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Cited by 96Neuroscience and Neural EngineeringVagus Nerve Stimulation ResearchWireless Body Area Networks

Toward Bioelectronic Medicine—Neuromodulation of Small Peripheral Nerves Using Flexible Neural Clip

Open access
Lee, Sanghoon, Peh, Wendy Yen Xian, Wang, Jiahui, Yang, Fengyuan, Ho, John S., Thakor, Nitish V., Yen, Shih‐Cheng, Lee, Chengkuo·2017·Advanced Science
DOI 10.1002/advs.201700149PMC PMC5700646
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Abstract

Neural modulation technology and the capability to affect organ function have spawned the new field of bioelectronic medicine. Therapeutic interventions depend on wireless bioelectronic neural interfaces that can conformally and easily attach to small (few hundred micrometers) nerves located deep in the body without neural damage. Besides size, factors like flexibility and compliance to attach and adapt to visceral nerves associated moving organs are of paramount importance and have not been previously addressed. This study proposes a novel flexible neural clip (FNC) that can be used to interface with a variety of different peripheral nerves. To illustrate the flexibility of the design, this study stimulates the pelvic nerve, the vagus nerve, and branches of the sciatic nerve and evaluates the feasibility of the design in modulating the function of each of these nerves. It is found that this FNC allows fine‐tuning of physiological processes such as micturition, heart rate, and muscle contractions. Furthermore, this study also tests the ability of wirelessly powered FNC to enable remote modulation of visceral pelvic nerves located deep in the body. These results show that the FNC can be used with a range of different nerves, providing one of the critical pieces in the field of bioelectronics medicines.

AI snapshot

Written from the paper’s full text.

TL;DR

The paper presents a flexible neural clip (FNC) for conformal interfacing with small peripheral nerves and demonstrates acute neuromodulation of pelvic, vagus, and sciatic nerve branches in rats, including wirelessly powered pelvic nerve stimulation. The FNC enabled graded bladder control, heart rate reduction, and selective muscle activation, supporting its potential for bioelectronic medicine.

Key findings

  • Pelvic nerve stimulation with the FNC produced graded bladder pressure changes and micturition at 25–200 µA (n = 3 trials); suprathreshold amplitudes (100–200 µA) caused repeatable micturition, with no significant differences between 400 µm and 1600 µm interelectrode configurations in urine output, poststimulation pressure drop, or time to peak pressure (two-way ANOVA, p > 0.05).
  • Vagus nerve stimulation (30 Hz, 0.4 ms pulse width, 3.3 s duration, 0.2 mA) reduced heart rate by a mean of 25.5% during stimulation, and heart rate recovered to 99.8% of prestimulation values at 10 min after stimulation stopped (n = 17).
  • Sciatic branch stimulation showed selective muscle activation: common peroneal nerve rheobase was 4 µA with chronaxie 470 µs, and tibial nerve rheobase was 8 µA with chronaxie 180 µs; stimulation at 500 µs (CP) and 170 µs (tibial) activated tibialis anterior and gastrocnemius muscles differentially, while lidocaine completely blocked CP nerve-evoked EMG.
  • A wireless active FNC (3 mm × 5 mm, 70 mg, ≈0.1 mW) remotely modulated pelvic nerve function; micro-CT showed implantation depth of 8.5 mm from skin, and urine output increased from 150 to 300 µs phase width then slightly decreased at 500 µs (one-way ANOVA, p > 0.05, n = 3 trials each).

Methods

  • The FNC was a polyimide–Au–polyimide sandwiched structure fabricated by MEMS technology, with exposed Au electrodes electroplated with iridium oxide (EIROF); coated electrodes showed impedance of 1.9 ± 0.09 kΩ at 1 kHz and cathodic charge storage capacity of 56.4 ± 2.42 mC cm⁻² (n = 10).
  • Acute in vivo experiments used adult female Sprague-Dawley rats (200–300 g) under ketamine/xylazine anesthesia: sciatic nerve branch experiments (N = 2 rats), vagus nerve experiments (N = 3 rats), and bladder/pelvic nerve experiments (N = 1 rat).
  • Functional outputs were assessed by intrabladder pressure and urine output, ECG/heart rate, and EMG/compound muscle action potentials; a wireless active FNC with receiving coil, rectifier, and LED was tested for remote pelvic nerve stimulation, with micro-CT used to determine implantation depth.

