WO2025166209A1 - Bioadhesive hydrogels and devices and systems thereof - Google Patents

Abstract

Embodiments of the present disclosure provide a hydrogel and devices that can be worn long-term, for example, on the scalp or other suitable target site, independently for extended periods without degradation in therapeutic efficacy efficacy. In some aspects, for example, the hydrogel is formed from a first monomer comprising one or more ion-forming moieties. In some implementations, the hydrogel is further formed from a polyol. In some aspects, the hydrogel is further formed from water. In some aspects, the first monomer and water have a ratio by weight from about 1:1 to about 1:4.

Description

BIO ADHESIVE HYDROGELS AND DEVICES AND SYSTEMS THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to United States Provisional Application No. 63/627,184, filed January 31, 2024, United States Provisional Application No. 63/559,465, filed February 29, 2024, and United States Provisional Application No. 63/673,306, filed July 19, 2024, the disclosures of which are incorporated herein by reference in their entireties.

BACKGROUND

Transcranial-focused ultrasound stimulation (tFUS) has been applied for therapeutic use in seizures, sleep disease modulation, traumatic brain injuries, and other neurodegenerative diseases. The current experimental and clinical settings to carry out tFUS uses commercial annular lead zirconate piezoelectric (PZT) transducers. The most significant challenges for these devices in long-term use by subjects are: (1) the bulkiness and size of the current system with heavily wired connections causing discomfort and unsuitable wearability; (2) requires ultrasound gel for acoustic coupling, which will dry in a couple of hours resulting in poor degradation of tFUS efficacy; and (3) lack of clinically acceptable and user-friendly methods of applying a device to the human scalp for long-term use. People presently cannot perform tFUS easily at a hospital or at home long-term without being trained personally to perform the procedure. There is a clear need for wearable tFUS devices that can be worn independently for several weeks on the scalp for the long term without neuromodulation degradation in efficacy.

Recent advances in wearable electronics have enabled personalized healthcare devices to monitor vital signs and physiological data continuously. In particular, the recording of neurological signals has gained increasing interest in recent years. Electroencephalography (EEG), which measures the electrical activity of the brain noninvasively, has been extensively used in brain-computer interfaces (BCIs) to allow severely paralyzed patients to control robotic devices, regain the ability to communicate speech and achieve better recovery after stroke. Other non-BCIs applications of EEGs include sleep monitoring, epileptic seizure, and enhancement of sports performance. The key element for long-term, wearable, and high- quality EEG monitoring is the electrode that can acquire high signal-to-noise ratio (SNR) signals over a long period of time. However, the standard electrolyte gel-based electrodes have limited recording stability owing to the volatilization of the gel, which significantly decreases the signal quality within several hours of application. The frequent re-application of electrolyte gel can introduce unnecessary non-stationarity to the system (i.e., frequent cleaning and re-setup of the acquisition system), change in signal recording positions, and possibly cause skin irritation. It remains a huge challenge to design a highly conductive, well- compliant, and stable electrode for long-term EEG acquisition in hairy scalps with a superior signal quality than prior-described gel-based electrodes.

This disclosure addresses the above, as well as other needs.

SUMMARY

In accordance with the purposes of the disclosed materials and methods, as embodied and broadly described herein, the disclosed subject matter, in one aspect, relates to compositions, devices, systems, and methods of making and using said compositions, devices, and systems.

