4.5958, σ=1.070; abnormal VA: n=4, μ=0.2946, σ=0.222), with the null hypothesis (H₀): the abnormal VA’s mean has no significant reduction of the well-functioning VA’s. The result from SPSS software yields a significant difference (t = 7.873, df = 3.258, p = 0.0015 < 0.05, one-tailed) with large effect size (Cohen’s d = 5.567), thus rejecting H₀ and supporting our claim.\nIn human trials, according to Fig. 7d, our claim is that dysfunctional VAs exhibit a >20% reduction in thrill intensity compared to well-functioning VAs. We perform a Welch’s t-test comparing the two groups’ thrill intensity (well-functioning VA: n=3, μ=5.022, σ=1.560; abnormal VA: n=6, μ=1.556, σ=1.289), with the null hypothesis (H₀): the abnormal VA’s mean is ≥80% of the well-functioning group’s. The result from SPSS software yields a significant difference (t = 2.758, df = 4.222, p = 0.024 < 0.05, one-tailed) with large effect size (Cohen’s d = 1.927), thus rejecting H₀ and supporting our claim.\nRevision:\n(Line 184~186, Results)\nThe thrill intensity gradually decreased with the increase of the stenosis level, and stenosis VA exhibit a significant reduction in thrill intensity compared to non-stenosis VA (n = 4, t = 3.598, df = 3.031, p = 0.018 < 0.05, Cohen’s d = 2.544, one-tailed Welch’s t-test, see Methods).\n(Line 249~251, Results)\nThe abnormal VA exhibit a significant reduction in thrill intensity compared to well-functioning VA (n = 4, t = 7.873, df = 3.258, p = 0.0015 < 0.05, Cohen’s d = 5.567, one-tailed Welch’s t-test, see Methods).\n(Line 326~329, Results)\nAccording to Figure 7d, their thill intensity exhibits a reduction of more than 20% in comparison with the well-functioning AVGs (n=6, t = 2.758, df = 4.222, p = 0.024 < 0.05, Cohen’s d = 1.927, one-tailed Welch’s t-test, see Methods).\n(Line 521~538, Methods)\nStatistical validation. In vitro experiments, according to Fig. 3e, our claim is that abnormal VA exhibit a significant reduction in thrill intensity compared to well-functioning VA. The Welch’s t-test comparing the two groups’ thrill intensity (well-functioning VA: n=4, μ=2.365, σ=0.035; abnormal VA: n=4, μ=1.490, σ=0.485) is performed by SPSS software, with the null hypothesis (H₀): the abnormal VA’s mean has no significant reduction of the well-functioning VA’s. The result yields a significant difference (p = 0.018 < 0.05), thus rejecting H₀ and supporting our claim. In animal experiments, according to Fig. 5d, our claim is that abnormal VA (Canine 2) exhibit a significant reduction in thrill intensity compared to well-functioning VA (Canine 1). The Welch’s t-test comparing the two groups’ thrill intensity (well-functioning VA: n=4, μ=4.5958, σ =1.070; abnormal VA: n=4, μ=0.2946, σ=0.222) is performed, with the null hypothesis (H₀): the abnormal VA’s mean has no significant reduction of the well-functioning VA’s. The result yields a significant difference (p = 0.0015 < 0.05), thus rejecting H₀ and supporting our claim. In human trials, according to Fig. 7d, our claim is that dysfunctional VAs exhibit a >20% reduction in thrill intensity compared to well-functioning VAs. The Welch’s t-test comparing the two groups’ thrill intensity (well-functioning VA: n=3, μ=5.022, σ=1.560; abnormal VA: n=6, μ =1.556, σ=1.289) is performed, with the null hypothesis (H₀): the abnormal VA’s mean is ≥80% of the well-functioning group’s. The result yields a significant difference (p = 0.024 < 0.05), thus rejecting H₀ and supporting our claim.\n3. While Doppler ultrasound is used as a reference, the manuscript does not quantitatively compare the sensor’s accuracy against clinical gold standards (e.g., sensitivity/specificity for stenosis detection). Add a receiver operating characteristic (ROC) analysis or Bland-Altman plots to validate diagnostic accuracy in human trials.\nResponse:\nWe sincerely thank the reviewer for their insightful comments. As suggested, Bland-Altman plots for validating diagnostic accuracy between our thrill sensor and clinical gold standards (e.g., Doppler ultrasound) in human trials have been added in the revision.\nFor original manuscript, we would like to respectfully explain the reason of not including quantitative accuracy comparison, which is, our thrill sensor measures vibrational signals, while Doppler ultrasound provides vessel flow rates - two distinct physiological parameters both reflect VA health condition, but their different dimensions make direct comparisons challenging.\nIn the revised manuscript, to facilitate meaningful comparison, we have normalized the thrill intensity and flow rate measurements (mL/min) to dimensionless quantities, and divided the analysis into two groups according to the separate correlation in Fig. 7g: well-functioning VAs (n=3) and abnormal VAs with stenosis (n=4).\nAs shown in newly added Supplementary Fig. 48(a) below, In the 3 patients with well-functioning VAs (flow rate: 768–1088 mL/min; thrill intensity: 3.57–6.67), the normalized Bland-Altman analysis shows a slightly higher mean bias (0.086) but still within clinically acceptable LoA (−0.20654 to 0.37902).\nAs shown in newly added Supplementary Fig. 48(b) below, in the 4 patients with abnormal VAs (flow rate: 626–1384 mL/min; thrill intensity: 1.28–3.55), the normalized Bland-Altman analysis reveals a mean bias of 0.00119 with narrow limits of agreement (LoA: −0.05759 to 0.05997), indicating a good agreement.\nWhile ROC analysis for stenosis detection requires a larger cohort, our Bland-Altman results demonstrate the sensor’s potential to discriminate stenosis characteristics (comparable reduced thrill intensity and flow rate at stenosis). Currently, we are conducting a larger-scale study involving real-time data collection from hemodialysis patients to more comprehensively compare the sensor's accuracy against clinical gold standards, and we will report these findings in future works.\nRevision:\n(Line 348~349, Results)\nAccording to Supplementary Figure 48, the Bland-Altman plots demonstrate the comparability between normalized thrill intensity and dimensionless blood flow rate.\n(Page 50, Supplementary Information)\nSupplementary Fig. 48 | Bland-Altman analysis of normalized thrill intensity and blood flow rate in patients with (a) well-functioning VAs, (b) abnormal VAs.\n4. The sensor’s performance over extended periods (e.g., hours/days) is not assessed. Include data on long-term stability, battery life under continuous operation, and robustness to environmental factors (e.g., temperature changes, sweat) to strengthen translational feasibility.\nResponse:\nWe would like to thank the reviewer for the detailed feedback. As suggested, the sensor’s performance over extended periods has been supplemented to the revised manuscript, including long-term human measurements, environmental robustness tests, battery life tests as well as related descriptions.\nIn terms of the long-term stability evaluation of our thrill sensor, we have included a patient monitoring case between the 6-month period as shown in Supplementary Fig. 5. On May 11, 2025 (two weeks post-percutaneous transluminal angioplasty, PTA), we performed thrill measurements on his repaired VA. When he was re-hospitalized 6 months later for recurrent venous stenosis, the same device demonstrated maintained measurement accuracy and stability upon repeated thrill monitoring. Throughout our study, merely two thrill sensors are reused, demonstrating consistent stability across all experimental conditions - including tests in 5 canines and 11 patients over an extended 1.5-year monitoring period (from June 2024 to November 2025). This robust performance primarily stems from our device design philosophy, where we prioritized translational potential and high stability by incorporating commercially available, mature components for all critical elements, including main and auxiliary accelerometers.\nIn terms of the environmental robustness of our thrill sensor, as suggested, we added the performance evaluation of the sensor under temperature changes and sweating conditions, as can be seen in newly added Supplementary Fig. 11 below. Specifically, we have measured carotid artery pulses in a healthy man while modulating neck skin temperature using a heating therapy lamp. The results demonstrate that our sensor consistently detects stable carotid pulses across three distinct phases: (1) baseline (20–23 s, unheated), (2) post-heating onset (120–123 s), and (3) during pronounced sweating (220–223 s). In each 3-s interval, the sensor records 4 pulses, aligning with the subject’s stable heart rate of 80 bpm. These findings confirm the sensor’s robustness to temperature fluctuations and sweat interference.