implants that use ultrasonic waves to stimulate tissue

专利摘要:
IMPLANTS THAT USE ULTRASOUND WAVES TO STIMULATE TISSUE. Described here are implantable devices configured to emit an electrical pulse. An exemplary implantable device includes an ultrasonic transducer configured to receive ultrasonic waves that power the implantable device and encode a trigger signal; a first electrode and a second electrode configured to be in electrical communication with a tissue and deliver an electrical pulse to the tissue in response to the trigger signal; and an integrated circuit comprising an energy storage circuit. Systems are also described that include one or more implantable devices and an interrogator configured to operate one or more implantable devices. Furthermore, a closed-loop system is described which includes a first device configured to detect a signal, an interrogator configured to emit a trigger signal in response to the detected signal, and an implantable device configured to emit an electrical pulse in response to receiving the trigger signal. In addition, computer systems useful for operating one or more implantable devices are described, as well as methods of electrically stimulating a tissue.
公开号:BR112019000288A2
申请号:R112019000288-0
申请日:2017-07-07
公开日:2021-06-08
发明作者:Michel M. Maharbiz；Dongjin Seo；Konlin Shen；Jose M. CARMENA；Ryan Neely；Elad Alon；Jan Rabaey
申请人:The Regents Of The University Of California；
IPC主号:

专利说明:

[0001] [0001] This application claims priority to US Provisional Application No. 62/359,672, filed July 7, 2016, entitled "NEURAL DUST AND ULTRASONIC BACKSCATER IMPLANTS AND SYSTEMS, AND APPLICATIONS FOR SUCH SYSTEMS", which is incorporated herein by reference. for all purposes. STATEMENT ON RESEARCH SPONSORED BY THE FEDERAL GOVERNMENT
[0002] [0002] This invention was made with government support under grant Nos HR0011-15-2-0006 granted by the Defense Advanced Research Projects Agency (DARPA) and R21-E027570 granted by the National Institute of Health (NIH). The government has certain rights in the invention. TECHNICAL FIELD
[0003] [0003] The present invention relates to implantable devices operated using ultrasound waves to emit an electrical pulse or stimulate tissue. BACKGROUND OF THE INVENTION
[0004] [0004] The emerging area of bioelectronic medicine seeks methods for deciphering and modulating the electrophysiological activity in the body to achieve therapeutic effects on target organs. Current approaches to interfacing with peripheral nerves, the central nervous system and/or muscles rely heavily on wires, creating problems of chronic use, whereas emerging wireless approaches have the size scalability needed to interrogate small diameter nerves. Furthermore, conventional electrode-based technologies do not have the ability to record from nerves with a high spatial resolution or to record independently from several discrete locations within a nerve bundle.
[0005] [0005] Recent technological advances and fundamental discoveries have renewed interest in implantable systems to interface with the peripheral nervous system. Early clinical successes with peripheral neurostimulation devices, such as those used to treat sleep apnea or the function of bladder control in paraplegics, have led clinical investigators to propose new disease targets ranging from diabetes to rheumatoid arthritis. However, currently known neurostimulation devices are generally external devices and are either totally incapable of stimulating deep tissue, not completely implantable, or are incapable of accurately stimulating a nerve without risking off-target stimulation. SUMMARY OF THE INVENTION
[0006] [0006] Provided herein are implantable devices configured to emit an electrical pulse to a tissue, systems comprising an implantable device and an interrogator to operate the implantable device, and closed-loop systems comprising a first device configured to detect a physiological system and an implantable device configured to emit an electrical pulse to tissue in response to an interrogator that receives the physiological signal. Computer systems configured to operate one or more implantable devices are further provided. Methods for stimulating a tissue are also provided.
[0007] [0007] In some embodiments, an implantable device is provided, comprising an ultrasound transducer configured to receive ultrasonic waves that power the implantable device and encode a trigger signal; a first electrode and a second electrode configured to be in electrical communication with a tissue and emit an electrical pulse to the tissue in response to the trigger signal; and an integrated circuit comprising an energy storage circuit. In some embodiments, the electrical pulse is a current pulse. In some embodiments, the electrical pulse is a voltage pulse.
[0008] [0008] In some embodiments, the first electrode and the second electrode are within tissue or in contact with tissue. In some embodiments, the tissue is muscle tissue, organ or nervous tissue. In some embodiments, the tissue is part of the peripheral nervous system or the central nervous system. In some embodiments, the tissue is skeletal muscle, smooth muscle, or cardiac muscle.
[0009] [0009] In some embodiments, the integrated circuit comprises a digital circuit. In some embodiments, the integrated circuit comprises a mixed-signal integrated circuit configured to operate the first electrode and the second electrode. In some embodiments, the integrated circuit comprises a power circuit that comprises the energy storage circuit.
[0010] [0010] In some embodiments, the implantable device comprises a body comprising the ultrasound transducer and the integrated circuit, wherein the body is about 5 mm or less in length at the longest dimension. In some embodiments, the body has a volume of about 5 mm or less. In some embodiments, the implantable device includes a non-responsive reflector.
[0011] [0011] In some embodiments, the implantable device comprises three or more electrodes.
[0012] [0012] In some embodiments, the integrated circuit comprises an analog-to-digital converter (ADC).
[0013] [0013] In some embodiments, the implantable device includes a modulation circuit configured to modulate a current flowing through the ultrasound transducer. In some embodiments, the modulated current encodes the information, and the ultrasound transducer is configured to emit ultrasonic waves that encode the information. In some embodiments, the information comprises a signal verifying that an electrical pulse has been emitted by the implantable device, a signal indicating an amount of energy stored in the energy storage circuit or a sensed impedance. In some embodiments, the implantable device includes a digital circuit configured to operate the modulation circuit. In some embodiments, the digital circuit is configured to transmit a digitized signal to the modulation circuit. In some embodiments, the digitized signal comprises a unique implantable device identifier.
[0014] [0014] In some embodiments, the ultrasound transducer is configured to receive ultrasonic waves from an interrogator comprising one or more of ultrasound transducers. In some embodiments, the ultrasound transducer is a piezoelectric bulk transducer, a micromachined piezoelectric ultrasound transducer (PMUT), or a capacitive micromachined ultrasound transducer (CMUT).
[0015] [0015] In some embodiments, the implantable device is implanted into a subject. In some embodiments, the subject is a human being.
[0016] [0016] In some embodiments, the implantable device is at least partially encapsulated by a biocompatible material. In some embodiments, at least a portion of the first electrode and the second electrode are not encapsulated by the biocompatible material.
[0017] [0017] Also provided herein is a system comprising one or more implantable devices and an interrogator comprising one or more ultrasonic transducers configured to transmit ultrasonic waves to the one or more implantable devices, wherein the ultrasonic waves energize the one or more implantable devices. In some embodiments, ultrasonic waves encode a trigger signal. In some embodiments, the system comprises a plurality of implantable devices. In some embodiments, the interrogator is configured to direct beam of transmitted ultrasonic waves to focus the ultrasonic waves, alternatively transmitted onto a first portion of the multiplicity of implantable devices, or to focus the transmitted ultrasound waves onto a second portion of the multitude of implantable devices. In some embodiments, the interrogator is configured to simultaneously receive backscattering of ultrasound from at least two implantable devices. In some embodiments, the interrogator is configured to either transmit ultrasonic waves to the plurality of implantable devices or receive ultrasound backscatter from the plurality of implantable devices using time division multiplexing, spatial multiplexing, or frequency multiplexing. In some embodiments, the interrogator is configured to be used by a subject.
[0018] [0018] Also provided herein is a closed loop system, comprising (a) a first device configured to detect a signal; (B) an interrogator comprising one or more ultrasonic transducers configured to receive ultrasound backscatter that encodes the electrophysiological signal and emits ultrasonic waves that encode a trigger signal; and (c) a second device configured to emit an electrical pulse in response to the trigger signal, wherein the second device is implantable, comprising an ultrasound transducer configured to receive ultrasonic waves that power the second device and encode a trigger signal; a first electrode and a second electrode configured to be in electrical communication with a tissue and emit an electrical pulse to the tissue in response to the trigger signal; and an integrated circuit comprising an energy storage circuit. In some embodiments, the signal is an electrophysiological pulse, a temperature, a molecule, an ion, pH, pressure, voltage, or bioimpedance.
[0019] [0019] In some embodiments of the closed-loop system, the first device is implantable. In some embodiments, the first device comprises a sensor configured to detect the signal from; an integrated circuit comprising a modulation circuit configured to modulate a current based on the detected signal, and a first ultrasonic transducer configured to output an ultrasonic backscatter that encodes the detected signal from tissue based on the modulated current. In some embodiments, the sensor comprises a first electrode and a second electrode configured to be in electrical communication with a second tissue. In some embodiments, the first fabric and the second fabric are the same fabric. In some embodiments, the first fabric and the second fabric are different fabrics.
[0020] [0020] In some embodiments of the closed-loop system, the first electrode and the second electrode of the second device are within tissue or contacting tissue. In some embodiments, the integrated circuit of the second device comprises a digital circuit. In some embodiments, the integrated circuit of the second device comprises a mixed-signal integrated circuit configured to operate the first electrode and the second electrode. In some embodiments, the integrated circuit comprises a power circuit that comprises the energy storage circuit.
[0021] [0021] In some embodiments of the closed-loop system, the tissue is muscle tissue, an organ or nervous tissue. In some embodiments, the first device and the second device are implanted in a subject. In some embodiments, the subject is a human being.
[0022] [0022] Further provided herein is a computer system including an interrogator comprising one or more ultrasound transducers; one or more processors; non-transient computer readable storage means for storing one or more programs configured to be executed by one or more processors, the one or more programs comprising instructions for operating the interrogator to emit ultrasonic waves encoding a trigger signal signaling a implantable device for delivering an electrical pulse to tissue. In some embodiments, the interrogator is operated to emit ultrasonic waves that encode the trigger signal in response to a detected physiological signal. In some embodiments, the physiological signal comprises an electrophysiological pulse, a temperature, a molecule, an ion, the pH, pressure, voltage, or bioimpedance. In some embodiments, the one or more programs comprise instructions for detecting the physiological signal based on backscatter ultrasound that encodes the physiological signal emitted from a second implantable device. In some embodiments, the one or more programs comprise instructions for determining a location or movement of the first implantable device or the second implantable device relative to the interrogator's one or more ultrasound transducers.
[0023] [0023] Also provided herein is a method of electrical stimulation of a tissue, comprising receiving ultrasonic waves in one or more implantable devices; converting energy from ultrasound waves to an electrical current that carries an energy storage circuit; receiving a trigger signal encoded in the ultrasound waves in one or more implantable devices; and emitting an electrical pulse that stimulates tissue in response to the trigger signal. In some embodiments, the trigger signal is transmitted in response to a detected physiological signal.
[0024] [0024] A method of electrical stimulation of a tissue is further provided, comprising ultrasonic wave emitters encoding a trigger signal from an interrogator comprising one or more ultrasound transducers for one or more implantable devices configured to emit a pulse to the tissue in response to receiving the trigger signal. In some embodiments, the trigger signal is transmitted in response to a detected physiological signal.
[0025] [0025] Also provided herein is a method of stimulating a tissue, comprising receiving ultrasonic waves in one or more implantable devices configured to detect a physiological signal; converting energy from ultrasound waves to an electrical current flowing through a modulation circuit; detect the physiological signal; modulating the electrical current based on the detected physiological signal; transduce the modulated electrical current into an ultrasound backscatter that encodes information related to the detected physiological signal; and the ultrasound backscatter emitter to an interrogator comprising one or more transducers configured to receive the backscatter of ultrasound; ultrasonic wave emitters from the interrogator to one or more implantable devices configured to emit an electrical pulse to tissue; converting energy from the ultrasound waves emitted from the interrogator to the one or more implantable devices configured to emit the electrical pulse to an electrical current that carries an energy storage circuit; ultrasonic wave emitters that encode a trigger signal from the interrogator; receiving the trigger signal to one or more implantable devices configured to emit the electrical pulse; and emitting an electrical pulse that stimulates tissue in response to the trigger signal.
[0026] [0026] In some embodiments of the method of stimulating a tissue, the physiological signal comprises an electrophysiological pulse, a temperature, a molecule, an ion, the pH, pressure, voltage or bioimpedance.
[0027] [0027] In some embodiments of the method of stimulating a tissue, the tissue is a muscle tissue, an organ, or a nerve tissue.
[0028] [0028] In some embodiments of the method of stimulating a tissue, the method comprises implanting one or more implantable devices into a patient. In some embodiments, the subject is a human being.
[0029] [0029] In some embodiments of the method of stimulating a tissue, the method comprises determining a location or movement of one or more implantable devices. BRIEF DESCRIPTION OF THE FIGURES
[0030] [0030] Fig. 1 is a schematic diagram of a neural dust system, including an external transceiver, a subdural interrogator, and a neural dust particle, as described in Seo et al, Neural dust: an ultrasonic, low power solution for chronic brain-machine interfaces, arXiv:
[0031] [0031] Fig. 2A is a block diagram of an exemplary interrogator for a system described herein. The illustrated interrogator includes an array of ultrasound transducers comprising a plurality of ultrasound transducers. Each of the ultrasound transducers in the array is operated by a channel, which includes a switch to alternatively configure the transducer to receive or transmit ultrasound waves. FIG. 2B is a schematic representation of another exemplary interrogator for a system described herein. The illustrated interrogator includes two ultrasound transducer arrays, with each set of ultrasound transducers including a plurality of ultrasound transducers. The interrogator also includes an integrated circuit (which may include a digital circuit, which may include a processor). The integrated circuit is connected to a user interface (which may include a monitor, keyboard, buttons, etc), a storage medium (ie non-transient memory), an input/output (which may be wireless, such as a Bluetooth), and a power source (such as a battery).
[0032] [0032] Fig. 3A shows a block diagram of an exemplary interrogator that could be used by an individual. The interrogator includes a wireless communication system (Bluetooth radio in the illustration), which can be used to communicate with a computer system. FIG. 3B shows an exploded view of a usable interrogator. The interrogator includes a battery, a wireless communication system, and a set of transducers. FIG. 3C shows the usable interrogator shown in FIG. 3B fully assembled with a harness for attachment to a subject. FIG. 3D illustrates the usable interrogator linked together, an object, ie a rodent (although it could be any other animal such as a human, dog, cat, horse, cow, pig, sheep, goat, chicken, monkey, rat or mouse ). The interrogator includes a set of transducers, which are attached to the subject's body by an adhesive. FIG. 3E illustrates a cross-section of the interrogator transducer assembly shown in FIGS. 3A-D.
[0033] [0033] FIG. 4 provides a schematic showing communication between a transducer from an interrogator and an implantable device having a miniaturized ultrasound transducer. The interrogator transmits ultrasound waves to the implantable device, and the ultrasound transducer emits miniaturized backscattered ultrasound modulated by the sensor. The backscatter is then received by the interrogator.
[0034] [0034] FIG. 5A shows a series of pulse cycles of ultrasound waves emitted by an interrogator. Upon receiving a trigger from the interrogator (eg, an FPGA), the interrogator's transceiver board generates a series of transmit pulses. At the end of the transmit cycle, the switch on the ASIC disconnects the transmit module and turns on the receive module. Cycles have a frequency of every 100 microseconds. FIG. 5B shows an enlarged view of the transmission pulse sequence (i.e., one cycle) shown in FIG. 5A, with the cycle having six pulses of ultrasonic waves at 1.85 MHz, the pulses recurring every 540 nanoseconds. FIG. 5C shows ultrasound backscatter emitted by an implantable device. Backscatter ultrasound reaches the interrogator transducer approximately 2tRayleig. FIG. 5D shows an enlarged view in ultrasound backscatter, which can be analyzed. Ultrasonic backscatter analysis can include filtering, rectifying and integrating the backscatter ultrasound waves. FIG. 5E shows an enlarged view of the filtered backscatter ultrasonic waves. Wave backscatter includes responsive regions, which are sensitive to changes in impedance for the miniaturized ultrasound transducer, and non-responsive regions that are not sensitive to changes in impedance for the miniaturized ultrasound transducer.
[0035] [0035] FIG. 6 illustrates an embodiment of an implantable device, with a miniaturized ultrasound transducer (identified as the "piezo") connected to an ASIC. The ASIC includes a power circuit, a stimulation circuit (which operates the implantable device to deliver the stimulating electrical pulse), and a modulation circuit (or "backscatter circuit"). The power circuit includes an energy storage capacitor ("cap"). Electrodes can be implanted into tissue.
[0036] [0036] FIG. 7 illustrates an embodiment of an implantable device configured to emit an electrical pulse. The implantable device includes a miniaturized ultrasound transducer, a power circuit that includes an energy storage circuit (which may include one or more capacitors ("cap"), a digital circuit, and a pair of electrodes.
[0037] [0037] FIG. 8A illustrates a schematic view of an exemplary implantable device including a miniaturized ultrasound transducer and an ASIC on a printed circuit board (PCB). FIG. 8B illustrates a schematic view of another exemplary implantable device including a miniaturized ultrasound transducer and an ASIC on a printed circuit board (PCB).
[0038] [0038] FIG. 9 illustrates a method of manufacturing an implantable device described herein.
[0039] [0039] FIG. 10 is a flowchart for a method of encapsulating an implantable device with amorphous silicon carbide.
[0040] [0040] FIG. 11 shows a closed-loop system for neural recording and stimulation. One or more implantable devices configured to detect an electrophysiological ultrasound pulse transmit backscatter to an external device (which includes an interrogator). Backscatter ultrasound encodes the electrophysiological pulse. The external device then transmits ultrasonic waves that encode a trigger signal to one or more implantable devices configured to emit an electrical pulse. Upon receipt of the trigger signal, the implantable device emits an electrical pulse that stimulates the tissue.
[0041] [0041] FIG. 12 illustrates an implantable device configured to detect an electrophysiological pulse having a miniaturized ultrasound transducer, a modulation circuit configured to modulate a current flowing through the miniaturized ultrasound transducer based on an electrophysiological signal detected by a pair of electrodes.
[0042] [0042] FIG. 13A illustrates an implantable device configured to detect an electrophysiological signal with a miniature ultrasound transducer, and the integrated circuit, and a pair of electrodes. The integrated circuit includes a modulation circuit, an AC-coupled amplifier chain, and a power circuit, which includes a full-wave rectifier and doubler, a reference, and a regulator. FIG. 13B illustrates an exemplary rectifier that can be used in the integrated circuit shown in FIG. 13 A. FIG. 13C illustrates an exemplary chain amplifier that can be used in the integrated circuit shown in FIG. 13 A.
[0043] [0043] FIG. 14A shows different geometries of pathways used to connect implantable device components. FIG. 14B shows a serpentine trace configuration for deformable interconnects.
[0044] [0044] FIG. 15 shows the relationship between time and temperature for curable paratate epoxy, an exemplary material for wire bonding fixation during implantable device fabrication.
[0045] [0045] FIG. 16 shows a recorded electroneurogram (POR) using an implantable device. The dotted line shows the signal recorded by the actual terrain electrode. A general profile including the action potentials of the compound was reconstructed from the obtained data, which coincides with the true terrain profile.
[0046] [0046] FIG. 17 illustrates a scheme for encapsulating an implantable device in silicon carbide.
[0047] [0047] FIG. 18 shows a schematic prototype assembly and PCB.
[0048] [0048] FIG. shows processing steps 19A-E to ensure that the desired miniaturized ultrasonic dimension (PZT) transducer is mounted on the PCB. In FIG. 19 A, epoxy solder paste is applied over the board. In FIG. 19B, a piezoelectric material is attached to the PCB. In FIG. 16C, the piezoelectric material is cut to form a piezoelectric ultrasound transducer in large quantities of the desired size. In FIG. 19D, the ultrasound transducer is wire connecting to the PCB. In FIG. 19E, the PCB and ultrasound transducer is encapsulated in PDMS.
[0049] [0049] FIG. 20 shows a scheme for measuring electrical impedance with a vector network analyzer (VNA),
[0050] [0050] FIG. 21A shows that the energy transfer efficiency measured in various bulk piezoelectric ultrasonic transducer sizes corresponds to simulated behavior. FIG. 21B shows that the measured impedance spectroscopy of a PZT crystal corresponds to a simulation. FIG. 21C shows that the power response collected from the miniaturized frequency ultrasonic transducer is approximately 6.1 MHz.
[0051] [0051] FIG. 22 is a schematic of an exemplary ultrasound transducer that can be used as part of an interrogator.
[0052] [0052] FIG. 23 is a schematic view of an installation for acoustic characterization with an ultrasonic transducer calibrated for power supply verification. The ultrasound wave receiver is separate from the ultrasound wave transmitter.
[0053] [0053] FIG. 24A shows the force of a 5 MHz output transducer as the hydrophone is moved outward from the surface of the transducer. FIG. 24B shows -rated peak is shifted left relative to water peak.
[0054] [0054] FIG. 25A shows the XZ cross section of the transducer output, which illustrates a Rayleigh distance and a clear transition from near field to Far field propagation. FIG. 25B shows the cross section of the XY beam showing a dB beam bandwidth of 6 to 2.2 mm.
[0055] [0055] FIG. 26A shows a 2D beam pad focused from an array of transducers in the XY plane. The measurement beam approximates the simulated beam in both X and Y dimensions. FIG. 26B shows the delay time applied for each transducer element in the ultrasound transducer array. FIG. 26C shows a simulated 2D XZ transverse beam pad.
[0056] [0056] FIG. 27A shows beam steering of a beam of ultrasound waves transmitted from an array of transducers. Underneath each beam pad is the delay by each transducer in the array to obtain the measuring beam pad, as shown in FIG. 27B. FIG. 27C shows the beam-cushion ID on the X-axis for each beam-cushion shown in FIG. 27A. The measured beam pad approximates the simulated beam pad.
[0057] [0057] FIG. 28 shows a simulated miniaturized scaling of ultrasonic transducer binding efficiency and received power in 5 mm of tissue.
[0058] [0058] FIGS. 29A-D provide an overview of an exemplary system comprising an implantable device. FIG. 29A shows an external transducer connecting and communicating an implantable device remotely placed in the body. Driven by a custom transceiver board, the transducer alternates between transmitting a series of pulses that power the device and listening to reflected pulses that are modulated by electrophysiological signals. FIG. 29B shows an implantable device anchored to the sciatic nerve of an anesthetized rat. The insert in FIG. 29B shows an implantable device with optional probes. FIG. 29C shows the components of an exemplary implantable device. The implantable device was mounted on a flexible PCB and includes a piezoelectric crystal, a single custom transistor, and a pair of recording electrodes. FIG. 29D shows a close-up of an implantable device on a flexible PCG with calibration leads to measure electrophysiological signal (ground truth) and voltages collected in the piezocrystal. During in vivo experiments, the calibration wires were removed.
[0059] [0059] FIG. 30 illustrates communication between an exemplary interrogator and an implantable device. The upper part of FIG. 30 is a schematic diagram of the information flow. The bottom of FIG. 30 represents time traces of the signals at each stage mentioned in the diagram shown at the top of the figure. In FIG. 30A, the FPGA of the interrogator generates a trigger signal to start recording. FIG. 30B shows an extracellular, electrophysiological potential presented for recording electrodes on an implantable device. FIG. 30C shows that upon receiving the trigger from the FPGA, the transceiver board generates a series of transmit pulses. At the end of the transmit cycle, the switch on the interrogator's ASIC disconnects the transmit module and turns on the receive module. FIG. 30D shows zoomed in on the transmit pulse sequence, showing 6 pulses at 1.85 MHz. FIG. 30E shows backscatter from the implantable device, which reaches the transducer at approximately 2tRayleigh. FIG. 30F shows magnified in backscatter waveforms. The backscatter waveform includes a large saturation signal that overlaps the transmitted pulses and conducts electrical passage and is ignored. Upon returning, backscattered pulses can be seen after the transmission window. FIG. 30G shows the backscattered waveforms to be filtered, rectified, and the area under the curve is calculated in or der to produce reconstructed waveforms. FIG. 30H shows the reconstructed waveform sampled at 10 kHz. Each point of the reconstructed waveform is calculated by calculating the area under the curve from the appropriate reflected pulses, received each 100 μβ.
