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Soft and stretchable organic bioelectronics for continuous intraoperative neurophysiological monitoring during microsurgery

Nature Biomedical Engineering (2023)Cite this article

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Abstract

In microneurosurgery, it is crucial to maintain the structural and functional integrity of the nerve through continuous intraoperative identification of neural anatomy. To this end, here we report the development of a translatable system leveraging soft and stretchable organic-electronic materials for continuous intraoperative neurophysiological monitoring. The system uses conducting polymer electrodes with low impedance and low modulus to record near-field action potentials continuously during microsurgeries, offers higher signal-to-noise ratios and reduced invasiveness when compared with handheld clinical probes for intraoperative neurophysiological monitoring and can be multiplexed, allowing for the precise localization of the target nerve in the absence of anatomical landmarks. Compared with commercial metal electrodes, the neurophysiological monitoring system allowed for enhanced post-operative prognoses after tumour-resection surgeries in rats. Continuous recording of near-field action potentials during microsurgeries may allow for the precise identification of neural anatomy through the entire procedure.

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Fig. 1: Advantages of soft PEDOT electrodes over conventional handheld probes for intraoperative neurophysiological monitoring.
Fig. 2: Soft PEDOT electrodes for conformable neural interfaces.
Fig. 3: Soft PEDOT electrodes for intraoperative CNAP monitoring.
Fig. 4: Soft PEDOT electrodes for reliable and consistent long-term CNAP monitoring.
Fig. 5: Minimal invasiveness without nerve damage induced by the soft PEDOT electrodes.
Fig. 6: Improved post-operative prognosis using soft PEDOT electrodes.

Data availability

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

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82071996). Part of the work was supported by the Wu Tsai Neuroscience Institute at Stanford University. Part of this work was performed at the Stanford Nano Shared Facilities (SNSF), supported by the National Science Foundation under award ECCS-2026822. We thank G. Jia and Z. Xue for administrative support; L. Yang for instrument support of CINM measurements; and D. Zhang, C. Zhang, X. Wang and Y. Wang for guidance with the project.

Author information

Author notes

  1. These authors contributed equally: Wenjianlong Zhou, Yuanwen Jiang.

Authors and Affiliations

  1. Department of Neurosurgery, Beijing Tiantan Hospital, National Center for Neurological Disorders, Capital Medical University, Beijing, China

    Wenjianlong Zhou, Qin Xu, Liangpeng Chen, Yuan Zhang, Xiudong Guan, Shunchang Ma, Peng Kang, Linhao Yuan, Deling Li & Wang Jia

  2. Department of Chemical Engineering, Stanford University, Stanford, CA, USA

    Yuanwen Jiang, Jian-Cheng Lai, Donglai Zhong, Jeffrey B.-H. Tok & Zhenan Bao

  3. Department of Neurophysiology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China

    Hui Qiao

  4. Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Department of Chemistry, School of Science, Tianjin University, Tianjin, China

    Yi-Xuan Wang

  5. Department of Electronic Engineering, Tsinghua University, Beijing, China

    Weining Li, Xuecheng Wang, Jiaxin Lei & Milin Zhang

  6. Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Yanru Du & Gehong Dong

  7. Department of Neurotomy, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China

    Shunchang Ma & Wang Jia

  8. China National Clinical Research Center for Neurological Diseases (NCRC-ND), Beijing, China

    Deling Li & Wang Jia

  9. Beijing Neurosurgical Institute, Capital Medical University, Beijing, China

    Deling Li

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  1. Wenjianlong Zhou
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Contributions

W.Z., Y.J., D.L., Z.B. and W.J. designed the study. Y.J., J.-C.L., D.Z. and Y.-X.W. performed material synthesis and characterizations. W.Z., Q.X., L.C., H.Q., Y.Z., W.L., X.W., J.L., X.G., S.M., P.K., L.Y. and M.Z. performed the animal experiments and cell culture. Y.D. and G.D. performed the histological staining. W.Z., Y.J., J.B.-H.T., D.L. and Z.B. wrote the manuscript with input from all co-authors.

Corresponding authors

Correspondence to Deling Li, Zhenan Bao or Wang Jia.

