Injectable ultrasonic metagels for intracranial monitoring

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Injectable ultrasonic metagels for intracranial monitoring

Over 10 million patients globally undergo invasive intracranial monitoring annually for conditions like traumatic brain injury (TBI), hydrocephalus, and intracranial hypertension, where real-time physiological data dictates survival and neurological outcomes1,2,3,4,5,6. Current clinical gold standards rely on wired sensors implanted via craniotomy, carrying a 7–15% infection risk, immobilizing patients, and requiring secondary removal surgeries7,8. These limitations perpetuate a critical care dilemma: the life-saving need for continuous brain monitoring versus the life-threatening risks of the monitoring itself. Concurrently, the emergence of wireless, minimally invasive, and bioresorbable sensors can offer continuous monitoring without associated risks7. Initial efforts focused on reducing device size9,10 and incorporating wireless communication11 to minimize invasiveness, exemplified by millimeter-scale pressure sensors12 and radio frequency identification-enabled implants13. Despite progress, challenges remain, including achieving precise and reliable measurements, ensuring biocompatibility and biodegradability, and integrating multiple sensing capabilities within a single device.

Injectable hydrogels have shown potential for creating flexible, biocompatible sensors with minimal invasiveness14,15. Typical single-nozzle injectable hydrogels cured by ultraviolet (UV) light post-injection face challenges in achieving sufficient flexibility due to the highly crosslinked network from UV-induced radical crosslinking and restricted fully implanted applications caused by poor UV light penetration16. Injectable hydrogels using multiple nozzles combine natural polymers (alginate, chitosan, and collagen) and synthetic polymers such as poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), and poly(N-isopropylacrylamide) (PNIPAM), with crosslinking agents in separate nozzles to initiate radical crosslinking upon mixing. Recent advances in the developed durable polyether urethane diacrylamide (PEUDAm) hydrogel combined with N-acryloyl glycinamide (NAGA), using ammonium persulfate (APS) and iron gluconate for rapid in-situ curing15 (Fig. 1a), achieved a high electric conductivity of 13.5 ± 0.8 mS cm-1. However, challenges remain with uncontrolled diffusion upon injection (Fig. 1b), signal interference, and the development of biocompatible and bioresorbable hydrogels free from cytotoxic residues such as persulfate initiators, inflammatory degradation byproducts, or non-resorbable synthetic additives that impede safe metabolic clearance.

Fig. 1: Injectable hydrogel and metagels.
figure 1

a Typical injectable hydrogel using a double-barreled syringe with a mixing head for redox initiation reaction, such as polyether urethane diacrylamide (PEUDAm) macromer and N-acryloyl glycinamide (NAGA) with ammonium persulfate (APS) and iron gluconate (IG) initiators. b Diffusion of traditional hydrogel injection. c Injectable metagels as wireless intracranial sensors using ultrasound reflection. d Metagel sample size and structure. e Measuring intracranial pressure (ICP) with a wired clinical sensor and metagel injection. a, b Reproduced from ref. 15, and c–e, reproduced from ref. 17, Springer Nature.

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Metagel design overcoming traditional hydrogel limitations

A recent publication in Nature introduces the metagel sensor, an injectable, bioresorbable, and wireless metastructured hydrogel designed for ultrasonic monitoring of intracranial signals, addressing these challenges through phononic crystal design and stimuli-responsive materials17. The study rethinks hydrogel sensor design to overcome three persistent challenges: (1) Controlled injection via pre-structured rigidity. Traditional hydrogels rely on in situ crosslinking, leading to diffusion-mediated shape loss (Fig. 1b). In contrast, metagels are pre-fabricated as 2 × 2 × 2 mm3 solid cubes using 3D-printed molds with periodic rods (Fig. 1c, d), ensuring shape stability during injection (Fig. 1e). This eliminates diffusion issues and enables precise implantation. (2) Enhanced acoustic reflection with phononic crystals. Homogeneous hydrogels generally produce weak ultrasound echoes. The metagel’s periodic air columns form a soft phononic crystal, creating a sharp resonant bandgap that enhances reflection by 50-fold compared to pure hydrogels. Environmental changes (pressure/pH/temperature) deform these air columns, shifting the reflection frequency and enabling noise-resistant sensing. (3) Biocompatible composition without cytotoxic additives. Unlike synthetic hydrogels using APS initiators, the metagel matrix combines PVA with natural polymers: carboxymethyl chitosan (CMC) for pressure sensing, PNIPAM for temperature responsiveness, and chitosan for pH detection.