\nIn terms of the battery life of our thrill sensor, as suggested, we added the battery evaluation. The battery life under continuous operation is 50 minutes, which is measured via wireless communication based on Bluetooth Low Energy (BLE) mode, as shown in newly added Supplementary Fig. 10 below.\nRevision:\n(Line 111~113, Results)\nAlso, comparison between two groups of distinct thrill signals reveals: (i) the recovery of thrill signal after percutaneous transluminal angioplasty (PTA) surgery of venous anastomosis stenosis (Fig. 1g, Supplementary Fig. 5, Supplementary Movie 1 and 2).\n(Line 125~129, Results)\nIn addition, powered by a Li-ion battery (UFX351525, 90 mAh, 4.2 V), the thrill sensor's low power consumption (1600 Hz sampling mode and Bluetooth Low Energy mode) enables 50 minutes of continuous monitoring and wireless data transmitting (Supplementary Fig. 10, and see Methods for detailed information on system design and preparation).\n(Line 132~134, Results)\nFurther environmental robustness testing under skin temperature variations (36 – 46°C) and sweating conditions confirmed stable pulse detection (see Supplementary Fig. 11).\n(Page 7, Supplementary Information)\nSupplementary Fig. 5 | Longitudinal monitoring of thrill variations in a patient with recurrent venous anastomosis stenosis. On May 11, 2025 (two weeks post-percutaneous transluminal angioplasty, PTA), ultrasound and angiography revealed residual stenosis, and the arterial anastomosis (P1) exhibited a pulsatile-high-frequency hybrid thrill, while the venous anastomosis (P3) demonstrated an even stronger thrill due to the Venturi effect induced by residual stenosis. After 6 months, on the morning of November 3, 2025, the patient was hospitalized for recurrent venous stenosis. Imaging confirmed significant restenosis, coinciding with loss of high-frequency vibrations at P1 (purely arterial pulse) and a further intensified thrill at P3, attributable to exacerbated Venturi effects from the narrowed vessel. After repeat PTA surgery that afternoon, successful dilatation was angiographically confirmed. The thrill at P1 reverted to the hybrid pulsatile-high-frequency characteristic, while the thrill at P3 weakened as the Venturi effect diminished with improved vessel patency.\n(Page 12, Supplementary Information)\nSupplementary Fig. 10 | Battery life of the thrill sensor under continuous operation on Bluetooth Low Energy (BLE) mode.\n(Page 13, Supplementary Information)\nSupplementary Fig. 11 | Performance of the thrill sensor under temperature changes and sweating conditions, measuring carotid artery pulse in a healthy man. Experimental parameters: ambient temperature (23°C); heating initiates at 60 s (neck skin temperature: 36°C); by 160 s, the skin temperature reached 46°C with observable sweating, and measurement continues for an additional 100 s.\n5. Although spatial thrill mapping is demonstrated, the resolution (10×10 mm²) is not compared against clinical alternatives (e.g., ultrasound probe footprint). Quantify the spatial resolution’s impact on stenosis localization accuracy and discuss limitations for detecting small (<5 mm) lesions.\nResponse:\nWe sincerely thank the reviewer for raising this insightful and critical point regarding spatial resolution and its implications for stenosis localization accuracy. We appreciate the opportunity to clarify these aspects. We fully acknowledge that the spatial resolution of our thrill sensor (10×10 mm²) is fundamentally different from that of ultrasound, which provides high-resolution 3D visualization of blood vessels, enabling precise localization of stenosis within its larger detection area (typically 40 mm in length). Importantly, while ultrasound excels in anatomical mapping, its large probe footprint (40 mm) inherently limits portability and continuous monitoring, which are key advantages of our compact, wearable thrill sensor. Our sensor’s 10×10 mm² resolution refers to its ability to detect abnormal vibrational signatures averaged over that area, rather than pinpointing the exact position of sub-resolution lesions (<5 mm) within the sensing zone.\nIn practical terms, if a stenosis smaller than 10 mm causes a measurable change in local thrill intensity, our sensor can flag its presence—but unlike ultrasound, it cannot visually distinguish whether the lesion is centered or offset within the detection area. However, this limitation must be weighed against the sensor’s unique benefits: its small form factor enables high-density spatial mapping (e.g., 4× finer sampling over a 40 mm span compared to a single ultrasound scan), wearability for prolonged monitoring, and rapid assessment without requiring the patient to remain perfectly still. These features make it suitable for early-stage screening and longitudinal tracking in outpatient or home settings, where ultrasound is impractical due to cost, size, and operator dependency.\nFurthermore, while ultrasound provides superior resolution for small lesions, its diagnostic utility in arteriovenous grafts (AVGs) is often constrained by user variability and difficulty in continuous assessment. Our sensor complements—rather than competes with—ultrasound by offering a low-cost, real-time warning system for hemodynamic changes that may indicate stenosis, even if absolute localization of lesions requires secondary confirmation.\nRevision:\n(Line 266~277, Results)\nTherefore, quantitative measurement and continuous monitoring of thrill distribution along the AVG are critically important for early stenosis detection. However, current clinical tools face inherent limitations when measuring thrill distribution: ultrasound probes, despite their high-resolution 3D imaging capability, have a large detection footprint (typically ~40 mm in length), which restricts portability and continuous monitoring, while commercial stethoscopes also have bulky auscultation heads (6–8 times the graft diameter, Supplementary Fig. 23). In contrast, the thrill sensor's design incorporates a compact detecting area, capable of measurement within a 10×10 mm2 area, which enables measurement of thrill distribution along the AVG. Although this resolution cannot pinpoint and image sub-5 mm lesions with ultrasound-level precision, it can detect localized abnormal vibration intensity averaged over the 10×10 mm² area. Such distributed monitoring offers potential for pinpointing approximate location of stenosis, assessing overall VA health condition and complementing existing modalities.\n6. The sensor distinguishes venous vs. arterial stenosis in vitro and in canines, but human data focus primarily on venous stenosis. Include examples of arterial stenosis in human trials and analyze whether thrill signatures differ significantly between stenosis types.\nResponse:\nWe sincerely thank the reviewer for the valuable suggestion. As suggested, we have supplemented the example of arterial stenosis in human trials and analyzed the thrill differences between the two distinct stenosis types.\nAs shown in revised Fig. 1h and newly added Supplementary Fig. 6 below, a comparison between the two thrill signals reveals the emergence of pulse signal at venous stenosis, whereas this phenomenon does not exist in the arterial stenosis. These results are consistent with the findings obtained from in vitro experiments via the benchtop system and the animal experiment.\nRevision:\n(Line 111~118, Results)\nAlso, comparison between two groups of distinct thrill signals reveals: (i) the recovery of thrill signal after percutaneous transluminal angioplasty (PTA) surgery of venous anastomosis stenosis (Fig. 1g, Supplementary Fig. 5, Supplementary Movie 1 and 2); (ii) the emergence of pulse signal at venous anastomosis stenosis, whereas this phenomenon does not exist in the arterial puncture-site stenosis (Fig. 1h and Supplementary Fig. 6); (iii) the change of thrill signal in a normal VA patient pre/post-hemodialysis (Supplementary Fig. 7); (iv) the comparison of thrill measurement results between patient self-attachment and doctor-attachment of the thrill sensor (Supplementary Fig. 8 and Supplementary Movie 3).\nRevised Figure 1g-h | The thrill sensor for continuous monitoring vascular access (VA) health condition. g Comparison of thrill signals before and after percutaneous transluminal angioplasty (PTA) surgery for venous anastomosis stenosis: pre-PTA, only a pulse-like vibration; post-PTA, thrill signal recovery. h Distinct thrill signatures in different stenosis locations: venous anastomosis stenosis, prominent pulse signal; arterial puncture-site stenosis: weakened thrill without pulse.\n(Page 8, Supplementary Information)\nSupplementary Fig. 6 | Comparison of thrill signals between venous and arterial stenosis in a human patient, which reveals the emergence of pulse signal at venous stenosis, whereas this phenomenon does not exist in the arterial stenosis.