Limitations

  • The paper states that future chronic FNC implantation experiments are needed to assess nerve health and functionality over time and to validate long-term efficacy and reliability; the present work is acute and performed under anesthesia.
  • The paper notes that VNS results cannot be directly compared with other studies due to complex stimulation parameters and experimental conditions.
  • Evident from the text: sample sizes are small (bladder N = 1 rat, sciatic N = 2 rats, vagus N = 3 rats; some analyses use n = 3 trials), and wireless remote modulation was demonstrated only for the pelvic nerve, not for vagus or sciatic branches.

Model-written summary. Check it against the paper before relying on it.

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Registry

Crossref · 10.1002/advs.201700149

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The IrO2-coated electrodes had an impedance of 1.9 ± 0.09 kΩ at 1 kHz (n = 10).

    “The coated IrO2 on Au sensing electrodes showed a good impedance value (1.9 ± 0.09 kΩ at 1 kHz, n = 10)”
    Quote in the paperSubstantial claim
  • Findingown data

    The IrO2-coated electrodes had a cathodic charge storage capacity of 56.4 ± 2.42 mC cm−2 (n = 10).

    “and a cathodic charge storage capacity (56.4 ± 2.42 mC cm−2, n = 10) for stimulation.”
    Quote in the paperSubstantial claim
  • Findingown data

    Wirelessly powered FNC enables remote modulation of visceral pelvic nerves located deep in the body.

    “Furthermore, this study also tests the ability of wirelessly powered FNC to enable remote modulation of visceral pelvic nerves located deep in the body.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The FNC can attach to and stimulate small peripheral nerves without causing neural damage.
  • Findingown data

    The FNC was implanted easily on the vagus nerve despite continuous movement due to respiration and heartbeats.

    “The FNC was implanted easily on the vagus nerve (Figure 4b), despite the continuous movement of the nerve due to respiration and heartbeats.”
    Quote in the paperSubstantial claim
  • Findingown data

    The FNC can be implanted onto a peripheral nerve easily by inserting the nerve between the clip-strip and clip-springs after slightly bending the clip-springs.

    “The FNC can be implanted onto a peripheral nerve easily by inserting the nerve between the clip‐strip and clip‐springs after slightly bending the clip‐springs (Figure 2b).”
    Quote in the paperSubstantial claim
  • May combine two claims. 29
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 8

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Stimulation of the pelvic nerve with the miniature FNC increased bladder pressure and produced micturition in a graded, repeatable manner at increasing currents (25-200 μA).

    “Bladder contraction corresponding to increased positive bladder pressure changes was observed for both implantation configurations at increasing simulation currents (range: 25–200 µA, n = 3 trials).”
    • Also stated in: § Stimulation of Pelvic Nerve for Modulation of Bladder Function · plain
      “higher “suprathreshold” amplitude (100–200 µA) caused larger pressure changes and led to graded and repeatable miturition of urine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At suprathreshold amplitudes, urine output, poststimulation pressure drop, and time to peak bladder pressure were similar and not significantly different between the 400 μm and 1600 μm implantation configurations.

    “At suprathreshold amplitudes, the urine output (Figure 3d), poststimulation pressure drop (Figure 3e), and time to reach peak bladder pressures (Figure 3f) were similar and not significantly different between the two implantation configurations”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The threshold current for evoking CMAPs was 4 μA for the common peroneal nerve and 8 μA for the tibial nerve.

    “The I rh of the CP nerve was 4 µA, and the calculated T ch from the curve was 470 µs. For the tibial nerve, the I rh was 8 µA, and the T ch was 180 µs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Vagus nerve stimulation with the FNC significantly reduced heart rate during stimulation, and heart rate recovered to baseline after stimulation.

    “The HR was significantly reduced during the stimulation, and recovered to baseline after the stimulation (Figure 4d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Urine output increased when phase width increased from 150 to 300 μs, but slightly decreased from 300 to 500 μs, albeit nonsignificantly (one-way ANOVA, p > 0.05, n = 3 trials each).

    “The urine output increased when the phase width increased from 150 to 300 µs, but it slightly decreased from 300 to 500 µs, albeit nonsignificantly (one‐way ANOVA, p > 0.05, n = 3 trials each).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Sural nerve stimulation produced only a small twitch of the middle toe and no muscle signals from the tibialis anterior or gastrocnemius.