Bioresorbability: kinetics, by-products, and safety

The metagel’s bioresorbability is validated through in vivo degradation kinetics, mass loss quantification, chemical by-product analysis, and clearance pathway characterization. In rat models, magnetic resonance imaging (MRI) tracking shows metagels maintain structural integrity for 24 days (functional period), then degrade gradually over 5–18 weeks17 (Fig. 2a, b); by 10 weeks, only residual fragments remain, and by 18 weeks, no macroscopic traces are observed. Larger metagels (3 × 3 × 3 mm3) in pigs exhibit similar kinetics, with 90% mass loss by 12 weeks. Quantitative mass loss analyses revealed that in vitro enzymatic degradation (lysozyme/trypsin-containing PBS) of PVA/CMC hydrogels (pressure-sensing matrix) results in 60% mass loss at 4 weeks. Degradation mechanisms vary by component: CMC breaks down via cation exchange (Al3+ replaced by Na⁺) and bioenzyme-induced hydrolysis, producing oligosaccharides, CO2, and H2O (Fig. 2c); PNIPAM undergoes thiol-disulfide exchange, yielding soluble polymer chains without inflammatory fragments18,19; and chitosan is hydrolyzed by lysozyme into glucosamine monomers20, which are metabolized in the liver. Clearance pathways include renal excretion of small molecules (<3 kDa) via urine and hepatic metabolism of larger fragments by Kupffer cells, degraded to CO2 and H2O. Inductively coupled plasma mass spectrometry detects no residual Al3+ or thiol species in liver/kidney tissues at 10 weeks, confirming no systemic accumulation17. Biocompatibility validation further supports safety: immunofluorescence staining shows no significant astrogliosis (glial fibrillary acidic protein, GFAP⁺) or microglial activation (cluster of differentiation 68, CD68⁺) at the implantation site up to 10 weeks (Fig. 2b). Serum chemistry (alanine transaminase, ALT; blood urea nitrogen, BUN) and inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) remain normal (Fig. 2d), confirming safety. This integration of controlled degradation kinetics, non-toxic by-products, and renal/hepatic clearance pathways ensures the metagel meets bioresorbable implant standards, supporting its potential for clinical translation.

Fig. 2: Biocompatibility and ultrasound responsiveness of metagel.
figure 2

a Magnetic resonance imaging tracking the degradation stages of metagel in live rats. b Immunofluorescence of brain tissue around metagel at 2, 5, and 10 weeks, showing no excess inflammation vs. controls (no metagel). c FTIR-ATR spectra of PVA/CMC, PVA/PNIPAM, and PVA/CS hydrogels. d Blood biochemistry of rats with metagel implantation at 14 and 30 days (mean ± S.D., n = 3 metagel; n = 2 controls; two-sided Student’s t-test; NS: not significant). e Anti-fatigue performance of pressure-responsive metagel: ultrasonic frequency shift over 2600 pressurization cycles, with pressure measurements from the first and last 8 cycles. f H&E staining of brain and kidney, 1 month post-implantation, showing no organ lesions or inflammation vs. controls. g Simulated sound reflection of pH-responsive metagel: scattered sound fields at pH 7/3 (7.8/9.2 MHz incident waves), and reflectance/transmittance across pH 3–7. Reproduced from ref. 17, Springer Nature. ALT (alanine aminotransferase), AST (aspartate aminotransferase), BUN (blood urea nitrogen), CREA (creatinine), TP (total protein), ALB (albumin), TG (triglycerides), CHO (cholesterol), GLU (glucose), Ca (calcium), P (phosphate).

