Ultrasound-triggered local anaesthesia

Abstract

On-demand relief of local pain would allow patients to control the timing, intensity and duration of nerve blocks in a safe and non-invasive manner. Ultrasound would be a suitable trigger for such a system, as it is in common clinical use and can penetrate deeply into the body. Here, we demonstrate that ultrasound-triggered delivery of an anaesthetic from liposomes allows the timing, intensity and duration of nerve blocks to be controlled by ultrasound parameters. On insonation, the encapsulated sonosensitizer protoporphyrin IX produced reactive oxygen species that reacted with the liposomal membrane, leading to the release of the potent local anaesthetic tetrodotoxin. Repeatable ultrasound-triggered nerve blocks were achieved in vivo, with the nerve-block duration depending on the extent and intensity of insonation. There was no detectable systemic toxicity and tissue reaction was benign in all groups. On-demand, personalized local anaesthesia could be beneficial for the management of relatively localized pain states and could potentially minimize opioid use.

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Fig. 1: Ability of ultrasound to trigger PPIX-loaded liposomes.
Fig. 2: Ultrasound-triggered dye release from Lipo–PPIX–SRho.
Fig. 3: TTX-loaded liposomes.
Fig. 4: Representative time courses of thermal latency after injections of liposomal formulations and subsequent insonation.
Fig. 5: Effect of ultrasound on thermal latency after injection of Lipo–PPIX–TTX + Lipo–DMED and subsequent insonation.
Fig. 6: Ultrasonography of Lipo–PPIX.

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Acknowledgements

This work was supported by a National Institutes of Health grant (GM073626 to D.S.K.). J.L.P. acknowledges the Ministerio de Economía y Competitividad, Spain, for PhD grants (BES-2013-064182 and EEBB-I-16-11313) associated with MAT2012-35556. We thank A. Schwartzman and the Massachusetts Institute of Technology NanoMechanical Technology Laboratory for assistance with the AFM measurements.

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A.Y.R., J.L.P., W.W. and D.S.K. designed the experiments. A.Y.R., J.L.P., B.W. and C.D.A. performed the experiments. A.Y.R., J.L.P., W.W., M.V.-R., R.L. and D.S.K. analysed the data. A.Y.R., J.L.P., R.L. and D.S.K. wrote the paper.

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Correspondence to Daniel S. Kohane.

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Two provisional patent applications (U.S.S.N. 62/239,164 and U.S.S.N. 62/329,721) have been filed concerning the technology presented in this work.

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Rwei, A.Y., Paris, J.L., Wang, B. et al. Ultrasound-triggered local anaesthesia. Nat Biomed Eng 1, 644–653 (2017). https://doi.org/10.1038/s41551-017-0117-6

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