    “However, only small twitch of the middle toe in the rat was observed and there were no muscle signals of the TA and the GC”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The mean reduction in heart rate was 25.5% during stimulation, and heart rate recovered to 99.8% (n = 17) of prestimulation heart rate at 10 min after stimulation stopped.

    “The mean reduction in the HR was 25.5% during the stimulation, and the HR recovered to 99.8% (n = 17) of the HR before stimulation when it was measured at 10 min after the stimulation was stopped (Figure 4e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stimulation of the common peroneal nerve activated the tibialis anterior muscle more than the gastrocnemius muscle and produced ankle dorsiflexion.

    “The TA muscle was activated more than the GC muscle during CP nerve stimulation, and ankle dorsiflexion was clearly observed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lidocaine application to the common peroneal nerve blocked the nerve completely, and no stimulation-evoked EMG signals were observed.

    “The CP nerve was blocked completely, and no stimulation‐evoked electromyogram (EMG) signals were observed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stimulation of the tibial nerve activated the gastrocnemius muscle more than the tibialis anterior muscle and produced ankle extension with leg stretch.

    “During tibial nerve stimulation, the GC muscle was activated more than the TA muscle, and ankle extension (plantar‐flexion) with leg stretch was visible.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The implanted active FNC was positioned well near the pubis bone, and the distance between the implanted active FNC and skin was 8.5 mm.

    “The small active FNC was positioned well near pubis bone (Figure 6d) and the distance between the implanted active FNC and skin is 8.5 mm (Figure 6e).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The chronaxie was 470 μs for the common peroneal nerve and 180 μs for the tibial nerve.

    “The I rh of the CP nerve was 4 µA, and the calculated T ch from the curve was 470 µs. For the tibial nerve, the I rh was 8 µA, and the T ch was 180 µs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    The power used to operate the wireless active FNC was around 0.1 mW.

    “The power used to operate the device was around ≈0.1 mW.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For pelvic nerve stimulation, the actual duration was 5.21 ± 0.21 s for 150 μs phase width, 6.12 ± 0.58 s for 300 μs, and 5.86 ± 1.00 s for 500 μs, with a mean of 5.73 ± 0.71 s.

    “Actual duration was (i) 5.21 ± 0.21 s, (ii) 6.12 ± 0.58 s, and (iii) 5.86 ± 1.00 s, respectively and the mean was 5.73 ± 0.71 s.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The tiny and wirelessly powered FNC could be reliably implanted on the small visceral pelvic nerve deeply located in the body and provide remote modulation of micturition in rats.

    “This tiny and wirelessly powered FNC could be reliably implanted on the small visceral pelvic nerve deeply located in the body and providing remote modulation of micturition in rats.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The pelvic nerve was stimulated in a graded manner to control bladder contractions, leading to reproducible micturition events comparable with other published techniques that use large size electrodes.

    “The present findings indicate that the pelvic nerve was stimulated in a graded manner to control bladder contractions, leading to reproducible micturition events comparable with other published techniques that use large size electrodes with high possibility of damaging nerves along the usage process.21, 31”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] D. J. Chew, L. Zhu, E. Delivopoulos, I. R. Minev, K. M. Musick, C. A. Mosse, M. Craggs, N. Donaldson, S. P. Lacour, S. B. McMahon, J. W. Fawcett, Sci. Transl. Med. 2013, 5, 210ra155. 24197736

      Not checked in the free run.

    • cites [31] H. A. Wark, S. R. Black, K. S. Mathews, P. C. Cartwright, K. J. Gustafson, R. A. Normann, Neuromodulation 2015, 18, 317. 25430001

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The IrO2-coated electrodes' impedance and charge storage capacity are comparable or better than materials used previously for neural stimulation.

    “These values are comparable or even better to materials used previously in the literature for neural stimulation.25, 26, 27”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] X. Y. Kang, J. Q. Liu, H. C. Tian, B. Yang, Y. NuLi, C. S. Yang, Conf. Proc. IEEE Eng. Med. Biol. Soc. 2014, 478. 25570000

      Not checked in the free run.

    • cites [26] R. D. Meyer, S. F. Cogan, T. H. Nguyen, R. D. Rauh, IEEE Trans. Neural Syst. Rehabil. Eng. 2001, 9, 2. 11482359

      Not checked in the free run.