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Mechanisms preventing post-injection migration

The metagel avoids post-injection migration through three interconnected mechanisms, validated by in vitro mechanical characterization, in vivo stability data, and cerebrospinal fluid (CSF)-mimetic environment testing. First, its pre-structured rigidity resists passive displacement: unlike diffusive in situ crosslinking hydrogels (Fig. 1b), metagels are fabricated as solid cubes via 3D-printed molds, with mechanical properties tailored for intracranial stability. Under physiological conditions (37 °C, PBS as CSF mimic), the pressure-sensing PVA/CMC matrix exhibits a compressive modulus of ~250 kPa, well within the stiffness range of brain parenchyma (1–300 kPa) to minimize mechanical mismatch and reduce tissue irritation. Additionally, the material demonstrates exceptional fatigue resistance, withstanding 2600 cycles of pressure loading (0–70 mmHg) while maintaining small degradation in modulus (Fig. 2e), ensuring structural integrity during physiological intracranial pressure fluctuations and acute trauma scenarios. Second, natural polymer-mediated tissue adhesion ensures anchorage: the PVA matrix blended with CMC and chitosan forms electrostatic interactions via CMC’s carboxyl groups (-COOH), which hydrogen bond with glycosaminoglycans (e.g., hyaluronic acid) in the brain extracellular matrix. In vitro adhesion assays demonstrate metagels adhere to porcine dura mater with a peel strength of ~0.8 N/cm, comparable to clinical fibrin glues (0.6–1.0 N/cm), reinforcing positional stability. Third, the metagel exhibits minimal foreign body response, a critical factor in preventing post-injection migration. Histological analysis via hematoxylin-eosin (H&E) staining reveals no fibrous capsule formation at the implantation site, even during peak degradation (5 weeks), eliminating a major driver of implant displacement (Fig. 2f). This is further supported by immunofluorescence staining showing no significant astrogliosis or microglial activation up to 10 weeks post-implantation (Fig. 2b), alongside serum cytokine profiling that confirms pro-inflammatory markers remain within normal ranges. The absence of chronic inflammation ensures stable positional integrity, as evidenced by in vivo frequency shift stability: the metagel’s reflective peak frequency (≈9 MHz) varies by only ±0.2 MHz over 24 days of monitoring, indicating no rotation, tilt, or migration relative to the external ultrasound probe. Positional stability is further validated by consistent sensing performance: over 24 days, metagel-derived intracranial pressure (ICP) waveforms (0.1 mmHg resolution) correlate strongly with clinical Codman probes (R2 = 0.98), with no frequency drift from positional changes6; meanwhile, the reflective peak frequency (≈9 MHz) remains stable (±0.2 MHz) in vivo, indicating no rotation or tilt relative to the external ultrasound probe (Fig. 2g).

Multiplexed sensing and signal integrity

Periodic air columns, hollow channels within the hydrogel matrix, form a phononic crystal reflects ultrasound with a centered frequency bandgap (Fig. 3a). Unlike conventional hydrogels, this engineered architecture creates a sharp, resonant bandgap reflection, where environmental changes (pressure/pH/temperature) deform the air columns and shift the reflection frequency. This frequency-domain sensing mechanism isolates signals from background noise such as tissue echoes, achieving 0.1 mmHg pressure resolution and overcoming signal interference. The PVA hydrogel matrix with biocompatibility and degradability (Fig. 3b), was combined with CMC for pressure, PNIPAM for temperature, and chitosan for pH (Fig. 3c). The fabricated metagels show superior capabilities in responding to various pH changes (Fig. 3d), detecting intracranial pressure changes from 0 to 70 mmHg with a resolution of 0.1 mmHg (Fig. 3e), monitoring vascular flow rates (Fig. 3f) and fluctuations with respiration patterns from saline injections and withdrawals (Fig. 3g), outperforming clinical ICP devices, and providing detailed pH imaging (Fig. 3h). During ultrasound imaging, metagels with embedded air columns provide clear signals compared to the nearly anechoic pure hydrogels (Fig. 3i). Variations in the size of the unit cells in metamaterials can impact the material’s acoustic bandgaps to affect ultrasound reflectiveness (Fig. 3j), enabling precise, non-invasive monitoring of environmental changes through deformation-induced shifts in reflected ultrasound frequencies (Fig. 3k). Metagels can monitor pH changes as small as 0.5 units (Fig. 3l), and in vitro tests have shown their superior range, resolution, and stability for pressure detection (Fig. 3m, n).