[0060] [0060] FIG. 31A shows de-graded, peak pressure normalized as a function of distance from the surface of an interrogator transducer showed a focus-graded by -8.9 mm to 1.85 MHz. FIG. 31B shows XY transverse bolstering beams and the corresponding 1-D stress plot at y = 0 at quasi-field, Rayleigh distance, and Far field showed focusing beam at Rayleigh distance. FIG. 31C shows that the transducer output pressure was a linear function of the input voltage (up to 32 V peak-to-peak). FIG 3 ID (reproduction of FIG. 5E) shows exemplary backscatter waveforms showing different backscatter regions. The backscatter waveform is found flanked (in time) by regions that correspond to reflections that derive from unresponsive regions; these correspond to pulses reflected from other device components. Measurement from unresponsive regions, which do not encode biological data) can be used as a reference. As a result of taking this differential measurement, any movements of the entire structure relative to the external transducer during the experiment can be subtracted. FIG. 31E shows a calibration curve obtained in the custom water tank installation showed the noise level of 0.18 mVrms. Figure 3 shows the effect of noise level as a function of the lateral deviation followed by the beampattern slope power. FIG. 31G shows a 1-D plot of off-axis voltage and transducer drop-off power at y = 0 the Rayleigh distance. FIG. 31H shows a graphical representation of the effective noise drop to the ground as an angular misalignment function. Angular misalignment results in a skewed beam pad: ellipsoidal as opposed to circular. This increases the radius of the focal point (Energy spread over a larger area); focal point distortion relaxes the constraint on misalignment.
[0061] [0061] FIG. 32A shows an experimental in-vivo setup for EMG recording of rat gastrocnemius muscle. The implantable device was placed over the exposed surface of the muscle and the wound was closed with surgical suture. The external ultrasound transducer pairs to the implantable device and the wireless data is recorded and displayed on the computer system (eg the laptop). FIG. 32B shows a comparison between the ground truth measurement and the reconstructed EMG signals over a number of runs. 20 ms samples were recorded and the interstimulus interval was 6 sec. FIG. 32C shows a power spectral density (PSD) of the recorded EMG signal, which showed 4.29e4 µV2/Hz and 3.11e4 µV2/Hz at 107 Hz for ground truth and reconstructed dust data, respectively, and various due harmonics. to the edges of the waveform. FIG. 32D shows wireless backscatter data recorded at t = 0 min and t = 30 min combined with R = 0.901.
[0062] [0062] FIG. 33A shows different intensities of EMG signals were recorded in vivo with electrodes on the PCB with different stimulation intensities. FIG. 33B shows similar EMG gradient responses were recorded wirelessly with the implantable device. FIG. 33C shows ground truth and EMG signal reconstruction from wireless backscatter data at response saturating pacing amplitude (100%) combined with R = 0.795 (R = 0.60, 0.64, 0.67, 0, 92 to 54%, 69%, 77%, 89%, respectively). In FIG. 33D, a quantitative comparison showed <0.4 mV salient feature set. In FIG. 33E, peak-to-peak voltage EMG showed an expected sigmoidal relationship with stimulation intensity.
[0063] [0063] FIG. 34A shows different intensities of ENG signals that were recorded in vivo with electrodes on the PCB with different stimulation intensities. FIG. 34B shows similar ENG gradient responses were recorded wirelessly with the particle. FIG. 34C shows ground truth and reconstruction of the ENG signal from the wireless backscatter data at response saturating stimulation amplitude (100%) combined with R = 0.886 (R = 0.822, 0.821, 0.69, 0.918, 0.87 to 44 %, 61%, 72%, 83%, 89%, respectively). In FIG. 34D, quantitative comparison showed <0.2 mV set of salient feature. In FIG. 34E, peak-to-peak voltage ENG showed an expected sigmoidal relationship with stimulation intensity.
[0064] [0064] FIG. 35A shows the recorded ENG time domain responses for different electrode spacing. FIG. 35B shows peak-to-peak ENG with different electrode spacings.
[0065] [0065] FIG. 36A shows ultrasound backscatter from an implantable device, with the implantable device implanted in the ultrasound coupling gel used to mimic the tissue. The backscatter includes a transmit pass-through conductor and ring down centered at 26 microseconds, and the backscatter miniaturized ultrasound transducer centered around 47 microseconds. FIG. 36B shows a narrowing in the backscatter region from the miniaturized ultrasound transducer (the sensitive region), which shows amplitude modulation as a result of an input signal to the implantable device.
[0066] [0066] FIG. 37 shows the digital data corresponding to the wireless ASCII characters 'Hello World' prepared from the implantable device by unipolar encoded backscatter pulse amplitude modulation. DETAILED DESCRIPTION OF THE INVENTION
[0067] [0067] The implantable device described herein includes a miniaturized ultrasound transducer (such as a miniaturized piezoelectric transducer) configured to receive ultrasonic waves that power the implantable device, a power circuit comprising an energy storage circuit, and two or more electrodes configured to emit an electrical pulse. The implantable device may also include a digital circuit or a mixed-signal integrated circuit configured to operate the electrodes. The implantable device can be implanted into a subject such that the electrodes surround tissue such as nerve tissue, muscle tissue or an organ and can emit an electrical pulse to stimulate the tissue. The miniaturized ultrasound transducer receives ultrasound energy from an interrogator (which can be external or implanted), which powers the implantable device. The interrogator includes a transmitter configured to transmit ultrasound waves to the implantable device. In some embodiments, the interrogator comprises a receiver, which can be integrated with the transmitter for a combined transceiver, and the receiver and transmitter can be arranged on the same device or on different devices. Mechanical energy from the ultrasound waves transmitted by the interrogator vibrates the miniaturized ultrasonic transducer into the implantable device, which generates an electrical current. Energy from electrical current can be stored in the energy storage circuit, which can include one or more capacitors. The interrogator can encode a trigger signal in the ultrasound waves that are transmitted to the implantable device, and, upon receipt of the trigger signal, the implantable device emits an electrical pulse (eg, by executing all or a portion of energy stored in the energy storage circuit). The trigger signal can be encoded, for example, to a predetermined signal or in response to some other signal (such as an electrophysiological signal detected in a closed-loop system). The implantable device may include a digital circuit, which is configured to decipher the encoded trigger signal, and operate the energy storage circuit and electrical pulse discharge electrodes.
[0068] [0068] The implantable device or electrodes form the implantable device that engage the tissue to emit the stimulatory electrical pulse. In some embodiments, the tissue is a nervous tissue (e.g., central nervous system tissue or peripheral nervous system), muscle tissue (such as, smooth muscle, skeletal muscle, or cardiac muscle), or an organ (e.g., large or small intestine, stomach, kidney, secretory gland (such as a salivary gland or mammary gland) or a bladder). In some embodiments, tissue engagement is such that the implantable device does not completely enclose the tissue. In some embodiments, the implantable device is in, implanted in, or adjacent to tissue. In some embodiments, the implantable device's electrodes engage tissue. For example, electrodes can be attached or implanted in nervous tissue (eg, through penetration of the perineum), muscle tissue, or an organ. In some embodiments, the one or more electrodes include a clamp electrode, which can partially surround tissue. In some embodiments, the implantable device is located close to the tissue, and electrodes may extend from the implantable device to reach the tissue.
[0069] [0069] Nervous tissue can be part of the central nervous system (such as the brain (eg, the cerebral cortex, basal ganglia, midbrain, medulla, pons, hypothalamus, thalamus, in the cerebellum, pallia, or hippocampus) or the medulla spinal), or part of the peripheral nervous system (such as a nerve, which may be a somatic nerve or a nerve in the automatic nervous system). Exemplary nerves include the sciatic nerve, the vagus nerve, branches of the vagus nerve, the tibial nerve, the nervie spenic, the splanchnic nerve, the pudendal nerve, the sacral nerve, the supra-orbital nerve, and the occipital nerve. Muscle tissue can be, for example, skeletal muscle, smooth muscle, or cardiac muscle. Exemplary muscles include gastrocnemius muscle, pelvic floor muscles, gastric smooth muscle, and cardiac muscle.
[0070] [0070] The implantable devices described herein can be implanted or used in a subject (i.e., an animal). In some embodiments, the individual is a mammal. exemplary subjects include a rodent (such as a mouse, rat or guinea pig), cat, dog, chicken, pig, cow, horse, sheep, rabbit, bird, bat, monkey, etc. In some modalities, the subject is a human being.
[0071] The electrical pulse may be useful, for example, to control limbs (ie functional electrical stimulation), which control bladder function, or for the treatment of sleep apnea or rheumatoid arthritis. See, for example, Tracey, The Inflammatory Reflex, Nature vol. 420, pp. 853-859 (2002).
[0072] [0072] Overall, in recent years, there has been an increasing interest in the use of recording and neural stimulation technologies to develop a new paradigm of closed-circuit neuromodulation therapy for disturbances in the central and peripheral nervous systems. As nerves carry both efferent and afferent signals to a variety of target organs, effective technologies will need high spatiotemporal resolution to record and stimulate from multiple sites. Furthermore, in order for these technologies to become clinically viable, they will need to be wire-less to avoid potential infections and adverse biological responses due to externalized connections or micro-motion of the implant within tissue. To address these issues, described here is an ultrasonic backscatter system to wirelessly power and communicate with implantable devices. One of the strengths of the technology is that, unlike conventional radio frequency technology, ultrasound-based systems appear scalable down to millimeter size scales or even smaller, and operate reliably to more than several centimeters deep implant opening the door to a new technological path in implantable electronics.
[0073] [0073] In some embodiments, the can be used to record, stimulate, or block signals (eg, electrophysiological signals) in the central or peripheral nervous system. Detected electrophysiological signals can be used to trigger the form and parameters of therapeutic stimulation, providing detailed feedback on real-time neural dynamics in the context of neurostimulation targets such as sleep apnea treatment or bladder function control for new targeted diseases ranging from diabetes to arthritis to arthritis.
[0074] [0074] In addition, provided herein are methods for wirelessly feeding and communicating with implantable sensors, down to millimeter size scales or smaller, embedded up to several centimeters in fabric that allows continuous monitoring of important vital signs of the body.
[0075] [0075] The implantable devices described here can be powered and can communicate at depths that were not possible with previous implantable systems. In some embodiments, an implantable device configured to detect a single electrophysiological includes a piezoelectric transducer, an application-specific integrated circuit (ASIC), and a pair of recording electrodes. One embodiment of the implant uses a single large piezoelectric transducer, recording or ASIC stimulation, and gold electrodes. Alternatively, the electrodes can be galvanized or electrochemically deposited with poly(3,4-ethylenectioxythiophene) (PEDOT), Pt or Pt-black in order to improve recording quality. Multi-site recording or simultaneous stimulation can be achieved by deploying a plurality of these particles at the desired locations or placing multiple pairs of electrodes on the particle and using on-chip multiplexers. Data from different pairs of electrodes can be encoded in any amplitude, frequency or phase of modulated waveform.
[0076] [0076] In some embodiments, an outdoor unit can interrogate a single particle by employing a single transducer to transmit ultrasonic energy or interrogate multiple particles by employing beamforming matrices. Arrays can be based on an array of bulk or capacitive piezoelectric transducers or ultra-micro-machined piezoelectric transducers (CMUTs, PMUTs). Both PMUTs and CMUTs are micro-electro-mechanical systems (MEMS) devices manufactured using semiconductor batch fabrication, with each MUT capable of transmitting and receiving acoustic waves.
[0077] [0077] In some embodiments, during use, the implantable device is placed either over, around or on the target nerve with the side of the electrode in contact with the target nerve. important connections can be routed out, either straight or serpentine, 10 thousand way as test points. The length of the tracks can be adjusted according to the application. Alternatively, the components can be split in half and mounted either on the top or on the bottom side of the board, together with the electrodes, in order to minimize the overall size. Mounting the double-sided platform can be more complex due to the necessary electrical and mechanical isolations between the ASIC and the piezoelectric transducer during connection to the wire or gluing flip-chip
[0078] [0078] In some embodiments, the system is implemented as a closed-loop medical therapeutic system. Such a system may include an ultrasound transceiver and configured to generate and receive ultrasound transmissions, and an implantable body device sized and configured to wrap but not entirely around the neural structure. The implantable device comprises a piezoelectric transducer and energy storage elements for harvesting power needed to operate the ASIC stimulation. The implantable device comprises a stimulation pulse generator circuit and leads coupled to the pulse generator circuit to produce stimulation pulses to electrically stimulate or block the neural structure. The implantable device further comprises an ultrasound backscatter communication system for communicating with external equipment via the ultrasound transceiver. In some embodiments, the system can include one or more of the following. The ultrasound transceiver can be additionally configured for body implantation. The system may further comprise external equipment coupled in communication with the ultrasound transceiver. External equipment can communicate wirelessly with the ultrasound transceiver. The implantable body device can further be configured to detect a biological condition, and communicate data indicative of the detected biological condition to external equipment. In such a case, the external equipment is configured to analyze the detected biological condition data, and to initiate, at the location indicated by the detected biological condition data analysis, ultrasound communication to the implanted device to generate stimulation pulses to stimulate or block the neural electrically structure. In some embodiments, external equipment directly detects the biological condition.
[0079] [0079] In some embodiments, the neural stimulation system may include multiple implantable bodily devices sized and configured to engage, but not entirely, around the neural structure. The implantable personal device may further be configured to communicate data indicative of the device's status to external equipment. The implantable body device can be configured to communicate data indicative of device operation to external equipment. Additionally, the implantable body device can even be configured to record and report detected biological conditions to provide feedback to adjust stimulation parameters.
[0080] [0080] A significant advantage of the implantable device described herein is the ability to emit a stimulating electrical pulse of nervous tissue or deep muscle tissue within a subject while being wirelessly fed. In some embodiments, the implantable device operates in a closed-loop system, and can emit a stimulatory electrical pulse in response to a sensed electrophysiological pulse. Additionally, implantable devices can remain in a subject for an extended period of time without the need to charge a battery or retrieve information stored on the device.
[0081] [0081] Electromagnetic power transfer (EM) is not a practice for powering small implantable devices, due to the attenuation of energy through tissue and the relatively large apertures (eg, antennas or coils) required to capture such energy. See, for example, Seo et al., Neural dust: an ultrasonic, low power solution for chronic brain-machine interfaces, arXiv:
[0082] [0082] Ultrasonic transducers have found application in various disciplines, including imaging, high-intensity concentrated ultrasound (HIFU), non-destructive testing of materials, communication, and power supply through steel walls, underwater communications, the energy supply, transcutaneous and energy harvesting. See, for example, Ishida et al., Insole Pedometer with Piezoelectric Energy Harvester and 2V Organic Circuits, IEEE J. Solid-State Circuits, vol. 48, no. 1, pp. 255-264 (2013); Wong et al., Advantages of Capacitive Micromachined Ultrasonics Transducers (CMUTs) for High Intensity Focused Ultrasound (HIFU), IEEE Ultrasonics Symposium, pp. 1313-1316 (2007); Ozeri et al., Ultrasonic Transcutaneous Energy Transfer for Powering Implanted Devices, Ultrasonics, vol. 50, no. 6, pp. 556-566 (2010) and Richards et al., Efficiency of Energy Conversion for Devices Containing a Piezoelectric Component, J. Micromech. Microeng., vol. 14, pp. 717-721 (2004). Unlike electromagnetism, using ultrasound as a mode of power transmission never came into widespread consumer application and was often overlooked because the efficiency of electromagnetism for short distances and large apertures is superior. However, on the scale of implantable devices and discussed here in tissue, the low acoustic velocity allows operation at significantly lower frequencies, and the acoustic loss in tissue is generally substantially less than the attenuation of electromagnetism in tissue.
[0083] [0083] The relatively low acoustic velocity of ultrasound results in substantially reduced wavelength compared to EM. Thus, for the same transmission distance, ultrasound systems are much more likely to operate in the far field, and hence to obtain greater spatial coverage than an EM transmitter. Furthermore, the acoustic loss in tissue is fundamentally less than the attenuation of electromagnetism in tissue, because acoustic transmission relies on tissue compression and rarefaction, rather than different electric/time-magnetic fields that generate displacement currents on the fabric surface.
[0084] [0084] In addition to turning on the implantable device, in some embodiments, the ultrasonic waves received by the implantable device may include a trigger signal. The trigger signal received by the miniaturized ultrasound transducer in the implantable device, and then encoded in the current generated by the transducer. The signal is then received by a digital signal, which can activate the energy storage circuit to release an electrical pulse transmitted by the electrode to tissue. The trigger signal can be transmitted by ultrasound waves in response to an input signal, such as a user operated input signal, or it can be responsive to a sensed electrophysiological signal. For example, in some embodiments, the trigger signal is transmitted in response to an electrophysiological signal detected by an implantable device transmitted to the interrogator.
[0085] [0085] In some embodiments, a "neural dust" system comprises tiny organism implantable devices referred to as neural dust or "particles", an implantable ultrasound transceiver that communicates with each of the particles using ultrasound transmissions and the transmissions of backscatter reflected from the particles, and an external transceiver that communicates wirelessly with the ultrasound transceiver. See Seo et al., Neural dust: an ultrasonic, low power solution for chronic brain-machine interfaces, arXiv: 1307.2196v1 (July 8, 2013) (“Seo et al., 2013”); Seo et al., Model validation of untethered, ultrasonic neural dust motes for cortical recording, J. Neuroscience Methods, vol. 244, pp. 114-122 (2014) (“Seo et al., 2014”); and Bertrand et al., Beamforming approaches for untethered, ultrasonic neural dust motes for cortical recording: a simulation study, IEE EMBC, vol. 2014, pp. 2625-2628 (2014). The powder neural system described in these documents is used for cortical recording (ie recording electrical signals from the brain). In that application, as shown in the documents, particles are implanted in brain tissue (cortex), the ultrasonic emitter-receiver is implanted under the dura mater, in the cortex, and the emitter-
[0086] [0086] Seo et al., 2013 and Seo et al., 2014 have shown that, in theory, the neural dust system can be used to develop small-scale implants (below mm scale) for wireless neural recording. Accurate detection of electrophysiological signals or tissue stimulation using an electrical pulse is enhanced by accurate determination of the location or movement of the implantable device. This ensures accurate assignment of a sensed signal to the tissue generating the signal, or accurate stimulation of target tissue, as well as filtering out signals that may be caused by movement. As described herein, the location and movement of implantable devices can be accurately determined using non-responsive ultrasound backscatter analysis. Furthermore, it has been found that implantable devices can transmit a digitized signal encoded in ultrasound backscatter. The digitized signal can allow increased reliability of electrophysiological signal detection (eg by filtering false positive signals), data compression (which can be particularly beneficial, for example when the implantable device includes a plurality of electrodes) , and may allow the inclusion of unique identifying signals in the ultrasound backscatter when using a plurality of implantable devices or when the implantable devices include a plurality of electrodes.
[0087] [0087] The miniature implantable systems that exist are wired or wireless, which create problems for chronic, everyday use, or emerging wireless approaches based on electromagnetics struggle to power and communicate with implanted devices in under-scale sizes millimeter or embedded more than centimeters into the fabric, maintaining power levels within established safety limits. Compared with existing technologies, the proposed implant has the advantage of easy fabrication, integration and scalability to implant dimensions and depth not achievable in the past.
[0088] [0088] In some embodiments, an implantable device useful in a closed-loop system stimulates tissue (such as muscle tissue, nervous tissue, or an organ) in response to the detected condition (such as, an electrophysiological signal, a temperature , a concentration of an analyte (eg, an ion, glucose, oxygen, etc.), or another molecule (such as a neurotransmitter, cytokine, hormone, or other signaling molecule or protein), pH, pressure , voltage, or bioimpedance) detected by the same or a different implantable device. The condition detected can be local or systemic. In some embodiments, the implantable device configured to detect an electrophysiological signal engages nervous tissue or muscle tissue, and can be used to report an electroneurogram or an electromyogram. In some embodiments, implantable devices can be configured to detect and report (through ultrasound backscatter) information relating to physiological conditions (such as temperature, pressure, pH or analyte concentration; see International Patent Application entitled "IMPLANTS USING ULTRASONIC BACKSCATTER FOR SENSING PHYSIOLGOICAL CONDITIONS" filed July 7, 2017, Attorney Docket No. 416272012040), radiation or radiolabeled cells and molecules (see international patent application entitled IMPLANTS USING ULTRASONIC BACKSCATTER FOR RADIATION DETECTION AND ONCOLOGY, filed July 7 of 2017, Attorney Docket No. 416272012140), the electrical impedance of tissue (see international patent application entitled: "IMPLANTS USING ULTRASONIC BACKSCATTER FOR SENSING ELECTRICAL IMPEDANCE OF TISSUE," filed July 7, 2017, Attorney Docket No. 416272012440) , and an electrophysiological pulse (see International Patent Application entitled "IMPLANTS USING ULTRASONIC BACKSCATTER FOR DETECTING ELECTROPHYSIOLOGICAL SIGNALS", filed on July 7, 2017, Case No. 416272012640); each such application is hereby incorporated by reference in its entirety for all purposes. Definitions
[0089] [0089] As used herein, the singular forms "a," "an," and "a" include the plural reference unless the context clearly dictates otherwise.
[0090] [0090] Reference to variations of "about" a value or parameter herein includes (e) describes that are directed to that value or parameter, per se. For example, the description refers to "about X" includes the description of "X".
[0091] [0091] The term "miniaturized" refers to any material or component of about 5mm or less (such as about 4mm or less, about 3mm or less, about 2mm or less, about 1mm or less, or about 0.5mm or less) long in the longest dimension. In certain embodiments, a "miniaturized" material or component has a largest dimension from about 0.1 mm to about 5 mm (e.g., about 0.2 mm to about 5 mm, about 0.5 mm to about 5mm, about 1mm to about 5mm, about 2mm to about 5mm, about 3mm to about 5mm, or about 4mm to about 5mm) in length. "Miniaturized" can also refer to any material or component with a volume of about 5 mm3 or less (such as about 4 mm3 or less, 3 mm3 or less, 2 mm3 or less, or 1 mm3 or less) . In certain embodiments, a "miniaturized" material or component has a volume of from about 0.5 mm3 to about 5 mm3, about 1 mm3 to about 5 mm3, about 2 mm3 to about 5 mm3, about 3 mm3 to about 5 mm3, or about 4 mm3 to about 5 mm3.
[0092] [0092] A "piezoelectric transducer" is a type of ultrasonic transceiver comprising the piezoelectric material. The piezoelectric material can be a crystal, ceramic, polymer, or any other natural or synthetic piezoelectric material.
[0093] [0093] A "non-responsive" ultrasound wave is an ultrasonic wave with a reflectivity independent of a detected signal. A "non-responsive reflector" is a component of an implantable device that reflects ultrasound waves so that the reflected waveform is independent of the detected signal.
[0094] [0094] The term "subject" refers to an animal.
[0095] [0095] Aspects and variations of the invention described herein are understood to include "consisting" and/or "consisting essentially of aspects and variations.
[0096] [0096] When a range of values is provided, it is to be understood that each intervening value between the upper and lower limit of that range and any other stated or intervening value in that indicated range is encompassed within the scope of the present disclosure. When the indicated range includes upper or lower limits, it varies excluding any such included limits are also included in this description.
[0097] [0097] It is to be understood that one, some or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. The section titles used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
[0098] [0098] The characteristics and preferences described above in relation to "embodiments" are distinct preferences and are not limited to just that particular embodiment; they can be freely combined with features from other embodiments, where technically feasible, and can form preferred combinations of features.
[0099] [0099] The description is presented to enable a person skilled in the art to make and use the invention and is provided in the context of a patent application and its requirements. Various modifications to the described embodiments will be readily apparent to those skilled in the art and the generic principles herein may be applied to other embodiments. Thus, the present invention is not intended to be limited to the embodiment shown, but is to be given the broadest scope consistent with the principles and features described herein. Furthermore, cross positions are to provide for organizational purposes and are not to be regarded as limiting. Finally, all patent disclosures and publications referred to in this application are hereby incorporated by reference for all purposes. Interrogator
[0100] [0100] The interrogator can communicate wirelessly with one or more implantable devices using ultrasonic waves, which are used to power and/or operate the implantable device. The ultrasonic waves emitted by the interrogator can encode a trigger signal, which signals the implantable device to emit an electrical pulse. The interrogator includes one or more ultrasonic transducers, which can function as an ultrasonic transmitter and/or an ultrasonic receiver (or as a transceiver, which can be configured to alternatively transmit or receive ultrasonic waves). The one or more transducers may be arranged as an array of transducers, and the interrogator may optionally include one or more transducer arrays. In some embodiments, transducer arrays may be evenly spaced, irregularly spaced, or sparsely placed. In some embodiments the matrix is flexible. In some embodiments, the matrix is flat, and in some embodiments the matrix is not flat. In some embodiments, the ultrasound transmission function is separated from the ultrasound reception function in separate devices. That is, optionally, the interrogator comprises a first device that transmits ultrasound waves to the implantable device, and a second device that receives ultrasound backscatter from the implantable device.
