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Injectable ultrasonic sensor for wireless monitoring of intracranial signals

Abstract

Direct and precise monitoring of intracranial physiology holds immense importance in delineating injuries, prognostication and averting disease1. Wired clinical instruments that use percutaneous leads are accurate but are susceptible to infection, patient mobility constraints and potential surgical complications during removal2. Wireless implantable devices provide greater operational freedom but include issues such as limited detection range, poor degradation and difficulty in size reduction in the human body3. Here we present an injectable, bioresorbable and wireless metastructured hydrogel (metagel) sensor for ultrasonic monitoring of intracranial signals. The metagel sensors are cubes 2 × 2 × 2 mm3 in size that encompass both biodegradable and stimulus-responsive hydrogels and periodically aligned air columns with a specific acoustic reflection spectrum. Implanted into intracranial space with a puncture needle, the metagel deforms in response to physiological environmental changes, causing peak frequency shifts of reflected ultrasound waves that can be wirelessly measured by an external ultrasound probe. The metagel sensor can independently detect intracranial pressure, temperature, pH and flow rate, realize a detection depth of 10 cm and almost fully degrade within 18 weeks. Animal experiments on rats and pigs indicate promising multiparametric sensing performances on a par with conventional non-resorbable wired clinical benchmarks.

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Fig. 1: Design of injectable and biodegradable metagel ultrasonic sensor.
Fig. 2: In vitro characterization of metagel ultrasonic sensor for monitoring multiple signals.
Fig. 3: In vivo sensing performance and biocompatibility of metagel ultrasonic sensor in a rat model.
Fig. 4: Wireless ICP monitoring in live minipigs.

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Data availability

All data supporting the findings of this study are available in the paper and its Supplementary Information. Source data are provided with this paper.

Code availability

The custom code (MATLAB script) for processing the original RF data acquired by ultrasound probe has been deposited to a public database (https://github.com/Cyberpunk2207/Metagel-ultrasonic-sensing.git)35.

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Acknowledgements

We thank the Medical Subcentre of HUST Analytical & Testing Centre, R. Zhai and Y. Ruan for their support in regard to taking of measurements. This work was supported by the National Natural Science Foundation of China (nos. T2350001, 52173280 and 52188102), the China Postdoctoral Science Foundation (no. 2022M711256), the HUST Interdisciplinary Research Project (no. 2023JCYJ044) and the Taihu Lake Innovation Fund for Future Technology, HUST (no. 2023A3).

Author information

Authors and Affiliations

Authors

Contributions

J.Z., X.C., X.J. and H.T. guided the whole research project. H.T., Y. Yang and J.Z. conceived the research. H.T. designed the models, conducted theoretical analysis and performed numerical calculations. Y. Yang prepared experimental samples. H.T., Y. Yang, Y.Z., T.K., Y. Yu, Y.T., X.L., N.L. and Y.H. performed in vitro experiments and tests. Z.L., Y. Yang and H.T. performed animal experiments. H.T., Y. Yang, Z.L., W.L., Y.H., X.J., X.C. and J.Z. wrote the manuscript with input from all authors. All authors participated in drafting the manuscript and interpreting the data.

Corresponding authors

Correspondence to Xiaobing Jiang, Xiaodong Chen or Jianfeng Zang.

Ethics declarations

Competing interests

J.Z., H.T., Y. Yang and Y.H. are inventors of a patent application (CN patent, application no. 202410082447.1) that covers the mechanism and design of metagel ultrasonic sensing. All remaining authors declare no competing interests.

Peer review

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Nature thanks Jules Magda and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data figures and tables

Extended Data Fig. 1 Degradation process of three hydrogel substrates.

a, Chemical structures of metagel components. b, Schematic of polymer network fracture process of three hydrogel matrices. c, Quantitative degradation records of three hydrogel matrices in vitro. Data are represented as mean value ±S.D. (n = 3 independent samples).

Extended Data Fig. 2 Simulated sound reflection of deformed metagel due to various environmental changes.

a, Scattered sound fields of metagels at different pressure. b, Peak frequency shifts of pressure-metagel when environmental pressure changes. c, Scattered sound fields of metagels at different temperature. d, Peak frequency shifts of temperature-metagel when environmental temperature changes. e, Scattered sound fields of metagels at different pH. f, Peak frequency shifts of pH-metagel when environmental pH changes.

Extended Data Fig. 3 The workflow of metagel-ultrasonic sensing.

A detailed description can be found in the Supplementary Information.

Extended Data Fig. 4 In vitro pressure and temperature measurements.

a, Experimental setup for pressure measurement. b, Range performance of pressure-metagel. c, Accuracy performance of pressure-metagel. d-f, Multiple tests of pressure-metagel recordings on days 1, 3, and 8, respectively. g-h, Setup for temperature measurement. i, Accuracy performance of temperature-metagel. j-l, Multiple tests of pressure-metagel recordings on days 1, 3, and 8, respectively.

Extended Data Fig. 5 Anti-fatigue properties of pressure-metagel.

a, Ultrasonic frequency shift of the metagel recorded during more than 2600 pressurization cycles. b-c, Pressure measured at the first 8 circles and the last 8 circles during the test, respectively.

Extended Data Fig. 6 Impact of individual factors on pressure, temperature, and pH metagels.

a, Schematic of experimental setup for multi-metagel measurement. For pressure measurement, the multi-metagel sample is placed in a sealed chamber. b-c, Photograph and ultrasonic image of multi-metagel sample, enabling concurrent monitoring of three metagels. d-f, Frequency response of three metagel to environmental changes in pressure, temperature, and pH, respectively.