\n7. The manuscript would benefit from a discussion of how the sensor would be integrated into existing clinical workflows (e.g., data interpretation protocols, alignment with current guidelines such as KDOQI) and cost-effectiveness compared to ultrasound.\nResponse:\nWe sincerely thank the reviewer for the constructive comment. While the primary focus of our current study is on quantitating the thrill intensity of vascular access, we fully acknowledge the reviewer’s important observation regarding the integration into existing clinical workflows and cost-effectiveness compared to ultrasound. This is a crucial perspective for translating our research into practice, and we are pleased to elaborate on these points.\nAs highlighted in the KDOQI 2019 guidelines (Guideline 13.2), regular physical examination by experienced practitioners is recommended for AVG monitoring, while routine surveillance using blood flow measurement or imaging (Guideline 13.5) and pre-emptive angioplasty (Guideline 13.7) are not suggested. Our thrill sensor bridges the gap between manual examination and instrumental surveillance—offering higher precision than physical checks (with quantitative, real-time thrill signal monitoring) while being more accessible and cost-effective than ultrasound.\nFor data interpretation protocols, the sensor's output is designed to align with clinical workflows: (1) Thrill signals are synchronized with ECG for temporal correlation (Fig. 1), (2) distributed thrill monitoring at multiple points (Fig. 6) enables stenosis localization, and (3) dynamic response tracking (Fig. 4) aids in trend analysis. Thresholds for abnormal signals can be established based on baseline measurements from well-functioning VAs (Fig. 7), with alerts triggered for deviations.\nRegarding cost-effectiveness, the sensor’s compact size (30 × 15 × 5 mm³) and lightweight design (~20 g) reduce manufacturing costs compared to bulkier ultrasound probes. Its wireless operation eliminates the need for specialized training or ancillary equipment (e.g., gel, transducers), lowering operational expenses. While ultrasound requires dedicated sessions with trained technicians, our sensor permits continuous, patient-friendly monitoring—potentially reducing missed diagnoses and unnecessary referrals for imaging (aligning with KDOQI Guideline 13.5’s caution against routine instrumental surveillance).\nWe have expanded these points in Discussion to clarify the sensor’s integration into clinical practice.\nRevision:\n(Line 374~385, Discussion)\nClinically, this approach converts subjective palpation into objective hemodynamic phenotyping, enabling continuous surveillance of thrill-flow coupling and earlier detection of functional decline or focal stenosis. The technology aligns with KDOQI 2019 guidelines (Section 13.2, 13.5, 13.7) by bridging the gap between manual examination and instrumental surveillance—offering quantitative results while avoiding unnecessary routine imaging. Its integration into clinical workflows is streamlined through ECG-synchronized thrill signal analysis for temporal correlation, multi-point monitoring for stenosis localization, and dynamic trend tracking with VA health condition. The sensor’s potential extends to (i) alerting patients and clinicians to impending dysfunction before critical flow loss, (ii) guiding targeted imaging or intervention to the lesion site, and (iii) reducing unnecessary whole graft revisions and associated morbidity. Further clinical validation and testing may lead to broad adoption in expanded patient cohorts with diverse VA types and situation.\nReviewer #2 (Remarks to the Author):\nWhat are the noteworthy results? --> The study reveals an interesting method to non-invasively detect and quantify Vascular Access problems.\nWill the work be of significance to the field and related fields? --> YES.\nHow does it compare to the established literature? --> The work is original and well-documented in 3 stages: in-vitro lab bench model, in-vivo animal model and in-vivo human tests (n=9).\nIf the work is not original, please provide relevant references. --> NA.\nDoes the work support the conclusions and claims, or is additional evidence needed? --> Sufficient evidence.\nAre there any flaws in the data analysis, interpretation and conclusions? Only one minor thing: Please add \"(n=9)\" in the abstract, so that the extent of in-human data is clear. Do these prohibit publication or require revision? --> Adding the n=9 would suffice for me.\nIs the methodology sound? --> YES.\nDoes the work meet the expected standards in your field? --> YES.\nIs there enough detail provided in the methods for the work to be reproduced? --> YES.\nIt is very rare that I review such a well-written manuscript with only one minor text revision. BRAVO!\nResponse:\nWe sincerely thank the reviewer for the positive comments and we are sorry for the lack of clarity regarding the missing number of in-vivo human tests in the abstract part of the original manuscript.\nRevision:\n(Line 23 ~ 27, Abstract)\nHere, we report wireless, non-invasive thrill sensors incorporating high-resolution accelerometers designed to be conformally placed on VA skin for the continuous monitoring of VA thrill signals, which we tested in multi-platform validation including in vitro benchtop system, canine models and patients (n=9).\nReviewer #3 (Remarks to the Author):\nThe manuscript “Wireless, Non-invasive, High-resolution Thrill Sensor for Continuous Vascular Access Monitoring of Hemodialysis Patients” describes a new technique dedicated for the surveillance of hemodialysis vascular access. It is based on a combination of high resolution accelerometers. The Authors present results of in vitro experiments, then in 2 dogs and in several patients on chronic hemodialysis.\nResponse:\nWe sincerely thank the reviewer for the time involved in reviewing the manuscript and appreciate the valuable comments. In this study, we have performed animal experiments on 5 canines covering different representative cases and conducted clinical trials involving 11 patients. Our original manuscript contained unclear descriptions of these experiments, which may have caused confusion for reviewers. In the revised manuscript, we have made corresponding modifications (as detailed in the following responses) to ensure more precise presentation of our research.\nKey results:\nThis is an interesting device that could bring new possibilities for diagnosing vascular access stenoses and flow decline, especially for tele-diagnosis.\nHowever, this manuscript describes rather a case series, with no clear statistical comparison of already used methods, such as Doppler ultrasonography.\nResponse:\nWe sincerely thank the reviewer for recognizing the potential of our newly developed thrill sensor in tele-diagnosis for vascular access (VA) monitoring. As suggested, Bland-Altman plots for statistical comparison of Doppler ultrasonography in human trials have been added in the revision.\nFor original manuscript, we would like to respectfully explain the reason of not including statistical comparison, which is, our thrill sensor measures vibrational signals, while Doppler ultrasonography provides vessel flow rates - two distinct physiological parameters both reflect VA health condition, but their different dimensions make direct comparisons challenging.\nIn the revised manuscript, to facilitate meaningful comparison, we have normalized the thrill intensity and flow rate measurements (mL/min) to dimensionless quantities, and divided the analysis into two groups according to the separate correlation in Fig. 7g: well-functioning VAs (n=3) and abnormal VAs (n=4).\nAs shown in newly added Supplementary Fig. 48(a) below, In the 3 patients with well-functioning VAs (flow rate: 768–1088 mL/min; thrill intensity: 3.57–6.67), the normalized Bland-Altman analysis shows a slightly higher mean bias (0.086) but still within clinically acceptable LoA (−0.20654 to 0.37902).\nAs shown in newly added Supplementary Fig. 48(b) below, in the 4 patients with abnormal VAs (flow rate: 626–1384 mL/min; thrill intensity: 1.28–3.55), the normalized Bland-Altman analysis reveals a mean bias of 0.00119 with narrow limits of agreement (LoA: −0.05759 to 0.05997), indicating a good agreement.\nThe Bland-Altman results demonstrate the sensor ’ s potential to discriminate stenosis characteristics (comparable reduced thrill intensity and flow rate at stenosis). Currently, we are conducting a larger-scale study involving real-time data collection from hemodialysis patients to more comprehensively compare the sensor's accuracy against clinical gold standards, and we will report these findings in future works.\nRevision:\n(Line 348~349, Results)\nAccording to Supplementary Figure 48, the Bland-Altman plots demonstrate the comparability between normalized thrill intensity and dimensionless blood flow rate.