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Nature Biomedical Engineering thanks Nick Donaldson, Peter Nakaji and Bozhi Tian for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Schematic (a) and photo (b) of the PEDOT electrodes wrapped around the facial-acoustic nerve complex.

The PEDOT device was implanted in a human cadaver skull via retrosigmoid approach from superior view of axial cross section. CN V: Trigeminal nerve; CN VII-VIII: Facial-acoustic nerve complex.

Extended Data Fig. 2 Microanatomy and structures affected by vestibular schwannomas (VS).

a, Schematic showing the relevant microanatomy of the cerebellopontine angle (CPA). b-c, Schematic (b) and MRI image (c) showing the effect of tumour growth on the adjacent cranial nerves, the brainstem, and the cerebellum. VS characteristically arise within the internal auditory canal, from one of the two vestibular divisions of the vestibulocochlear nerve. CN V: Trigeminal nerve; CN VII-VIII: Facial-acoustic nerve complex; CN IX-XI: Glossopharyngeal nerve, vagus nerve and accessory nerve.

Extended Data Fig. 3 The whole process of retrosigmoid craniotomy in a rabbit model.

a-c, A linear, vertically oriented occipital incision was used in the surgery. d, After removing the bone, the dura was exposed. e, The dura was then opened, exposing the facial-acoustic nerve complex with the cerebellum retracted. f, Soft PEDOT electrodes were wrapped around the facial-acoustic nerve complex for subsequent neurophysiological monitoring. CN VII-VIII: Facial-acoustic nerve complex.

Extended Data Fig. 4 PEDOT electrodes can be multiplexed for nerve for facial-acoustic nerve complex identification.

Three groups of unidentified nerves were exposed after retracting the cerebellum of an anesthetized rabbit. Soft PEDOT electrodes were wrapped around each visible nerve for facial-acoustic nerve complex identification. Electromyography (EMG, 1 mA, single stimulation) was used in CN V, CN VII and CN XI identification, cochlear nerve action potentials (CNAP) was used in CN VIII identification. The P values for comparison of the amplitudes are as follows: for the CN V (n = 3 rabbits), P < 0.001 compared with the rest; for the CN VII (n = 3 rabbits), P < 0.001 compared with the rest; for the CN VIII (n = 3 rabbits), P < 0.001 compared with the rest; for the CN XI (n = 3 rabbits), P < 0.001 compared with the rest. All error bars denote s.d. *P < 0.05; **P < 0.01; ***P < 0.001; unpaired, two-tailed student’s t-test was used. CN V: Trigeminal nerve; CN VII-VIII: Facial-acoustic nerve complex; CN IX-XI: Lower cranial nerves (Glossopharyngeal nerve, vagus nerve and accessory nerve).

Source data

Extended Data Fig. 5 Soft PEDOT electrode for intra-operative cochlear nerve action potentials (CNAP) monitoring.

a, Photos of the PEDOT (left) and Au (left) electrodes wrapped around the facial-cochlear nerve complex for CNAP recording. b, CNAP values were measured from the PEDOT (up) and Au (down) device. c, PEDOT electrode could consistently record higher CNAP amplitudes than those from the Au electrode. (n = 11 nerves, P < 0.001). All error bars denote s.d. *P < 0.05; **P < 0.01; ***P < 0.001; unpaired, two-tailed student’s t-test was used for c. CN VII-VIII: Facial-acoustic nerve complex.

Source data

Extended Data Fig. 6 PEDOT electrodes for real-time auditory monitoring.

a, Schematic and variation of cochlear nerve action potentials (CNAP) waveforms measured by PEDOT electrodes during nerve tugging. * denotes the time point of nerve tugging. b, Schematic and variation of CNAP waveforms measured by Au during nerve tugging. * denotes the time point of nerve tugging. c, Comparison of response latencies of CNAP recorded by PEDOT or Au electrodes during nerve tugging. (n = 4 rabbits, P = 0.427). d, Comparison of recovery latencies of CNAP recorded by Au or PEDOT electrodes during nerve tugging. (n = 4 rabbits, P < 0.001). e, Percentage of CNAP amplitude after physical nerve tugging recorded by Au or PEDOT electrodes. (n = 4 rabbits, P < 0.001). All error bars denote s.d. *P < 0.05; **P < 0.01; ***P < 0.001; unpaired, two-tailed student’s t-test was used for c-e. Schematics in a and b were created with BioRender.com.