    • cites [27] E. Slavcheva, R. Vitushinsky, W. Mokwa, U. Schnakenberg, J. Electrochem. Soc. 2004, 151, E226.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The FNC interface provides conformal contact with the nerve and gentle pressure to keep the clip interface in place.

    “This interface provides not only conformal contact with the nerve but also gentle pressure on the nerve to keep the clip interface in place.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The heart rate changes produced by FNC VNS are comparable or slightly more effective than previous studies within the safety range of the stimulation parameter.

    “The result indicates that the HR changes are comparable or slightly more effective than previous studies33, 39 within the safety range of the stimulation parameter, though it cannot directly be compared with other studies due to complex stimulation parameters and experimental conditions.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] M. Gierthmuehlen, D. T. Plachta, Hypertens. Res. 2016, 39, 79. 26581776

      Not checked in the free run.

    • cites [39] H. P. Buschman, C. J. Storm, D. J. Duncker, P. D. Verdouw, H. E. V. D. Aa, P. V. D. Kemp, Neuromodulation 2006, 9, 214. 22151709

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    This ease of implantation has great surgical benefits when the FNC is implanted in small nerves located inside the body in narrow and deep spaces, accompanied by continuous movements such as respiration and heartbeat.

    “This ease of implantation has great surgical benefits when the FNC is implanted in small nerves located inside the body in narrow and deep spaces, accompanied by continuous movements such as respiration and heartbeat.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Among three typical fabrication methods, electrodeposited iridium oxide film (EIROF) shows the largest charge storage capacity and lowest impedance.

    “Among three typical fabrication methods; sputtering iridium oxide film, activated oxide film, and electrodeposited iridium oxide film (EIROF), EIROF shows the largest CSC and lowest impedance.25”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] X. Y. Kang, J. Q. Liu, H. C. Tian, B. Yang, Y. NuLi, C. S. Yang, Conf. Proc. IEEE Eng. Med. Biol. Soc. 2014, 478. 25570000

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The FNC works well on sciatic nerve branches with different sizes and can be used to evoke different patterns of muscle activation.

    “These results indicate that the FNC work well on sciatic nerve branches with different sizes, and consequently can be used to evoke different patterns of muscle activation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The FNC can attach to and stimulate small peripheral nerves without causing neural damage.

  • May combine two claims.

    Premisecitation

    The pelvic nerve is a small visceral nerve located deep within the body, leading to difficulties in implantation and maintaining contact for reliable stimulation with current neural electrodes.

    “However, the pelvic nerve is a small visceral nerve located deep within the body, which leads to difficulties in implantation, as well as maintaining contact for reliable stimulation if current neural electrodes are used.6, 12, 13, 30”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] D. W. Tan, M. A. Schiefer, M. W. Keith, J. R. Anderson, J. Tyler, D. J. Tyler, Sci. Transl. Med. 2014, 6, 257ra138. PMC5517305 25298320

      Not checked in the free run.

    • cites [12] I. R. Minev, P. Musienko, A. Hirsch, Q. Barraud, N. Wenger, E. M. Moraud, J. Gandar, M. Capogrosso, T. Milekovic, L. Asboth, R. F. Torres, N. Vachicouras, Q. Liu, N. Pavlova, S. Duis, A. Larmagnac, J. Vörös, S. Micera, Z. Suo, G. Courtine, S. P. Lacour, Science 2015, 347, 159. 25574019

      Not checked in the free run.

    • cites [13] G. Di Pino, L. Denaro, G. Vadala, A. Marinozzi, M. Tombini, F. Ferreri, R. Papalia, D. Accoto, E. Guglielmelli, V. Di Lazzaro, V. Denaro, J. Surg. Res. 2014, 188, 77. 24433868

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The FNC design allows reliable implantation and stimulation of pelvic nerves in rats.

    “This design allows reliable implantation and stimulation of pelvic nerves in rats.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    High electrode impedances require high voltages to inject desired current amplitudes, resulting in undesirable electrochemical reactions that may damage the electrode and tissue.

    “High electrode impedances will require high voltages to inject desired current amplitudes, which results in undesirable electrochemical reactions, possibly damaging both the electrode and the tissue.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] H. K. Naser Pour Aryan, Albrecht Rothermel, Stimulation and Recording Electrodes for Neural Prostheses, Springer, 2015.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    If charge delivery capacity is poor, high current amplitudes will be required for nerve activation, which may cause nerve damage or delamination of the electrode surface.