In one aspect, a hydrogel is provided. In some additional non-limiting aspects, the hydrogel can be formed from a) a first monomer including one or more ion-forming moieties. In some additional non-limiting aspects, the hydrogel can be further formed from b) a polyol. In some additional non-limiting aspects, the hydrogel can be further formed from c) water. In some additional non-limiting aspects, the first monomer and water can have a ratio by weight from about 1 : 1 to about 1 :4. In some additional non-limiting aspects, the polyol can be present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

In some additional non-limiting aspects, the first monomer can include one or more anion-forming moieties, one or more cation-forming moieties, or combinations thereof. In some additional non-limiting aspects, the first monomer can include one or more anion- forming moieties. In some additional non-limiting aspects, the first monomer can include vinyl sulfonic acid, styrene sulfonic acid, allyl sulfonic acid, ethyl acrylate sulfonic acid, butyl acrylate sulfonic acid, acryl sulfonic acid, methacryl sulfonic acid, 2-acrylamido-2- methylpropane sulfonic acid, vinyl carboxylic acid, styrene carboxylic acid, allyl carboxylic acid, acryl carboxylic acid, methacryl carboxylic acid, 2-acrylamido-2-methylpropane carboxylic acid, isoprene carboxylic acid, polyacrylic acid, salts thereof, or combinations thereof. In some additional non-limiting aspects, the first monomer can include 2-acrylamido- 2-methylpropane sulfonic acid (AMPS) or a salt thereof. In some additional non-limiting aspects, the first monomer can include one or more cation-forming moieties. In some additional non-limiting aspects, the first monomer can include vinyl pyridine (such as 2- vinyl pyridine or 4- vinyl pyridine), an aminoethyl methacrylate (such a 2-aminoethyl methacrylate or 2-(dimethylamino)ethyl methacrylate), or 2,2,6,6-tetramethyl-piperidenyloxyl-4-yl methacrylate, or a combination thereof.

In some additional non-limiting aspects, the polyol can include glycerol, trimethylolpropane, pentaerythritol, ethylene glycol, 1,5-butanediol, 1,2,5-hexanetriol, diethylene glycol, triethylene glycol, maltitol, sorbitol, xylitol, erythritol, isomalt, malic acid, a polyalkylene glycol (such as polyethylene glycol or polypropylene glycol), a polyvinyl alcohol, a polyether polyol, a polyester polyol, or combinations thereof. In some additional non-limiting aspects, the polyol can include glycerol.

In some additional non-limiting aspects, the hydrogel can be formed from a), b), and c), and further from d) a crosslinker. In some additional non-limiting aspects, the crosslinker can include N,N-methylenebis(acrylamide), N,N-dimethylacrylamide (DMAA), or poly (ethylene glycol) diacrylate (PEGDA), or a combination thereof. In some additional nonlimiting aspects, the hydrogel can be substantially crosslinked.

In some additional non-limiting aspects, the hydrogel can be formed from a), b), and c), optionally d), and further from e) an initiator. In some additional non-limiting aspects, the initiator can be a photoinitiator. In some additional non-limiting aspects, the photoinitiator can include 2-hydroxy-4’-(2-hydroxyethoxy)-2-methylpropiophenone, 4,4’-azo-bis(4- cyanopentanoic acid), or 4-benzoylphenyl acrylate (4-ABP), or a combination thereof. In some additional non-limiting aspects, the initiator can be a radical initiator. In some additional non-limiting aspects, the radical initiator can include an azo compound, an organic peroxide, an inorganic peroxide, or a combination thereof. In some additional non-limiting aspects, the radical initiator can include azobisisobutyronitrile (AIBN), 1,1’- azobis(cyclohexanecarbonitrile) (ABCN), di-tert-butyl peroxide, benzoyl peroxide, methyl ethyl ketone peroxide, acetone peroxide, a peroxydisulfate salt (such as ammonium persulfate), or a combination thereof. In some additional non-limiting aspects, the radical initiator can include ammonium persulfate. In some additional non-limiting aspects, the radical initiator can be used in combination with a catalyst. In some additional non-limiting aspects, the catalyst can include tetramethylethylenediamine (TMEDA). In some additional non-limiting aspects, the hydrogel can be adhesive. In some additional non-limiting aspects, the hydrogel can be adhesive to a biological tissue or organ, for example, skin. In some additional non-limiting aspects, the hydrogel can have an adhesion force of about 1 N/m or greater, as determined by ASTM D2861-87(1998) (August 1, 2017).

