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A biochemical sensor with continuous extended stability in vivo

Nature Biomedical Engineering volume 9, pages 1517–1530 (2025)Cite this article

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Abstract

The development of biosensors that can detect specific analytes continuously, in vivo, in real time has proven difficult due to biofouling, probe degradation and signal drift that often occur in vivo. By drawing inspiration from intestinal mucosa that can protect host cell receptors in the presence of the gut microbiome, we develop a synthetic biosensor that can continuously detect specific target molecules in vivo. The biomimetic multicomponent sensor features the hierarchical nano-bio interface design with three-dimensional bicontinuous nanoporous structure, polymer coating and aptamer switches, balancing small-molecule sensing and surface protection in complex biological environments. Our system is stable for at least 1 month in undiluted serum in vitro or 1 week implanted within the blood vessels of free-moving rats, retaining over 50% baseline signal and reproducible calibration curves. We demonstrate that the implanted system can intravenously track pharmacokinetics in real time even after 4 days of continuous exposure to flowing blood within rat femoral vein. In this way, our work provides a generalizable design foundation for biosensors that can continuously operate in vivo for extended durations.

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Fig. 1: A biologically inspired approach for long-term, stable electrochemical sensing in complex biological matrices.
Fig. 2: SENSBIT performance after a month-long incubation in human serum in vitro.
Fig. 3: SENSBIT exhibits greatly reduced surface contamination in human whole blood.
Fig. 4: In vivo real-time kanamycin monitoring over several hours with SENSBIT.
Fig. 5: Impact of week-long sensor–blood interface in free-moving rats.
Fig. 6: Intravenous real-time monitoring of kanamycin pharmacokinetics during anaesthesia with SENSBIT after 1, 2 or 4 days of i.v. implantation in free-moving rats.

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Data availability

The main data supporting the findings of this study are available within the paper and its supplementary information files. Extra data are available from the corresponding author upon request. Source data for Figs. 1–6 are provided with this paper.

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Acknowledgements

This work was supported by the Helmsley Trust, Wellcome LEAP SAVE programme, Stanford Material and Child Health Research Institute pilot grant and the National Institutes of Health (NIH, OT2OD025342). Part of this work was performed at the Stanford Nano Shared Facilities (SNSF), Stanford Nanofabrication Facility (SNF) and Stanford University Cell Sciences Imaging Core Facility (RRID:SCR_017787), supported by the National Science Foundation under award ECCS-2026822 and ECCS-1542152. We thank the Canary Center at Stanford for Cancer Early Detection for providing facilities and the Stanford Veterinary Service Center for their assistance with animal care and training. Viability and cell proliferation assays were performed by N. Quispe Calla at Stanford Transgenic, Knockout and Tumor Model Center. Flow cytometry analysis for this project was done on instruments in the Stanford Shared FACS Facility. Y.C. was supported by the T. S. Lo Graduate Fellowship at Stanford University. Z.O. was supported by the Wu Tsai Neurosciences Institute at Stanford University. Y.C. also thanks E. Sullivan of the Technical Communications Program at Stanford for thoughtful feedback on writing, and E. Bagley and N. Torres for lab management support.

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Author notes

  1. These authors contributed equally: Yihang Chen, Kaiyu X. Fu.

Authors and Affiliations

  1. Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA

    Yihang Chen & Zihao Ou

  2. Department of Radiology, Stanford University, Stanford, CA, USA

    Yihang Chen, Kaiyu X. Fu, Jean Won Kwak, Jun-Chau Chien, Vladimir Kesler, Hnin Yin Yin Nyein, Michael Eisenstein & H. Tom Soh

  3. Department of Electrical Engineering, Stanford University, Stanford, CA, USA

    Kaiyu X. Fu, Jun-Chau Chien, Vladimir Kesler, Hnin Yin Yin Nyein, Michael Eisenstein & H. Tom Soh

  4. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA

    Kaiyu X. Fu

  5. Department of Comparative Medicine, Stanford University, Stanford, CA, USA

    Renee Cotton

  6. Department of Bioengineering, Stanford University, Stanford, CA, USA

    H. Tom Soh

  7. Chan Zuckerberg Biohub, San Francisco, CA, USA

    H. Tom Soh

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Contributions

Y.C. and K.X.F. conceived the project. H.T.S. supervised the project. Y.C. and K.X.F. initiated the idea of using a hierarchical nanoarchitecture for long-term stable biosensing in complex biological matrices. Y.C., K.X.F. and H.T.S. designed the experiments. Y.C. performed the experiments, and collected and analysed the data. Y.C. and Z.O. conducted the optical experiments and image analysis. R.C. performed animal surgeries and trained Y.C. Y.C., J.W.K and J.-C.C. worked on improving intravenous microwire probes. V.K. and H.Y.Y.N. advised on electrochemical sensing. Y.C., K.X.F., M.E and H.T.S. co-wrote the paper. All authors discussed the results and commented on the paper.

Corresponding author

Correspondence to H. Tom Soh.

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Competing interests

Y.C., K.X.F. and H.T.S. are listed as co-inventors on a patent application related to this work filed at the US Patent and Trademark Office (No. PCT/US2024/060103). All other authors declare no competing interests.

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Nature Biomedical Engineering thanks Yi Zhang 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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Supplementary Table 1, Notes 1–5, Figs. 1–29, Videos 1 and 2, and References.

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Supplementary Video 1 (download MP4 )

Intravenous implantation. Successful intravenous access was confirmed on the basis of blood flow after retracting the implanted probes.

Supplementary Video 2 (download MP4 )

Multiday implantation in free-moving rat. The rat was able to move freely while the implanted electrode probes were constantly subjected to blood flow and mechanical strain.

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Chen, Y., Fu, K.X., Cotton, R. et al. A biochemical sensor with continuous extended stability in vivo. Nat. Biomed. Eng 9, 1517–1530 (2025). https://doi.org/10.1038/s41551-025-01389-6

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