[0101] [0101] In some embodiments, the interrogator may receive ultrasound backscatter from an implantable device, an implantable device such configured to detect an electrophysiological voltage and emit ultrasound backscatter, which encodes information indicative of the detected electrophysiological voltage signal. In some embodiments, the trigger signal encoded by the ultrasound waves emitted from the interrogator and received by the implantable device configured to emit an electrical pulse is transmitted in response to an ultrasound-encoded backscatter information received with respect to the detected electrophysiological signal.
[0102] [0102] An exemplary interrogator is shown in FIG. 2A. The illustrated interrogator shows a transducer array with a plurality of ultrasound transducers. In some embodiments, the transducer array includes one or more, two or more, 3 or more, 5 or more, 7 or more, 10 or more, 15 or more, 20 or more, 25 or more, 50 or more, 100 250 or more or more, 500 or more, 1,000 or more, 2,500 or more, 5000 or more, or 10,000 or more or more transducers.
[0103] [0103] Fig. 2B illustrates another interrogator embodiment. As shown in FIG. 2B, the interrogator includes one or more transducers 202. Each transducer 202 is connected to a transmitter/receiver switch 204 which may alternatively configure the transducer to transmit or receive ultrasonic waves. The transmitter/receiver switch is connected to a processor 206 (such as, a central processing unit (CPU), a custom dedicated ASIC processor, a field programmable port array (FPGA), microcontroller unit (MCU), or a unit graphics processing (GPU)). In some embodiments, the interrogator further includes an analog-to-digital (ADC) or digital-to-analog (DAC) converter. The interrogator may also include a user interface (such as a display, one or more buttons to control the interrogator, etc.), a memory, a power source (such as a battery), and/or an input port. / output (which can be wired or wireless).
[0104] [0104] In some embodiments, the interrogator is deployable. An implanted interrogator may be preferred when implantable devices are implanted in a region blocked by a barrier that does not easily transmit ultrasound waves. For example, the interrogator can be deployed subcranially, either subdurally or supradurally. A subcranial interrogator can communicate with implantable devices that are implanted in the brain. Since the ultrasonic waves are impeded by the skull, the implanted subcranial interrogator allows communication with implantable devices implanted in the brain. In another example, an implantable interrogator can be implanted as part of, behind, or inside another implanted or prosthetic device. In some embodiments, the deployed interrogator may communicate with and/or be triggered by an external device, for example by EM or RF signals.
[0105] [0105] In some embodiments, the interrogator is external (ie, not deployed). By way of example, the external interrogator can be a wearable one, which can be secured to the body by a strap or adhesive. In another example, the external interrogator might be a wand, which can be picked up by a user (such as a healthcare professional). In some embodiments, the interrogator can be carried to the body by means of suturing, simple surface tension, a garment-based attachment device such as a cloth wrap, a glove, an elastic band, or by subcutaneous attachment. . The interrogator transducer or transducer assembly can be positioned separately from the rest of the transducer. For example, the array of transducers can be attached to a subject's skin at a first location (such as, proximal to one or more implanted devices), and the remainder of the interrogator can be located in a second position, with a tethering string. transducer or matrix transducer for the rest of the interrogator. FIG. 3A-E shows an example of a usable external interrogator. FIG. 3A shows a block diagram of the interrogator which includes a transducer array comprising a plurality of transducers, an ASIC comprising a channel for each transducer in the transducer matrix, a (lithium polymer (lipo) in the illustrated example) battery, and a wireless communication system (such as a Bluetooth system). FIG. 3B illustrates an exploded view of a wearable interrogator, including a printed circuit board (PCB) 302, which includes the ASIC, a wireless communication system 304, a battery 306, an ultrasonic transducer assembly 308, and a wire. 310 Tie the 308 ultrasound transducer assembly to the ASIC. FIG. 3C shows the usable interrogator 312 shown in FIG. 3B with a 314 beam, which can be used to secure the interrogator to a subject. FIG. 3D shows the assembled interrogator 316 connected to an individual, with the transducer assembly 308 connected at a first location, and the rest of the interrogator connected to a second location. FIG. 3E shows a schematic cross-section of an exemplary ultrasound transducer assembly 308, which includes a circuit board 318, pathways 320 attaching each transducer 322 to circuit board 318, a metallized polyester film 324, and a backing layer of 326 absorption. The 324 metallized polyester film can provide a common and acoustically matched base for the transducers, while the 326 absorption support layer (such as tungsten powder filled with polyurethane) can reduce the feel of individual transducers.
[0106] [0106] The specific design of the transducer array depends on the desired depth of penetration, the opening size, and the size of the transducers in the array. The Rayleigh distance, R, of the transducer is calculated as:
[0107] [0107] The individual transducers of a set of transducers can be modulated to control the Raleigh distance and the position of the ultrasound beam of waves emitted by the matrix transducer through a process of beam formation or beam conduction. Techniques such as linearly constrained minimum variance (LCMV) beamforming can be used to communicate a plurality of implantable devices with an external ultrasound transceiver. See, for example, Bertrand et al., Beamforming Approaches for Untethered, Ultrasonic Neural Dust Motes for Cortical Recording: a Simulation Study, IEEE EMBC (Aug. 2014). In some embodiments, beam conduction is accomplished by adjusting the power or phase of ultrasound waves emitted by transducers in an array.
[0108] [0108] In some embodiments, the interrogator includes one or more instructions for guiding the beam guiding ultrasound waves using one or more transducers, instructions for determining the relative location of one or more implantable devices, instructions for monitoring relative motion from the one or more implantable devices, instructions for recording the relative movement of the one or more implantable devices, and instructions for deconvoluting backscatter from a plurality of implantable devices. Communication between an implantable device and an interrogator
[0109] [0109] The implantable device and the interrogator communicate wirelessly with each other via ultrasound waves. The implantable device receives ultrasonic waves from the interrogator through a miniaturized ultrasound transducer in the implantable device. Ultrasonic vibrations from the miniature transducer on the implantable device generate a voltage between the transducer's electrical terminals, and current flows through the device, including, if present, an integrated circuit. The current can be used to charge an energy storage circuit, which can store energy to be used to emit an electrical pulse, for example, after receiving a trigger signal. The trigger signal can be transmitted from the interrogator to the implantable device, signaling that an electrical pulse must be emitted. In some embodiments, the trigger signal includes information about the electrical pulse to be emitted, such as frequency, amplitude, pulse length, or pulse shape (e.g., alternating current, direct current, or pulse pad). A digital circuit can decipher the trigger signal and operate the electrodes and electricity storage circuit to emit the pulse.
[0110] [0110] In some embodiments, ultrasound backscatter is emitted from the implantable device, which may encode information related to the implantable device or the electrical pulse emitted by the implantable device. For example, ultrasound backscatter can encode a verification signal, which verifies that the electrical pulse has been emitted. In some embodiments, an implantable device is configured to detect an electrophysiological signal, and information about the detected electrophysiological signal can be transmitted to the interrogator by ultrasound backscatter. To encode ultrasound signals in backscatter, the current flowing through the miniaturized ultrasound transducer is modulated as a function of encoded information, such as a sensed electrophysiological signal. In some embodiments, the current modulation can be an analog signal, which can be, for example, directly modulated by the detected electrophysiological signal. In some embodiments, current modulation encodes a digitized signal, which can be controlled by a digital circuit on the integrated circuit. The backscatter is received by an external ultrasound transceiver (which may be the same or different from the external ultrasound transceiver that transmitted the initial ultrasonic waves). Electrophysiological signal information can thus be encoded by changes in the amplitude, frequency, or phase of the backscattered ultrasound waves.
[0111] [0111] Fig. 4 illustrates an interrogator in communication with an implantable device. The external ultrasound transceiver emits waves of ultrasound ("carrier waves"), which can pass through tissue. Carrier waves cause mechanical vibrations on the miniature ultrasound transducer (eg, a miniaturized bulk piezoelectric transducer, a PUMT, or a CMUT). Voltage across the miniaturized ultrasound transducer is generated, which transmits a current that flows through an integrated circuit in the implantable device. The current flowing through the miniaturized ultrasonic transducer causes the transducer in the implantable device to emit ultrasonic backscatter waves. In some embodiments, a detected electrophysiological signal, either directly or indirectly (such as, if an integrated circuit) modulates the current flowing through the miniature ultrasound transducer, the backscatter waves encoding information relating to the detected electrophysiological signal. Backscatter waves can be detected by the interrogator, and can be analyzed to recognize the electrophysiological signal detected by the implantable device.
[0112] [0112] Communication between the interrogator and the implantable device may utilize a pulse-echo method of transmitting and receiving ultrasonic waves. In the pulse-echo method, the interrogator transmits a series of interrogation pulses at a predetermined frequency, and then receives backscatter echoes from the implanted device. In some embodiments, the pulses are from about 200 nanoseconds (ns) to about 1000 ns in length (such as about 300 ns to about 800 ns in length, about 400 ns to about 600 ns in length, or about in
[0113] [0113] Fig. 5 illustrates an ultrasonic pulse-echo communication loop between the interrogator and the implantable device. FIG. 5A shows a series of pulse cycles with a frequency of every 100 microseconds. During pulse transmission, the transducers in the set are configured to transmit the ultrasonic waves. After the pulses are transmitted, the transducers are configured to receive the backscattered ultrasound waves. FIG. 5B shows a zoom-in view of a cycle, which shows six pulses of ultrasonic waves, with a frequency of every 540 nanoseconds. Ultrasonic backscatter waves detected by the interrogator are shown in the
[0114] [0114] The frequency of the ultrasonic waves transmitted by the transducer can be set according to the excitation frequency, or resonance frequency of the miniaturized ultrasonic transducer in the implantable device. In some embodiments, ultra-miniaturized transducers are broadband devices. In some embodiments, ultrasonic transducers are narrowband miniaturized. For example, in some embodiments the pulse frequency is between about 20% or less, within about 15% or less, within about 10% or less, within about 5% or less of the resonant frequency of the miniaturized ultrasound transducer. In some embodiments, the pulses are set at a frequency about the resonant frequency of the miniaturized ultrasound transducer. In some embodiments, the frequency of the ultrasound waves is between about 100 kHz and about 100 MHz (such as, between about 100 kHz and about 200 kHz, between about 200 kHz and about 500 kHz, between about 500 kHz and about 1 MHz, between about 1 MHz and about 5 MHz, between about 5 MHz and about 10 MHz, between about 10 MHz and about 25 MHz, between about 25 MHz and about 50 MHz, or between about 50 MHz and about 100 MHz). In some embodiments, the frequency of the ultrasound waves is about 100 kHz or more, about 200 kHz or more, about 500 kHz or more, about 1 MHz or more, about 5 MHz or more, about 10 MHz or more, about 25 MHz or greater, or about 50 MHz or more.
[0115] [0115] In some embodiments, the backscattered ultrasound is digitized by the implantable device. For example, the implantable device can include an oscilloscope or analog-in-digital (ADC) and/or a memory, which can digitally encode information on current (or impedance) fluctuations. The digitized current fluctuations, which can encode information, are received by the ultrasound transducer, which then transmits digitized acoustic waves. Digitized data can compress analog data, for example, using singular value decomposition (SVD) and least squares-based compression. In some embodiments, compression is performed by a correlation or pad detection algorithm. The backscatter signal can go through a nonlinear transformation series, such as, 4 th order Butterworth bandpass filter integration rectification of backscatter regions to generate a reconstruction data point in a single instant of time. Such transformations can be done either in hardware (ie coded) or in software.
[0116] [0116] In some embodiments, the digitized data may include a unique identifier. The unique identifier may be useful, for example, in a system comprising a plurality of implantable devices and/or an implantable device comprising a plurality of electrode pairs. For example, the unique identifier may identify the implantable device of origin when from a plurality of implantable devices, for example when transmitting information from the implantable device (such as a confirmation tone). In some embodiments, an implantable device comprises a plurality of pairs of electrodes, which may simultaneously or alternatively emit an electrical pulse by a single implantable device. Different pairs of electrodes, for example, can be configured to emit an electrical pulse in different tissues (eg different nerves or different muscles) or in different regions of the same tissue. The digitized circuit can encode a unique identifier to identify and/or verify which electrode pairs emitted the electrical pulse.
[0117] [0117] In some embodiments, the digitized signal compresses the size of the analog signal. The reduced size of the digitized signal can allow more efficient reporting of encoded information in ultrasound backscatter. By compressing the size of information transmitted through scanning, potentially overlapping signals can be transmitted accurately.
[0118] [0118] In some embodiments, an interrogator communicates with a plurality of implantable devices. This can be accomplished, for example, using multiple-input, multiple-output (MIMO) system theory. For example, communication between the interrogator and the plurality of implantable devices using time division multiplexing, spatial multiplexing, or frequency multiplexing. In some embodiments, two or more (such as, 3, 4, 5, 6, 7, 8, 9, 10, 12 or more, about 15 or more, about 20 or more, about 25 or more, about of 50 or more, or about 100 or more) implantable devices communicate with the interrogator. In some embodiments, about 200 or less implantable devices (such as about 150 or less, about 100 or less, about 50 or less, about 25 or less, about 20 or less, about 15 or less, about 12 or less, or about 10 or less implantable devices) are in communication with the interrogator. The interrogator can receive a combined backscatter from the plurality of implantable devices, which can be deconvoluted, thus extracting information from each implantable device. In some embodiments, interrogator centers the ultrasonic waves transmitted from a set of transducers to an implantable device, namely through beam conduction. The interrogator centers the ultrasonic waves transmitted to a first implantable device, receives backscatter from the first implantable device, focuses ultrasound waves transmitted to a second implantable device, and receives backscatter from the second implantable device. In some embodiments, the interrogator transmits ultrasonic waves to a plurality of implantable devices, and then receives ultrasound waves from the plurality of implantable devices.
[0119] [0119] In some embodiments, the interrogator is used to determine the location or velocity of the implantable device. Velocity can be determined, for example, by determining the position or movement of a device over a period of time. The location of the implantable device can be a relative location, such as the relative location on transducers over the interrogator. Knowledge of the location or movement of the implantable device allows knowledge of the precise location of the electrophysiological signal detected in tissue. By determining the location of the implantable device and associating the location with the detected electrophysiological signal, it is possible to characterize or monitor tissue at a more localized point. A plurality of transducers on the interrogator, which can be disposed on the same set of transducers or two or more different transducer arrays, can collect ultrasonic backscatter waves from an implantable device. Based on the differences between the backscatter waveform coming from the same implantable device and the known location of each transducer, the position of the implantable device can be determined. This can be done, for example, by triangulation, or by grouping and maximum probability. The differences in backscatter may be based on responsive backscatter waves, unresponsive backscatter waves, or a combination of these.
[0120] [0120] In some embodiments, the interrogator is used to control the movement of the implantable device. Movement of the implantable device that can be tracked by the interrogator includes lateral and angular movement. Such movement may arise, for example, due to movement of one or more organs such as the liver, stomach, small or large intestine, kidney, pancreas, gallbladder, bladder, ovaries, uterus, or of the spleen, bone or cartilage (which it can be a result, for example, of the subject's breathing or movement), or variations in blood flow (such as due to a pulse). Movement of the implantable device can be tracked, for example, by monitoring changes in non-responsive ultrasound waves. In some embodiments, movement of the implantable device is determined by comparing the relative location of the implantable device at a first time point to the relative location of the implantable device at a second time point. For example, as described above, the location of an implantable device can be determined using a plurality of transducers on which the interrogator (which can be in a single array or in two or more arrays). A first location of the implantable device can be determined at a first time point, and a second location of the implantable device can be determined at a second time point, and a motion vector can be determined based on the first location at the first and second time point. location at the second time point. implantable device
[0121] [0121] An implantable device configured to emit an enclosed electrical pulse includes a miniaturized ultrasound transducer (such as a miniaturized piezoelectric transducer, a capacitive micro-machined ultrasound transducer (CMUT), or a micro-machined ultrasound transducer piezoelectric (PMUT)) configured to receive ultrasonic waves that power the implantable device, a power circuit that comprises an energy storage circuit, and two or more electrodes configured to engage tissue and emit an electrical pulse. In some embodiments, ultrasonic waves encode a trigger signal. The implantable device is configured to emit the electrical pulse upon receipt of the trigger signal. In some embodiments, the implantable device includes an integrated circuit. The integrated circuit can include, for example, the power circuit and a digital circuit. The digital circuit or a mixed-signal integrated circuit can activate the power circuit and the electrical pulse emission signal electrodes. In some embodiments, for example when the implantable device is configured to emit ultrasound backscattering information, the integrated circuit may include a modulation circuit, which is operable by the digital circuit.
[0122] [0122] The implantable device can envelop the tissue to apply an electrical pulse to the tissue. In some embodiments, electrodes are placed inside, placed over, placed near, or in electrical communication with the tissue to be stimulated. In some embodiments, the electrodes are positioned in contact with tissue. The tissue can be, for example, nerve tissue, muscle tissue, or an organ tissue. For example, the nervous tissue can be central nervous system nervous tissue (such as the brain or spinal cord), or peripheral nervous system nervous tissue (eg, a nerve). Muscle tissue can be, for example, skeletal muscle, cardiac muscle or smooth muscle. In some embodiments, the electrical pulse stimulates an action potential in the tissue. In some embodiments, the electrical pulse blocks an action potential in a tissue.
[0123] [0123] In some embodiments, the electrical pulse emitted by the implantable device is a direct current pulse or an alternating current pulse. In some embodiments, the electrical pulse comprises a plurality of pulses, which can be separated by a dwell time. In some embodiments, the electrical pulse is about 1 microsecond (μβ) or more (such as, about 5 or more, about 10 or more, about 20 μβ or more, about 50 μβ or more, about 100 μβ or more, about 250 μβ or more, about 500 μβ or more, about 1 millisecond (ms) or more, about 5 ms or more, about 10 ms or more, about 25 ms or more, about 50 ms or more, about 100 ms or more, about 200 ms or more, or about 500 ms or more). In some embodiments, the electrical pulse is about
[0124] [0124] In some embodiments, the electrical pulse is about 1 microamp (μΑ) or more (such as, about 5 μΑ or more, about 10 μΑ or more, about 25 μΑ or more, about 50 μΑ or more, about 100 μΑ or more, about 250 μΑ or more, about 500 μΑ or more, about 1 milliampere (mA) or more, about 5 mA or more, about 10 mA or more, or about of 25 mA or more). In some embodiments, the electrical pulse is about 50 mA or less (such as, about 25 mA or less, about 10 mA or less, about 5 mA or less, about 1 mA or less, about 500 μΑ or less, about 250 μΑ or less, about 100 μΑ or less, about 50 μΑ or less, about 25 μΑ or less, about 10 μΑ or less, about 5 μΑ or less, or about 1 μΑ or less.
[0125] [0125] In some embodiments, the electrical pulse has a current frequency of about 0.1 Hz or more (such as,
[0126] [0126] In some embodiments, the implantable device generates a pulse of tension in the tissue. In some embodiments, the voltage is about 50 mV or more (such as about 100 mV or more, about 250 mV or more, about 500 mV or more, about 1V or more, about 2, 5V or more, about 5V or more, or about 10V or more). In some embodiments, the voltage is about 20V or less (such as, about 15V or less, about 10V or less, about 5V or less, about 2.5V or less, about 1V or less, about 500 mV or less, about 250 mV or less, or about 100 mV or less).
[0127] [0127] In some embodiments, the implantable device comprises a plurality of electrodes. In some embodiments, electrodes are paired. electrode pairs can be formed from two electrodes; thus, an implantable device with three electrodes can have three pairs of electrodes. The electrophysiological signal can be detected between the electrodes of the electrode pairs. In some embodiments, the implantable device comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more, or 15 or more pairs of electrodes. In some embodiments, the implantable device comprises 2, 3, 5, 6, 7, 8, 9, 10 or more electrodes. In some embodiments, the implantable device includes an even number of electrodes, and in some embodiments, the implantable device includes an odd number of electrodes. In some embodiments, the implantable device includes a multiplexer, which can select the electrodes in the electrode pair to deliver the electrical pulse.
[0128] [0128] Two or more electrodes interface with (or engage) tissue (eg, nerve tissue or muscle tissue). Electrodes do not need to be placed linearly across the tissue. For example, electrodes may involve a nerve along an axis transverse to the nerve, which may emit an electrical pulse in the transverse direction. Two or more electrodes may involve a nerve along the transverse axis at any angle, such as, directly opposite (ie, 180°), or less than 180° (such as, about 170° or less, about 160 ° or less, about 150° or less, about 140 ° or less, about 130 ° or less, about 120 ° or less, about 110 ° or less, about 100 ° or less, about 90 ° or less, about 80° or less, about 70° or less, about 60° or less, about 50° or less, about 40° or less, or about 30° or less).
[0129] [0129] In some embodiments, the electrodes of an electrode pair are separated by about 5 mm or less (such as about 4 mm or less, about 3 mm or less, about 2 mm or less, about 1.5 mm or less, about 1 mm or less, or about 0.5 mm or less). In some embodiments, the electrodes of the electrode pair are separated by about 0.5 mm or more (such as about 1 mm or more, about 1.5 mm or more, about 2 mm or more, about 3 mm or more, or about 4 or more. In some embodiments, the electrodes are separated by about 0.5 mm to about 1 mm, about 1 mm to about 1.5 mm, about 1.5 mm. mm to about 2 mm, to about 2 mm to about 3 mm, about 3 mm to about 4 mm, or about 4 mm to about 5 mm.
[0130] [0130] In some embodiments, the implantable device includes a power circuit, which includes an energy storage circuit. The energy storage circuit can include one or more capacitors. The energy from the ultrasound waves is converted into a current by the miniaturized ultrasound transducer, and can be stored in the energy storage circuit. The energy can be used to operate the implantable device, such as supplying power to the digital circuit or one or more amplifiers, or it can be used to generate the electrical pulse used to stimulate tissue. In some embodiments, the supply circuit further includes, for example, a rectifier and/or a charge pump.
[0131] [0131] In some embodiments, the integrated circuit includes one or more digital circuits or mixed-signal integrated circuits, which may include a memory and one or more circuit blocks or systems for the use of the implantable device. These systems may include, for example, an on-board microcontroller or processor, a finite state machine implementation, or digital circuitry capable of executing one or more programs stored in the implant or provided via ultrasound communication between the interrogator and an implantable device . In some embodiments, the digital circuit includes an analog-to-digital converter (ADC), which can convert an encoded analog signal into ultrasound waves emitted from the interrogator so that the signal can be processed by the digital circuit. The digital circuit can also operate the power circuit, for example, to generate the electrical pulse to stimulate tissue. In some embodiments, the digital circuit receives the trigger signal encoded in the ultrasound waves transmitted by the interrogator, and operates the power circuit to discharge the electrical pulse in response to the trigger signal.
[0132] [0132] In some embodiments, the implantable device emits ultrasound backscatter that encodes the information. Ultrasound backscatter can be received by the interrogator, for example, and decrypted to determine the encoded information. Information can be encoded using a modulation circuit (or "backscatter circuit"). The modulation circuit can modulate the current flowing through the miniaturized ultrasound transducer, which modulates the backscatter of ultrasound.
[0133] [0133] Fig. 6 illustrates an embodiment of a miniaturized ultrasound transducer (identified as the "piezo") connected to an ASIC. The ASIC includes a power circuit and an optional modulation circuit (or "backscatter circuit"). The power circuit includes an energy storage capacitor ("cap"). In addition, the implantable device includes a stimulation circuit (eg, a digital circuit) which can activate the supply circuit and electrodes, which are implanted in or positioned against the tissue to be stimulated.
[0134] [0134] Fig. 7 illustrates an embodiment of an implantable device configured to emit an electrical pulse. The implantable device includes a miniature ultrasound transducer, a power circuit that includes an energy storage circuit (which may include one or more capacitors ("cap"), an integrated digital circuit or multi-signal circuit, and an pair of electrodes.The ultrasound transducer is connected to the power circuit, which allows the energy from the ultrasound waves to be stored in the energy storage circuit.The power circuit is connected to the digital or multi-signal circuit of the integrated circuit so that the digital circuit or multi-signal integrated circuit can operate the power circuit, the digital circuit or multi-signal integrated circuit is also connected to the ultrasonic transducer. When a trigger signal is encoded in Ultrasonic waves received by the ultrasonic transducer, the integrated digital circuit or multi-signal circuit can detect the trigger signal.the digital or multi circuit circuit -Integrated signal can then operate the power circuit to release the energy stored in the cir energy cuit, thus emitting an electrical pulse using the electrodes.
