Fabrication And Application Of Ultrasound-driven Implantable Electrical Nerve Stimulator

Nervous system diseases are a global medical problem.Traditional chemical and biological drugs show some promise for therapeutic application in a variety of nervous system diseases,but the clinical effect is insufficient and prone to various complications.In recent years,with the rapid development of microelectronic technology,implantable neuromodulation device is an emerging technology which leads to the development of novel precise clinic treatments.Implantable neuromodulation devices have been successfully applied in clinical due to their advantages of less injury and less complication.However,the energy storage capacities of batteries are limited and the long-term use of neurostimulators is challenging.Therefore,the exploration of new generation neuromodulation devices with wireless power supply technology,invasive implantation,systematic control and high safety factor is an emerging research field.Based on the technology requirements of wireless power supply programmable and minimally invasive implantation,and combined with the advantages of ultrasound in biomedical applications,this research proposes the strategy of ultrasound-driven implantable nerve stimulator for neurostimulator regulation.To realize the application of ultrasound-driven nanogenerator in neural regulation,we constructed three new high-performance nanogenerators and combined with ultrasound wireless energy transmission technology,expanded the application of battery-free neurostimulator in neural regulation of small animals.The research work has been carried out as follow:(1)Based on the synergistic enhancement of composite piezoelectric materials by doping piezoelectric polymers into the inorganic piezoelectric materials,a piezoelectric thin film nanogenerator was constructed.The ultrasound-driven piezoelectric thin film nanogenerator can generate tens of microamps of current.The directly electrical neurostimulation was successfully achieved by subcutaneously implanted piezoelectric thin film nanogenerators with thickness of around 30 μm,and the electrical-stimulation parameters can be well controlled with precise ultrasound parameters,including acoustic pressure,pulse width and pulse interval.(2)To solve the inherent piezoelectric properties of lead-free piezoelectric materials,the piezoelectric/triboelectric composite structure was designed to harvest energy from the piezoelectric and triboelectric effects at the same time,and improve the output of piezoelectric nanogenerator.Ultrasound-driven piezoelectric/triboelectric composite film nanogenerators can generate several hundred microamps of current exceeding the threshold of rat deep brain stimulation.With rat Parkinson’s disease as a model,the ultrasound-driven piezoelectric/triboelectric composite film nanogenerator was worked as a battery-free nerve deep brain stimulator,and the composite film nanogenerator successfully realized deep brain stimulation for the treatment of Parkinson’s disease in rats.(3)In order to improve the efficiency of ultrasound energy conversion,a new hydrogel nanogenerator with similar acoustic impedance to tissue was constructed.Under ultrasound excitation,the hydrogel nanogenerator can produce a high output current of milliamps,which is comparable to the output current of commercial bulky neurostimulators.With the systemic inflammatory rat model produced by endotoxinas,the alternating current pulse stimulation of the vagus nerves by the ultrasound-responsive hydrogel nanogenerator shows great effectiveness in the inhibition of pro-inflammatory cytokines.In this work,we developed ultrasound-powered battery-free neurostimulator based on soft implantable high-performance nanogenerator which can be driven by programmable ultrasound pluses remotely,and demonstrate the successful application of nanogenerator in neuromodulation.Ultrasound-driven nanogenerator was provided a novel strategy for the development of implantable soft high-performance nanogenerators as programmable battery-free neurostimulators.Ultrasound-driven battery-free stimulation technology would open up a new avenue to realize the nervous system diseases treatment by programmable battery-free neurostimulators in small animal.