Fig. 3: Injectable metagels for wireless intracranial monitoring.
figure 3

a Metagels’ working principle based on environment-induced microdeformation. b Biodegradation of metagels in rat brain. c Metagel chemical components and degradation processes. d pH-responsive curves of PVA/CS metagels from three independent samples (mean ± standard deviation). e ICP fluctuations measured by clinical ICP sensor, commercial manometer, and metagel; manometer and metagel detected respiratory fluctuations, but the ICP sensor (yellow) cannot. f Flow rate assessment recording rapid microvibrations from simulated vascular pulsations by a pressure metagel. g Real-time ICP changes during periodic saline, I, injections, and II, withdrawals from the spinal canal. h Acidic droplets-induced pH distribution across gelatin and spatial pH distribution mapping. i Photograph (top) and ultrasound image (bottom) of metagel and pure hydrogel. j Metagels with varying lattice constants, a, and their impact on energy bands. k Schematic of peak frequency shifts in metagel due to deformation. l Continuous pH variations monitored by pH metagel and a wired commercial pH sensor. m Real-time wireless tracking of ICP changes during cyclic compression of a rat’s abdomen. n Comparison of a pressure metagel and a commercial manometer. Reproduced from ref. 17, Springer Nature.

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Multisensor arrays and spectral separation

The compact design enables precise injection while maintaining high functionality, including the capability for multiplexed sensing via arrays of implanted metagel cubes. For such multi-cube implantation, the metagel system employs three complementary strategies to achieve spectral separation of resonances without interference, validated in vitro and in vivo: spatial resolution via ultrasound localization, where the external 128-element phased array ultrasound probe achieves 1 mm spatial resolution, allowing discrimination of metagels implanted as close as 1 mm apart, as demonstrated in rat brain experiments with a 3 × 5 metagel array (15 sensors, 3 mm spacing) showing distinct reflection peaks for each element with no overlap in B-mode ultrasound images; temporal multiplexing via high-speed scanning, utilizing the ultrasound system’s pulse repetition frequency (PRF) of 10 kHz to enable cyclic sequential scanning of multiple metagels with a time interval of 0.1 ms, making inter-sensor crosstalk negligible during the scanning window given that environmental changes (e.g., pressure/pH fluctuations) occur on millisecond-to-second timescales; and material-specific frequency tuning by adjusting the lattice constant (a) and air-filling ratio (d/a) of the phononic crystal to engineer distinct resonance frequencies pressure metagels with a = 0.28 mm and d/a = 0.7 resonate at 9.13 MHz, temperature metagels with a = 0.26 mm and d/a = 0.65 at 9.76 MHz, and pH metagels with a = 0.30 mm and d/a = 0.75 at 8.52 MHz ensuring non-overlapping reflection peaks with Δf > 0.5 MHz between channels. Quantitative characterization of the metagel’s acoustic properties reveals Q-factors calculated as f₀/Δf (where f₀ is the resonance frequency and Δf is the full-width at half-maximum of the reflection peak) of approximately 65 for pressure metagels (f₀ = 9.13 MHz, Δf = 0.14 MHz), 54 for temperature metagels (f₀ = 9.76 MHz, Δf = 0.18 MHz), and 41 for pH metagels (f₀ = 8.52 MHz, Δf = 0.21 MHz), with a bandwidth range of 0.14–0.21 MHz suitable for physiological monitoring. Crosstalk characterization demonstrates spatial interference <5% with 1 mm sensor spacing (measured as the ratio of cross-talk signal to main signal) and spectral crosstalk <3% for metagels with Δf > 0.5 MHz, with multivariate analysis in pig models showing <2% signal overlap when co-implanting pressure, temperature, and pH sensors. Preclinical validation in rat TBI models confirms multiplexed monitoring with a 2 × 2 metagel array, achieving simultaneous detection of intracranial pressure, cortical temperature (35–39 °C, 0.1 °C resolution), and extracellular pH (6.8–7.6, 0.0012 pH unit resolution), with all signals decoupled using linear regression models.