[0135] [0135] The implantable devices are miniaturized, which allows for comfortable and long-term implantation, while limiting tissue inflammation that is often associated with implantable devices. The body forms the core of the miniaturized implantable device (eg, the ultrasound transducer and integrated circuit), and the electrodes branch from the body and envelop the tissue to deliver an electrical pulse to stimulate the tissue. In some embodiments, the longest dimension of the implantable device or implantable device body is about 5 mm or less, about 4 mm or less, about 3 mm or less, about 2 mm or less, about 1 mm or less, about 0.5 mm or less, or about 0.3 mm or less in length. In some embodiments, the longest dimension of the implantable device or implantable device body is about 0.2 mm or more, about 0.5 mm or more, about 1 mm or more, about 2 mm or more, or about 3mm or larger on the longest dimension of the device. In some embodiments, the longest dimension of the implantable device or implantable device body is about 0.2 mm to about 5 mm in length, about 0.3 mm to about 4 mm in length, about 0. 5mm to about 3mm long, about 1mm to about 3mm long, or about 2mm long.
[0136] [0136] In some embodiments, one or more of the electrodes are on the device body, for example a pad on the device body. In some embodiments, one or more of the electrodes extend from the body of the implantable device, to any desired length, and can be implanted to any depth within tissue. In some embodiments, an electrode is about 0.1 mm in length or more, such as about 0.2 mm or more, about 0.5 mm or more, about 1 mm in length or more, about 5mm long or more, or about 10mm long or more. In some embodiments, the electrodes are about 15mm or less, in length, such as about 10mm or less, about 5mm or less, about 1mm or less, or about 0.5mm or less in length. In some embodiments, the first electrode is placed in the implantable device body and the second electrode extends from the implantable device body.
[0137] [0137] In some embodiments, the implantable device has a volume of about 5 mm or less (such as about 4 mm or less 3, 3 mm 3 or less, 2 mm, 3 or less, or 1 mm3 or less ). In certain embodiments, the implantable device has a volume of about 0.5 mm from about 3 to about 5 mm 3 , about 1 mm from 3 to about 5 mm 3 , about 2 mm 3 to about 5 mm 3 , about 3 mm from 3 to about 5 mm 3 , or about 4 mm from 3 to about 5 mm. The reduced size of the implantable device allows implantation of the device using a biopsy needle.
[0138] [0138] In some embodiments, the implantable device is implanted into a subject. The subject can be, for example, a vertebrate animal such as a mammal. In some embodiments, the subject is a human, dog, cat, horse, cow, pig, sheep, goat, chicken, monkey, rat, or mouse.
[0139] [0139] In some embodiments, the implantable device or a portion of the implantable device (such as the miniaturized ultrasound transducer and the integrated circuit) is encapsulated by a biocompatible material (e.g., a biocompatible polymer), e.g., a copolymer of N-vinyl-2-pyrrolidinone (NVP) and N-butylmethacrylate (BMA), polydimethylsiloxane (PDMS), parylene, polyimide, silicon nitride, silicon dioxide, silicon carbide, aluminum oxide, niobium, or hydroxyapatite. Silicon carbide can be amorphous silicon carbide or crystalline silicon carbide. The biocompatible material is preferably impermeable to water to avoid damage or interference from electronic circuits within the device. In some embodiments, the implantable device or a portion of the implantable device is encapsulated by a ceramic material (eg, alumina or titanium oxide) or a metal (eg, steel or titanium). In some embodiments, the electrodes or a portion of the electrodes are not encapsulated by the biocompatible material.
[0140] [0140] In some embodiments, the miniaturized ultrasound transducer and the ASIC is disposed on a printed circuit board (PCB). The electrodes can optionally be arranged on the printed circuit board, or can otherwise be connected to the integrated circuit. FIG. 8A and 8B illustrate exemplary implantable device configurations including a PCB. FIG. 8A shows piezoelectric transducer 802 and an ASIC 804 disposed on a first side 806 of printed circuit board 808. A first electrode 810 and second electrode 812 are disposed on a second side 814 of printed circuit board 808. FIG. 8B seeds the piezoelectric transducer 814 on a first side 816 of the printed circuit board 818, and the ASIC 820 on the second side 822 of the printed circuit board 818. A first electrode 824 initiated on the first side 816 of the printed circuit board, and a second electrode 826 is initiated on second side 822 of printed circuit board 818. first electrode 824 and second electrode 826 may extend from PCB 818 to be configured to be in electrical connection with each other across tissue.
[0141] [0141] The miniaturized ultrasound transducer of the implantable device may be a micro-machined ultrasound transducer, such as a micro-machined capacitive ultrasound transducer (CMUT) or a micro-machined piezoelectric ultrasonic transducer (PMUT), or it can be a piezoelectric transducer large quantities. Bulk piezoelectric transducers can be any natural or synthetic material such as a crystal, ceramic or polymers. Exemplary bulk piezoelectric transducer materials include barium titanate (BaTi03), lead zirconate titanate (PZT), zinc oxide (ZO), aluminum nitride (A1N), quartz, berlinite (AlPO4), topaz, langasite (La3Ga5SiO14), gallium orthophosphate (GaP04), lithium niobate (LiNb03), lithium tantalum (LiTa03), potassium niobate (KNb03), sodium tungstate (Na2W03), bismuth ferrite (BiFe03), polyvinylidene (di) vinylidene fluoride (PVDF), and magnesium, lead niobate titanate (PMN-PT).
[0142] [0142] In some embodiments, the bulk piezoelectric transducer is miniaturized approximately cubic (ie, a ratio of about one aspect: 1:1 (length:width:height) In some embodiments, the piezoelectric transducer is plate-shaped , with an aspect ratio of about 5:1 or greater, in either length or aspect width, such as, about 7:5:1 or greater, or about 10:10:1 or greater. In some embodiments , the miniaturized bulk piezoelectric transducer is long and narrow, with an aspect ratio of about 3:1:1 or greater, and wherein the longer dimension is aligned with the propagation direction of the carrier ultrasound wave. , a dimension of the bulk piezoelectric transducer is equal to half the wavelength (λ) corresponding to the excitation frequency. or resonance frequency of the transducer. at the resonance frequency, the ultrasound wave incident on each face of the transducer will suffer an 180° phase shift to reach the opposite phase, causing the largest displacement between the two faces. In some embodiments, the height of the piezoelectric transducer is about 10 µm to about 1000 µm (such as, about 40 µm to about 400 µm, about 100 µm to about 250 µm, about 250 µm to about 500 µm, or about 500 µm to about 1000 µm). In some embodiments, the height of the piezoelectric transducer is about 5 mm or less (such as about 4 mm or less, about 3 mm or less, about 2 mm or less, about 1 mm or less, about 500 μm or less, about 400 μm or less, 250 μm or less, about 100 μm or less, or about 40 μm or less). In some embodiments, the height of the piezoelectric transducer is about 20 µm or more (such as, about 40 µm or more, about 100 µm or more, about 250 µm or more, about 400 µm or more, about 500 µm or more, over 1 mm or more, about 2 mm or more, about 3 mm or more, or about 4 mm or more) in length.
[0143] [0143] In some embodiments, the ultrasound transducer has a length of about 5 mm or less, such as about 4 mm or less, about 3 mm or less, about 2 mm or less, about 1 mm or less, about 500 µm or less, about 400 µm or less, 250 µm or less, about 100 µm or less, or about 40 µm or less) in its longest dimension. In some embodiments, the ultrasound transducer has a length of about 20 µm or more (such as, about 40 µm or more, about 100 µm or more, about 250 µm or more, about 400 µm or more, about 500 µm or more, about 1 mm or more, about 2 mm or more, about 3 mm or more, or about 4 mm or more) in its longest dimension.
[0144] [0144] The miniaturized ultrasound transducer is connected to two electrodes; the first electrode is connected to a first face of the transducer and the second electrode is connected to a second face of the transducer, wherein the first face and second face are opposite sides of the transducer along one dimension. In some embodiments, the electrodes comprise silver, gold, platinum, black platinum, poly (3,4-ethylenedioxythiophene (PEDOT), a conductive polymer (such as conductive or polyimide PDMS), or nickel. operated in cut mode and where the axis between the metallized faces (ie electrodes) of the transducer are orthogonal to the transducer's movement.
[0145] [0145] In some embodiments, implantable devices are configured to engage with nervous tissue. In some embodiments, the engagement of nervous tissue does not completely involve the nervous tissue. In some embodiments, the nervous tissue is part of the central nervous system, such as the brain (e.g., the cerebral cortex, basal ganglia, midbrain, medulla, pons, hypothalamus, thalamus, in the cerebellum, palliium, or hippocampus) or the spinal cord . In some embodiments, brain tissue coupling includes electrodes that are implanted into the tissue, while the body of the implantable device is located outside of the tissue. In some embodiments, the nervous tissue is part of the peripheral nervous system, such as a peripheral nerve. In some embodiments, the implantable device is coupled with a muscle, such as skeletal muscle, cardiac muscle, or smooth muscle. In some embodiments, the implantable device electrodes are involved with muscle, such as skeletal muscle, smooth muscle, or cardiac muscle. Fabrication of an implantable device
[0146] [0146] Implantable devices can be manufactured by connecting a miniaturized ultrasound transducer (such as a large quantity piezoelectric transducer, a CMUT, or a PMUT) with a first electrode on a first face of the piezoelectric transducer, and a second electrode to a second face of the transducer, where the first face and second face are on opposite sides of the transducer. The first electrode and the second electrode can be connected to an integrated circuit, which can be arranged on a printed circuit board (PCB). The integrated circuit includes a power circuit that includes an energy storage circuit. In some embodiments, the integrated circuit includes a digital circuit (or a multi-signal integrated circuit) and/or a modulation circuit. Two or more electrodes are also connected to the integrated circuit, and it is configured to be in electrical connection with each other through tissue. Connecting the components to the PCB can include, for example, connecting wire, soldering, flip-chip connecting or collision gluing to gold.
[0147] [0147] Certain piezoelectric materials are commercially obtainable, such as PZT foils of varying thickness (eg, PSI-5A4E, from Piezo Systems, Woburn, MA, or from PZT 841, APC International, Mackeyville, PA). In some embodiments, a sheet of piezoelectric material is cut to a desired size, and the cut piezoelectric material is attached to the electrodes. In some embodiments, the electrodes are attached to the sheet of piezoelectric material, and the sheet of piezoelectric material is cut to the desired size with the electrodes attached to the piezoelectric material. Piezoelectric material can be cut using a segmentation saw with a ceramic blade to cut sheets of piezoelectric material into individual piezoelectric transducer. In some embodiments, a laser cutter is used to data or singulate the piezoelectric material. In some embodiments, patterned engraving is used to dice or singulate the piezoelectric material.
[0148] [0148] The electrodes can be connected to the top and bottom of the faces of piezoelectric transducers, with the distance between the electrodes being defined as the height of the piezoelectric transducer. Examples of electrodes may comprise one or more of silver, gold, platinum, black platinum, poly(3,4-ethylenedioxythiophene (PEDOT), a conductive polymer (such as conductive or polyimide PDMS) or nickel. Electrode is connected to the piezoelectric transducer by electroplating or vacuum depositing the electrode material on the face of the piezoelectric transducer. In some embodiments, the electrodes are soldered onto the piezoelectric transducer using a solder and adequate flux. In some embodiments, the electrodes are bonded. to the piezoelectric transducer using an epoxy (such as a silver epoxy) or low temperature solder (for example, by using a solder paste).
[0149] [0149] In an exemplary embodiment, solder paste is applied to a pad on a printed circuit board (PCB), either before or after the integrated circuit is connected to the PCB. The size of the pad on the circuit board may depend on the desired size of the piezoelectric transducer. By way of example only, if the desired piezoelectric transducer size is about 100 µm x 100 µm x 100 µm, the pad can be about 100 x 100 µm µm. The pad functions as the first electrode for the implantable device. A piezoelectric material (which may be larger than that of the mouse) is placed over the pad, and is held to the pad by the applied solder paste, resulting in a piezoelectric-PCB assembly. The piezoelectric-PCB assembly is heated to cure the solder paste, thereby gluing the piezoelectric transducer to the PCB. If the piezoelectric material is larger than the pad, the piezoelectric material is cut to the desired size, for example, using a segment saw or a laser cutting insert. portions of the unbound piezoelectric material (for example, portions of the piezoelectric material that do not overlap the pad) are removed. A second electrode is connected to the piezoelectric transducer and the PCB, for example, forming a connecting wire between the top of the piezoelectric transducer and the PCB, which completes the circuit. The binding wire is made using a wire made from any conductive material such as aluminum, copper, silver or gold.
[0150] [0150] The integrated circuit and the miniaturized transducer can be connected on the same side of the printed circuit board or on opposite sides of the printed circuit board. In some embodiments, the PCB is a flexible PCB, the integrated circuit and miniaturized transducer are attached to the same side of the printed circuit board, and the PCB is bent,
[0151] [0151] Optionally, the device or a part of the device is encapsulated in the or a part of the device is encapsulated with a biocompatible material (eg a biocompatible polymer), eg an N-vinyl-2-pyrrolidinone (NVP) copolymer and n-butylmethacrylate (BMA), polydimethylsiloxane (PDMS, e.g., Sylgard 184, Dow Corning, Midland, MI), parylene, polyimide, silicon nitride, silicon dioxide, aluminum oxide, niobium, hydroxy apatite, or carbide of silicon. Silicon carbide can be amorphous silicon carbide or crystalline silicon carbide. In some embodiments, biocompatible material (e.g., amorphous silicon carbide) is applied to the device by chemical vapor-enhanced plasma deposition (PECVD) or sputtering. PECVD can use precursors such as S1H4 and CH4 to generate silicon carbide. In some embodiments, the implantable device or a portion of the implantable device is encased in a ceramic (eg, alumina or titanium oxide) or metal (eg, steel or titanium) suitable for medical implantation.
[0152] [0152] Fig. 9 illustrates an exemplary way of making the implantable device described herein. At step 902, an application-specific integrated circuit (ASIC) is connected to a PCB. The PWB can include two or more electrodes to emit an electrical pulse to stimulate tissue. A solder (such as a silver epoxy) can be applied to the PCB (for example, on a first pad disposed on the PCB), and the ASIC can be placed over the solder.
[0153] [0153] In some embodiments, the implantable device or a portion of the implantable device is encapsulated in a film amorphous silicon carbide (a-SiC). FIG. 10 illustrates a method of fabricating an implantable device encapsulated in a-SiC film. In step 1002, a polyimide layer is applied to a smooth surface. In step 1004, an a-SiC layer is applied to the polyimide layer. This can be done, for example, using plasma-enhanced chemical vapor deposition (PECVD), using SiH4 and CH4 as precursors. In step 1006, one or more gates are engraved on the a-SiC layer. In some embodiments, the gates are also engraved on the polyimide layer. Access ports to provide portions of the implantable device that are not encapsulated by an a-SiC, such as portions of a sensor or an electrode that will come into contact with tissue after implantation. In some embodiments, pickling comprises reactive-ion pickling. In step 1008, the implantable device is attached to the a-SiC layer. The implantable device can be pre-assembled before being attached to the a-SiC layer, or it can be built on top of the a-SiC. In some embodiments, a printed circuit board (PCB), miniaturized ultrasonic transducer, and sensor is attached to the a-SiC layer. The miniaturized ultrasound transducer and sensor do not need to come into direct contact with the a-SiC layer as they can be connected to the PCB. The ultrasonic bonding of the miniaturized transducer or sensor to the PCB can occur before or after the fixation of the PCB to the a-SiC layer. In some embodiments, the miniaturized ultrasonic transducer or sensor PCB link comprises ultrasonic transducer link wire from the miniaturized sensor or to the PCB. In some embodiments, the sensor includes a part that interfaces with ports recorded in the a-SiC layer. In some embodiments, an ASIC is connected to the printed circuit board, which can occur before or after attaching the PCB to the a-SiC layer. At step 1010, an exposed portion of the implantable device is coated with a layer of a-SiC. In some embodiments, the exposed portion of the implantable device is coated with a layer of a-SiC using PECVD. In step 1012, the implantable device is embossed, thereby releasing the implantable device from the SiC layer. Closed Circuit Recording and Stimulation Systems
[0154] [0154] There is still a need for new electrode-based recording technologies that can detect abnormalities in physiological signals and be used to update stimulation parameters in real time. Features of such technologies include, preferably, high-density, stable recordings of a large number of channels in individual nerves, wireless and implantable modules to allow characterization of functionally specific neural and electromyographic signals, and scalable device platforms that can interfacing with small nerves 100 mm or less in diameter, as well as specific muscle fibers. current approaches to recording peripheral nerve activity below this target; for example, known uses of wrist electrodes are limited to recording compound activity from the entire nerve. -Single intrafascicular electrodes can record from multiple locations within a single fascicle, but do not allow high-density recording from discrete locations in multiple fascicles. Likewise, surface EMG matrices allow recording of very high density but not capturing fine detail from deep or small muscles. Recently, wireless devices to allow untethered recording in rodents and non-human primates, as well as mm-scale integrated circuits for neurosensing applications have been developed. See, for example, Biederman et al., A
[0155] [0155] In some embodiments, a wireless powered scalable implantable ultrasound backscatter system, which is used to record, stimulate and/or block signals in the central region and/or the peripheral nervous system. As shown in FIG. 11, The implant is batteryless and embedded close to a single or groups of neurons or implanted in either a nerve or muscle. A single or a group of external units (ie interrogators) placed external forces and communicates with a single or a group of implants. In one embodiment, the implant and wireless measurements report recorded electrophysiological signatures back to the source through backscatter modulation. Alternatively, implant harvests acoustic waves and converts them into electrical energy to power application-specific integrated circuits (ASIC). The ASIC is used to generate a series of pulses to stimulate target nerves electrically or acoustically. Existing clinical neural recording and stimulation solutions are limited to recording and stimulating from the entire nerve or a large population of neurons and do not allow for high-density recording from multiple discrete locations. Other known clinical solutions are large and heavy for long-term use.
[0156] [0156] In some embodiments, the closed-loop system comprises an interrogator and an implantable device configured to stimulate a tissue in response to a detected electrophysiological signal. In some embodiments, the implantable device is configured to detect the electrophysiological signal. In some embodiments, a second implantable device is configured to detect the electrophysiological signal. Implantable devices can be implanted in a large, closed network loop. For example, in some embodiments, the closed loop system includes a plurality of implantable devices configured to detect an electrophysiological signal and a plurality of implantable devices configured to emit an electrical pulse to stimulate tissue. Implantable Devices for Detecting an Electrophysiological Signal
[0157] [0157] The implantable device configured to detect an electrophysiological signal includes a miniaturized ultrasound transducer (such as a miniaturized piezoelectric transducer, a capacitive micro-machined ultrasound transducer (CMUT), or a piezoelectric micro-machined ultrasound transducer (PMUT)) configured to emit ultrasound encoding backscatter of a detected electrophysiological signal, a backscatter circuit (ie, a modulation circuit) configured to modulate a current flowing through the miniaturized ultrasound transducer based on the detected electrophysiological signal, and a first electrode and a second electrode configured to detect the electrophysiological signal in tissue. In some embodiments, the implantable device includes an integrated circuit, which may include the modulation circuit, a digital circuit (or integrated signal multi-circuit), and/or a power circuit. Backscatter ultrasound emitted from the miniaturized ultrasound transducer can encode information related to the detected electrophysiological signal, and is received by an interrogator. The interrogator can be the same interrogator that is used to operate implantable devices configured to emit the electrical pulse that stimulates tissue, or a different interrogator.
[0158] [0158] The modulation circuit (or "backscatter circuit) includes a switch, such as an on/off switch, or a field effect transistor (FET). An exemplary FET that can be used with some embodiments of the device Implantable is a metal-oxide-semiconductor field effect transistor (MOSFET). The modulation circuit can change the impedance of a current flowing through the miniature ultrasound transducer, and the variation in the current flowing through the transducer encodes the electrophysiological signal.
[0159] [0159] Fig. 12 illustrates an exemplary implantable device for recording electrophysiological signals. The implantable device includes a miniaturized ultrasound transducer 1202, a modulation circuit of 1204, a first electrode of 1206, and a second electrode of 1208. The first electrode 1206 and second electrode 1208 are configured to engage tissue (e.g., nerve or muscle tissue) to detect an electrophysiological signal. The modulation circuit includes a transistor of 1210, which includes a drain of 1212, the source of 1214, and a gate 1216. Gate 1216 is connected to the first electrode of 1206. A resistor bridge of 1218 comprising a first resistor 1220 and a second resistance bridge of 1222 to drain 1212 and the source of
[0160] [0160] In some embodiments the integrated circuit includes one or more digital circuits or multi-signal integrated circuits, which may include a memory and one or more circuit blocks or systems for using the implantable device. These systems can include, for example, an on-board microcontroller or processor, a finite state machine implementation, or digital circuitry capable of executing one or more programs stored in the implant or provided via ultrasound communication between the interrogator and implant. In some embodiments, the digital circuit includes an analog-to-digital converter (ADC), which can convert an analog signal from electrodes configured to detect the electrophysiological pulse into a digital signal. In some embodiments, the digital circuit includes a digital-to-analog converter (DAC), which converts the digital signal to an analog signal, before directing the signal to a modulator. In some embodiments, the integrated digital or multi-signal circuitry operates the modulation circuit (which may also be referred to as a "backscatter circuit"). In some embodiments, the integrated digital circuit or multi-signal circuit transmits a signal to the phase modulation circuit that encodes the sensitive detected current and voltage. In some embodiments, the digital integrated circuit or multi-signal circuit can drive the modulation circuit (which may also be referred to as the "backscatter circuit"), which connects to the miniaturized ultrasound transducer. The integrated digital circuit or multi-signal circuit can also operate one or more amplifiers, which amplifies the current directed to the switch.
[0161] [0161] In some embodiments, the digital circuit encodes a unique identifier of a digitized signal that comprises the electrophysiological signal. The unique identifier may identify the implantable device from which the ultrasound backscatter originates (e.g., in a system with a plurality of implantable devices), or may identify which electrodes on the implantable device detected the electrophysiological signal.
[0162] [0162] In some embodiments, the digitized circuit compresses the size of the analog signal. The reduced size of the digitized signal can allow more efficient reporting of detected electrophysiological signals encoded in the ultrasound backscatter. This can be useful, for example, when an implantable device includes a plurality of pairs of electrodes that simultaneously or roughly simultaneously detect an electrophysiological signal. By compressing the electrophysiological signal size through digitization, potentially overlapping signals can be accurately transmitted.
[0163] [0163] In some embodiments the integrated circuit filters out false electrophysiological signals. In some embodiments, filtering is performed by the digital circuit. An unfiltered voltage fluctuation can cause changes in the modulated current, which is encoded in the ultrasound backscatter, which can be recorded as a false positive. To limit false positives, current modulation can be filtered out, for example by requiring the electrophysiological signal to be above a predetermined threshold to cause modulation of the current flowing through the ultrasound transducer. In some embodiments, a peak detector is used to filter out false positive electrophysiological signals.
[0164] [0164] In some embodiments, the implantable device includes one or more amplifiers. Amplifiers can, for example, amplify an electrophysiological signal. This can happen, for example, before the signal is transmitted to the digital circuit.
[0165] [0165] In some embodiments, the integrated circuit includes a power circuit, which is configured to power components of the implanted device. The power circuit can include, for example, a rectifier, a charge pump, and/or an energy storage capacitor. In some embodiments, the energy storage capacitor is included as a separate component. Ultrasonic waves that induce a voltage differential in the miniaturized ultrasound transducer provide power to the implantable device, which can be controlled by the power circuit.
[0166] [0166] In some embodiments, the implantable device comprises a plurality of pairs of electrodes. electrode pairs can be formed from two electrodes; thus, an implantable device with three electrodes can have three pairs of electrodes. The electrophysiological signal can be detected between the electrodes of the electrode pairs. In some embodiments, the implantable device comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more, or 15 or more pairs of electrodes. In some embodiments, the implantable device comprises 2, 3, 5, 6, 7, 8, 9, 10 or more electrodes. In some embodiments, the implantable device includes a tin multiplexer that can select electrodes in the electrode pair to detect an electrophysiological signal.
[0167] [0167] In some embodiments, the electrodes of an electrode pair are separated by about 5 mm or less (such as, about 4 mm or less, about 3 mm or less, about 2 mm or less, about 1.5 mm or less, about 1 mm or less, or about 0.5 mm or less). In some embodiments, the electrodes of the electrode pair are separated by about 0.5 mm or more (such as about 1 mm or more, about 1.5 mm or more, about 2 mm or more, about 3 mm or more, or about 4 or more. In some embodiments, the electrodes are separated by about 0.5 mm to about 1 mm, about 1 mm to about 1.5 mm, about 1.5 mm. mm to about 2 mm, to about 2 mm to about 3 mm, about 3 mm to about 4 mm, or about 4 mm to about 5 mm.