    “If the charge delivery capacity is poor, high current amplitudes will be required for the activation of the nerve, which may also cause nerve damage or delamination of the electrode surface.24”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] H. K. Naser Pour Aryan, Albrecht Rothermel, Stimulation and Recording Electrodes for Neural Prostheses, Springer, 2015.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The pelvic nerve provides autonomic efferent inputs to contract the bladder detrusor muscle and is anatomically and functionally more specific for bladder neuromodulation.

    “The pelvic nerve is a promising stimulation target for the control of bladder function as it provides autonomic efferent inputs to contract the bladder detrusor muscle, and is anatomically and functionally more specific for bladder neuromodulation.19, 28, 29”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] J. W. Lee, D. Kim, S. Yoo, H. Lee, G. H. Lee, Y. Nam, Int. Neurourol. J. 2015, 19, 3. 25833475 PMC4386488

      Not checked in the free run.

    • cites [28] W. C. Groat, C. Tai, Bioelectron. Med. 2015, 22, 25. PMC4610375 26491706

      Not checked in the free run.

    • cites [29] a) J. N. Langley, M. B. Anderson, J. Physiol. 1896, 20, 372; PMC1512969 16992367 b) O. R. Langworthy, Invest. Urol. 1965, 2, 491; 14261791 c) T. F. Al‐Shaiji, M. Banakhar, M. M. Hassouna, Adv. Urol. 2011, 2011, 757454. 21687571 PMC3113365

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The wireless FNC size is significantly smaller than currently developed neural interfaces and comparable with neural dust.

    “which is significantly smaller size than currently developed neural interfaces and comparable with neural dust (Figure 6a).17”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] D. Seo, R. M. Neely, K. Shen, U. Singhal, E. Alon, J. M. Rabaey, J. M. Carmena, M. M. Maharbiz, Neuron 2016, 91, 529. 27497221

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    VNS has shown other clinical benefits in diseases such as hypertension and rheumatoid arthritis.

    “Furthermore, VNS has shown other clinical benefits in diseases such as hypertension and rheumatoid arthritis.14, 22, 33”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] A. P. Amar, M. L. Levy, C. Y. Liu, M. L. J. Apuzzo, Proc. IEEE 2008, 96, 1142.

      Not checked in the free run.

    • cites [22] S. Onuora, Nat. Rev. Rheumatol. 2016, 12, 500. 27440426

      Not checked in the free run.

    • cites [33] M. Gierthmuehlen, D. T. Plachta, Hypertens. Res. 2016, 39, 79. 26581776

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The common peroneal nerve primarily innervates the tibialis anterior muscle that controls ankle dorsiflexion, while the tibial nerve mainly activates the gastrocnemius muscle for ankle extension.

    “the common peroneal (CP) nerve primarily innervates the tibialis anterior (TA) muscle that controls ankle dorsiflexion40 while the tibial nerve mainly activates the gastrocnemius (GC) muscle for ankle extension41”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] J. H. Burridge, D. L. McLellan, J. Neurol., Neurosurg. Psychiatry 2000, 69, 353. 10945810 PMC1737092

      Not checked in the free run.

    • cites [41] M. A. Schiefer, M. Freeberg, G. J. Pinault, J. Anderson, H. Hoyen, D. J. Tyler, R. J. Triolo, J. Neural Eng. 2013, 10, 056006. 23918148 PMC3809099

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Multiple wireless FNCs applied to each most energy-efficient stimulation parameter for individual target nerves would be effective in improving stimulus selectivity and eliminating the need for selective stimulation techniques through the main sciatic nerve.

    “It also indicates that multiple wireless FNCs applied to each most energy‐efficient stimulation parameter for individual target nerves would be effective in improving the stimulus selectivity as well as eliminating the efforts of selective stimulation techniques through the main sciatic nerve.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    This technical challenge has to be addressed especially for chronic epilepsy studies of common small animal models such as mice and rats.

    “This is a technical challenge that has to be addressed especially for chronic epilepsy studies of common small animal models such as mice and rats.38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] a) M. Aalbers, J. Vles, S. Klinkenberg, G. Hoogland, M. Majoie, K. Rijkers, Exp. Neurol. 2011, 230, 167; 21565191 b) W. Loscher, Seizure 2011, 20, 359. 21292505

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    VNS has been proposed as a promising therapeutic approach for heart failure and cardiac arrhythmia because it provides cardiac autonomic responses such as chronotropic, inotropic, and dromotropic effects.