\n(Page 50, Supplementary Information)\nSupplementary Fig. 48 | Bland-Altman analysis of normalized thrill intensity and blood flow rate in patients with (a) well-functioning VAs, (b) abnormal VAs.\nThe blood velocity waves change with the distance from anastomosis or with the shape of vein/graft. The flow depends not only on the anatomy, but also on the hydration status, heart failure etc.\nResponse:\nWe sincerely thank the reviewer for raising this important point. We completely agree that both anatomical and physiological factors will influence blood velocity waves and thrill intensity in vascular access. Currently, we are conducting follow-up studies focusing on continuous and long-term monitoring in different hemodialysis patients, specifically investigating how these physiological factors (hydration status, heart failure etc.) may affect thrill characteristics. These important clinical correlations will be systematically analyzed and reported in our future work.\n2 biomodels (dogs!) and a small group of patients are not sufficient for the validation of the new non-invasive device.\nResponse:\nWe sincerely apologize for any confusion caused by our initial description of the animal experiments. While we firstly present 2 representative canine cases (1 well-functioning and 1 post-PTA repaired AVG) in Figure 4 to illustrate the sensor's stenosis detection capability, we should have made it clearer that the complete study actually involved 5 canine models in total. The additional 3 dogs (2 well-functioning and 1 newly implanted) are used for validating thrill mapping along the AVG as shown in Figure 6.\nSimilarly, we have now expanded our clinical cohort from the original 9 patients to 11 patients, including pre/post-PTA thrill monitoring of a recurrent venous stenosis patient, a new arterial puncture-site stenosis patient, and a normal hemodialysis patient. The complete details of 5 canines and all patients have been thoroughly documented in the revised manuscript and Supplementary Information.\nRevision:\n(Line 198 ~ 199, Results)\nThe animal experiments were performed on 5 canine models to verify the adaptability of the thrill sensor in real scenarios (Fig. 4-6, Supplementary Fig. 17 and 18).\n(Line 449 ~ 451, Methods)\nA 4-year-old male Labrador dog (Canine 5: 4 year/26 kg) from Weifang Shengnuo Ex-perimental Animal Breeding Co., Ltd. was used for experiments of newly implanted VA.\nValidity:\nThe device is adequately described, but only graphical comparison with other methods (ultrasound, stethoscope) is presented.\nAs this is a new non-invasive device, I would expect a detailed comparison in at least in dozens of patients, including the information of their stenosis (angiography, ultrasound) and flow.\nResponse:\nWe sincerely thank the reviewer for highlighting the importance of rigorous validation. We admit that our thrill sensor and other methods (ultrasound, stethoscope) measure different parameters (vibration signals vs. flow/audio characteristics) which reflect VA health condition through distinct mechanisms, making direct quantitative comparisons challenging without larger sample sizes.\nPreviously, we have 9 patients (3 with well-functioning AVGs, 3 with residual stenosis at the AVGs’ venous anastomosis, 3 with irregular lesion inside AVGs) in the original manuscript. And now we have supplemented our dataset with 1 arterial puncture-site stenosis patient and 1 normal hemodialysis patient, bringing our total patient cohort to 11 cases.\nWhile this remains a pilot-scale study primarily aimed at demonstrating the sensor's basic functionality for VA monitoring, we have included all available patient details (including angiography images, ultrasound images, and Doppler flow measurements) in the Supplementary Information. A comprehensive statistical comparison with gold-standard methods will indeed require future large-scale clinical trials involving dozens of patients - a critical next step we are actively undertaking, where we will systematically correlate our thrill sensor outputs with ultrasound/angiography/stethoscope findings across diverse stenosis conditions and report in future works.\nSignificance:\nThe device could be clinically very useful, but this manuscript does not confirm it.\nResponse:\nWe sincerely appreciate the reviewer's recognition of our device's potential clinical utility, and agree that this pilot study alone cannot fully confirm its diagnostic significance. As this represents the first translational validation of a fundamentally new sensing modality (high-resolution thrill monitoring) for vascular access surveillance, our current work primarily establishes technical feasibility through: 1) controlled in-vitro experiments validating measurement principles, 2) canine studies demonstrating anatomical correlations, and 3) initial human testing showing detectable signal differences between normal and stenotic VAs. While we have now expanded our clinical dataset to 11 patients, we completely agree that broader multicenter trials with longitudinal outcome data will be essential to conclusively demonstrate clinical impact - particularly for detecting stenosis progression and predicting adverse events. These critical next steps are already being planned as part of our device development roadmap, building upon the foundational evidence presented in this manuscript.\nData and methodology:\nThe manuscript is extremely long, with many figures that show either the similar anatomy (dogs) or widely known facts of flow changes along a graft/vein.\nSome figures are complicated and their description is in the main text instead of a legend.\nAnalytical approach:\nSee above.\nResponse:\nWe sincerely thank the reviewer for these valuable suggestions to improve our manuscript's clarity and conciseness. In direct response to these concerns, we have:\n(1) substantially revised Figure 4 by removing redundant canine anatomy images while retaining only the most clinically relevant ultrasound flow information;\n(2) maintained Figure 6's demonstration of quantitative thrill signal variations along 10 measuring points - which to our knowledge represents the first quantitative mapping of “the widely known facts of thrill changes along a graft” that was previously only subjectively assessed through palpation by experienced clinicians;\n(3) completely rewritten all figure legends to ensure they now contain fully self-contained descriptions with improved clarity.\nThese changes have reduced redundancy while preserving the innovative aspects of our methodology that advance beyond conventional qualitative assessments.\nRevision:\n(The legend of Figure 1 to Figure 7)\nFig 1 | The thrill sensor for continuous monitoring vascular access (VA) health condition. a Schematic illustration of a patient with vascular access (VA) in the forearm, equipped with a wireless thrill sensor. b Schematic of well-functioning VA and its corresponding high-frequency, broadband thrill acceleration signal. c Schematic of early-stage stenosis in VA, resulting in reduced-amplitude, more irregular thrill signal. d Schematic of advanced-stage stenosis in VA, resulting in markedly diminished thrill signal. e Simultaneous recordings from a canine model with well-functioning VA, VA thrill acceleration by the thrill sensor, VA thrill sound by a commercial digital stethoscope, and VA pleth by an ECG monitor. f Continuous monitoring of VA thrill changes during dynamic movement: a patient gradually raises his arm from 0° to 90°. g Comparison of thrill signals before and after percutaneous transluminal angioplasty (PTA) surgery for venous anastomosis stenosis: pre-PTA, only a pulse-like vibration; post-PTA, thrill signal recovery. h Distinct thrill signatures in different stenosis locations: venous anastomosis stenosis, prominent pulse signal; arterial puncture-site stenosis: weakened thrill without pulse.\nFig 2 | Details of the thrill sensor design and the fundamental monitoring results. a Top view of the unencapsulated thrill sensor holds between the thumb and index finger, with a schematic of its electronic system structure. b Carotid pulse signals measured by the thrill sensor in a healthy male subject under different physiological conditions: sitting, speaking, and walking. c Simultaneous recording of VA thrill and motion artifacts in a male patient with a well-functioning VA. The raw signal (pink) contains both the VA thrill and limb motion (blue), and the real thrill signal (purple) is isolated after applying motion-artifact cancellation method. d Schematic decomposition of the real thrill signal from a well-functioning VA. The signal is composed of two components: the arterial pulse, which contributes to the overall amplitude, and the high-frequency, weak vibration which is responsible for the rapid fluctuations.