Source data

Extended Data Fig. 7 Hearing preservation without nerve damage after continuous intra-operative neurophysiological monitoring by soft PEDOT electrodes.

a-b, Comparison of brainstem auditory evoked potentials (BAEP) amplitude (a) and latency (b) with and without soft PEDOT electrodes wrapping. P values for comparing the BAEP amplitudes and latencies are as follows: I, pre-operation (n = 8 rabbits) vs post-operation (n = 6 rabbits), P = 0.549; II, pre-operation (n = 8 rabbits) versus post-operation (n = 6 rabbits), P = 0.025; III, pre-operation (n = 8 rabbits) versus post-operation (n = 6 rabbits), P = 0.742; IV, pre-operation (n = 8 rabbits) versus post-operation (n = 6 rabbits), P < 0.001; V, pre-operation (n = 8 rabbits) versus post-operation (n = 6 rabbits), P = 0.258; 0 - I, pre-operation (n = 8 rabbits) versus post-operation (n = 6 rabbits), P = 0.676; I - II, pre-operation (n = 8 rabbits) versus post-operation (n = 6 rabbits), P = 0.076; II - III, pre-operation (n = 8 rabbits) versus post-operation (n = 6 rabbits), P = 0.299; III - IV, pre-operation (n = 8 rabbits) versus post-operation (n = 6 rabbits), P = 0.035; IV - V, pre-operation (n = 8 rabbits) versus post-operation (n = 6 rabbits), P = 0.154. c-d, Comparison of BAEP amplitude (c) and latency (d) with and without rigid electrodes wrapping. P values for comparing the BAEP amplitudes and latencies are as follows: I, pre-operation (n = 8 rabbits) versus post-operation (n = 8 rabbits), P = 0.005; II, pre-operation (n = 8 rabbits) versus post-operation (n = 8 rabbits), P < 0.001; III, pre-operation (n = 8 rabbits) versus post-operation (n = 8 rabbits), P = 0.058; IV, pre-operation (n = 8 rabbits) versus post-operation (n = 8 rabbits), P < 0.001; V, pre-operation (n = 8 rabbits) versus post-operation (n = 8 rabbits), P = 0.002; 0 - I, pre-operation (n = 8 rabbits) versus post-operation (n = 8 rabbits), P < 0.001; I - II, pre-operation (n = 8 rabbits) versus post-operation (n = 8 rabbits), P < 0.001; II - III, pre-operation (n = 8 rabbits) versus post-operation (n = 8 rabbits), P < 0.001; III - IV, pre-operation (n = 8 rabbits) versus post-operation (n = 8 rabbits), P = 0.987; IV - V, pre-operation (n = 8 rabbits) versus post-operation (n = 8 rabbits), P = 0.236. e, Comparison of BAEP amplitude with soft PEDOT electrodes wrapping and with rigid electrodes wrapping. P values for comparing the BAEP amplitudes are as follows: I, PEDOT electrodes (n = 6 rabbits) versus rigid electrodes (n = 8 rabbits), P = 0.049; II, PEDOT electrodes (n = 6 rabbits) versus rigid electrodes (n = 8 rabbits), P < 0.001; III, PEDOT electrodes (n = 6 rabbits) versus rigid electrodes (n = 8 rabbits), P = 0.206; IV, PEDOT electrodes (n = 6 rabbits) versus rigid electrodes (n = 8 rabbits), P = 0.820; V, PEDOT electrodes (n = 6 rabbits) versus rigid electrodes (n = 8 rabbits), P = 0.009. All error bars denote s.d. *P < 0.05; **P < 0.01; ***P < 0.001; NS, not significant; unpaired, two-tailed student’s t-test was used for a-e. I: wave I – potentials in the auditory nerve (distal part); II: wave II – potentials at proximal part of cochlear nucleus; III: wave III – potentials at lower pons, superior olivary nucleus; IV: wave IV - potentials at upper pons; V: wave V - potentials at lower midbrain.