[0168] [0168] Fig. 13A illustrates an implantable device, with a miniaturized ultrasound transducer, an integrated circuit, and a first electrode and second electrode. The integrated circuit includes a modulation circuit, which is configured to receive a signal based on a detected electrophysiological signal, and modulate a current flowing through the ultrasound transducer based on the received signal. The integrated circuit further includes an AC-DC power supply circuit, which includes a full-wave rectifier and doubler, as well as components for referencing or regulating the supplied power. FIG. 13B illustrates an exemplary rectifier that can be used with the implantable device. FIG. 13C illustrates the exemplary architecture for an AC-coupled amplifier chain. The electrophysiological signal ("neural V") is detected using the electrodes, and is amplified by the current amplifier before the signal is transmitted to the modulation circuit.
[0169] [0169] The implantable devices are miniaturized, which allows for comfortable and long-term implantation, while limiting tissue inflammation that is often associated with implantable devices. The body forms the core of the miniaturized implantable device (eg, the ultrasound transducer and the integrated circuit), and the electrodes branch from the body and envelop the tissue. In some embodiments, the longest dimension of the implantable device or implantable device body is about 5 mm or less, about 4 mm or less, about 3 mm or less, about 2 mm or less, about 1 mm or less, about 0.5 mm or less, or about 0.3 mm or less in length. In some embodiments, the longest dimension of the implantable device or implantable device body is about 0.2 mm or more, about 0.5 mm or more, about 1 mm or more, about 2 mm or more, or about 3mm or larger on the longest dimension of the device. In some embodiments, the longest dimension of the implantable device or implantable device body is about 0.2 mm to about 5 mm in length, about 0.3 mm to about 4 mm in length, about 0. 5mm to about 3mm long, about 1mm to about 3mm long, or about 2mm long. The electrodes can extend from the device to any desired length, and can be implanted to any depth within tissue. In some embodiments, an electrode is about 0.1 mm or more in length, such as about 0.2 mm or more, about 0.5 mm or more, about 1 mm or more,
[0170] [0170] In some embodiments, the implantable device has a volume of about 5 mm or less (such as about 4 mm or less 3, 3 mm 3 or less, 2 mm, 3 or less, or 1 mm3 or less ). In certain embodiments, the implantable device has a volume of about 0.5 mm from about 3 to about 5 mm 3 , about 1 mm from 3 to about 5 mm 3 , about 2 mm 3 to about 5 mm 3 , about 3 mm from 3 to about 5 mm 3 , or about 4 mm from 3 to about 5 mm.
[0171] [0171] In some embodiments, the implantable device is implanted into a subject. The subject can be, for example, a vertebrate animal such as a mammal. In some embodiments, the subject is a human, dog, cat, horse, cow, pig, sheep, goat, chicken, monkey, rat, or mouse.
[0172] [0172] In some embodiments, the implantable device or a portion of the implantable device (such as the miniaturized ultrasound transducer and the integrated circuit) is encapsulated by a biocompatible material (for example, a biocompatible polymer), for example a copolymer of N-vinyl-2-pyrrolidinone (NVP) and n-butylmethacrylate (BMA), polydimethylsiloxane (PDMS), parylene, polyimide, silicon nitride, silicon dioxide, silicon carbide, aluminum oxide, niobium, or hydroxyapatite. Silicon carbide can be amorphous silicon carbide or crystalline silicon carbide. The biocompatible material is preferably impermeable to water to avoid damage or interference from electronic circuits within the device. In some embodiments, the implantable device or a portion of the implantable device is encapsulated by a ceramic material (eg, alumina or titanium oxide) or a metal (eg, steel or titanium). In some embodiments, the electrodes or a portion of the electrodes are not encapsulated by the biocompatible material.
[0173] [0173] The miniaturized ultrasound transducer of the implantable device may be a micro-machined ultrasound transducer, such as a micro-machined capacitive ultrasound transducer (CMUT) or a micro-machined piezoelectric ultrasonic transducer (PMUT), or it can be a piezoelectric transducer large quantities. Bulk piezoelectric transducers can be any natural or synthetic material such as a crystal, ceramic or polymers. Exemplary bulk piezoelectric transducer materials include barium titanate (BaTi03), lead zirconate titanate (PZT), zinc oxide (ZO), aluminum nitride (AIN), quartz, berlinite (A1P04), topaz, langasite (La3Ga5SiO14), gallium orthophosphate (GaP04), lithium niobate (LiNb03), lithium tantalum (LiTa03), potassium niobate (KNb03), sodium tungstate (Na2W03), bismuth ferrite (BiFe03), polyvinylidene (di) vinylidene fluoride (PVDF), and magnesium, lead niobate titanate (PMN-PT).
[0174] [0174] In some embodiments, the piezoelectric bulk transducer is miniaturized approximately cubic
[0175] [0175] The miniaturized ultrasound transducer is connected to two electrodes; the first electrode is connected to a first face of the transducer and the second electrode is connected to a second face of the transducer, wherein the first face and second face are opposite sides of the transducer along the height dimension. In some embodiments, the electrodes comprise silver, gold, platinum, black platinum, poly(3,4-ethylenedioxythiophene (PEDOT), a conductive polymer (such as conductive PDMS or polyimide), a carbon fiber, or nickel.
[0176] [0176] In some embodiments, implantable devices are configured to engage with nervous tissue. In some embodiments, the engagement of nervous tissue does not completely involve the nervous tissue. In some embodiments, the nervous tissue is part of the central nervous system, such as the brain (e.g., the cerebral cortex, basal ganglia, midbrain, medulla, pons, hypothalamus, thalamus, in the cerebellum, palliium, or hippocampus) or the spinal cord . In some embodiments, brain tissue coupling includes electrodes that are implanted into the tissue, while the body of the implantable device is located outside of the tissue. In some embodiments, the nervous tissue is part of the peripheral nervous system, such as a peripheral nerve.
[0177] [0177] In some embodiments, the implantable device is used to detect epileptic activity. See, for example, Mohseni et al., Guest editorial: Closing the loop via advanced neurotechnologies, IEEE Transactions on Neural Systems and Rehabilitation Engineering, vol. 20, no. 4, pp. 407-409 (2012). In some embodiments, the implantable device is used to optimize a cochlear implant. See, for example, Krook-Magnuson et al.,
[0178] [0178] In some embodiments, the implantable device is coupled with a muscle, such as skeletal muscle, smooth muscle, or cardiac muscle. In some embodiments, implantable device electrodes are involved with muscle, such as skeletal muscle, cardiac muscle, or smooth muscle. EXEMPLICAL ACHIEVEMENTS
[0179] [0179] Embodiment 1. An implantable device, comprising: an ultrasonic transducer configured to receive ultrasonic waves that power the implantable device and encode a trigger signal; a first electrode and a second electrode configured to be in electrical communication with a tissue and emit an electrical pulse to the tissue in response to the trigger signal; and an integrated circuit comprising an energy storage circuit.
[0180] [0180] Embodiment 2. The implantable device of embodiment 1, wherein the electrical pulse is a current pulse.
[0181] [0181] Embodiment 3. The implantable device of embodiment 1, wherein the electrical pulse is a voltage pulse.
[0182] [0182] Embodiment 4. The implantable device of any one of embodiments 1-3, wherein the first electrode and the second electrode are within tissue or in contact with tissue.
[0183] [0183] Embodiment 5. The implantable device of any one of embodiments 1 to 4, wherein the integrated circuit comprises a digital circuit.
[0184] [0184] Embodiment 6. The implantable device of any one of embodiments 1 to 5, wherein the integrated circuit comprises a hybrid integrated circuit configured to operate the first electrode and the second electrode.
[0185] [0185] Embodiment 7. The implantable device of any one of embodiments 1 to 6, wherein the integrated circuit comprises a power circuit comprising the energy storage circuit.
[0186] [0186] Embodiment 8. The implantable device of any one of embodiments 1 to 7, comprising a body comprising the ultrasound transducer and the integrated circuit, wherein the body is about 5 mm or less in length in the plus dimension. long.
[0187] [0187] Embodiment 9. The implantable device of any one of embodiments 1 to 8, comprising a non-responsive reflector.
[0188] [0188] Embodiment 10. The implantable device of any one of embodiments 1 to 9, wherein the tissue is muscle tissue, organ or nerve tissue.
[0189] [0189] Embodiment 11. The implantable device of any one of embodiments 1 to 10, wherein the tissue is part of the peripheral nervous system or the central nervous system.
[0190] [0190] Embodiment 12. The implantable device of any one of embodiments 1 to 10, wherein the tissue is skeletal muscle, smooth muscle, or cardiac muscle.
[0191] [0191] Embodiment 13. The implantable device of any one of embodiments 1 to 12, comprising three or more electrodes.
[0192] [0192] Embodiment 14. The implantable device of any one of embodiments 1 to 13, wherein the integrated circuit comprises an analog-to-digital converter (ADC).
[0193] [0193] Embodiment 15. The implantable device of any one of embodiments 1 to 14, wherein the implantable device comprises a modulation circuit configured to modulate a current flowing through the ultrasound transducer.
[0194] [0194] Embodiment 16. The implantable device of embodiment 15, wherein the modulated current encodes the information, and the ultrasound transducer is configured to emit ultrasonic waves that encode the information.
[0195] [0195] Embodiment 17. The implantable device of embodiment 16, wherein the information comprises a verification signal that an electrical pulse has been emitted by the implantable device, a signal indicating an amount of energy stored in the energy storage circuit, or from a impedance detected.
[0196] [0196] Embodiment 18. The implantable device of any one of embodiments 15 to 17, wherein the implantable device includes a digital circuit configured to operate the modulation circuit.
[0197] [0197] Embodiment 19. The implantable device, of embodiments 18, wherein the digital circuit is configured to transmit a digitized signal to the modulation circuit.
[0198] [0198] Embodiment 20. The implantable device of embodiment 19, wherein the digitized signal comprises a unique implantable device identifier.
[0199] [0199] Embodiment 21. The implantable device of any one of embodiments 15 to 20, wherein the modulation circuit comprises a switch.
[0200] [0200] Embodiment 22. The implantable device of embodiment 21, wherein the switch comprises a field effect transistor (FET).
[0201] [0201] Embodiment 23. The implantable device of any one of embodiments 1 to 22, wherein the ultrasound transducer has a length of about 5 mm or less, in the longest dimension.
[0202] [0202] Embodiment 24. The implantable device of any one of embodiments 1 to 23, wherein the body has a volume of about 5 mm3 or less.
[0203] [0203] Embodiment 25. The implantable device of any one of embodiments 1 to 24, wherein the body has a volume of about 1 mm 3 or less.
[0204] [0204] Embodiment 26. The implantable device of any one of embodiments 1 to 25, wherein the ultrasound transducer is configured to receive ultrasound waves from an interrogator comprising one or more ultrasound transducers.
[0205] [0205] Embodiment 27. The implantable device of any one of embodiments 1 to 26, wherein the ultrasound transducer is a large quantities piezoelectric transducer.
[0206] [0206] Embodiment 28. The implantable device of embodiment 27, wherein the bulk ultrasound transducer is approximately cubic.
[0207] [0207] Embodiment 29. The implantable device of any one of embodiments 1 to 26, wherein the ultrasound transducer is an ultrasonic micro-machined piezoelectric transducer (PMUT) or a capacitive micro-machined ultrasound transducer (CMUT) .
[0208] [0208] Embodiment 30. The implantable device of any one of embodiments 1 to 29, wherein the implantable device is implanted in a subject.
[0209] [0209] Embodiment 31. The implantable device of embodiment 30, in which the subject is a human being.
[0210] [0210] Embodiment 32. The implantable device of any one of embodiments 1 to 31, wherein the implantable device is at least partially encapsulated by a biocompatible material.
[0211] [0211] Embodiment 33. The implantable device of embodiment 32, wherein at least a portion of the first electrode and the second electrode are not encapsulated by the biocompatible material.
[0212] [0212] Embodiment 34. The implantable device of embodiment 32 or 33, wherein the biocompatible material is a copolymer of N-vinyl-2-pyrrolidinone (NVP) and n-butyl methacrylate (BMA), polydimethylsiloxane (PDMS), parylene, polyimide, silicon nitride, silicon dioxide,
[0213] [0213] Embodiment 35. The implantable device of any one of embodiments 32 to 34, wherein the biocompatible material is a ceramic or a metal.
[0214] [0214] Embodiment 36. A system comprising one or more implantable devices according to any one of embodiments 1-35 and an interrogator comprising one or more ultrasound transducers configured to transmit ultrasound waves to the one or more implantable devices, in than the source of ultrasonic waves from one or more implantable devices.
[0215] [0215] Embodiment 37. The system of embodiment 36, wherein the ultrasonic waves encode a trigger signal.
[0216] [0216] Embodiment 38. The system of embodiment 36 or 37, wherein the system comprises a plurality of implantable devices.
[0217] [0217] Embodiment 39. The system of embodiment 38, wherein the interrogator is configured to direct beam of transmitted ultrasonic waves to focus the ultrasonic waves, alternatively transmitted onto a first portion of the multitude of implantable devices or to focus the ultrasound waves transmitted over a second portion of the plurality of implantable devices.
[0218] [0218] Embodiment 40. The system of embodiment 38, wherein the interrogator is configured to simultaneously receive ultrasound backscatter from at least two implantable devices.
[0219] [0219] Embodiment 41. The system of embodiment 38, wherein the interrogator is configured to transition ultrasonic waves to the plurality of implantable devices or receive ultrasound backscatter from the plurality of implantable devices, using time division multiplexing, multiplexing spatial, or frequency multiplexing.
[0220] [0220] Embodiment 42. The system according to any one of embodiments 38 to 41, wherein the interrogator is configured for use by a subject.
[0221] [0221] Embodiment 43. A closed loop system, comprising: (A) a first device configured to detect a signal; (B) an interrogator comprising one or more ultrasonic transducers configured to receive ultrasonic backscatter encoding the signal and emit ultrasonic waves that encode a trigger signal; and (C) a second device configured to emit an electrical pulse in response to the trigger signal, wherein the second device is implantable, comprising: an ultrasonic transducer configured to receive ultrasonic waves that power the second device and encode a trigger signal; a first electrode and a second electrode configured to be in electrical communication with a tissue and emit an electrical pulse to the tissue in response to the trigger signal; and an integrated circuit comprising an energy storage circuit.
[0222] [0222] Embodiment 44. The system of embodiment 43, wherein the signal is an electrophysiological pulse, a temperature, a molecule, an ion, the pH, pressure, voltage, or bioimpedance.
[0223] [0223] Embodiment 45. The system of embodiment 43 or 44, wherein the first device is implantable.
[0224] [0224] Embodiment 46. The system according to any one of embodiments 43 to 45, wherein the first device includes: a sensor configured to detect the signal of; an integrated circuit comprising a modulation circuit configured to modulate a current based on the detected signal, and a first ultrasonic transducer configured to output an ultrasonic backscatter which encodes the detected signal from tissue based on the modulated current
[0225] [0225] Embodiment 47. The system of embodiment 46, wherein the sensor comprises a first electrode and a second electrode configured to be in electrical communication with a second tissue and detect and electrophysiological signal.
[0226] [0226] Embodiment 48. The system of embodiment 47, wherein the first fabric and the second fabric are the same fabric.
[0227] [0227] Embodiment 49. The system of embodiment 47, wherein the first fabric and the second fabric are different fabrics.
[0228] [0228] Embodiment 50. The system according to any one of embodiments 43-49, wherein the first electrode and the second electrode of the second device are within the first or tissue in contact with tissue.
[0229] [0229] Embodiment 51. The system according to any one of embodiments 43 to 50, wherein the integrated circuit of the second device comprises a digital circuit.
[0230] [0230] Embodiment 52. The system of any one of embodiments 43 to 51, wherein the integrated circuit of the second device comprises a mixed-signal integrated circuit configured to operate the first electrode and the second electrode.
[0231] [0231] Embodiment 53. The system according to any one of embodiments 43 to 52, wherein the integrated circuit comprises a power circuit comprising the energy storage circuit.
[0232] [0232] Embodiment 54. The system according to any one of embodiments 43 to 53, wherein the first implantable device or the second implantable device comprises a body comprising the ultrasound transducer and the integrated circuit, wherein the body is of about 5 mm or less in length on the longest dimension.
[0233] [0233] Embodiment 55. The system according to any one of embodiments 43 to 54, wherein the tissue is muscle tissue, an organ or nervous tissue.
[0234] [0234] Embodiment 56. The system according to any one of embodiments 43 to 55, wherein the first device and the second device are implanted in a subject.
[0235] [0235] Embodiment 57. The system of embodiment 56, in which the subject is a human being.
[0236] [0236] Embodiment 58. A computer system, comprising: an interrogator comprising one or more ultrasound transducers; one or more processors; computer readable non-transient storage means storing one or more programs configured to be executed by one or more processors, the one or more programs comprising instructions for operating the interrogator to emit ultrasonic waves that encode a trigger signal that signals a device implantable to deliver an electrical pulse to tissue.
[0237] [0237] Embodiment 59. The computer system of embodiment 58, wherein the interrogator is operated to emit ultrasonic waves encoding the trigger signal in response to a detected physiological signal.
[0238] [0238] Embodiment 60. The computer system of embodiment 58, wherein the physiological signal comprises an electrophysiological pulse, a temperature, a molecule, an ion, the pH, pressure, voltage or bioimpedance.
[0239] [0239] Embodiment 61. The computer system of embodiment 59 or 60, wherein the one or more programs comprise instructions for detecting the physiological signal based on backscatter ultrasound that encodes the physiological signal emitted from a second implantable device.
[0240] [0240] Embodiment 62. The computer system according to any one of embodiments 59 to 61, wherein the one or more programs comprise instructions for determining a location of the first implantable device or the second implantable device with respect to one or more more than ultrasound to interrogator transducers.
[0241] [0241] Embodiment 63. The computer system, according to any one of embodiments 59 to 62, wherein the one or more programs comprise instructions for detecting movement of the first implantable device or the second implantable device.
[0242] [0242] Embodiment 64. The computer system according to embodiment 63, wherein the movement comprises lateral movement.
[0243] [0243] Embodiment 65. The computer system, of embodiment 63 or 64, wherein the movement comprises an angular movement.
[0244] [0244] Embodiment 66. A method of electrically stimulating a tissue, comprising: receiving ultrasonic waves to one or more implantable devices; converting energy from ultrasound waves to an electrical current that carries an energy storage circuit; receiving a trigger signal encoded in the ultrasound waves in one or more implantable devices; and emitting an electrical pulse that stimulates tissue in response to the trigger signal.
[0245] [0245] Embodiment 67. A method of electrically stimulating a tissue, comprising ultrasonic wave emitters that encode a trigger signal from an interrogator comprising one or more ultrasonic transducers for one or more implantable devices configured to emit an electrical pulse to the tissue in response to receiving the trigger signal.
[0246] [0246] Embodiment 68. The method of embodiment 66 or 67, wherein the trigger signal is transmitted in response to a detected physiological signal.
[0247] [0247] Embodiment 69. The method of embodiment 69, wherein the physiological signal comprises an electrophysiological pulse, a temperature, a molecule, an ion, the pH, pressure, voltage or bioimpedance.
[0248] [0248] Embodiment 70. The method according to any one of embodiments 66 to 69, wherein the tissue is a muscle tissue, an organ or a nerve tissue.
[0249] [0249] Embodiment 71. The method, according to any one of embodiments 66 to 70, comprising implanting one or more implantable devices into a patient.
[0250] [0250] Embodiment 72. The method, of embodiment 71, in which the subject is a human being.
[0251] [0251] Embodiment 73. The method, according to any one of embodiments 66 to 72, comprising determining a location of one or more implantable devices.
[0252] [0252] Embodiment 74. The method, according to any one of embodiments 66 to 73, comprising detecting an angular or lateral movement of one or more implantable devices.
[0253] [0253] Embodiment 75. A method of stimulating a tissue, comprising: receiving ultrasonic waves to one or more implantable devices configured to detect a physiological signal; converting energy from ultrasound waves to an electrical current flowing through a modulation circuit; detect the physiological signal; modulate the electrical current based on the physiological sensed signal; transduce the modulated electrical current into an ultrasound backscatter that encodes information related to the detected physiological signal; and the ultrasound backscatter emitter to an interrogator comprising one or more transducers configured to receive the backscatter of ultrasound; ultrasonic wave emitters from the interrogator to one or more implantable devices configured to emit an electrical pulse to tissue; converting energy from the ultrasound waves emitted from the interrogator to the one or more implantable devices configured to emit the electrical pulse to an electrical current that carries an energy storage circuit; ultrasonic wave emitters that encode a trigger signal from the interrogator; receiving the trigger signal to one or more implantable devices configured to emit the electrical pulse; and emitting an electrical pulse that stimulates tissue in response to the trigger signal.
[0254] [0254] Embodiment 76. The method of embodiment 75, wherein the physiological signal comprises an electrophysiological pulse, a temperature, a molecule, an ion, the pH, pressure, voltage, or bioimpedance.
[0255] [0255] In abbreviated form, the implantable device assembly steps are as follows:
[0256] [0256] The ASIC measures 450 µm by 500 µm by 500 µm and is manufactured by a 65 nm process from Taiwan Semiconductor Manufacturing Company. Each chip contains two transistors with 5 gates each: source, drain, gate, center, and bulk. Each FET uses the same volume, so large amounts pad or pad can be connected to, but transistors differ in that the transistor padded out to the top row does not contain a step resistance bias grid that the transistor pads in the row inferior does. The chip additionally contains smaller pads for electroplating. The same process can be applied for ASICs with more complex circuitry and therefore more pads. These pads were not used in this example. Three versions of the FET have been etched out: Template 1: Long channel FET with threshold voltage: 500 mV Template 2: Short channel FET with 500 mV threshold voltage Template 3: Native FET with threshold voltage at 0 mV
[0257] [0257] Confirmation of electrical characteristics of these FETs were measured using a specially designed CMOS characterization board, which contained one set of pads as wire binding targets and a second set of pads on which the wires were soldered to. A sourcemeter (2400 Sourcemeter, Keithley Instruments, Cleveland, OH) was used to supply V DS to the FET and measure I DS - An adjustable power supply (E3631A, Agilent, Santa Clara, CA) was used to modulate V GS and the IV characteristics of the FETs were obtained. Uncharacteristic IV curves for type 2 dies were consistently measured, and by measuring impedance, they found that the short channel of the 2s die would be short out of the FET.
[0258] [0258] The piezoelectric element is lead-zirconium titanate (PZT). It is purchased as a disk from APC International and cut into cubes into .750 μm x 750 μm x 750 μm cubes using a wafer saw (DAD3240, Disco, Santa Clara, CA) with a ceramic blade (PN-010-CX '270-080 - H). This mote size was chosen as it maximized energy transfer efficiency. For more details, see Seo et al., Neural dust: an ultrasonic, low power solution for chronic brain-machine interfaces, arXiv:
[0259] [0259] The implantable device was implanted into the sciatic nerve of a Long-Evans rat. The nerve is a large-diameter bundle of nerves that innervates the hind limb. The nerve is between 1 and 1.4 mm in diameter, and its size and accessibility make it an ideal candidate for device implantation. While several iterations of the implantable device were made, the following example describes the development of two versions implanted in mouse models.