In some additional non-limiting aspects, the hydrogel can exhibit an attenuation of sound of about 10% or less.

In some additional non-limiting aspects, the hydrogel can exhibit substantially no swelling over a period of about 30 days.

In some additional non-limiting aspects, the hydrogel can be moldable. In some additional non-limiting aspects, the hydrogel can be provided as a film.

In another aspect, an article is provided. In some additional non-limiting aspects, the article can include a hydrogel as described herein. In some additional non-limiting aspects, the article can be a wearable device. In some additional non-limiting aspects, the article can be a focused ultrasound device (FUS).

In another aspect, a method is provided of manufacturing a hydrogel as described herein. In some additional non-limiting aspects, the method can include mixing a first monomer comprising one or more ion-forming moieties and water to form a first mixture. In some additional non-limiting aspects, the first monomer and water can have a ratio by weight from about 1:1 to about 1:4. In some additional non-limiting aspects, the method can further include adding a polyol to the first mixture to form a second mixture. In some additional nonlimiting aspects, the polyol can be present in an amount from about 10% to about 60% by weight based on the weight of the hydrogel. In some additional non-limiting aspects, the method can further include crosslinking the second mixture to form the hydrogel. In some additional non-limiting aspects, the method can be performed in the presence of an initiator and optionally a catalyst.

In another aspect, a wearable device is provided. In some additional non-limiting aspects, the wearable device can include a housing containing an acoustic lens and the hydrogel as described herein. In some additional non-limiting aspects, the wearable device can further include at least one electrical connector operatively coupled to the acoustic lens and hydrogel. In some additional non-limiting aspects, the wearable device can be configured to be worn in proximity to a subject’s head. In some additional non-limiting aspects, the hydrogel can include a coating on a surface of the acoustic lens. In some additional non- limiting aspects, the acoustic lens can include polydimethylsiloxane (PDMS). In some additional non-limiting aspects, the wearable device can include a self-focusing ultrasound transducer or ultrasound device, or a combination thereof. In some additional non-limiting aspects, the wearable device can be used for at least one of neuromodulation, stimulation, or heating, or a combination thereof.

In some additional non-limiting aspects, the wearable device can used for treatment of at least one of: Parkinson’s disease, epilepsy, Alzheimer’s disease, stroke, traumatic brain injury, psychiatric disorders (e.g., depression, anxiety, obsessive-compulsive disorder), pain, (e.g., brain stimulation, spinal cord stimulation, or peripheral stimulation), peripheral chronic joint pain, overactive bladder syndrome, sleep disorders (e.g., sleep apnea, redness leg syndrome), carpal tunnel syndrome, visual prosthetics and/or blindness, or mood disorders, or any combination thereof.

In some additional non-limiting aspects, the wearable device can be in electronic communication with at least one of a controller and an ultrasound generator. In some additional non-limiting aspects, the controller can be configured, via computer readable instructions or electronic circuitries, to provide control signals for controlling operations of the wearable device.

In another aspect, a system is provided. In some additional non-limiting aspects, the system can include at least one wearable device as described herein. In some additional nonlimiting aspects, the system can include an ultrasound generator in electronic communication with the at least one wearable device. In some additional non-limiting aspects, the system can include a controller operatively coupled to the ultrasound generator and the at least one wearable device.

In another aspect, a method of manufacturing a wearable device described herein is provided. In some additional non-limiting aspects, the method can include preparing a substrate. In some additional non-limiting aspects, the method can include preparing a mold that defines a pattern for the acoustic lens. In some additional non-limiting aspects, the method can include disposing (e.g., pouring) an elastomer (e.g., PDMS) into at least a portion of the mold to form the acoustic lens. In some additional non-limiting aspects, the method can include integrating the at least one electrical connector with the acoustic lens. In some additional non-limiting aspects, the method can include integrating (e.g., applying) a hydrogel described herein with the acoustic lens. In some additional non-limiting aspects, the at least one electrical connector can include a piezoelectric material. In some additional non-limiting aspects, the method can further include positioning the mold within the housing prior to disposing the elastomer. In some additional non-limiting aspects, preparing the mold can include creating the pattern using a laser etching scheme. In some additional non-limiting aspects, preparing the mold can include transfer printing the pattern onto the substrate to create the mold.