\nFig 3 | Performance of the thrill sensor on the in vitro benchtop system. a Schematic of the VA benchtop system, illustrating the principle and components. b Schematic of the measurement point and stenosis positions on the mimic VA. Stenosis is induced by inserting PTFE cylindrical tubes into the vein (blue) or artery (red) section of the mimic VA to simulate venous and arterial stenosis, respectively. c Time-domain signals of the VA thrill acceleration for a well-functioning VA (0% stenosis) and a dysfunctional VA (60% stenosis). The amplitude of the thrill signal is significantly reduced in the stenotic condition. d Spectrograms of the VA thrill signal for a well-functioning VA and a dysfunctional VA. The characteristic center frequency shifts from 200 Hz to 40 Hz, indicating a reduction of high-frequency thrill. e Thrill intensity as a function of stenosis degree. The thrill intensity decreases progressively with increasing stenosis, showing a significant reduction at advanced stages (>50%). f Spectrogram and time-domain signal of the VA thrill in severe vein stenosis. The prominent 1–2 Hz spike corresponds to the emergence of an arterial pulse signal. g Spectrogram and time-domain signal of the VA thrill in severe artery stenosis, with no emergence of the pulse.\nFig 4 | Animal application of the thrill sensor and VA stenosis assessment. a Schematic of the animal model and the sensor placement. b Comparison of the VA thrill signal (purple) and the normal artery pulse signal (red) recorded simultaneously from the same canine, showing the VA thrill as a high-frequency vibration superimposed on the arterial pulse. The spectrogram reveals a characteristic frequency band of 100–200 Hz for VA thrill. c Results from Canine 1 with a well-functioning VA (AVG). The thrill sensor and commercial digital stethoscope are used to monitor the VA thrill signal at four different stenosis levels (0%, 37%, 68%, 76% flow reduction), with Doppler ultrasound measurements (PS, ED, TAMEAN, VolFlow) for reference. d Results from Canine 2 with a repaired VA (AVG) after percutaneous transluminal angioplasty (PTA) surgery. The thrill sensor and commercial digital stethoscope are used to monitor the VA thrill signal at four different stenosis levels (0%, 48%, 66%, 79% flow reduction), with Doppler ultrasound measurements for reference.\nFig 5 | Animal application of the thrill sensor during rapid and continuous VA changes. Schematic of vein-side stenosis(a) and artery-side stenosis (b) in Canine 1 induced by finger pressure. The thrill sensor and commercial digital stethoscope simultaneously monitor the VA thrill signal. The Doppler ultrasound image shows a 56% / 57% flow reduction, and the thrill signal decreases continuously, demonstrating the sensor's rapid response. c Time-domain thrill signals monitored by the thrill sensor and commercial digital stethoscope, and Doppler ultrasound images during PTA surgery in Canine 2, including: occlusion (no blood flow detected), half revascularization (402.36 mL/min), and full revascularization (808.07 mL/min). d Histogram of thrill intensity variation calculated from the above cases of Canine 1 and Canine 2. The thrill intensity is significantly lower in the high-risk state compared to the healthy state (critical flow rate = 400 mL/min, p = 0.0021, Welch’s t-test). e Time-domain thrill signals and the histogram of thrill intensity during the rapid process of severe stenosis (more than 80% stenosis within 8s) in Canine 3. The thrill intensity decreases from 0.98 to 0.06 in vein-side stenosis and from 0.79 to 0.02 in artery-side stenosis. f Comparison of thrill signals during severe stenosis in Canine 3. The pulse signal emerges at severe vein-side stenosis (blue curve), but not in severe artery-side stenosis (purple curve).\nFig 6 | Animal application of the thrill sensor for spatial mapping the thrill distribution along the VA (arteriovenous graft, AVG). a Photo and Doppler ultrasound images of Canine 1’s well-functioning AVG. The monitoring points (P1–P10) are distributed along the graft from the arterial anastomosis (P1) to the venous anastomosis (P10), with P6 at the U-turn. b Time-domain thrill signals at each monitoring point (P1–P10) along the AVG of Canine 1. c Distribution of thrill intensity, depth, and blood flow rate along the AVG of Canine 1. The thrill intensity decreases from P1 to P6, reaching a minimum, and then increases towards P9. d Photo and Doppler ultrasound images of Canine 2’s repaired AVG with residual stenosis at venous anastomosis (P10). e Time-domain thrill signals at each monitoring point (P1–P10) along the AVG of Canine 2. f Distribution of thrill intensity, depth, and blood flow rate along the AVG of Canine 2. The thrill intensity shows overall reduction but a singularity increase at P10. g Colormap of thrill intensity along the newly implanted AVG (Canine 5) on Day 1 and Day 7. The thrill intensity increases significantly from Day 1 to Day 7. h Colormap of thrill intensity along the well-functioning and 6-month mature AVGs (Canine 1, 3, and 4). The thrill intensity is highest at the arterial anastomosis and decreases towards the U-turn, then increases towards the venous anastomosis. i Colormap of thrill intensity along the abnormal AVG (Canine 2) with residual stenosis. The thrill intensity is significantly reduced overall, but a notable increase at the venous anastomosis.\nFig 7 | Clinical application of the thrill sensor in hemodialysis patients. a Photo and digital subtraction angiography (DSA) or Doppler ultrasound images of well-functioning AVGs in three patients (Patient A, B, and C). The monitoring points (P1–P10) are distributed along the graft from the arterial anastomosis (P1) to the venous anastomosis (P10), with P6 at the U-turn. b Thrill intensity histogram and time-domain thrill signals at key monitoring points (P1, P6, P10) for each patient with a well-functioning AVG. The thrill intensity is highest at P1 and decreases towards P6, reaching a minimum, and then increases towards P10. c Photo and DSA images of abnormal AVGs with residual stenosis at venous anastomosis in three patients (Patient D, E, and F). d Thrill intensity histogram and time-domain thrill signals at key monitoring points for each patient with an abnormal AVG with residual stenosis. The thrill intensity is reduced overall, with a notable increase singularity at P10. e Photo and DSA images of abnormal AVGs with irregular lesions in three patients (Patient G, H, and I). Patient G’s AVG exhibits a morphological 90° turn, Patient H’s AVG has graft ectasia, and Patient I’s AVG has a non-drug-eluting stent implanted near the venous anastomosis. f Thrill intensity histogram and time-domain thrill signals at key monitoring points for each patient with an abnormal AVG with irregular lesions. The thrill intensity is reduced overall, with a notable increase singularity at the lesion point. g Correspondence between the thrill intensity and blood flow rate in the AVGs of 9 patients. The thrill intensity exhibits a positive correlation with the blood flow rate in well-functioning AVGs (Patient A–C) and a significant thrill intensity reduction in abnormal AVGs (Patient D–I). h Diagram of the thrill intensity distribution along the AVGs of 9 patients.\nSuggested improvements:\nI would recommend examining a group of patients with the new device and an established method in various scenarios: 1. pre- and post hemodialysis; 2. Known stenosis vs. normal fistula/graft; 3. Rest/movement of the patient; 4. Self attachment of the device by the patients.\nResponse:\nWe sincerely thank the reviewer for the valuable suggestion and supplement these scenarios:\n1. pre- and post-hemodialysis:\nWe have monitored the VA thrill changes in a normal hemodialysis patient pre-and-post hemodialysis, with assessments conducted 1 hour before hemodialysis and 10 minutes after hemodialysis, as shown in newly added Supplementary Fig. 7 below. Before hemodialysis, the thrill distribution matches that of a normal well-functioning VA, with the arterial anastomosis exhibiting a stronger thrill compared to the venous anastomosis. After hemodialysis, a tourniquet is applied to the puncture sites for hemostasis, exerting localized pressure on the VA. This results in a slight reduction in thrill intensity at the inflow segments (P1: arterial anastomosis and P2: graft U-turn) compared to pre-hemodialysis measurements. In contrast, the thrill at the outflow segment (P3: venous anastomosis) becomes significantly stronger post-hemodialysis, likely due to altered hemodynamics from the tourniquet -induced compression.