[0260] [0260] The implantable device substrate integrates the ASIC with the recording and piezoelectric element electrodes. The first version of the implantable device PCB used custom designed ones purchased from O Working Plates (Oakland, CA) as substrate. The PCBs were made from FR-4 and were 30 mil (about 0.762 millimeters) thick. The dimensions of the plate were 3mm x 1mm. This design was the first attempt at an integrated communication and sense platform, so the pad size and spacing was chosen to facilitate assembly at the larger size cost. To conserve real-state PCBs, each face of the PCB included pads for either the piezoelectric element or the ASIC and their respective connections to the PCB. Furthermore, two recording pads were placed on the ASIC-face of the board. All exposed electrodes were plated with ENIG by Working Plates. The cushion for the ASIC to sit on was 500 µm by 500 µm, chosen to fit the mold size. The target pad binding wire size was chosen to be 200 µm by 200 µm and spaced approximately 200 µm away from the mold edge in order to give sufficient slack for binding wire
[0261] [0261] In the second implantable device iteration, three major concerns were addressed: 1) size, 2) ease of wire binding, 3) implant/communication. First, to thin the board the FR-4 substrate was replaced by a 2 mil (approximately 50.8 µm) thick polyimide flexible PCB (AltaFlex, Santa Clara, CA) as well as diluting the ASIC (Grinding and Diced Services Inc., San Jose, CA) at 100 μηι. To facilitate binding, the ASIC and PZT coupon were transferred to the same side, with only the recording electrodes on the back side of the substrate. Although placing the ASIC and PZT coupon on the same side of the board imposes a limit on how much the substrate size can be reduced, the spacing between the electrodes restricts the length of the board to at least 2mm. To push minimization efforts of ASIC binding pads were reduced to 100 μm per 100 μm, but the spacing between 200 μm binding pads and the ASIC itself had to be maintained to provide space for the binding wire. The fastening pads for the PZT coupon were also reduced and placed closer to the edge of the board, with the justification that the PZT coupon does not have to fully sit on the board, but could hang off the board. In addition, the location of the pads relative to the ASIC has also been modified to facilitate connection. In the original design, the pad-link layout around the ASIC required two wire bindings to cross. This is not impossible, but very difficult to avoid shorting the pads. So the pad layout has been shifted so that titles are relatively straight paths. Finally, in the course of animal experiments, it was found that alignment of the implantable device was very difficult. To combat this, four 1-inch test leads that extended out of the board were added, two of which connected directly to the source and drain of the energy harvesting device could be measured and used as an alignment metric. The other two conductors connect to the door and center ports in order to get a true floor signal. In order to avoid confusion about which lead belonged to which door, the pathways were given unique geometries. See FIG. 14A.
[0262] [0262] There was some fear that the test leads could be easily broken or would easily displace the particle if force was applied to them. Thus, a serpentine-featured version was designed. Serpentine strokes (FIG. 14B) have often been used to allow deformable interconnects, as their structure allows them to "accordion" outward. Conceptually, the serpentine tracking design can be through a series of support arms in series by means of tie rods.
[0263] [0263] Along with the drawings presented, a miniature version of the implantable device using both sides of the substrate was also designed and assembled. In this design, the board measures approximately 1.5mm by 0.6mm by 1mm. Due to the miniaturization of the board, a 5 mil silver "tail" wire was attached to the device for recording. This version has not been tested in vivo.
[0264] [0264] The ASIC and PZT coupon were bonded to the PCB substrate using adhesives. There are three major concerns for choosing an adhesive: 1) the adhesive must fix the ASIC and PZT tightly enough that the ultrasound energy from the bonding wire does not shake the components, 2) due to sub-millimeter scales and locations of components/substrate chips, application of the adhesive was done relatively accurately, and 3) the adhesive must be electrically conductive.
[0265] [0265] Cubed ASIC and PZT were originally bonded to the substrate using a PCB from temperature-curing solder paste. solder paste consists of powdered metal solder suspended as spheres in the flux. When heat is applied, the solder balls start to melt and fuse together. However, it has been found that curing of the solder paste would often result in translating either the rotation of the PZT coupon or mote during reflux. This presented PZT alignment and energy harvesting problems, as well as bonding wire problems due to the bonding pads not being properly positioned from the chip. However, it was found that a two-part epoxy silver, which simply consists of silver particles suspended in epoxy, was able to cure without repositioning the chip or coupon.
[0266] [0266] The connections between the top of the PZT and the PCB, as well as the ASIC and the PCB were performed by bonding wire of 1 mil Al wire using an ultrasonic wedge bonder (740DB, West Bond, Scotts Valley, CA) ; In this bonding method, the Al wire is threaded through the wedge of the bondhead and ultrasonic energy "rubs" the Al wire against the substrate, generating frictional heat. This heat results in welding two materials together.
[0267] [0267] The lead wire for the ASIC was difficult to avoid short circuits due to the size of the CMOS chips and the foot size of the lead wire. This problem was accentuated by the positioning of the lead wire targets in the first version of the implantable device plate, which forced the two lead feet to be placed along the smaller width of the ASIC pad, rather than the length. While thinner gold wire was available to use for bonding, the difficulty of bonding gold thermosonically with a Wedge Bonder made it impractical to use gold wire for bonding with this equipment. Also, in order to effectively bond wire, it is important to have a flat and fixed substrate; therefore, our original design of having the ASIC and PZT on different sides of the board often caused problems during the wire-bonding process in our first version of implantable boards. In this way, the substrate design choices made in the second iteration of the implantable device (moving ASIC and PZT to the same side, repositioning the inserts to provide straight paths for binding wire targets) greatly improved binding wire yield.
[0268] [0268] Lastly, because an ultrasound binder was used, it was found that binding to the PZT resulted in a build-up rate that would damage the chip once the PZT was fully bound to the substrate. To avoid this, the device's source and drain test leads were discharged to Earth ground directly before the PZT lead wire.
[0269] [0269] The final step in the implantable device assembly is encapsulation. This step achieves two objectives: 1) isolating the PZT, bonding pads, and ASIC from aqueous environments and 2) protecting the bonding wires between the ASIC / PZT coupon and the PCB. At the same time, there must be some method to remove or prevent the encapsulant from covering the recording electrodes. Additionally, the encapsulant must not impede device implantation. Finally, although not essential, it is of interest to choose an encapsulant that is optically transparent so that the device can be inspected for physical defects if some damage occurs during encapsulation.
[0270] [0270] The first encapsulant used was Crystal Bond (509', SPI Supplies, West Chester, PA). Crystal Bond is an adhesive that is solid at room temperature, but begins to soften' at 71°C and melts with a viscous liquid at 121°C. After removing the heat from the Crystal Bond, it re-solidifies within minutes, allowing for good control. To encapsulate the implantable device, a small flake of Crystal Binding was padded with a razor blade and placed directly over the device. The plate was then heated using a hot plate, first bringing the temperature to around 70°C when the flake would start to deform and then slowly increasing the temperature until the binding. crystal has become completely liquid. Once the edge of the expanded liquid crystal bonding drop passed the furthest bonding wire, but not the recording pad, the heating plate was turned off and the plate was quickly transferred off the plate onto a cooling mandrel, where o Crystal binding would re-solidify.
[0271] [0271] Although crystal binding was effective, it was found that UV curable epoxide could give us better selectivity and biocompatibility, as well as fast curing. First, a light-curable acrylic (3526, Loctite, Dusseldorf, Germany) was tested, which cures on exposure to ultraviolet light. A sewing needle was used as an applicator to obtain high precision and the epoxy was cured with a 405 nm laser spot for 2 minutes. This epoxy worked well, but not medical-grade and therefore not suitable for a biological implant. Thus, a medical grade UV curable epoxy (OG116-31, EPO-TEK, Billercia, MA) was attempted. The epoxide was cured in a UV chamber (Flash, Asiga, Anaheim Hills, CA) with 92 mW/cm at 365 nm for 5 minutes. While this epoxy was slightly less viscous than the Loctite epoxy, using a sewing needle again as an allowed applicator for selective encapsulation. As an insulator and protection mechanism for lead wires; epoxy was very effective, but it leaked during prolonged submersion in water (~1 hour). A second medical grade epoxide, which aimed at stability of up to one year, was considered (301-2, EPO-TEK, Billerica, MA), but was found not to be sufficiently viscous and necessary oven-baking during curing. Despite the instability of ultraviolet epoxy, the duration of use was adequate for acute in vivo experiments.
[0272] [0272] To improve the stability of the encapsulant, C-parylene has also been considered as an encapsulating material. Parylene-C is an FDA approved biocompatible polymer that is chemically and biologically inert, a good barrier and electrical insulator, and extremely conformable when vapor deposited). Parylene-C vapor deposition is achieved by vaporizing Parylene C-dimer powder at temperatures above 150 °C. The Parylene C-dimer vapor is then heated to 690 °C in order for pyrolysis to occur, cleaving the Parylene C-dimer into monomers. The monomer then fills the chamber, which is kept at room temperature.
[0273] [0273] The following provides additional details for the fabrication of the implantable device.
[0274] [0274] Before starting to work with PCBs, ASICs, or PZT coupons, prepare two sample holders for the dust plates. To do this, simply take two glass slides (3mm x 1mm x 1mm slides work well) and place a strip of double-sided tape on the slide lengthwise. The tape will be used to fix the dust particles in place so that the rest of the steps can be performed. On one of the slides, also add a piece of Kapton tape (3M) from the sticky side up on top of the double-sided tape. This slide will be the slide used for curing, as the high curing temperature can cause problems with the double sided tape adhesive.
[0275] [0275] Then mix a small amount of silver paste by weighing to a 1:1 ratio of part A and part B in a weigh boat. A large amount of silver-epoxy is not required for the assembly process. Shown below is about 10 g of epoxy (5 g of each part), which is more than enough for three plates. Note that epoxy mixed with silver has a shelf life of two weeks if placed at 4° C. So leftover epoxy can and should be refrigerated when not in use. Also, older epoxies (several days to a week) tend to be slightly more viscous than fresh epoxy which can make application easier,
[0276] [0276] The substrates arrive panelized and will have to be removed. Each board is attached to the panel at multiple attachment points on the probes and Vias - these attachment points can be cut using a micro-scalpel (Feather Safety Razor Co., Osaka, Japan). Once the PCB has been individualized, using either carbon fiber tipped tweezers or ESD plastic tweezers, place the individualized PCB into the high temperature sample holder.
[0277] [0277] The minced/diluted mold are sent in cutting tape, which can make it complicated to remove the mold. In order to reduce the adhesion between the matrix and the tape, it can be useful to deform the tape. With carbon tip tweezers or ESD plastic, the tape is gently pressed and the tweezers work in a circular motion around the matrix. To check if the mold has been released, gently poke the chip with the tip of the tweezers. If the mold does not come off easily, continue to press the tape around the chip. Once the chip comes loose, carefully place the chip in the high temperature sample holder along its edge. It is advisable to take the sample holder to the chip instead of the other way around so that the chip is not in transit, Care must be taken in this step to avoid losing or damaging the die. Never force a mold onto tape, as excessive force can cause a chip to fly off the tape.
[0278] [0278] Then attach the mold using silver epoxy. Under a microscope, use a pin or something equally good to apply a small amount of silver epoxy to the CMOS block on the PCB. At this step, it is better to err on the side of too little epoxy than too much epoxy, as more silver glue can always be applied, but removing the silver glue is not trivial. Small amounts of uncured epoxide can be dampened with the same tool used for the application, just ensure the epoxy has been wiped off the tool.
[0279] [0279] Once the epoxide has been placed over the pad, the ASIC can be placed over the epoxy. Due to a CAD error, some of the chips were reflected. It is important to take care that the chips that are reflected have been oriented the right way on the board to ensure that no wires need to cross during the lead wire.
[0280] [0280] Once the ASICs have been situated on the plates correctly, the epoxy silver can be cured by placing it in an oven at 150°C for 15 minutes. Note that different temperatures can be used if necessary - see FIG. 15 for more details. After the silver epoxy has been cured, double the adhesion control by carefully pushing on each die, if the die moves; a second coat of epoxy silver will be required.
[0281] [0281] To prepare for wire binding, move the holder devices for the high temperature sample to titrate the normal sample. This change is necessary because the adhesion of double sided tape is stronger than that of Kapton tape so wire binding will be easier. A piece of double-sided tape should be good enough to secure the sample holder to support the lead wire piece. It's best to ensure that the part holder hasn't been previously covered with double-sided tape so that the test leads don't accidentally get stuck to anything. If necessary, cleanroom tape can be used to provide additional tightening of the sample holder.
[0282] [0282] Ensure the lead wire is in good condition by making titles on the supplied test-substrate using pad settings. Ensuring that the lead wire is in good condition is important, as a damaged wedge will not adhere well and effectively only damage the ASIC pads. Forward connections (first connection on matrix, second connection on substrate) should be made in the following order: 1. Gate. 2. mass. 3. Center. 4. Drain. 5. Source. While it is not critical that bonds be made in this order, in this order it minimizes the number of substrate reorientations and prevents accidental damage to the bonds due to the bondhead. small angle adjustments of the part holder can be made to facilitate bonding; it is imperative that this bond be as straight as possible. In the case where the foot of the second binding erects from the substrate, changing the number of bonds to a binding and footing again may help. If proper adhesion cannot be made, a potential solution is to bond the bonding foot and substrate using epoxy silver. Also, shorts caused by two feet of touching titles can be resolved by very carefully cutting out the transition metal using a microscalpel.
[0283] [0283] Known job binding parameters can be found in Table 2, below. These parameters are simply guidelines and should be modified as needed. Needing excess power (greater than 490) is typically indicative of a problem: substrate fixation (both PCB to glass slide and CMOS to PCB), wedge condition, and pad condition should all be checked. In the case of pad condition, pads damaged due to previous wire binding attempts typically require more power - in some cases the devices are recoverable, but attempts to bond with power greater than 600 usually result in too much damage to the pads for a good union. Table 2: Parameters for ASIC Westbond 7400B Al Bond # Force Time 1 (ASIC) 420 40 ms 2 (Substrate) 420 40 ms
[0284] [0284] Post-wire bonding, the device must undergo electrical tests to ensure proper bonding. If using a one-matrix type, the IV characteristics should be more or less as shown in Table 3. Table 3: Typical IV characteristics for type 1 mold under V dS Vgs Ids 0 V 0.5 A
[0285] [0285] After confirming that the FET is properly turned on, the PZT coupon should be turned on. This is done in a similar way to attaching the ASIC: place some epoxy silver using a sewing needle on the appropriate pad. It's best to place the epoxy dab at the back end of the pad (towards the end of the board) since the PZT coupon will not be centered on the pad, but put off so that the coupon is hanging off the board. Keep in mind that the polarity of the PZT coupon has a small effect on its efficiency. To determine whether or not the coupon is in the correct position, check if the bottom face is larger than the top face. Due to the path of the saw cut into cubes, the bottom of the valley is a little bigger than the top of the coupon. So the edges of the bottom face can be seen from a top-down view, then the coupon was placed in the same orientation as it was when the disc was cut into cubes.
[0286] [0286] The PZT link wire is made in a similar way to the ASIC (link later, the PZT to the PCB). However, a crucial change is that the drainage and source pathways must be backfilled. There is a grounding port next to the Westbond that can be accessed via a banana connector. As a guide, the parameters shown in Table 4 have been known to work. Table 4: Parameters for PZT Westbond 7400B Al
[0287] [0287] A successful binding may require several attempts depending on how well the PZT coupon is bound to the substrate. The additional attempts that are made, the worse the mechanical structure of the PZT becomes (the silver coating will get damaged) so it is better to try to optimize the process very quickly. Bonds that fail due to foot detachment usually imply not enough power. Bonds that fail due to wire breakage in the foot usually involve a lot of energy.
[0288] [0288] After a successful connection is made, it is always good to do another electrical test to ensure that the PZT connection has not damaged the ASIC.
[0289] [0289] As a final step, the test leads were soldered to the pathways and encapsulating the device, the test leads are 3 mil silver wires. Note that these wires are insulated: the insulation can be removed by placing the wire near a flame (not the flame) and following the molten plastic and shrinking.
[0290] [0290] After soldering wires, the device can now be encapsulated. The encapsulant is medical grade OG116-31 UV curable epoxy and must be dispensed using a sewing needle. An effective method is to place a large drop of epoxy over the PZT coupon and a large drop over the ASIC. Using a clean needle, push the drop through the plate so that the entire top of the tray is coated. The epoxy should wet the board, but not overflow, due to its surface tension. Once the main body of the board is coated, the pathways must also be coated, as well as the side faces of the piezo. The plate can then be cured in a UV chamber for about 5 minutes. It was found that the test leads might occasionally come in contact with something in the UV chamber and short the ASIC. So, before putting the board into the chamber, it's good to break the wires down or put it in some tape in order to insulate them from any chamber surfaces.
[0291] [0291] After curing, the back must be coated. In particular, the exposed PZT coupon that hangs over the plate, as well as the back side of the test leads and the two paths on the back of the plate, which connect the electrodes to the top side of the plate. This part can be a little tricky due to the small space between the backside pathways and the electrodes, so it's best to start with a very small amount of epoxy and place it near the edge of the plate, then drag the epoxy towards to the routes. The back of the board must be cured in the same way as the top side. Once the board is completely encapsulated, a final electrical test must be done, and upon passage, the implantable device is now complete. Example 2 - Configuration for Testing Implantable Devices
[0292] [0292] Implantable testing has always been complicated due to the thinness of the probes that extend out of the board. Stapling in and out of these pathways for IV measurements often resulted in pulling the ends out of the device's body. Also, due to the test leads, it is difficult to carry out water-tank test measurements; as electronics exposed to water would result in shorts. In order to get around this problem, a PCB is designed to serve as a test for implantable device measurements. The PCBs (Bay Area Circuits, Fremont, CA) were made of FR-4 and 60 mil thick; which includes four lanes, distributed on the plate to match the layout of the two plate version of implantable devices.
[0293] [0293] The Gold header pins (Strip Header Pin, 3M, Austin, TX) were soldered to the tracks so that they extended from the board on both sides of the board. This allowed us to place our devices on top of the test bed, and tap into the implantable, accessing the header pins. Then, to isolate the pathways, plastic caps made of polyethylene terephthalate (PETG) were 3D printed (X Flashforge Creator, FlashForge, Jinhua, China). These plugs have been printed with a groove so that a gasket can be placed inside the groove and create a waterproof seal around the header pins. Plugs were attached to the compression plate and created by drilling 2mm holes through the PCB and lid using a micromill (47158, loading port, Camarillo, CA) and screwing the lid and plate together. . The wires extending from the test stand were soldered to the header pins and the pins were then encapsulated. To measure the sealing effectiveness, the plates were submerged in a 6M aqueous solution of NaCl and the resistance between the pins was measured using a script A
[0294] [0294] One version of the implantable device was a 1mm x 3mm x 1mm PCB made of FR-4 with a piezoelectric PZT, silicon AS! C, and encapsulated using crystal bonding. These were implanted into the sciatic nerve of an adult male Long-Evans rat anesthetized with a mixture of IP ketamine and xylazine. A true soil measurement was obtained using a tungsten microwire with a 28G stainless steel needle electrode placed on the animal's foot as a reference. Nerve activity was evoked using electrical stimulation and backscatter data was acquired by sending and receiving pressure waves using a transducer (V323-SU-F1 Olympus, Waltham, MA).
[0295] [0295] The original signal between the powder particle was then calculated from the backscatter data using MATLAB. A representative plot of the reconstructed signal versus the ground truth is shown in FIG. 16.
[0296] [0296] The reconstructed implantable device data followed the overall true soil profile, capturing the composite nerve action potential, but several features present in the reconstructed data (such as the "dips" found from the first to the third second) could not be explained.
[0297] [0297] A second version of the implantable device was approximately 0.8mm x 3mm x 1mm, and used a polyimide substrate and a medical grade UV curable epoxy as an encapsulation. A crucial change was the addition of probes into one. Long, allowing the voltage across the piezoelectric element to be measured as well as taking true terrestrial measurements by touching the recording electrodes. The same device implant protocol was used in two versions as it was used in one version, but signal reconstruction with backscatter was done in real-time using an original transceiver board. Example 3 - Implantable Devices Encapsulated in Silicon Carbide
[0298] [0298] Rather than an epoxy encapsulant, silicon carbide (SiC) may be a more effective material to insulate and protect the implantable device. SiC is formed by the covalent bond of Si and C, forming tetrahedrally oriented molecules with short bond length and thus high bond strength, giving high chemical and mechanical stability. Amorphous SiC (a-SiC) has been well received by the biomedical community as a coating material as it can be deposited at much lower temperatures than normally required by crystalline SiC and is an electrical insulator. Deposition of um-SiC is generally accomplished via plasma augmented chemical vapor deposition (PECVD) or spraying. Ongoing research using a sputtered-SiC has shown that it is difficult to achieve a SiC pinhole-free layer. Instead, PECVD using S1H 4 and CH 4 as precursors is able to produce impressive, SiC-free pinhole films.
[0299] [0299] Furthermore, implanted a-SiC has shown impressive biocompatibility. Previous studies have shown that a 50 µm iridium axis coated with a-SiC implanted in rabbit cortex for -20 days did not show the usual chronic inflammatory response of macrophages, lymphocytes, monocytes recruited to the insertion site. See Hess et al., PECVD silicon carbide as a thin film packaging material for microfabricated neural electrodes, Materials Research Society Symposium Proceedings, vol. 1009, doi: 10.1557/PROC-1009-U04-03 (2007).
[0300] [0300] It is interesting to consider an approach to implantable devices that involves building the silicon devices with a silicon carbide encapsulant for a truly chronic implant. One possible process is shown in FIG. 17. One of the biggest challenges here is to ensure that the SiC debt PECVD does not deplete the piezoelectric material. In order to have contamination free films, it is important to deposit at a minimum temperature of 200°C but below the Curie temperature of the piezoelectric transducer. Example 4 - Energy transfer to and backscatter of a miniaturized ultrasonic transducer
[0301] [0301] A set of experiments were performed with PZT due to the relative ease of obtaining PZT crystals with variable geometry. PZT metallized sheets of various thicknesses were obtained (PSI-5A4E, from Piezo Systems, Woburn, MA and PZT 84, APC International, Mackeyville, PA) with a minimum thickness of PZT 127 µm. PZT was fully encapsulated in silicon PDMS for biocompatibility.
[0302] [0302] The most commonly used method for ceramic PZT molding is to use a wafer plate cutting saw with a suitable ceramic blade to cut PZT sheets into individual PZT crystals. The minimum cut resolution is determined by the blade cut and can be as small as 30 µm.
[0303] [0303] Another possible option is to use a laser cutter. Unlike saw plate cutting, laser cutting performs the cuts by focusing a high-powered laser beam onto a material, which melts, vaporizes, removes, and scratches the piece. The precision of laser cutting can be up to 10 µm and is limited by the laser wavelength. However, for the treatment of sensitive samples, such as PZT ceramic, the temperature at the cut site can be detrimental to the piezoelectric performance of the material. Excimer ceramic laser cutting uses UV laser to cut with excimer of noble gases, but as laser cutting it is extremely expensive and no suitable services are available right now. As a result, a dicing saw was used to make all the cuts.
[0304] [0304] In order to conduct or extract electrical energy from the PZT, an electrical connection is made to both the top and bottom plates. The materials typically used as an electrode for PZT are silver or nickel. Silver is generally used for a wide variety of non-magnetic and AC applications and silver in the form of flakes in the suspension of a glass frit is usually traced to ceramic and fired. For high direct current electric field applications, silver is likely to migrate and bridge between the two plates. As a result, nickel, which has good corrosion resistance and which does not electro-migrate as easily, can be galvanized or vacuum deposited as an alternative.
[0305] [0305] Both materials can be welded with proper soldering and flux. For example, silver is soluble in tin, but a charged silver solder can be used to prevent the elimination of silver on the electrode. Phosphorus content from nickel plating can make soldering tricky, but correct flux can remove surface oxidation. However, during soldering, in order to avoid going beyond the Curie point and depoling the PZT sample, the soldering temperature should be between 240 and 300 °C. Even at these temperatures, as PZT is also pyroelectric, care must be taken not to exceed 2 - 4 seconds of soldering time.
[0306] [0306] Alternatively, the electrical connection can be made using either epoxy silver or low temperature solder using solder paste. Two-part silver epoxy pads can provide sufficient electrical conductivity and can be cured at room temperature overnight. However, joints tend to be fragile and can easily break during testing. The bond can be reinforced using a non-conductive epoxy as an encapsulation, but this additional layer introduces a mechanical load to the PZT and can significantly lower its quality factor. Low temperature solder paste on the other hand undergoes a phase change between the temperature of 150 and 180 °C and can provide excellent electrical bonding and a bonding resistance that is comparable to that obtained with flash soldering. Therefore, the low temperature soldering approach was used.
[0307] [0307] The segmentation wafer is capable of cutting PZT into small 10 µm crystals. However, samples that are less than 1mm in dimension are extremely difficult to handle with forceps and binding. Furthermore, due to the variation in the length of the wire used to interface with the top and bottom plates of PZT crystals (and therefore the parasitic inductance and capacitance introduced by the wire) and the amount of solder paste dispensed across a number of samples, the impedance spectroscope measurements were inconsistent.