In an alternative aspect, a hydrogel is provided formed from: a) a first monomer comprising one or more ion-forming moieties; b) a polyol; c)a salt; and d) water. In some additional non-limiting aspects, the first monomer and water can have a ratio by weight from about 1:1 to about 1:4. In some additional non-limiting aspects, the polyol can be present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

In another alternative aspect, a hydrogel is provided formed from: a) a first monomer comprising one or more ion-forming moieties; b) a polyol; c) water; d) a crosslinker; e) a radical initiator; and f) a salt. In some additional non-limiting aspects, the first monomer and water can have a ratio by weight from about 1:1 to about 1:4. In some additional non-limiting aspects, the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

The details of one or more aspect of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the disclosure will be apparent from the description, the drawings, and the claims.

DESCRIPTION OF DRAWINGS

FIGs. 1A-1E depict a representative Self-Focusing Acoustic Transducer (SFAT) using an Air-Cavity Fresnel Lens (ACFAL) as described as an example herein. FIG. 1A shows a schematic of the bioadhesive hydrogel in accordance with certain aspects described herein. FIG. IB shows an example view of a wearable device in accordance with certain aspects described herein. FIGS. 1C shows an example view of a wearable device in accordance with certain aspects described herein. FIG. ID illustrates an example method for fabricating an example wearable device in accordance with certain aspects described herein. FIG. IE is a schematic diagram showing an example system in accordance with certain aspects described herein.

FIGs. 2A-2H depict a representative Miniaturized and Bioadhesive-Coupled

Ultrasound Transducer (MiniUlTra) as described in the examples. (FIG. 2A) Illustration of MiniUlTra that continuously adheres to the scalp targeting the primary somatosensory cortex (SI) with high adhesion force, low acoustic attenuation and miniaturized transducer. (FIG. 2B) Mechanism of suppression of P27-N20 complex in somatosensory evoked potential (SEP) through focused ultrasound stimulation locally at the SI. (FIG. 2C) Schematic of layered structure of MiniUlTra that assembles the piezoelectric with PDMS-based ACFAL and bioadhesive hydrogel integrated into a compact 3D-printed housing. (FIG. 2D) Side-view of layered schematic including chemical structure of bioadhesive hydrogel and its’ adhesion mechanisms (FIG. 2E and FIG. 2F) Optical images of design and fabricated SFAT- ACFAL and bioadhesive hydrogel. (FIG. 2G) Adhesion of MiniUlTra on skin. (FIG. 2H) Demonstration of MiniUlTra on the scalp for SI targeted neuromodulation.

FIG. 3A-3H depict and provide data regarding a representative Self-Focusing Acoustic Transducer (SFAT) using Air-Cavity Fresnel Lens (ACFAL) as described in the examples. (FIG. 3A) Schematic of experimental setup for characterization of SFAT- ACFAL. (FIG. 3B) Comparison of acoustic field distribution and intensity with Pristine PZT (left) and with PDMS-based ACFAL (right) in free-field water. (FIG. 3C) Normalized radial acoustic intensity profile in free-field and with the presence of a macaque skull at focal depth 10 mm. (FIG. 3D) Normalized uniaxial acoustic intensity profile in free-field and with the presence of a macaque skull. (FIG. 3E) Acoustic pressure (MPa) and intensity (ISPPA) calibration curve measured when SFAT-ACFAL at varying driving amplitude using ultrasound generator system. (FIG. 3F) Measured waveform of ultrasound pulse using stimulation paradigm of 360ps with and without macaque skull. (FIG. 3G) Thermal effect of SFAT-AFAL on macaque skull measured with infrared camera on varying stimulation parameters. (FIG. 3H) Electrical impedance and phase of SFAT-ACFAL.