\n2. Known stenosis vs. normal fistula/graft:\nWe have monitored thrill variations in a recurrent venous anastomotic stenosis patient at different stages of VA dysfunction and intervention, as shown in newly added Supplementary Fig. 5 below. First, on May 11, 2025 (two weeks post-percutaneous transluminal angioplasty, PTA), ultrasound and angiography revealed residual stenosis despite a high flow rate (>1500 mL/min). At this stage, the arterial anastomosis (P1) exhibited a pulsatile-high-frequency hybrid thrill, while the venous anastomosis (P3) demonstrated an even stronger thrill due to the Venturi effect induced by residual stenosis. Second, on the morning of November 3, 2025, the patient was hospitalized for recurrent venous stenosis (ultrasound flow: 330 mL/min). Imaging confirmed significant restenosis, coinciding with loss of high-frequency vibrations at P1 (purely arterial pulse) and a further intensified thrill at P3, attributable to exacerbated Venturi effects from the narrowed vessel. Finally, after repeat PTA that afternoon (post-PTA flow: 570 mL/min), successful dilatation was angiographically confirmed. The thrill at P1 reverted to the hybrid pulsatile-high-frequency characteristic, while the thrill at P3 weakened as the Venturi effect diminished with improved vessel patency.\n3. Rest/movement of the patient:\nThe thrill sensor exhibits rapid and sensitive responses to continuous variations in thrill at the patient's VA. As the patient continuously raised the VA arm, the sensor was able to detect an increase in the VA thrill signal (Fig. 1f), thereby demonstrating its excellent dynamic performance.\nFigure 1f | The thrill sensor for continuous monitoring vascular access (VA) health condition.\nf Continuous monitoring of VA thrill changes during dynamic movement: a patient gradually raises his arm from 0° to 90°.\n4. Self attachment of the device by the patients:\nTo evaluate the reliability of patient self-attached thrill sensor measurements, we have compared thrill intensity results obtained from self-attachment of the device by patients with those from doctor-attachment at the same location, as shown in newly added Supplementary Fig. 8 below. Statistical analysis using the Wilcoxon signed-rank test reveals no significant difference in calculated thrill intensity between the two methods (p = 0.176, not significant [ns]; significance thresholds: p > 0.05 [ns], p < 0.05 [*], p < 0.01 [**], p < 0.001 [***], p < 0.0001 [****]). These findings suggest that patient self-attached placement provides comparable accuracy to clinician-assisted placement, supporting its feasibility for independent at-home monitoring of VA thrill.\nRevision:\n(Line 111~118, Results)\nAlso, comparison between two groups of distinct thrill signals reveals: (i) the recovery of thrill signal after percutaneous transluminal angioplasty (PTA) surgery of venous anastomosis stenosis (Fig. 1g, Supplementary Fig. 5, Supplementary Movie 1 and 2); (ii) the emergence of pulse signal at venous anastomosis stenosis, whereas this phenomenon does not exist in the arterial puncture-site stenosis (Fig. 1h and Supplementary Fig. 6); (iii) the change of thrill signal in a normal VA patient pre/post-hemodialysis (Supplementary Fig. 7); (iv) the comparison of thrill measurement results between patient self-attachment and doctor-attachment of the thrill sensor (Supplementary Fig. 8 and Supplementary Movie 3).\nRevised Figure 1g-h | The thrill sensor for continuous monitoring vascular access (VA) health condition. g Comparison of thrill signals before and after percutaneous transluminal angioplasty (PTA) surgery for venous anastomosis stenosis: pre-PTA, only a pulse-like vibration; post-PTA, thrill signal recovery. h Distinct thrill signatures in different stenosis locations: venous anastomosis stenosis, prominent pulse signal; arterial puncture-site stenosis: weakened thrill without pulse.\n(Page 7, Supplementary Information)\nSupplementary Fig. 5 | Longitudinal monitoring of thrill variations in a patient with recurrent venous anastomosis stenosis. On May 11, 2025 (two weeks post-percutaneous transluminal angioplasty, PTA), ultrasound and angiography revealed residual stenosis, and the arterial anastomosis (P1) exhibited a pulsatile-high-frequency hybrid thrill, while the venous anastomosis (P3) demonstrated an even stronger thrill due to the Venturi effect induced by residual stenosis. After 6 months, on the morning of November 3, 2025, the patient was hospitalized for recurrent venous stenosis. Imaging confirmed significant restenosis, coinciding with loss of high-frequency vibrations at P1 (purely arterial pulse) and a further intensified thrill at P3, attributable to exacerbated Venturi effects from the narrowed vessel. After repeat PTA surgery that afternoon, successful dilatation was angiographically confirmed. The thrill at P1 reverted to the hybrid pulsatile-high-frequency characteristic, while the thrill at P3 weakened as the Venturi effect diminished with improved vessel patency.\n(Page 9, Supplementary Information)\nSupplementary Fig. 7 | Monitoring of VA thrill changes in a normal hemodialysis patient pre-hemodialysis and post-hemodialysis. Before hemodialysis, the thrill distribution matches that of a normal well-functioning VA, with the arterial anastomosis exhibiting a stronger thrill compared to the venous anastomosis. After hemodialysis, a tourniquet is applied to the puncture sites for hemostasis, exerting localized pressure on the VA, which leads to a slight reduction in thrill intensity at the inflow segments (P1, P2) and a significant increase at the outflow segment (P3).\n(Page 10, Supplementary Information)\nSupplementary Fig. 8 | Evaluation of patient self-attachment of the thrill sensor. a Image showing a female patient self-attaching the thrill sensor to her AVG. b Comparison of thrill intensity between self-attachment and doctor-attachment methods.\nClarity and context:\nThe manuscript is too long and complicated but it does not support the use of the new device adequately.\nReferences:\nThe list of references is rather short when one looks at the length of the manuscript.\nResponse:\nWe sincerely apologize for the manuscript's length and appreciate this opportunity to improve its clarity. We admit that the current detailed presentation stems from our systematic, three-phase prototype validation (in vitro → animal → preliminary clinical) required for this developmental stage, but we have taken concrete steps to address these concerns:\n(1) streamlined redundant content while preserving essential validation data;\n(2) expanded our references from 38 to 50 to better establish clinical and technical context.\nThese revisions maintain the rigorous technical documentation needed for evaluating this early-stage device while better balancing thoroughness with readability, in preparation for the larger clinical trials that will more definitively establish clinical utility.\nRevision:\n(Line 548~658, References)\n1. Carney, E. F. The impact of chronic kidney disease on global health. Nat. Rev. Nephrol. 16, 251-251 (2020).\n2. Bello, A. K. et al. Epidemiology of haemodialysis outcomes. Nat. Rev. Nephrol. 18, 378-395 (2022).\n3. Perlman, R. L. et al. Quality of life in chronic kidney disease (CKD): a cross-sectional analysis in the renal research institute - CKD study. Am. J. Kidney Dis. 45, 658-666 (2005).\n4. Jadoul, M., Aoun, M. & Imani, M. M. The major global burden of chronic kidney disease. Lancet Glob. Health. 12, e342-e343 (2024).\n5. Jager, K. J., Kovesdy, C., Langham, R., Rosenberg, M., Jha, V. & Zoccali, C. A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases. Nephrol. Dial. Transpl. 34, 1803-1805 (2019).\n6. Bikbov, B. et al. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 395, 709-733 (2020).\n7. Pastan, S. & Bailey, J. Dialysis therapy. New Engl. J. Med. 338, 1428-1437 (1998).\n8. Himmelfarb, J. & Ikizler, T. A. Hemodialysis. New Engl. J. Med. 363, 1833-1845 (2010).\n9. Queeley, G. L. & Campbell, E. S. Comparing treatment modalities for end-stage renal disease: a meta-analysis. Am. Health Drug Benef. 11, 118-125 (2018).\n10. Pecoits, R. et al. Capturing and monitoring global differences in untreated and treated end - stage kidney disease, kidney replacement therapy modality, and outcomes. Kidney Int. Suppl. 10, E3-E9 (2020).\n11. Liyanage, T. et al. Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet 385, 1975-1982 (2015).\n12. Collins, A. J. & Chan, C. T. Intensive hemodialysis: time to give the therapy greater consideration. Am. J. Kidney Dis. 68, S1-S4 (2016).\n13. Lok, C. E., Huber, T. S., Orchanian-Cheff, A. & Rajan, D. K. Arteriovenous Access for Hemodialysis: A Review. JAMA 331, 1307-1317 (2024).\n14. Deng, Y. J. et al. A soft thermal sensor for the continuous assessment of flow in vascular access. Nat. Commun. 16, 38 (2025).