[0308] [0308] Therefore, 31 mil-thick two-layer FR-4 PCB where all the short electrical interconnections and embedding them stray wires and the board was fabricated. The fabricated plate, which includes numerous test structures and a module to individually characterize 127 µm, 200 µm, and 250 µm coarse PZT crystals are shown with dimensions in the
[0309] [0309] In order to avoid directly handling tiny PZT crystals, FIGS. 19A-E outline a process flow of adapting to connecting PZT to the PCB. As shown in FIG. 19A, solder paste is dispensed using a pump at constant pressure and for a controlled amount of time into one of the pads on the upper side. The inserts are either 250 µm, 200 µm, or 127 µm based on the thickness of the PZT used. FIG. 19B shows a PZT piece larger than the mouse (which can be easily handled) is placed on top to cover the inserts. The plate and piezo assembly is baked in an oven to cure the solder paste. Therefore, PZT crystals are now bonded to pre-welded beaten electrodes. FIG. 19C shows a dicing saw insert makes a total of four cuts along the edges of the pad with the solder paste using alignment markers on the board, with non-bonded areas falling out and leaving an array of small crystals. PZT connected to PCB. FIG. 19D shows single lead wire makes electrical contact between the top plate of the PZT and an electrode on the PCB, completing the circuit. Finally, FIG. 19E shows the entire assembly is encapsulated in PDMS (Sylgard 184, Dow Corning, Midland, MI) to protect the lead wire and provide insulation.
[0310] [0310] Since the piezoelectric material is an electro-mechanical structure, its electrical and mechanical properties have been characterized. The following test setup details and techniques for performing such measurements.
[0311] [0311] Any electrical appliance can be modeled as a black box using a mathematical construct called two-port network parameters. The properties of the circuits are specified by an array of numbers and the device response to signals applied to their input can be easily calculated without solving for all the internal voltages and currents in the network. There are several different types of two-port network parameters, such as Z-parameters, Y-parameters, S-parameters and ABCD-parameters, etc, and the conversion between different parameters can be easily derived. The device that allows us to extract these parameters is called a vector network analyzer (VNA). A VNA incorporates directional couplers to decompose the voltage across each gate into incident and reflected waves (based on impedance mismatch), and calculate the ratio between these waves to calculate scattering or S-parameters.
[0312] [0312] Before taking measurements using a VNA, it is necessary to calibrate the instrument as the internal directional pairs are not ideal. Calibration also allows us to shift the measurement reference plane to the ends of the cable, ie, calibrate out parasites from the cable. There are several calibration pads, but the most commonly used are open, short, and load calibration procedures. The measurement scheme is shown in FIG. 20. Staples, which are soldered over the ends of the coaxial cable, are used to interface with the top/bottom plates. Staple parasites were not significant below 100 MHz.
[0313] [0313] As an example, a VNA (E5071C ENA, Agilent Technologies, Santa Clara, CA) was used to measure the electrical properties of a (250 µm) PZT crystal. It was noted that the measured capacitance of the PZT crystal vastly differs from the capacitance expected from a simple parallel plate capacitance model due to significant stray capacitances from the PCB and the bracket (clamp and connector). Since the VNA coefficients from the previously delineated calibration step moved only the measurement plane to the cable ends, open/short/load calibration structures fabricated on the same plate were used to enclose the board and fixture parasites. The measured PZT response matched the expected response after calibration.
[0314] [0314] Using this calibration technique, the PZT impedance can be graphed as a function of frequency, as shown in FIG. 2 IB. From this plot, however, it is extremely difficult to determine if there is any electro-mechanical resonance. When the result of the simulation with air support (without mechanical clamping) was coated, it was observed that the impedance spectroscopy corresponds well with the measurement at low and high frequencies, with the exception of a noticeable peak at the resonance frequency of about 6 MHz and its harmonics. After fixing and loading one side of PZT with PCB (FR-4), it was found that a significant dampening of the resonance peaks from air support. Despite the lack of observable resonance in the measurement, a small balloon of about 6 MHz was observed, and the mechanical quality factor Q m can be calculated using the following equations: where fa and fr represent anti-resonant (where impedance is maximized) and resonance frequency (where the impedance is minimized), Z r represents an impedance at resonance, and C p represents the low-frequency capacitance. The quality factor that is calculated from the measurement is about 4.2 compared to 5.1 in the simulation. According to the data sheet, the Q unloaded from the PZT is -500, indicating that FR-4 support and wire -bonds are causing a significant degradation of the quality factor. Despite the drastic reduction in the mechanical Q of the PZT crystals, experiments have shown that the backscattered signal level only decreased by about -19.
[0315] [0315] In the electrical characterization configuration, the VNA has a signal generator to provide the necessary data for the characterization. In order to perform an acoustic characterization of PZT, acoustic waves were generated and cast on the sample to be used as an input. This can be achieved with commercially available broadband ultrasonic transducers.
[0316] [0316] Fig. 22 shows the composition of a representative transducer, which consists of an active piezoelectric element, support, and wear plate. The bracket is generally made of a material with high attenuation and high density to control the vibration of the transducer by absorbing radiant energy from the back face of the active element, while the wear plate is used to protect the transducer element from of the test environment and to serve as a corresponding layer.
[0317] [0317] Ultrasound power transfer testing was performed using the House-Built configuration shown in FIG. 23. A single 5MHz or 10MHz transducer element (6.3mm and 6.3mm active area, respectively, -30mm focal length, Olympus, Waltham, MA) was mounted on a 2-axis phase translating controlled by computer (Velmex, Bloomfield, NY). The transducer output was calibrated using a hybrid capsule hydrophone (HGL-0400, Onda, Sunnyvale, CA). Mounting prototypes were placed in a water container in such a way that the transducers could be immersed in the water at a distance of approximately 3 cm directly above the prototypes. A programmable pulse generator (33522B, Agilent Technologies Santa Clara, CA) and radio frequency amplifier (A150, ENI, Rochester, NY) were used to drive transducers at specified frequencies with 10 cycle sinusoidal pulse trains and a frequency of pulse-repeat (PRF) of 1 kHz. Received signals were amplified with a radio frequency amplifier (BT00500-alphas-CW, Tomco, Stepney, Australia), connected to an oscilloscope (TDS3014B, Tektronix, Beaverton OR) to collect ultrasound signals and record them using MATLAB.
[0318] [0318] Fig. 24A and FIG. 24B show a representative measurement of 5 MHz transducer energy as a function of the distance between the transducer surface and the hydrophone (z-axis) output. The peak pressure in water was obtained at -33 mm away from the transducer surface (FIG. 24A), while the -rated peak (at 0.3 dB / cm / MHz) was at -29 mm (FIG. 24B ). FIG. 25A shows the XZ-rated scan output of the transducer, which show both short-field and Far-field beam splatters and a Rayleigh distance or a focal point at -29 mm, corresponding to the de-rated peak in FIG. 24B. FIG. 25B shows an XY-scan cross-section of the beam at the focal point of -29 mm, in which the 6 dB beam width measured about 2.2 mm.
[0319] [0319] The total integrated acoustic output power of the transducer at various frequencies plus the 6 dB bandwidth of the beam was nominally maintained at a spatial peak temporal average pTA of 29.2 μW /cm2, which results in a -1 µW total output power at the focal point, with a peak rarefaction pressure of 25 kPa and a mechanical index (MI) of 0.005. Both the MI and IMTPE-rated were far below the FDA regulatory limit of 720 mW/cm and 1.9, respectively (FDA 2008).
[0320] [0320] Fig. 21 A shows the measured energy transfer efficiency of the fully assembled prototype with cable loss calibrated out for various implantable device transducer sizes, compared to the analytical predictions made for this same configuration. measured results by matching the simulated model behavior very closely on all transducer sizes, with the exception of some smaller transducer dimensions,
[0321] [0321] The electrical voltage response collected in a (250 µm) PZT frequency crystal is shown in FIG. 21C. The resonance frequency was measured to be 6.1 MHz, which corresponds to the change in the predicted resonance frequency for a cube due to Poisson's coefficient and the associated mode coupling between resonance modes along each of the three axes of the cube. . Furthermore, the calculated Q of 4 corresponded to the electrically measured Q of the PZT.
[0322] [0322] The experimental result indicates that the power coupling analysis model for very small PZT nodes using ultrasound is accurate down to at least -100 µm scale and probably lower. It remains to be seen just how shopping a transducer can be manufactured prior to loss of function. Note that measurements from even smaller nodes (<127 µm) were limited not by the prototype assembly process but by the commercial availability of PZT substrates. Moving forward, it used to be the considerable amount of research and techniques that have gone into micro- and nanoelectromechanical RF resonators (see Sadek et al., Wiring nanoscale biosensors with piezoelectric nanomechanical resonators, Nano Lett., vol. 1769-1773 (2010); Lin et al., Low phase noise array-composite micromechanical wine-glass disk oscillator, IEEE Elec. Dev. Meeting, pp. 1-4 (2005)) and thin-film piezoelectric transducer (see Trolier-McKinstry et al., Thin film piezoelectrics for MEMS, J. Electroceram., vol. 12, pp. 7-17 (2004)) to facilitate extremely small (10 µm) transducers and truly evaluate scale theory. Example 5 - Beam forming using ultrasonic transducer array
[0323] [0323] In this example, an ultrasonic beamforming system capable of interrogating individual implantable sensors through backscattering in a distributed, ultrasound-based recording platform is presented. A custom ASIC drives an array of 7 x 2 PZT transducers with 3 cycles of 32V square wave with a specific programmable delay time to focus the beam on the 800μm neural powder particle placed 50mm apart. The acoustic-to-electrical measurement efficiency converting the mote receiving to water is 0.12% and the overall system provides 26.3% of the power from the 1.8V power supply to the transducer output unit, consumes 0.75 UJ in each phase of transmit, and has a change of
[0324] [0324] In this highly distributed and asymmetric system, in which the number of implanted devices outnumber interrogating transceivers by an order of magnitude, beamforming can be used to efficiently interrogate a wide variety of implantable devices. Investigation into beamforming algorithms, exchanges, and performance on the implantable device platform has demonstrated that cooperation between different interrogators is useful to obtain sufficient interference suppression from nearby implantable devices. See Bertrand et al., Beamforming approaches to untethered ultrasonic neural dust motes for cortical recording: a simulation study, IEEE EMBC, 2014, pp. 2625-2628 (Aug. 2014). This example demonstrates an implementation of an ultrasound beamforming system for the interrogator and implantable device system shown in the hardware FIG. 2A. The ASIC (see, for example, Tang et al., Integrated ultrasonic system for measuring body-fat composition, 2015 IEEE International Solid-State Circuits Conference – (ISSCC) Digest of Technical Papers, San Francisco, CA, 2015, pp. 1 -3 (Feb. 2015); Tang et al., Miniaturizing Ultrasonic System for Portable Health Care and Fitness, IEEE Transactions on Biomedical Circuits and Systems, vol. 9, no. 6, pp. 767-776 (Dec. 2015)) , has 7 identical channels, each with 6 delay control bits with 5 ns resolution for transmitting the forming beam, and integrates high voltage level shifters and a receive/transmit switch that isolates any electrical passage holes.
[0325] [0325] The ASIC operates on a single 1.8V supply and generates a 32V square wave to drive piezoelectric transducers via integrated charge pumps and level shifters. The system provides -32.5% of source power of 1.8V for 32V output voltage and -81% of 32V for output load (each transducer element is 4.6 pF). The ASIC block diagram is shown in FIG. 2A; circuit details to enable low power consumption by measurement can be found in in Tang et al., Integrated ultrasonic system for measuring body-fat composition, 2015 IEEE International Solid-State Circuits Conference – (ISSCC) Digest of Technical Papers, San Francisco, CA, 2015, pp. 1-3 (Feb. 2015). The ASIC is manufactured in 0.18μm CMOS with high voltage transistors. The chip area is 2.0mm and includes the complete system except for the digital controller, ADCs, and two off-chip blocking capacitors.
[0326] [0326] The creation of a set of transducers is a strong function of the desired depth of penetration, aperture size, and element size. Quantitatively, the Rayleigh distance, R, of the matrix can be calculated as follows: where D is the aperture size and λ is the wavelength of the ultrasound in the propagation medium. By definition, Rayleigh distance is the distance at which the beam radiated by the matrix is fully formed; in other words, the pressure field converges to a natural focus at a Rayleigh distance and, in order to maximize the received power, it is preferable to place the receiver at a Rayleigh distance where the scattering beam is the minimum.
[0327] [0327] The operating frequency is optimized for the element size. A preliminary study in a water tank showed that maximum energy efficiency is achieved with an (800 μm) 3 PZT crystal, which has a post-encapsulation resonance frequency of 1.6 MHz, resulting in λ - 950 μm. The step between each element is chosen to be an odd multiple of half the wavelength in order to beamform effectively. As a result, for this demonstration of beamforming capabilities, the global aperture is ~14mm, which results in a 50mm Rayleigh distance. At 50mm, given the element size of 800 μm, each element is far enough away from the field (R = 0.17mm); therefore, the single element beam pad must be omni-directional enough to allow for beam formation.
[0328] [0328] There are several transmit and receive beamforming techniques that can be implemented. In this document, the delay-and-sum time beamforming transmission algorithm is chosen such that the signals constructively interfere in the target direction. This algorithm is capable of demonstrating beam guidance and maximum power transfer to various implantable devices. In order to accommodate backscatter communication to multiple implantable devices simultaneously, more sophisticated algorithms may be required. These can include delay-and-sum beamforming, linear constrained minimum-variance beamforming, convex-beamforming optimized for a single beam, 'multicast' beamforming w/convex optimization, maximum kurtosis beamforming, robust minimal distortion-response variance of adaptive beamforming, polyadic tensor decomposition, and multi-Rx-channel time-domain data pulse response particle deconvolution. A detailed treatment of one aspect of this problem is described in Bertrand et al., Beamforming approaches for untethered ultrasonic neural dust motes for cortical recording: a simulation study, IEEE EMBC, 2014, pp. 2625-2628 (Aug. 2014).
[0329] [0329] Each of the 7 channels is driven by 3 cycles of 32V square wave with a specific programmable delay time such that the energy is focused on the observation distance of 50mm. The delay time applied for each channel is calculated based on the difference in propagation distance to the focus point from the center of the matrix and the propagation velocity of the ultrasound wave in the middle.
[0330] [0330] Ultrasound was used to characterize the propagation behavior of the ultrasound wave in water with the identification matrix described above. Simulated XY (Fig. 26A) and XZ (FIG. 26C) cross-section beam bolsters approach the measurement as shown, despite not modeling the PDMS package.
[0331] [0331] Water is used as a means to measure the beam forming system, as it exhibits similar acoustic properties as tissue. Premetallized lead zirconate titanate (PZT) sheets (APC International, Mackeyville, PA) are diced with a wafer vi to 800 μm x 800 μm x 800 μm crystals (parallel capacitance 4.6 pF each), which is the size of each transmission element. Each PZT element is electrically wired to the corresponding channel on the ASIC, using a copper and epoxy conductive foil for the lower terminal and a bonding wire for the upper terminal. The matrix is encapsulated in PDMS (Sylgard 184, Dow Corning, Midland, MI) to protect the lead wire and provide insulation. The factor of PZT crystal post encapsulation quality is ~7. The matrix is organized into 7 groups of 2 x 1 elements, with the step of ~5/2λ~2.3mm. The matrix measures approximately 14mm x 3mm. Finally, the entire assembly is enclosed in a cylindrical tube with a diameter of 25 mm and a height of 60 mm and the tube is filled with water.
[0332] [0332] The 2D beam pad of the transducer and output assembly are calibrated using a capsule hydrophone (HGL-0400, Onda, Sunnyvale, CA). The hydrophone is mounted on a computer-controlled 2D translating stage (Velmex, Bloomfield, New York). The hydrophone has an acceptance angle (-6dB at 5 MHz) of 30°, which is sufficient to pick up the beam given its 50 mm transmission distance and scan range (± 4 mm).
[0333] [0333] The XY transverse beam pad measured with the matrix overlay is shown in FIG. 26 A. The delay applied for each transducer in the array (element) is shown in FIG. 26B. The -6dB beam width at the focal point is 3.2mm ~ 3λ. The flexibility of the ASIC allows for both wide and granular scheduling of delays. The matrix pressure peak level at the 50mm before and after beamforming is ~6kPa and ~20kPa, respectively. A 3X in output pressure wave transmitted after beamforming corresponds to simulation. The simulation also checks whether the Rayleigh distance from the matrix is 50 mm, as shown in FIG. 26C.
[0334] [0334] Furthermore, in order to verify the ability to interrogate various implantable devices, the beam-conduction ability of the array was verified, as shown in FIG. 27A (showing beam conduction at three different positions in the XY plane), with the time delay for each beam position shown below in fig. 27B. The ID beam direction matches very closely with the simulation, as shown in FIG. 27C. Note that the beam conduction range is limited to ±4 mm due to the mechanical construction of the matrix rather than the electronic capability.
[0335] [0335] The hydrophone is replaced with an implantable device (with a μm x 800 x 800 μm μm mass piezoelectric transducer 800) and placed at a transmission distance of 50 mm to verify the power connection. The peak-to-peak open circuit voltage measured at the mote is 65 mV, for a pulse transmission of 2.56 μβ duration. The average acoustic spatial peak power integrated across the -6dB beamwidth at the focal point is μν 750, which is 0.005% of the FDA safety limit. The maximum harvestable power in the particle is 0.9 μν, resulting in a measured acoustic-to-electrical conversion efficiency of 0.12%. The measured result is in agreement with the binding model (see Seo et al., Neutral ultrasound disengaged powder particle validation model for cortical recording, J. Neurosci. Methods, vol. 244, pp. 114-122 ( 2015)). The system delivers 26.3% of the power from the 1.8V power supply to the transducer output drive (defined as driving efficiency) and consumes 0.75 µJ in each transmit phase.
[0336] [0336] The ultrasonic backscatter communication capability of the system is verified by measuring the difference in the backscatter voltage level as the input to the backscatter circuit (see Seo et al., Dust-Free Ultrasonic Mote Validation Model for cortical recording, J. Neurosci. Methods, vol. 244, pp. 1 14-122 (2015)), and is fitted with a DC power supply. The transmission time and system duration are 3 μβ and 80 μβ, leaving a -77 μβ window for reception. A 2 x 1 element in the center of the matrix is used to receive backscatter. The output of the receiving crystals is amplified and digitized for processing. The measured backscatter sensitivity is -0.5% per volt applied to the input of the backscatter circuit, which is in accordance with the simulation. The overall system performance is summarized in Table 5. Table 5: System Performance Summary Voltage source 1.8 V Voltage output 32 V Number of channels 7 Operating frequency 1.6 MHz
[0337] [0337] Our measurements with the ultrasound beamforming system suggest that transmission beamforming alone can provide sufficient signal-to-noise ratio (SNR) to allow multiple interrogation sensors on the neural dust platform. The decrease in SNR with miniaturization of the dust grain can be largely mitigated by implementing a receiving beamform. Furthermore, in order to increase the interrogation rate, one could explore an alternative multiplexing means such as spatial multiplexing where multiple particles are interrogated at the same time with the same transmission beam. However, it is important to consider the system design trade-off between processing/communication load and power consumption. Furthermore, sufficient interference suppression from nearby dust particles is necessary to achieve the required SNR.
[0338] [0338] Acoustic-to-electrical efficiency at 0.12% currently dominates the efficiency (Pfiarvested ) of the overall system. Despite such low power connection efficiency, if ~1% of the FDA safety regulation .8V supply (average peak space of 1.9W/cnr) can be transmitted, it is possible to harvest up to 0.92V peak-to-voltage peak and 180 μν to the ultrasonic transducer 800 μm from 50 mm distance in water.
[0339] [0339] Furthermore, the low efficiency of the power binding in this demonstration is attributed to such a wide transmission distance, as determined by the matrix aperture and the element size. By peripheral nerve intervention, for example, the desired transmission distance is approximately 5 mm, which includes the thickness of the skin, tissue, etc. In order to be in the far field of the array, the aperture should be ~4.4mm. Further scaling of each element can reduce the overall dimensions of the die opening and transmission distance down to the desired 5mm. Simulation indicates that acoustic-to-electrical efficiency of up to 1% can be achieved in water with a 100 μm receiving ultrasound transducer.
[0340] [0340] For transmission in tissue, assuming 3dB loss / cm / MHz in tissue, FIG. 28 shows the scale of both the link efficiency and received power level given operation, at 1% of the FDA safety limit. Despite this very conservative loss at 100 μm, the simulation indicates that it is possible to harvest up to 0.6 V of peak-to-peak voltage and 75 μν. Therefore, wireless energy transfer into tissue using this platform is feasible. Furthermore, this power level is sufficient to operate the low power, high efficiency energy capture and charge pump circuits, similar to the ASIC presented here, for output voltages that are suitable for electrically stimulating nearby neurons and detect physiological conditions through sensors. Example 6 - Wireless Recording in the Peripheral Nervous System with Ultrasonic Neural Dust
[0341] [0341] The following example demonstrates implantable device systems for recording neural signals. The example shows that ultrasound is effective in providing power to mm-scale tissue devices; Likewise, passive, battery-free backscatter communication allows high-fidelity transmission of electromyogram (EMG) and electroneurogram (Eng) signals from anesthetized rats. These results highlight the potential of an ultrasound-based neural interface system to advance future bioelectronics-based therapies. The example further provides methods for determining the location and movement of the implantable device.
[0342] [0342] The implantable device system was used in vivo to report electroneurogram recordings (ENG) from the sciatic nerve of a peripheral nervous system, and an electromyogram recording (EMG) from a gastrocnemius muscle of a subject rat. The system includes an external ultrasound transceiver board that powers and communicates with the millimeter-scale sensor implanted in either a nerve or muscle. See FIG. 29A. The implantable device includes a piezoelectric crystal, a single custom transistor, and a pair of recording electrodes. See figures. 29B, 29C and 29D.
[0343] [0343] During operation, the external transducer alternates between a) emitting a series of six ns 540 pulses every 100 and b) listening for any reflected pulses. The entire sequence of transmission, reception and reconstruction events are detailed in FIG. 30A-H; this sequence is repeated every 100 y & during the operation. Briefly, the pulses of ultrasound energy emitted by the external transducer impinge on the piezocrystal and are, in part, reflected back to the external transducer.
[0344] [0344] An implantable device was fabricated on a 50 μm thick polyimide flexible printed circuit board (PCB) with an ultrasonic piezocrystal transducer (0.75 mm x 0.75 mm x 0.75 mm) and a transistor. custom (0.5mm x 0.45mm) attached to the topside of the board with a conductive silver paste. Electrical connections between components are made using aluminum wire and gold conductor traces. Exposed gold recording pads on the underside of the plate (0.2mm x 0.2mm) are 1.8mm apart and make contact over the nerve or muscle to record electrophysiological signals. recorded signals are sent to the transistor input via micro-paths. In addition, some implants were fitted with 0.35 mm wide, 25 mm long, flexible conductors, compatible with test points for simultaneous voltage measurement through the piezocrystal and direct wire measurement of the extracellular potential between the pair of electrodes used by the transducer ultrasound (this, wired direct recording of extracellular potential as the true ground measurement is referred to below, which is used as a control for the reconstructed ultrasound data). The entire implant is encapsulated in a medical grade UV-curel epoxy to protect wire from bindings and provide insulation. A single implantable device measures approximately 0.8mm x 3mm x 1mm. The size of implants is limited only by our use of commercial polyimide backplane technology, which is commercially accessible to anyone; relying on more aggressive mounting techniques with in-house polymer modeling would produce implants not much larger than piezocrystal dimensions (producing an implant ~1mm).
[0345] [0345] Further details on Implantable Device Assembly. Lead zirconate titanate (PZT) sheets (841, APC Int., Mackeyvile, PA) with -12 µm of silver shot were cut to the desired dimensions using a dicing saw (DAD3240, Disco, Santa Clara, CA ) with a ceramic blade (PN CX-010-270-080-H). The PZT coupon cubes, along with the usual transistor, were bonded to a 50 μm thick polyimide flexible PCB with gold dip (Altaflex, Santa Clara, CA) using a thin layer of two-part silver epoxy with 1:1 ratio. mixture (H20E, Epotek, Billerica, MA). The board was cured at 150°C, which is far below the melting temperature of polyimide and the Curie temperature of PZT, for 10 minutes. The custom transistor was wire-wired using an ultrasonic aluminum target-wire wire (7400B, West Bond, Scotts Valley, CA) to pre-model. In order to prevent charge build-up on the PZT of the wedge contact, upper and lower PZT contacts were discharged to a thin metal sheet before PZT upper contact bonding wire to close the circuits. Medical-grade, UV-curable epoxy (OG116-31, Epotek) was used to protect the lead wire and provide insulation. The platform was then cured in the UV chamber (Flash, Asiga, Anaheim Hills, CA) with 92 mW/cm @ 365 nm for 3 minutes.