Wireless ultrasound interrogation

As a passive ultrasound-interrogated device requiring no internal power, its wireless operation relies on external ultrasound probes to detect reflected frequency shifts, with key characteristics validated in vitro and in vivo: the metagel functions as a passive phononic crystal resonator, detectable in tissue-mimicking phantoms at depths up to 10 cm with a signal-to-noise ratio (SNR) of 18 dB exceeding typical intracranial target depths (2–5 cm in humans) and resonance frequency (9.13 MHz) varies by <0.3 MHz up to 10 cm to ensure stable sensing; in animal models, signals are reliably detected through 1–2 cm of brain tissue in rats via 5.8 mm craniotomy window and 2 cm in pigs (8 mm burr hole), maintaining stable performance for 24 days.

Two miniaturized ultrasound systems enable handheld use: a single-element probe (10 MHz, 6 mm diameter) comparable to clinical transducers, and a 128-element phased array probe (10 MHz, 15 × 20 mm active area) mountable on flexible adhesive patches for ambulatory monitoring in freely moving rats. Coupling is achieved via standard aqueous glycerin-based ultrasound gel (0.5 mm thickness), which ensures acoustic transmission through skin and hair. Rat studies show no significant SNR loss compared with direct craniotomy contact, while pig models maintain SNR > 20 dB even with an unshaved scalp. However, ~10 MHz ultrasound faces critical challenges with intact skulls: the original study explicitly notes that all in vivo data were acquired via craniotomy (5.8 mm burr hole in rats, 8 mm in pigs), as human skull bone strongly attenuates and distorts high-frequency ultrasound at 15–20 dB/cm. This attenuation would reduce signal amplitude below detection thresholds in intact skull models, necessitating cranial drilling to validate the metagel’s core sensing mechanism. Despite this limitation, the 10 MHz system demonstrates robust safety and alignment tolerance. Acoustic pressure (peak negative pressure = 20–50 kPa) and safety indices (mechanical index=0.008, thermal index = 0.002) are well within FDA limits, while angular misalignment (±15°) and lateral offsets (<1 mm) cause <5% frequency variation, ensuring stability during physiological motion. Future solutions to address skull attenuation could include low-frequency metagel variants (3–5 MHz) with larger lattice constants (a = 0.5–0.8 mm), reducing attenuation to 5–8 dB/cm, and integrating acoustic lenses/gel-based coupling layers to focus ultrasound through bone.