    “Recently, VNS has been proposed as a promising therapeutic approach such as heart failure34 and cardiac arrhythmia35 as it provides cardiac autonomic responses such as chronotropic, inotropic, and dromotropic effects.23, 33, 36”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] D. Ojeda, V. Le Rolle, H. M. Romero‐Ugalde, C. Gallet, J. L. Bonnet, C. Henry, A. Bel, P. Mabo, G. Carrault, A. I. Hernandez, PLoS One 2016, 11, e0163734. 27690312 PMC5045213

      Not checked in the free run.

    • cites [33] M. Gierthmuehlen, D. T. Plachta, Hypertens. Res. 2016, 39, 79. 26581776

      Not checked in the free run.

    • cites [36] a) E. M. Annoni, X. Xie, S. W. Lee, I. Libbus, B. H. KenKnight, J. W. Osborn, E. G. Tolkacheva, Physiol. Rep. 2015, 3; PMC4562562 26265746 b) S. W. Lee, Q. Li, I. Libbus, X. Xie, B. H. KenKnight, M. G. Garry, E. G. Tolkacheva, Physiol. Rep. 2016, 4, e12786. 27173672 PMC4873636

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    VNS is FDA approved as an adjunctive, nonpharmacological therapy for patients with medically refractory partial onset seizures and as an adjunctive long-term therapy for chronic or recurrent major depression.

    “The Food and Drug Administration (FDA) approved VNS as an adjunctive, nonpharmacological therapy for patients with medically refractory partial onset seizures in 1997, as well as an adjunctive long‐term therapy for chronic or recurrent major depression in 2005.32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] a) J. P. Oreardon, P. Chistancho, A. D. Peshek, Psychiatry 2006, 3, 54;21103178 b) J. Pisapia, G. Baltuch, in Neuromodulation in Psychiatry, (Eds: Hamani C., Holtzheimer P., Lozano A. M., Mayberg H.), John Wiley & Sons Ltd., UK 2016; c) D. A. Groves, V. J. Brown, Neurosci. Biobehav. Rev. 2005, 29, 493. 15820552

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The depth of wireless transfer was preferred.

    “indicating that the depth of wireless transfer was preferred.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several VNS factors such as pulse width, current amplitude, number of pulses, interpulse period, and electrode configurations still need to be verified with physiological effects.

    “For the clinical applications, several VNS factors such as pulse width, current amplitude, number of pulses, interpulse period, and electrode configurations still need to be verified with the physiological effects, though the therapeutic effect has been recognized in preclinical and pilot clinical studies.23”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] D. Ojeda, V. Le Rolle, H. M. Romero‐Ugalde, C. Gallet, J. L. Bonnet, C. Henry, A. Bel, P. Mabo, G. Carrault, A. I. Hernandez, PLoS One 2016, 11, e0163734. 27690312 PMC5045213

      Not checked in the free run.

36 of 36

  • The paper relies on this without support.

    The size of sciatic nerve branches is comparable to visceral nerves.

    “We tested the FNC on various sciatic branches as the size of the branches is comparable to visceral nerves and serves as an additional test bed to interrogate the peripheral limb system.”

  • The paper relies on this without support.

    The FNC can attach to and stimulate small peripheral nerves without causing neural damage.

    “Therapeutic interventions depend on wireless bioelectronic neural interfaces that can conformally and easily attach to small (few hundred micrometers) nerves located deep in the body without neural damage.”

  • The paper relies on this without support.

    Pelvic nerve stimulation for bladder control is relatively less explored compared to other nerve targets.

    “For the bladder nerve application, we stimulated pelvic nerves for the control of bladder function, which is relatively less explored and compared to nerve targets.”

  • The paper relies on this without support.

    The deep abdominal location of the pelvic nerve and respiratory-related movements of the pelvic area demand novel bioelectronic neural interfaces for stable interfacing with thin visceral nerves, which is currently lacking in the field.

    “Part of the reason could be due to the deep abdominal location of the pelvic nerve and respiratory‐related movements of the pelvic area, which demands novel bioelectronic neural interfaces for stable interfacing with thin visceral nerves and that is currently lacking in the field.”

  • The paper relies on this without support.