[0346] [0346] A custom integrated circuit operates aboard the external transceiver and allows for low-noise interrogation. An ultrasound, the external transceiver board interfaces with that implantable device by both supplying power (transmit (TX) mode) and receiving reflected signals (receiving (RX) mode). This system is a low-power, programmable, and portable transceiver board that drives a commercially available external ultrasound transducer (V323-SU, Olympus, Waltham, MA). The transceiver board exhibited a classified focus-
[0347] [0347] Reflections from non-piezocrystal interfaces provide a built in reference for artifacts of temperature movement and oscillation. The entire system was submerged and featured a custom-built water tank with manual 6 degrees of freedom (DOF) linear translation and rotation phases (Thorlabs Inc., Newton, NJ). Distilled water was used as a propagation medium, which exhibits tissue-like acoustic impedance, at 1.5 MRayls. For the initial calibration of the system, a current source (2400-LV, Keithley, Cleveland, OH) was used to mimic extracellular signals by forcing electrical current at different current densities through 0.127 mm thick platinum wires (773000, AM Systems, Sequim, WA) immersed in the tank. The implantable device was submerged in the current path between the electrodes. As current was applied between the wires, a potential difference across the implant electrodes emerged. This potential difference was used to mimic extracellular electrophysiological signals during the tank test.
[0348] [0348] Further details on electrical and ultrasound characterization of water mounting. The custom transistor was electrically tested with a precision current meter (2400-LV, Keithley) and a DC power supply (3631 A, Agilent, Santa Clara, CA). To characterize the piezocrystal before assembly, an impedance plot was obtained with an impedance analyzer (4285A, Agilent) using two-terminal measurements with the open / short / load calibration scheme. The impedance of exposed gold recording pads (0.2 mm x 0.2 mm), separated by 1.8 mm at the bottom of the PCB, was measured in phosphate buffer (PBS IX) with an electrochemical impedance spectroscope (nanoZ, White Matter LLC, Mercer Island, WA). The device formed the active electrode and a silver wire formed the reference electrode. Ultrasonic characterization of the transducer was performed in a custom-built water tank. A hydrophone capsule (HGL-0400, Onda Corp., Sunnyvale, CA) with 20 dB preamp (AH-2020, Onda Corp.) was mounted on a computer-controlled 2D translating stage (XSlide, Velmex Inc., Bloomfield , NY) and a single transducer element (V323-SU, Olympus) was used to calibrate the output pressure and characterize 2.25 MHz beam bolsters. Ultrasonic energy transfer sensitivity and communication verification was performed in a smaller water tank with the transducer mounted in manual translation and rotation stages (Thorlabs Inc.). The outline of the implantable device was modeled on an acrylic piece extruded with a UV-laser and the implantable device was fixed to the acrylic stage with nylon screws.
[0349] [0349] To interrogate the implantable device, six ns 540 pulses every 100 were emitted by the external transducer. See FIG. 30. These emitted pulses reflect off the neural dust particle and produce backscatter pulses back to the external transducer. Reflected backscatter pulses were recorded by the same emitter-receiver board. The received backscatter waveform has four regions of interest; These are reflective pulses from four distinct interfaces (FIG 3 Id.): 1) the water-polymer boundary encapsulation, 2) the top surface of the piezoelectric crystal, 3) the piezo-PCB boundary, and 4) the back of the Printed circuit board. As expected, the backscatter amplitude of the piezoelectric crystal reflected signals (second region) changed as a function of potential changes to the recording electrodes. Pulses reflected from other interfaces did not respond to changes in potential at the recording electrodes. Importantly, pulses from other non-responsive regions were used as a signal level reference, making the system robust to motion or heat-induced artifacts (since reflected pulses from all interfaces change with physical disturbances or neural powder particle but only pulses from the second region change as a function of electrophysiological signals). In a water tank, the system showed a linear response to changes in recording electrode potential and a noise level of -
[0350] [0350] EMG and ENG can be tetherlessly recorded in vivo in rodents. EMG responses from the gastrocnemius muscle of adult Long-Evans rats under anesthesia were recorded using the implantable device system. The implantable device ("dust") was placed over the exposed surface of the muscle, the skin and surrounding connective tissue were then replaced, and the wound was closed with surgical suture (Fig. 32A). The ultrasound transducer was positioned 8.9 mm away from the implant (a Rayleigh distance from the external transducer) and commercial ultrasound gel (Aquasonic 100, Parker Labs, Fairfield, NJ) was used to improve coupling. The system was aligned using a manual manipulator maximizing the tension collected in the piezocrystal measured from the flexible connections. Ag/AgCl hook wire electrodes were placed approximately 2 cm distally over the sciatic nerve trunk to stimulate responses from large amounts of muscle fibers. The 200 duration stimulation pulses were applied every 6 seconds and data were recorded for 20 ms around the stimulation window (Fig. 32B). The spectral power density (PSD) of the reconstructed data with various harmonics due to the edges of the waveform is shown in FIG. 32C. This process can be continued indefinitely, within the limits of the anesthesia protocol; a comparison of data obtained after 30 minutes of continuous recording did not show any appreciable degradation in recording quality (Fig. 32D).
[0351] [0351] EMG recruitment curves were obtained with both true ground and wireless dust backscatter by varying the amplitude of stimulation (FIGS. 33A and 33B). Reconstruction of the EMG signal from the backscatter wireless data was sampled at 10 kHz, whereas the wired, ground-true measurement was sampled at 100 kHz with a background noise of 0.02 mV. The two signals the amplitude of the saturating response (100%) combined with R = 0.795 (FIG. 33C). The difference between wired and wireless data was ±0.4 mV (Fig. 33D). The salient feature of the EMG implantable device response was approximately 1 ms narrower than the field truth, which caused the largest error in the frame difference (FIG. 33C and 33D). Skeletal muscle fiber responses occurred 5 ms after stimulation and persisted for 5 ms. EMG peak-to-peak voltage shows a sigmoidal response as a function of stimulation intensity (Fig. 33E). Error bars indicate the error of measurements from two rats and 10 samples of each per stimulation amplitude. The minimum signal detected by the implantable device is about 0.25 mV, which is in good agreement with the background noise measurement taken in a water tank.
[0352] [0352] A similar setup was prepared to measure the electroneurogram (POR) response from the main branch of the sciatic nerve in anesthetized rats. The sciatic nerve was exposed by separating the posterior thigh muscles and the powder particle was placed neural and sutured to the nerve, with recording electrodes making contact with the perineurium. A similar graded response was measured in both ground truth and wireless backscatter from the implantable device by varying the amplitude of the stimulation current delivered to bipolar stainless steel electrodes placed on the foot (FIGS. 34A and 34B). The two signals the amplitude of the saturating response (100%) combined with R = 0.886 (Figure 34C.); the mean error was ±0.2 mV (Fig. 34D). Peak-to-peak ENG voltage showed a sigmoidal response with error bars indicating uncertainties from two rats and 10 samples each per stimulation amplitude. The minimum signal detected by the implantable device was again at 0.25 mV (Fig. 34E).
[0353] [0353] More details on experience setting and surgical procedures. All animal procedures were performed in accordance with the regulations of the University of California Berkeley Animal Care and Use Committee. Adult male Long-Evans rats were used for all experiments.
[0354] [0354] Transmission of ultrasounds in vivo. A 2.25 MHz single element transducer (V323-SU, Olympus NDT, Waltham, MA) was used to generate pulses from 6 to 1.85 MHz. The transducer had a measured half power bandwidth (HPBW) of more 2.5 MHz. In order to measure the loss of transmission through tissue, various thicknesses of skin found near the gastrocnemius muscle of a male Long-Evans rat was placed between the transducer and the implantable device. The tension collected in the piezocrystal with and without tissue was obtained and the 8.9 mm of tissue resulted in 10 dB of tissue attenuation.
[0355] [0355] ENG recording with different electrode spacing. Etching electrodes with different spacing were fabricated on a 50 μm thick flexible printed circuit board (PCB) polyimide board. There were a total of 5 electrodes, each measuring 0.2mm x 0.2mm, and one of them was used as the reference electrode. Other electrodes were spaced 0.3 mm, 0.8 mm, 1.3 mm, and 1.8 mm, respectively, apart from the reference electrode. The spacing plate was placed in contact with the perineurium of the main branch of the sciatic nerve bundle (distal) and sutured to the nerve. Bipolar Ag-AgCl hook electrodes placed around the sciatic (proximal) nerve trunk were used for stimulation. -Simulating constant current of a single biphasic pulse with a duration of 0.5 ms every 1 second was delivered using an isolated stimulator pulse (2100, AM Systems, Sequim, WA). Signals recorded at various spacing between electrodes were amplified (loox) by a battery-powered differential amplifier with an internal bandpass filter (DAM50, WPI, Sarasota, FL) set at 10 Hz - 1 KHz (Fig. 35A) . As expected, the peak-to-peak voltage observed at the electrode increased with spacing at least quadratically. The amplitude saturated after the 1.3mm spacing, which confirms that the electrode spacing of 1.8mm on the recording sensor was sufficient to capture the maximum, saturated ENG response (FIG. 35B).
[0356] [0356] The calculation of acoustic intensity. Several parameters are established by the American Institute of Ultrasound in Medicine and the National Electronics Manufacturers Administration (NEMA) to assess the safety of an ultrasound system. The acoustic output power of the diagnostic ultrasound system is limited by spatial peak-ranked values of mean-pulse intensity (ISPPA), with spatial peak of temporal mean intensity (IMTPE), and mechanical index (MI). These de-rated values are calculated by multiplying the measured values in water by an attenuation factor of 0.3 dB / cm / MHz to simulate the effects on the tissue. A capsule hydrophone (HGL-0400, Onda Corp.) with 20 dB pre-amplification (AH-2020, Onda Corp., Sunnyvale, CA) was mounted on a computer-controlled 2D translating stage (XSlide, Velmex Inc., Newton, NJ) and immersed in a custom-built water tank to calibrate the 2.25 MHz pressure of a single transducer element (V323-SU, Olympus NDT) output. 6-cycles of square waves at 1.85 MHz, with a peak input voltage of 5 V were launched every 1 ms (10 kHz pulse repetition frequency (PRF)) to the transducer. The hydrophone was placed a Rayleigh distance from the transducer (8.9 mm). The full pulse intensity (PII) is defined as: , where P is the instantaneous peak pressure, and z 0 is the characteristic acoustic impedance of the medium. In case of
[0357] [0357] or in vivo, acute recordings in a stationary, anesthetized mouse model were used to collect compound action potentials from the main branch of the sciatic nerve as well as evoked EMG from the gastrocnemius muscle. The system performance was equivalent to conventional electrophysiological recordings employing microelectrodes and wired electronics. One of the main strengths of the demonstrated technology is that, unlike conventional radio frequency technology, ultrasound-based systems appear scalable down to <100 µm size, opening the door to a new technological path in implantable electronics. Physical limits on how small a good radio frequency receiver can be due to the long wavelengths of radio frequency energy (millimeters to centimeters) and the high degree of radio frequency energy absorption in tissue (which heats tissue and limits tissue full power that can be sent to an implant). Ultrasonic Systems rate much better in both areas, allowing the design of extremely small receivers. Furthermore, the extreme miniaturization of lower power electronics allows for useful electronic recording to be incorporated into such small packages. Flat, low-profile piezo-transducer with adequate impedance matching would allow for a wearable transceiver plate small enough to awake, supporting rodent neurophysiology. In addition, wearable, battery-powered multiple element arrays would allow beam guidance of the ultrasound beam, with several advantages: 1) the implantable devices can be kept on axis even in the face of relative motion between the implantable device and external transducer ; 2) multiple implantable devices could be interrogated by scanning the electronically focused beam; and 3) post-surgical adjustment of implantable device location would be facilitated. Additional de-noising of the transceiver electronics unit should also help to lower the noise level. In addition, calculated scale predictions suggest that <500 µm scale implantable devices are viable. To do this, a number of material and microfabrication challenges exist, including the use of microfabricated back panels, solder assembly microbumping of components (instead of the conventional bonding wire approach used here) and the use of thin film encapsulants (instead of of medical grade epoxy), such as parylene. The distance transition from PZT piezocrystals to BaTi03 biocompatible single crystal transducers is also contemplated; taken together, these developments would pave the way for chronic studies of neural and muscle tissue recording. Example 7 - Digital communication link between implantable devices and interrogator
[0358] [0358] A system that includes an implantable device and an interrogator having a set of transducers is validated with a bench-top configuration simulating an in vivo environment. The ultrasound coupling gel serves as a tissue ghost due to its acoustic impedance, which is similar to that of target biological tissues (approximately 1.5 MRayl). An implantable device with a large piezoelectric transducer with direct connections to the two transducer contact electrodes is placed in the tissue phantom, and the interrogator transducer array is coupled to the gel. Both elements are connected to precision-controlled stages for precise positioning. The set of transducers is placed 14 mm away from the powder particle, which corresponds to an 18.6 round-trip time of flight assuming an acoustic velocity of 1.540 m/s in ultrasound coupling gel. The transducer array is animated with six 1.8 MHz, 0-32 V rectangular pulses, and the backscatter signal is digitized with 2000 samples at 17 Msps and 12 bits of resolution. For time domain backscatter inspection, complete backscatter waveforms are filtered in real-time on the device and sent to the client via a wired, serial connection. In normal operation, the algorithm of complete modulation extraction is applied to the backscatter data in the apparatus in real time, compressing the backscatter signal to four bytes. The processed data is transmitted through SSP's Bluetooth protocol to a remote client and transmitted through the graphical interface in real time.
[0359] [0359] Fig. 36A shows the filtered backscatter signals collected with the described experimental setup. Signals are collected, while piezocrystal powder particle electrodes are short-circuited and open configurations. The change in impedance due to switch activity results in a peak backscatter amplitude that is 11.5 mV greater in the open switch setting, a modulation depth of 6.45%. (FIG. 36B). The long duration of the echo from the particle indicates touch transducer despite a dampening support layer. As long as the response of the transducer system is dampened under the spread of the backscatter signal in the time domain, demodulation is successful as long as the backscatter from the implanted device is captured within the ROI.
[0360] [0360] Using zero-level amplitude modulated pulse anti-feedback coding, a backscatter sensor cisco is modulated to send an ASCII message 1 1 - predetermined character ("Hello World"). The modulation of the device's acoustic impedance is obtained by deriving the piezoelectric transducer through a digital command switch, where a high level corresponds to the open configuration and a low level corresponds to the closed configuration. FIG. 37 shows the modulated values on the transducer and the corresponding modulation values extracted from the interrogator. The noise value and absolute margin of extracted signal values depend on a variety of factors such as mote distance, orientation, and size; however, the extracted waveform remains representative of the modulated signal on the powder particle, which varies by a linear scale factor.
[0361] [0361] Wirelessly transmitting backscatter value extracted from implantable device modulated by "Hello World" demonstrates the device's real-time communication link with implanted devices.
Interrogation of a two state backscatter system provides a robust demonstration of the system's wireless communication link with both an deployable sensor and a remote client.
This wireless communication link invites developments towards closed-circuit neuromodulation systems to connect the brain with external devices.

权利要求:
Claims (34)
[1]
1. Implantable device characterized by the fact that it comprises: an ultrasonic transducer configured to receive ultrasonic waves that feed the implantable device and encode a trigger signal; a first electrode and a second electrode configured to be in electrical communication with a tissue and deliver an electrical pulse to the tissue in response to the trigger signal; and an integrated circuit comprising an energy storage circuit.
[2]
2. Implantable device according to claim 1, characterized in that the electrical pulse is a current pulse or a voltage pulse.
[3]
3. Implantable device according to any one of claims 1 or 2, characterized in that the first electrode and the second electrode are inside the tissue or in contact with the tissue.
[4]
4. Implantable device according to any one of claims 1 to 4, characterized in that the integrated circuit comprises: a digital circuit and/or a mixed-signal integrated circuit configured to operate the first electrode and the second electrode; and/or an energy circuit comprising the energy storage circuit.
[5]
5. Implantable device according to any one of claims 1 to 4, characterized in that it comprises a body comprising the ultrasound transducer and the integrated circuit, wherein the body is about 5 mm or less in length at the longer dimension.
[6]
6. Implantable device according to any one of claims 1 to 5, characterized in that the tissue is: muscle tissue, organ tissue, or nervous tissue or part of the peripheral nervous system, or part of the central nervous system, or skeletal muscle, or smooth muscle, or cardiac muscle.
[7]
7. Implantable device according to any one of claims 1 to 6, characterized in that it comprises three or more electrodes.
[8]
8. Implantable device according to any one of claims 1 to 7, characterized in that the integrated circuit comprises an analog-to-digital converter (ADC).
[9]
9. Implantable device according to any one of claims 1 to 8, characterized in that the implantable device comprises a modulation circuit configured to modulate a current flowing through the ultrasound transducer.
[10]
10. Implantable device according to claim 9, characterized in that the modulated current encodes the information, and the ultrasound transducer is configured to emit ultrasonic waves that encode the information.
[11]
11. Implantable device according to claim 10, characterized in that the information comprises a verification signal that an electrical pulse has been emitted by the implantable device, a signal indicating an amount of energy stored in the energy storage circuit, or of a detected impedance.
[12]
12. Implantable device according to any one of claims 9 to 11, characterized in that the implantable device includes a digital circuit configured to operate the modulation circuit.
[13]
13. Implantable device according to claim 12, characterized in that the digital circuit is configured to transmit a digitized signal to the modulation circuit.
[14]
14. Implantable device according to claim 13, characterized in that the digitized signal comprises a unique implantable device identifier.
[15]
15. Implantable device according to any one of claims 1 to 14, characterized in that it comprises a body comprising the ultrasound transducer and the integrated circuit, wherein the body has a volume of about 5 mm3 or less.
[16]
16. Implantable device according to any one of claims 1 to 15, characterized in that the ultrasound transducer is configured to receive ultrasound waves from an interrogator comprising one or more ultrasound transducers; Optionally, where the ultrasound transducer is a piezoelectric bulk transducer, a micro-machined ultrasonic piezoelectric transducer (PMUT), or a capacitive micro-machined ultrasound transducer (CMUT).
[17]
17. Implantable device according to any one of claims 1 to 16, characterized in that the implantable device is implanted in a subject, optionally, in which the subject is a human.
[18]
18. Implantable device according to any one of claims 1 to 25, characterized in that the implantable device is at least partially encapsulated by a biocompatible material, optionally, in which at least a portion of the first electrode and the second electrode are not encapsulated by the biocompatible material.
[19]
19. A system characterized by the fact that it comprises one or more implantable devices as defined by any one of claims 1 to 18 and an interrogator that comprises one or more ultrasonic transducers configured from transit ultrasonic waves to the one or more implantable devices, in which wave energy ultrasound to one or more implantable devices.
[20]
20. System according to claim 19, characterized in that the ultrasonic waves encode a trigger signal.
[21]
21. System according to claim 19 or 290, characterized in that the system comprises a plurality of implantable devices; optionally, wherein the interrogator is configured to radiate transmitted ultrasonic waves to alternatively direct the transmitted ultrasonic waves to a first portion of the plurality of implantable devices or focus the transmitted ultrasonic waves to a second portion of the plurality of implantable devices; and/or optionally, wherein the interrogator is configured to simultaneously receive ultrasonic backscatter from at least two implantable devices; and/or optionally, wherein the interrogator is configured to either transmit ultrasonic waves to the plurality of implantable devices or receive ultrasonic backscatter from the plurality of implantable devices using time division multiplexing, spatial multiplexing, or frequency multiplexing.
[22]
22. System according to any one of claims 19 to 21, characterized in that the interrogator is configured to be used by a subject.
[23]
23. Closed circuit system characterized in that it comprises: (a) a first device configured to detect a signal, optionally, in which the first device is implantable; (b) an interrogator comprising one or more ultrasonic transducers configured to receive ultrasonic backscatter encoding the signal and emit ultrasonic waves that encode a trigger signal; and (c) a second device configured to emit an electrical pulse in response to the trigger signal, wherein the second device is implantable, comprising: an ultrasonic transducer configured to receive ultrasonic waves that power the second device and encode a trigger signal; a first electrode and a second electrode configured to be in electrical communication with a tissue and emit an electrical pulse to tissue in response to the trigger signal; and an integrated circuit comprising an energy storage circuit.
[24]
24. System according to claim 23, characterized in that the first device includes: a sensor configured to detect the signal of; an integrated circuit comprising a modulation circuit configured to modulate a current based on the detected signal, and a first ultrasonic transducer configured to output an ultrasonic backscatter that encodes the detected signal from tissue based on the modulated current.
[25]
25. System according to claim 24, characterized in that the sensor comprises a first electrode and a second electrode configured to be in electrical communication with a second tissue, optionally, first tissue and the second tissue are the same tissue.
[26]
26. System according to any one of claims 24 or 25, characterized in that the integrated circuit of the second device comprises a digital circuit, and/or the integrated circuit of the second device comprises a mixed-signal integrated circuit configured to operate the first electrode and the second electrode
[27]
27. A closed-loop system characterized in that it comprises: (a) an implantable device configured to detect a physiological signal and emit an electrical pulse in response to a trigger signal, comprising: a sensor configured to detect the physiological signal; an ultrasonic transducer configured to receive ultrasonic waves that energize the implantable device and encode the trigger signal and output ultrasonic backscatter coding information related to the physiological signal based on a modulated current; a first electrode and a second electrode configured to be in electrical communication with a tissue and deliver an electrical pulse to the tissue in response to the trigger signal; and an integrated circuit comprising an energy storage circuit; and (b) an interrogator comprising one or more ultrasonic transducers configured to receive ultrasonic backscatter that encodes the signal and emits ultrasonic waves that encode the trigger signal.
[28]
28. System according to any one of claims 23 to 27, characterized in that the physiological signal is an electrophysiological pulse, a temperature, a molecule, an ion, pH, pressure, voltage, voltage or bioimpedance.
[29]
29. Computer system characterized by the fact that it comprises: an interrogator comprising one or more ultrasound transducers; one or more processors; computer readable non-transient storage medium storing one or more programs configured to be executed by one or more processors, the one or more programs comprising instructions for: operating the interrogator to emit ultrasonic waves encoding a trigger signal signaling a implantable device for delivering an electrical pulse to tissue, and determining a location or movement of the first implantable device or the second implantable device relative to the interrogator's one or more ultrasonic transducers.
[30]
30. Computer system according to claim 29, characterized in that the interrogator is operated to emit ultrasonic waves that encode the trigger signal in response to a detected physiological signal.
[31]
31. Computer system according to claim 30, characterized in that the physiological signal comprises an electrophysiological pulse, a temperature, a molecule, an ion, pH, pressure, voltage or bioimpedance.
[32]
32. Computer system according to any one of claims 29 to 31, characterized in that the one or more programs comprise instructions to detect the physiological signal based on backscatter ultrasound that encodes the physiological signal emitted from a second implantable device.
[33]
33. Method of electrical stimulation of a tissue characterized by the fact that it comprises: reception of ultrasonic waves to one or more implantable devices; converting energy from ultrasound waves to an electrical current that carries an energy storage circuit; receiving a trigger signal encoded in ultrasound waves in one or more implantable devices; and emit an electrical pulse that stimulates tissue in response to the trigger signal.
[34]
34. A method of stimulating a tissue characterized in that it comprises: receiving ultrasonic waves in one or more implantable devices configured to detect a physiological signal; converting energy from ultrasound waves to an electrical current flowing through a modulation circuit;
detect the physiological signal; modulate the electrical current based on the detected physiological signal; transduce the modulated electrical current into an ultrasound backscatter that encodes information related to the detected physiological signal; and outputting the ultrasound backscatter to an interrogator comprising one or more transducers configured to receive the ultrasound backscatter; deliver ultrasonic waves from the interrogator to one or more implantable devices configured to deliver an electrical pulse to tissue; converting energy from the ultrasound waves emitted from the interrogator to the one or more implantable devices configured to emit the electrical pulse into an electrical current that carries an energy storage circuit; emit ultrasonic waves that encode a trigger signal from the interrogator; receiving the trigger signal in one or more implantable devices configured to emit the electrical pulse; and emitting an electrical pulse that stimulates tissue in response to the trigger signal.

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法律状态:
2019-07-30| B12F| Other appeals [chapter 12.6 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201662359672P| true| 2016-07-07|2016-07-07|

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US62/359,672|2016-07-07|

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PCT/US2017/041264|WO2018009912A1|2016-07-07|2017-07-07|Implants using ultrasonic waves for stimulating tissue|

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