Challenges and clinical prospects

However, the application of the metagel sensor for continuous and precise monitoring of intracranial physiology presents several challenges that remain partially unsolved: (1) The impact of inter-individual biological variability (pH, enzyme activity) on degradation rates, which could lead to premature signal loss or retained debris; (2) the trade-off between high-frequency ultrasound sensitivity (~10 MHz) and deep-tissue attenuation, necessitating transducer designs such as PVDF piezoelectric polymers and acoustic lenses; (3) The need for real-time calibration algorithms such as LMS adaptive filtering, and convolutional neural networks (CNNs) to mitigate motion artifacts and tissue heterogeneity21. Ensuring consistent and predictable biodegradation rates of hydrogel materials in various biological environments is a major challenge, as variations in pH, enzyme activity, and patient-specific conditions can affect the degradation rate, potentially leading to premature degradation or the need for surgical removal. Developing biodegradable polymers with tunable degradation rates in various tissue environments and evaluating their biocompatibility through in vitro and in vivo testing is crucial for ensuring safe and effective non-invasive use22. The structure of injectable metagel is influenced by pressure, temperature, and pH, which change the reflected ultrasound frequency for monitoring; however, as the metagel degrades, its structure also changes, thus leading to noise, artifact, or unstable signal recordings8. Additionally, tissue variability and body movement can interfere with the ultrasound signals, potentially affecting the accuracy of the sensor’s measurements23,24. Further adoption of signal processing algorithms such as least mean squares (LMS) adaptive filtering25,26, discrete wavelet transform (DWT)27, and machine learning methods (e.g., CNN-based noise suppression28 can enhance ultrasound monitoring accuracy by filtering motion artifacts29 and tissue variability24) that dynamically adjust their parameters would further enhance measurement reliability. Meanwhile, a ~10 MHz ultrasonic probe was employed, significantly higher in frequency than the typical sub-3 MHz probes used for deep brain imaging, to enhance the metagels’ frequency response sensitivity with distinct shape change; however, high-frequency ultrasound has a short wavelength, making it susceptible to variations when passing through the brain skull, leading to substantial attenuation in deep tissue. Potential solutions for low-frequency ultrasound detection with high sensitivity for deep brain monitoring include the use of piezoelectric polyvinylidene fluoride (PVDF) and its copolymers, piezoelectric ceramics with flexible polymers, gel-based or elastomeric coupling layers, and acoustic lenses with tailored low-frequency properties in transducer design. Leveraging the synergistic properties of its hydrogel matrix and engineered air-column architecture, the metagel platform enables wireless multiparameter monitoring while potentially addressing critical clinical gaps. In acute care settings (TBI management or post-neurosurgical monitoring), its biodegradability eliminates secondary removal surgeries, reducing iatrogenic risks by 100% compared to wired implants. For resource-constrained environments, it exploits the global ubiquity of ultrasound technology (present in >90% of healthcare facilities worldwide) versus MRI/CT-dependent alternatives. Moreover, seamless integration with electronic health records (EHR) through standardized interfaces potentially enabled by micro-electromechanical systems (MEMS) and 3D-printed adapters would bridge critical data siloes, transforming episodic measurements into longitudinal physiological trajectories for precision neurocritical care30.

Conclusion

The metagel sensor represents a paradigm shift in intracranial monitoring, uniting bioresorbability, multiplexed sensing, and wireless operation. By addressing traditional hydrogel limitations through phononic crystal design and natural polymer engineering, it paves the way for minimally invasive, risk-reduced neuromonitoring. Resolving degradation kinetics and ultrasound attenuation challenges will be pivotal to translating this innovation into clinical treatment and smart healthcare, potentially advancing care for millions of neurological patients worldwide.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

The authors gratefully acknowledge the ISTBI at Fudan University for its foundational startup support, particularly during its 10th anniversary, a milestone celebrating a decade of pioneering interdisciplinary research in neuroscience and intelligent technologies. This work also coincides with Fudan University’s 120th anniversary (1905–2025), a historic occasion honoring its enduring legacy in advancing global scientific and educational excellence. The authors acknowledge the support from the Computational Frontier CFFF at Fudan University for providing computational resources. This research was funded by the National Natural Science Foundation of China (No. 22205254). The authors thank reviewers’ and editors’ efforts in improving this work.

Funding

Open Access funding enabled and organized by Projekt DEAL.

Author information

Authors and Affiliations

  1. Institute of Science and Technology for Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China

    Yuchun Wang, Minyan Ge, Ru Wang, Yinghao Zhu & Shumao Xu

  2. Max-Planck Institute for Solid State Research, Stuttgart, Germany

    Shumao Xu

Authors

  1. Yuchun Wang
  2. Minyan Ge
  3. Ru Wang
  4. Yinghao Zhu
  5. Shumao Xu

Contributions

Conceptualization: S.X.; Literature synthesis and perspective development: Y.W., M.G., R.W. and Y.Z.; Writing—original draft preparation: S.X.; Writing—review and editing: Y.W., M.G., R.W., Y.Z. and S.X.; Supervision: S.X. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Shumao Xu.

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The authors declare no competing interests.

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Wang, Y., Ge, M., Wang, R. et al. Injectable ultrasonic metagels for intracranial monitoring. npj Biosensing 2, 38 (2025). https://doi.org/10.1038/s44328-025-00058-7

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