\n15. Tian, Y. Q. et al. Self-adaptive epidermal blood flow sensor for high-flux vascular access monitoring of hemodialysis patients. npj Flex. Electron. 8, 62 (2024).\n16. Santoro, D. et al. Vascular access for hemodialysis: current perspectives. Int. J. Nephrol. Renov. 7, 281-294 (2014).\n17. Lawson, J. H., Niklason, L. E. & Roy-Chaudhury, P. Challenges and novel therapies for vascular access in haemodialysis. Nat. Rev. Nephrol. 16, 586-602 (2020).\n18. Hsiao, J. F. et al. Vascular changes at the puncture segments of arteriovenous fistula for hemodialysis access. J. Vasc. Surg. 52, 669-673 (2010).\n19. Rothuizen, T. C., Wong, C. Y., Quax, P. H. A., van Zonneveld, A. J., Rabelink, T. J. & Rotmans, J. I. Arteriovenous access failure: more than just intimal hyperplasia? Nephrol. Dial. Transpl. 28, 1085-1092 (2013).\n20. Andrea, G., Ricardo, S., Jasmin, V. & Sanabria, M. Factors associated with vascular access failure in hemodialysis patients in Colombia. Nephrol. Dial. Transpl. 34, (2019).\n21. Salman, L. et al. A multicenter randomized clinical trial of hemodialysis access blood flow surveillance compared to standard of care: the hemodialysis access surveillance evaluation (HASE) study. Kidney Int. Rep. 5, 1937-1944 (2020).\n22. MacRae, J. M. et al. Arteriovenous access failure, stenosis, and thrombosis. Can. J. Kidney Health Dis. 3, 2054358116669126 (2016).\n23. Besarab, A. Access monitoring is worthwhile and valuable. Blood Purificat. 24, 77-89 (2006).\n24. Wiese, P. & Nonnast-Daniel, B. Colour Doppler ultrasound in dialysis access. Nephrol. Dial. Transpl. 19, 1956-1963 (2004).\n25. Faratro, R., Jeffries, J., Nesrallah, G. E. & MacRae, J. M. The care and keeping of vascular access for home hemodialysis patients. Hemodial. Int. 19, S80-S92 (2015).\n26. Robbin, M. L. et al. Arteriovenous fistula development in the first 6 weeks after creation. Radiology 279, 620-629 (2016).\n27. Gilpin, V. & Nichols, W. K. Vascular access for hemodialysis: Thrills and thrombosis. J. Vasc. Nurs. 28, 78-83 (2010).\n28. Manov, J. J., Mohan, P. P. & Vazquez-Padron, R. Arteriovenous fistulas for hemodialysis: brief review and current problems. J. Vasc. Access. 23, 839-846 (2022).\n29. Bartholomew, J. R. From the Masters: Lessons learned about the vascular medicine history and physical examination from the past and present. Vasc. Med. 26, 361-366 (2021).\n30. Lok, C. E. et al. KDOQI clinical practice guideline for vascular access: 2019 update. Am. J. Kidney Dis. 75, S1-S164 (2020).\n31. Trerotola, S. O. et al. Physical examination versus normalized pressure ratio for predicting outcomes of hemodialysis access interventions. J. Vasc. Interv. Radiol. 14, 1387-1393 (2003).\n32. Chiang, P. Y., Chao, P. C. P., Tarng, D. C. & Yang, C. Y. A novel wireless photoplethysmography blood-flow volume sensor for assessing arteriovenous fistula of hemodialysis patients. IEEE T. Ind. Electron. 64, 9626-9635 (2017).\n33. Chao, P. C. P. et al. A portable, wireless photoplethysomography sensor for assessing health of arteriovenous fistula using class-weighted support vector machine. Sensors 18, 3854 (2018).\n34. Chiang, P. Y., Chao, P. C. P., Yang, C. Y. & Tarng, D. C. Theoretical developments and clinical experiments of measuring blood flow volume (BFV) at arteriovenous fistula (AVF) using a photoplethysmography (PPG) sensor. Microsyst. Technol. 24, 4587-4603 (2018).\n35. Nguyen, D. H., Chao, P. C. P., Shuai, H. H., Fang, Y. W. & Lin, B. S. Achieving high accuracy in predicting blood flow volume at the arteriovenous fistulas of hemodialysis patients by intelligent quality assessment on PPGs. IEEE Sens. J. 22, 5844-5856 (2022).\n36. Zhou, G. R. et al. Deep learning analysis of blood flow sounds to detect arteriovenous fistula stenosis. npj Digit. Med. 6, 163 (2023).\n37. Wang, J. J., Sharma, A. K., Liu, S. H., Zhang, H. L., Chen, W. X. & Lee, T. L. Prediction of vascular access stenosis by lightweight convolutional neural network using blood flow sound signals. Sensors 24, 5922 (2024).\n38. Chung, T. L. et al. Prediction of arteriovenous access dysfunction by Mel spectrogram-based deep learning model. Int. J. Med. Sci. 21, 2252-2260 (2024).\n39. Lin, H. Y. H. et al. The application of blood flow sound contrastive learning to predict arteriovenous graft stenosis of patients with hemodialysis. Plos One 19, e0308385 (2024).\n40. Hicks, C. W., Wang, P. Q., Kernodle, A., Lum, Y. W., Black, J. H. & Makary, M. A. Assessment of Use of Arteriovenous Graft vs Arteriovenous Fistula for First-time Permanent Hemodialysis Access. JAMA Surg. 154, 844-851 (2019).\n41. Maya, I. D., Oser, R., Saddekni, S., Barker, J. & Allon, M. Vascular access stenosis: Comparison of arteriovenous grafts and fistulas. Am. J. Kidney Dis. 44, 859-865 (2004).\n42. Leon, C. et al. Accuracy of physical examination in the detection of arteriovenous graft stenosis. Semin. Dialysis 21, 85-88 (2008).\n43. Fumagalli, G., Trovato, F., Migliori, M., Panichi, V. & De Pietro, S. The forearm arteriovenous graft between the brachial artery and the brachial vein as a reliable dialysis vascular access for patients with inadequate superficial veins. J. Vasc. Surg. 70, 199-207 (2019).\n44. Berardinelli, L. Grafts and graft materials as vascular substitutes for haemodialysis access construction. Eur. J. Vasc. Endovasc. 32, 203-211 (2006).\n45. Ku, D. N. Blood flow in arteries. Annu. Rev. Fluid. Mech. 29, 399-434 (1997).\n46. Ene-Iordache, B. & Remuzzi, A. Blood flow in idealized vascular access for hemodialysis: a review of computational studies. Cardiovasc. Eng. Techn. 8, 295-312 (2017).\n47. Remuzzi, A. & Ene-Iordache, B. Novel paradigms for dialysis vascular access: upstream hemodynamics and vascular remodeling in dialysis access stenosis. Clin. J. Am. Soc. Nephro. 8, 2186-2193 (2013).\n48. Oliver, M. J. The science of fistula maturation. J. Am. Soc. Nephrol. 29, 2607-2609 (2018).\n49. Paulson, W. D., Ram, S. J. & Zibari, G. B. Vascular access: anatomy, examination, management. Semin. Nephrol. 22, 183-194 (2002).\n50. Yevzlin, A., Agarwal, A. K., Salman, L. & Asif, A. Handbook of Dialysis: Fifth Edition Ch. 8 (Wolters Kluwer Health, Philadelphia, 2014).\nReviewer #4 (Remarks to the Author):\nWireless, Non-invasive, High-resolution Thrill Sensor for Continuous Vascular Access Monitoring of Hemodialysis Patients\nThe authors present a new innovation in the field of vascular access and monitoring of hemodialysis patients. The article is original and clearly articulates the pressing need for new technologies to improve outcomes for CDK-ESRD patients. The article presents a new type of wearable thrill detector to replace standard auscultation of auditory signals with a stethoscope, invented by Rene Laennec in 1816. The article compares standard techniques compared to the proposed wearable thrill detection in normal and failing AV access. The device compensates for everyday artefacts such as movement and shivering and was tested on the bench using a mock vascular circuit using various degrees of occlusion. Validation then turned to a preclinical model that paralleled existing technologies such as a digital stethoscope and could be compared with ultrasound doppler. However, despite showing that changes could be detected across the graft length there were less convincing elements when results were spatially mapped. The article manages to cover the gamut from bench testing, preclinical and then to include human studies which should be congratulated. They work confirms the relationship between thrill intensity and flow which is diminished on stenosis or ectasia. However, care should be taken as previous attempts at wearable detectors, despite achieving commercial success are less well tolerated by the end users, both clinician, nursing team and patient which surely limits their impact and future success.\nResponse:\nWe sincerely thank the reviewer for the insightful summary and comments on our work and we have carefully addressed all the points raised during the revision.\nMajor concerns:\n1. 80% of VA is in the form of fistulas and yet the authors direct their technology to 10-15% of AVGs without explanation – this needs to be addressed please and put in context of the VA field.\nResponse:\nWe sincerely thank the reviewer for highlighting this important point regarding our focus on arteriovenous grafts (AVGs) despite their lower prevalence compared to arteriovenous fistulas (AVFs). We agree that the original manuscript did not adequately justify this emphasis, and we appreciate the opportunity to clarify our rationale. As suggested, we have restructured our explanation (previously in Results) to appear earlier in Introduction. We hope this restructured presentation could better contextualizes our work within the broader VA field.