Extended Data Fig. 7 Combined effect of environmental pressure and temperature changes on three metagels.

a, Experimental setup for assessing variations in two environmental factors: pressure is manipulated by adjusting liquid volume in a closed chamber, while temperature or pH is altered by completely replacing the chamber’s liquid with one of different temperature or pH. b, Photograph displaying a multi-metagel sample in a closed chamber. c, Frequency response of three metagels to environmental pressure changes at initial environmental temperatures of 36 °C, and initial pH of 7.6. Throughout the experiment, the solution temperature gradually decreases. d, Decoupled pressure, temperature, and pH from the data in c.

Extended Data Fig. 8 In vivo biocompatibility of metagel in rats.

a, b, Blood cell analysis and blood biochemistry of the rats with metagel implanted, respectively. WBC: white blood cell, P14 days = 0.76, P30 days = 0.74, Lymph: lymphocyte, P14 days = 0.45, P30 days = 0.78, Mon: monocyte, P14 days = 0.70, P30 days = 0.53, Gran: granulocyte, P14 days = 0.77, P30 days = 0.76, RBC: red blood cell, P14 days = 0.07, P30 days = 0.82, HGB: hemoglobin, P14 days = 0.18, P30 days = 0.78, HCT: hematocrit, P14 days = 0.11, P30 days = 0.83, PLT: platelet, P14 days = 0.44, P30 days = 0.48, ALT: alanine aminotransferase, P14 days = 0.69, P30 days = 0.65, AST: aspartate aminotransferase, P14 days = 0.56, P30 days = 0.80, BUN: blood urea nitrogen, P14 days = 0.06, P30 days = 0.18, CREA: creatinine, P14 days = 0.22, P30 days = 0.12, TP: creatinine, P14 days = 0.06, P30 days = 0.42, ALB: albumin, P14 days = 0.52, P30 days = 0.66, TG: triglycerides, P14 days = 0.26, P = 0.1930 days, CHO: cholesterol, P14 days = 0.62, P30 days = 0.86, GLU: glucose, P14 days = 0.17, P30 days = 0.56, Ca: calcium, P14 days = 0.22, P30 days = 0.76, P: phosphate, P14 days = 0.97, P30 days = 0.35. Statistical analysis was performed by two-sided Student’s t-test. Data are represented as mean value ±S.D. (n = 2 independent rats for the control group, n = 3 independent rats for metagel group). c, H&E staining images displaying the microstructure of brain, kidney, liver and subcutis tissues in rats one month after metagels implantation. Scale bar: 100 μm. No distinct difference is found between the implantation and control rats, indicating no organ lesion or inflammatory reaction caused by metagel.

Extended Data Fig. 9 The pH-metagel array for pH imaging.

This figure presents pH imaging using the pH-metagel array system. The array comprises 15 pH-metagels arranged in a 3 × 5 matrix with 3 mm spacing. Scale bar, 3 mm. The introduction of acidic droplets at specific points leads to a pH distribution across the gelatin, detectable by the metagel array system and subsequently mapped to create a spatial pH distribution image.

Extended Data Table 1 Comparison of metagel-ultrasonic sensing (this work) and existing wireless implantable sensors

Supplementary information

Supplementary Information

Supplementary Notes 1–25 including Tables 1–7, Figs. 1–44 and references.

Reporting Summary

Supplementary Video 1 Mechanism of metagel ultrasonic sensing.

This video illustrates the sensing mechanism, encompassing environmental physiological parameters, deformation of the metagel structure and the peak frequency shift of reflected ultrasound (external readout).

Supplementary Video 2 Real-time pressure measurements in vitro.

This video demonstrates real-time pressure measurements using the metagel sensor alongside a commercial manometer. The unit used for the commercial manometer is cmH2O; the manometer is calibrated to zero at an initial pressure of 6.6 cmH2O.

Supplementary Video 3 Morphological changes of metagels in response to variation in temperature or pH.

This video captures subtle deformations in the temperature metagel and pH metagel corresponding to changes in environmental temperature and pH conditions, respectively.

Supplementary Video 4 Injection process for metagel.

This video shows the injection of metagel with a syringe into a gelatin-based brain model.

Supplementary Video 5 Real-time flow rate measurement in vitro.

This video presents real-time flow rate measurement using the metagel sensor at different pumping rates.

Supplementary Video 6 Metagel implantation process in a rat model.

This video shows metagel implantation into the rat brain using a puncture needle with the assistance of a stereotaxic apparatus.

Supplementary Video 7 Observation of rat activity 1 month post metagel implantation;

the rat exhibited free movement and a strong inclination to explore.

Supplementary Video 8 Fluctuations in the fluid column within a volume-measuring tube.

This video demonstrates cyclic rises and falls in intracranial pressure in the live pig synchronized with respiration.

Supplementary Video 9 Delivery of metagel array.

The video shows the delivery of multiple metagels into a gelatin medium.

Supplementary Video 10 Overview of this work.

This video provides an introduction, highlights advancements and presents the key results of our work. Some segments in this video include excerpts from Supplementary Videos 1–9.

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Tang, H., Yang, Y., Liu, Z. et al. Injectable ultrasonic sensor for wireless monitoring of intracranial signals. Nature 630, 84–90 (2024). https://doi.org/10.1038/s41586-024-07334-y

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