Source data

Extended Data Fig. 8 Long term biocompatibility.

a, Schematic of the biocompatibility study and longitudinal-section slice of sciatic nerve labelled by the inflammatory biomarker ER-HR3 for soft PEDOT, rigid and sham control. Soft PEDOT electrodes or rigid electrodes were wrapped around the sciatic nerve of the rats for 2 weeks, respectively. b, Histogram showing the mean fluorescence intensity of ER-HR3 for soft PEDOT, rigid and sham control (n = 4 nerves). The P values for comparison of the ER-HR3 intensities are as follows: for sham and the soft PEDOT electrodes, P < 0.001; for sham and the rigid electrodes, P < 0.001. for soft PEDOT and rigid electrodes, P < 0.001. All error bars denote s.d. *P < 0.05; **P < 0.01; ***P < 0.001; unpaired, two-tailed student’s t-test was used for b. Schematics in a were created with BioRender.com.

Source data

Extended Data Fig. 9 Correlation between cochlear nerve action potentials (CNAP) signals and degrees of nerve damage.

a-f, Photos of the same rabbit sciatic nerve under various degrees of sharp damage using micro-scissors and corresponding evoked Electromyography (EMG) signals. g, Comparison of evoked EMG amplitudes with soft PEDOT electrodes under various degrees of sharp damage. P values for comparing the EMG amplitudes are as follows: G 0 (n = 4 nerves) versus G I (n = 4 nerves), P = 0.007; G I (n = 4 nerves) versus G II (n = 4 nerves), P = 0.005; G II (n = 4 nerves) versus G III (n = 4 nerves), P = 0.007; G III (n = 4 nerves) versus G IV (n = 4 nerves), P = 0.011; h, Amplitudes of Brainstem auditory evoked potentials (BAEP) and CNAP under various degrees of cochlear nerve damage. CNAP was recorded from soft PEDOT electrodes wrapping around the nerve. P values for comparing the amplitudes are as follows: CNAP: No damage (n = 4 nerves) versus Severe damage (n = 4 nerves), P < 0.001; BAEP (V I): No damage (n = 4 nerves) versus Severe damage (n = 4 nerves), P < 0.001; BAEP (V I): No damage (n = 4 nerves) versus Severe damage (n = 4 nerves), P < 0.001. All error bars denote s.d. *P < 0.05; **P < 0.01; ***P < 0.001; paired, two-tailed student’s t-test was used for g; unpaired, two-tailed student’s t-test was used for h.

Source data

Extended Data Fig. 10 Neural stimulation for facial nerve evaluation.

a, Schematic of neural stimulation for facial nerve evaluation. b-c, Schematic and evoked electromyography (EMG) waveforms by stimulating the facial nerves using PEDOT electrodes (b) and commercial metal electrodes (c) at 4 mA. d, Comparison of evoked EMG amplitudes by PEDOT electrodes and conventional metal electrodes at 4 mA (n = 9 nerves, P < 0.001). All error bars denote s.d. *P < 0.05; **P < 0.01; ***P < 0.001; unpaired, two-tailed student’s t-test was used for d. Schematics in a, b and c were created with BioRender.com.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–12, Table 1 and video captions.

Reporting Summary

Supplementary Video 1

BAEP monitoring.

Supplementary Video 2

CNAP monitoring.

Supplementary Video 3

Comparison of response (recovery) latency between BAEP and CNAP signals under single cochlear nerve tugging.

Supplementary Video 4

The slow response and long recovery latency of BAEP signals under repeated nerve tugging.

Supplementary Video 5

Temporal cochlear nerve tugging under continuous CNAP monitoring.

Supplementary Video 6

Gait study of sciatic nerve schwannoma model.

Supplementary Video 7

Gait comparison between rat monitored with PEDOT electrodes and commercial metal electrodes.

Supplementary Video 8

Electrical stimulations with PEDOT electrodes.

Supplementary Video 9

Comparison of electrical-stimulation efficiency between soft PEDOT electrodes and conventional metal electrodes.

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Zhou, W., Jiang, Y., Xu, Q. et al. Soft and stretchable organic bioelectronics for continuous intraoperative neurophysiological monitoring during microsurgery. Nat. Biomed. Eng (2023). https://doi.org/10.1038/s41551-023-01069-3

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