\nSpecifically, there are four key reasons for targeting AVGs:\n(1) Greater clinical need: AVGs exhibit more complex stenosis characteristics and are harder to assess via physical exam due to variable depth, creating an unmet need for objective monitoring.\n(2) Guideline context: KDOQI recommends regular physical examination for AVGs (13.2: KDOQI recommends regular physical examination or check of the AVG, by a knowledgeable and experienced health practitioner, to detect clinical indicators of flow dysfunction of the AVG) but discourages routine AVG surveillance by imaging (13.5: KDOQI does not suggest routine AVG surveillance by measuring access blood flow, pressure monitoring, or imaging for stenosis, that is additional to regular clinical monitoring, to improve AVG patency. 13.7: KDOQI does not recommend pre-emptive angioplasty of AVGs with stenosis, not associated with clinical indicators, to improve access patency), positioning our sensor as an ideal middle ground.\n(3) Growing patient population: AVGs become essential and life-sustaining when AVFs fail in long-term hemodialysis patients.\n(4) Technical feasibility: AVGs’ standardized PTFE material simplifies sensor development compared to native vessels.\nRevision:\n(Line 75 ~ 83, Introduction)\nWhile arteriovenous fistulas (AVFs) represent the majority of VA cases, this study focuses on arteriovenous grafts (AVGs) because: (1) AVGs exhibit more complex stenosis characteristics than AVFs, occurring at arterial/venous anastomosis, mid-graft, or puncture sites; (2) AVGs’ variable depth makes thrill assessment via palpation particularly challenging, creating an unmet need for objective monitoring tools that KDOQI guidelines (Section 13.2, 13.5, 13.7) highlight, which recommending regular physical examination while discouraging routine AVG surveillance by imaging; (3) AVGs become essential and life-sustaining when AVFs fail in long-term hemodialysis patients; and (4) AVGs’ standardized PTFE material facilitates sensor development.\n2. Fig 6 – I am unsure how the thrill detection can be deconvoluted successfully between well functioning AVGs and abnormal VA data from the animal model. This data show a wide variation in the intensity drops across the in and outflow. Specifically, across the arterial to venous segments which show a 95%, 57%, 24% increases in normal grafts but a 70% increase, 60% decrease and 38% decrease in the abnormal AVGs. These changes, not withstanding that Canine 5 was measured at two different time points, Day 1 and Day 7 needs further explanation. Please expand on this apparent variation and include when were the other measures made for consistency please?\nResponse:\nWe sincerely thank the reviewer for the insightful comments, and we are sorry for any confusion and misleading of experiment conclusions regarding the animal model presented in Figure 6.\nUpon re-evaluating the data, we have recognized that the initial binary grouping (Well-functioning VA vs. Abnormal VA) oversimplifies the complex physiological states being studied. The key issue is combining two fundamentally different conditions under the \"abnormal VA\" category: Canine 2, which has a pathologically stenosed venous anastomosis after 6-month VA maturation, leading to a 70% increase in thrill intensity across the arterial to venous segments due to turbulent flow at the stenosis site; Canine 5 (measured at Day 1 and Day 7 post-implantation), which shows decreasing intensity characteristics (60% and 38% decreases) across the arterial to venous segments, similar to well-functioning VA but at lower absolute values, reflecting its early maturation phase rather than pathology.\nTo address this, we have restructured Figure 6 with three clearly defined groups, as shown in Revised Figure 6g-i:\n(1) Newly implanted VA (Canine 5): Demonstrates the natural progression of graft maturation, with thrill intensity increasing significantly from Day 1 to Day 7 (approximately 2-fold enhancement), while maintaining the characteristic decrease across the arterial to venous segments (60% decrease on Day 1, 38% on Day 7) seen in patent grafts.\n(2) Well-functioning and 6-month mature VA (Canines 1, 3, 4): Shows the fully developed hemodynamic profile of patent grafts, with high absolute thrill intensities and the characteristic decrease across the arterial to venous segments (95%, 57%, 24% decreases), which reflecting stable, laminar VA flow.\n(3) Abnormal VA (Canine 2): Exhibits a unique reversal of the normal characteristic (70% increase in thrill intensity across the arterial to venous segments) due to pathological flow disturbance at the stenotic anastomosis, serving as a distinct diagnostic signature.\nAll measurement timepoints are now explicitly labeled (Day 1/Day 7 for Canine 5; 6-month matured for others), representing the continuum from implantation (physiological adaptation), maturation to pathology (stenosis).\nRevision:\n(Line 303 ~ 308, Results)\nFigure 6g-i summarize the AVG thrill intensity colormap of 5 experimental dogs. The dogs are divided into three distinct groups: newly implanted AVG (Canine 5), well-functioning and 6-month mature AVGs (Canine 1, 3, and 4) and abnormal AVGs (Canine 2). The findings reveal that the well-functioning group exhibits a significantly stronger thrill intensity in comparison to the newly implanted and the abnormal group (Supplementary Fig. 32), while the abnormal group shows a unique increase in thrill intensity across the arterial to venous anastomosis.\nRevised Figure 6g-i | Animal application of the thrill sensor for spatial mapping the thrill distribution along the VA (arteriovenous graft, AVG). g Colormap of thrill intensity along the newly implanted AVG (Canine 5) on Day 1 and Day 7. The thrill intensity increases significantly from Day 1 to Day 7. h Colormap of thrill intensity along the well-functioning and 6-month mature AVGs (Canine 1, 3, and 4). The thrill intensity is highest at the arterial anastomosis and decreases towards the U-turn, then increases towards the venous anastomosis. i Colormap of thrill intensity along the abnormal AVG (Canine 2) with residual stenosis. The thrill intensity is significantly reduced overall, but a notable increase at the venous anastomosis.\nMinor:\n• Pg 9 Ln72 “type stenosis 36” I assume is a non superscripted reference for correction.\nResponse:\nWe sincerely thank the reviewer for this valuable suggestion and we are sorry for the “non-superscripted” mistakes in references and measurement units. We have searched and revised the whole manuscript.\nRevision:\n(Line 264 ~ 265, Results)\nIn patients undergoing maintenance hemodialysis, stenosis inside the graft is also a prevalent type of stenosis41.\n(Line 271 ~ 273, Results)\nIn contrast, the thrill sensor's design incorporates a compact detecting area, capable of measurement within a 10×10 mm2 area.\n• Note. Other wearable devices have been attempted (see Alio) but gained less traction than expected. When used in practice they get in the way of the delivery of vascular access and are not favored by patients or nursing staff – this should be considered.\nResponse:\nWe sincerely thank the reviewer for raising this insightful note. We completely agree that wearable medical devices often face challenges in clinical practice, even after regulatory approval. Our device aims to address some of these limitations by featuring a more compact design with customizable placement to avoid interfering with vascular access, while providing high-resolution real-time thrill monitoring. We fully recognize that this is just a small step toward improving wearable device acceptance."}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have addressed all my concerns comprehensively and made substantial improvements to the manuscript. The revisions have significantly strengthened the paper's quality and scientific rigor. I am satisfied with the responses and have no further requests for revision. Therefore, I recommend acceptance of the manuscript in its present form.", "reviewer_3": "I have no further objections, the Authors responded accordingly.", "reviewer_4": "There are some minor typographical or syntax that needs addressing:Eg,\nLn266 In patients undergoing maintenance hemodialysis, stenosis inside the graft is also a prevalent type of stenosis41 - duplication of the word stenosis\nThe authors have not addressed the concern that additional wearables can intefer witht he dialysis canulation and are not supported by patients or nurses. Perhaps if the authors alude to the temporary nature of the wearable device that may help miigate the end users concerns ? Or if the wearable is proposed outside dialysis sessions ?Perhaps around Ln 272 in the same paragraph ?\nOtherwise all other concerns have been addressed"}, "author_response": ""}]

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