Neural Stimulation in vitro and in vivo by Photoacoustic Nanotransducers

Abstract

Neuromodulation is an invaluable approach for study of neural circuits and clinical treatment of neurological diseases. Here, we report semiconducting polymer nanoparticles based photoacoustic nanotransducers (PANs) for neural stimulation. Our PANs strongly absorb light in the near-infrared second window and generate localized acoustic waves. PANs can also be surfacemodified to selectively bind onto neurons. PAN-mediated activation of primary neurons in vitro is achieved with ten 3-nanosecond laser pulses at 1030 nm over a 3 millisecond duration. In vivo neural modulation of mouse brain activities and motor activities is demonstrated by PANs directly injected into brain cortex. With millisecond-scale temporal resolution, sub-millimeter spatial resolution and negligible heat deposition, PAN stimulation is a new non-genetic method for precise control of neuronal activities, opening potentials in non-invasive brain modulation.. then utilized the magneto-thermal effect of the paramagnetic nanoparticles to activate these channels 18 . In these studies, significant local temperature rise, exceeding the thermal threshold of the ion channels, e.g. 43 ˚C in the case of TRPV 1, was observed, thus raising concerns over safety of thermally activated brain stimulation. The Khizroev group used the magneto-electric nanoparticles under an applied magnetic field to perturb the voltage-sensitive ion channels for neuron modulation 19 . Notably, these magnetic stimuli-based techniques deliver a spatial precision relying on the confinement of the magnetic field, which is on the millimeter to centimeter scale.New technologies and concepts are still sought to achieve non-invasive, genetic free and precise neural stimulation.Here, we report the development and application of photoacoustic nanotransducers (PANs) to enable non-genetic neural stimulation in cultured primary neurons and in live brain (Figure 1a).Our PANs, based on synthesized semiconducting polymer nanoparticles, efficiently generate localized ultrasound by an optoacoustic process upon absorption of nanosecond pulsed light in the NIR-II window (1000 nm to 1700 nm) (Figure 1b). The NIR-II light has the capability of centimeter-deep tissue penetration 20,21 , which is beyond the reach of visible light currently used in optogenetics. We further modified the PAN surface for non-specific binding to neuronal membrane and specific targeting of mechanosensitive ion channels, respectively. We showed that upon excitation at 1030 nm PANs on the neuronal membrane successfully activated rat cortical neurons, confirmed by real time fluorescence imaging of GCaMP. We then demonstrated in vivo motor cortex activation and invoked subsequent motor responses through PANs directly injected into a mouse living brain. Importantly, the heat generated by the ns laser pulses is confined inside the PAN, resulting in a transient temperature rise during the photoacoustic process, evident by COMSOL simulations. Collectively, our finding shows photoacoustic nanotransducers as a new Collectively, we have ...

Nanotransducers for wireless neuromodulation

“…3 Despite advances in the development of light-sensitive ion channels and pumps, 15 deep brain stimulation, 16 transcranial magnetic stimulation, 17 optogenetics, 18,19 infrared neural stimulation, 20 optoelectrical stimulation, 21 magnetothermal modulation, 22 transcranial ultrasound stimulation, 23 optogenetics using upconversion nanoparticles (UCNPs), 24 photovoltaic neuromodulation, 25 optothermal stimulation, 26 magnetomechanical stimulation, 27 optouncaging, 28 sonogenetics, 29 sonoelectrical stimulation, 30 magnetoelectrical modulation, 12 magnetogenetics, 31,32 transcranial magneto-acoustic stimulation, 33 magneto-uncaging, 34 sonouncaging, 35 sonochemogenetics, 36 sono-optogenetics. 38,39 (B) optical 9,[40][41][42][43][44]64 and magnetic transducers 7,13,22,50,51 for thermal modulation; (C) nanotransducers for mechanical modulation (left, optomechanical transducers 10,61,92 ; middle, magnetomechanical transducers; 14,52 right, genetically encoded transducers 31,32,…”

“…Review emerging strategy for neuromodulation. 92 Huang et al 61 used targeted photoacoustic nanotransducers based on semiconducting polymer nanoparticles to stimulate neural activities. Nanosecond laser pulse in the second NIR region (3 ns, 3.3 kHz, 21 mJ/cm 2 ) of photoacoustic nanotransducers induced localized acoustic waves to activate neurons.…”