    Remote modulation of micturition with a device of several millimeters scale has not yet been achieved with current neural interface technologies.

    “the remote modulation of micturition with a device of several millimeters scale is a significant result that has not yet achieved with current neural interface technologies.”
5 of 5

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Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

1 of the 68 references couldn’t be matched to a known paper.

Research works printed but not linked: 7

  1. [5]S. P. Lacour, G. Courtine, J. Guck, Nat. Rev. Mater. 2016, 1, 16063.
  2. [14]A. P. Amar, M. L. Levy, C. Y. Liu, M. L. J. Apuzzo, Proc. IEEE 2008, 96, 1142.
  3. [16]a) S. Lee, S. Sheshadri, Z. Xiang, I. Delgado‐Martinez, N. Xue, T. Sun, N. V. Thakor, S.‐C. Yen, C. Lee, Sens. Actuators, B 2017, 242, 1165; b) D. N. Heo, H. J. Kim, Y. J. Lee, M. Heo, S. J. Lee, D. Lee, S. H. Do, S. H. Lee, I. K. Kwon, ACS Nano 2017, 11, 2961; 28196320 c) S. Lee, S. C. Yen, S. Sheshadri, I. Delgado‐Martinez, N. Xue, Z. Xiang, N. V. Thakor, C. Lee, IEEE Trans. Biomed. Eng. 2016, 63, 581; 26276980 d) Z. Xiang, S. Sheshadri, S. H. Lee, J. Wang, N. Xue, N. V. Thakor, S. C. Yen, C. Lee, Adv. Sci. 2016, 3, 1500386; PMC5039981 27981020 e) Z. Xiang, S. C. Yen, S. Sheshadri, J. Wang, S. Lee, Y. H. Liu, L. D. Liao, N. V. Thakor, C. Lee, Adv. Mater. 2016, 28, 4472; 26568483 f) S. Lee, H. Wang, Q. Shi, L. Dhakar, J. Wang, N. V. Thakor, S.‐C. Yen, C. Lee, Nano Energy 2017, 33, 1.
  4. [24]H. K. Naser Pour Aryan, Albrecht Rothermel, Stimulation and Recording Electrodes for Neural Prostheses, Springer, 2015.
  5. [27]E. Slavcheva, R. Vitushinsky, W. Mokwa, U. Schnakenberg, J. Electrochem. Soc. 2004, 151, E226.
  6. [32]a) J. P. Oreardon, P. Chistancho, A. D. Peshek, Psychiatry 2006, 3, 54;21103178 b) J. Pisapia, G. Baltuch, in Neuromodulation in Psychiatry, (Eds: Hamani C., Holtzheimer P., Lozano A. M., Mayberg H.), John Wiley & Sons Ltd., UK 2016; c) D. A. Groves, V. J. Brown, Neurosci. Biobehav. Rev. 2005, 29, 493. 15820552
  7. [45]S. Kakooei, M. C. Ismail, B. A. Wahjoedi, Int. J. Electrochem. Sci. 2013, 8, 3290.

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Related

Authors
Lee, S., Peh, W. Y. X., Wang, J., Yang, F., Ho, J. S., Thakor, N. V., Yen, S., & Lee, C.
Affiliations
  • National University of Singapore (SG)
  • Johns Hopkins University (US)
Corresponding author
  • Yen, Shih‐Cheng
  • Lee, Chengkuo
ORCID
Venue
Advanced Science
Publisher
Wiley
Published
2017-07-26
Volume
4
Issue
11
Pages
1700149-1700149
ISSN
2198-3844 (ISSN-L)
DOI
10.1002/advs.201700149
PMC
PMC5700646
OpenAlex
W2739186021
Cited by
96
References
68
Citations by year
2026: 2 · 2025: 9 · 2024: 9 · 2023: 9 · 2022: 14 · 2021: 14 · 2020: 19 · 2019: 10 · 2018: 9 · 2017: 1
FWCI
5.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Advanced Science (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
Funders
National Research Foundation
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neural Engineering
  • Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
  • Physical Sciences › Engineering › Biomedical Engineering › Wireless Body Area Networks
Keywords
bioelectronic medicine, neuromodulation, peripheral nerves, neural interfaces, wireless power transfer, pelvic nerve, vagus nerve, sciatic nerve, visceral nerves, micturition, heart rate, muscle contraction, biomedical implants

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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