FIGs. 4A-4K depict and provide data regarding a representative bioadhesive hydrogel as described in the examples. (FIG. 4A) Comparison of ultrasound intensity decreases according to thickness changes in bioadhesive hydrogel and commercial gel (Aquasonic 100, Parker), (n = 6 for each thickness). F(GI. 4B) Comparison of acoustic time-of-flight (ToF) for ultrasound transmission through water, PET, and hydrogel. (FIG. 4C) Acoustic impedance of the hydrogel for 7 days (n = 4 each day) compared to commercial gel, water, and human skin. (FIG. 4D) Peak-pressure attenuation of bioadhesive hydrogel under 22°C/25% humidity and 37°C/25% humidity over 35 days (n = 4). (FIG. 4E) Peak-pressure attenuation of bioadhesive hydrogel under 22°C/75% humidity and 37°C/85% humidity over 35 days (n = 4). (FIG. 4F) Weight change of the bioadhesive hydrogel and commercial gel under 22°C/25% humidity (CG: Commercial Gel, HG: Bioadhesive hydrogel, n = 4). (FIG. 4G) Weight change of the bioadhesive hydrogel and commercial gel under 22°C/75% humidity (solid line) and 37°C/85% humidity (dashed line) conditions (CG: Commercial Gel, HG: Bioadhesive hydrogel, n = 4). (FIG. H) Chemical structure of the bioadhesive hydrogel integrated ACFAL by grafting the bioadhesive hydrogel to benzophenone (BZP) treated PDMS. (FIG. 41) Improvement of adhesion force with BZP-treated PDMS (n = 4). (FIG. 4J) Adhesion force of the bioadhesive hydrogel according to glycerol loading change (n = 5). (FIG. 4K) Adhesion force of the 20-cycle attachment/detachment test of the bioadhesive hydrogel on skin (n = 4).

FIGs. 5A-5GD provide data regarding the evaluation of neuromodulation in somatosensory evoked potential using a representative SFAT-ACFAL as described in the examples. (FIG. 5A) Schematic representation of experimental setup. (FIG. 5B) Illustration of EEG electrode and SFAT-ACFAL placement in 10-20 EEG montage with its corresponding targeting of left SI with FUS at CP3. (FIG. 5C) Grand average of epochs where median nerve (MN) stimulation occurs at t = 0 ms and FUS or sham begins at t = -100 ms (indicates SEP under FUS+, SEP under sham, and where significant difference was observed P27-N20 complex in SEP). (FIG. 5D) Summary of effect of FUS compared to sham in P27-N20 and N33-P27 complexes of SEP. Suppression of early onset P27-N20 complex observed across C3, P3, and CP5 in SEP by FUS (n = 5 per group, Wilcoxon signed-rank test, 4 male and 1 female). All plots show mean ± s.e.m unless otherwise mentioned, *P < 0.05, **P < 0.01, and ***P < 0.001 (Tables 1-4).

FIGs. 6A-6D provide data regarding the long-term suppression of the P27-N20 complex in somatosensory evoked-potential (SEP) using a representative MiniUlTra as described in the examples. (FIG. 6A) Long-term experimental protocol for evaluating efficacy of hydrogel. The hydrogel was fabricated a day before the first session (DO). Three sessions per subject, each consisting of 10 trials of 3 minutes, each trial consisting of 120 epochs (tFUS/Sham) on day 1 (DI), 7 (D7) and 28 (D28). Each subject had their personal hydrogel with the device, which was stored in room temperature and -30% humidity. (FIG. 6B) Optical image of prepared hydrogel compared to commercial ultrasound gel with the corresponding sessions. (FIG. 6C) Grand average epochs comparing effects of sham and FUS with median nerve (MN) stimulation on SEP across days 1, 7 and 28 using hydrogel. MN stimulation occurs at t = 0 ms and FUS or sham begins at t = -100 ms (indicates SEP under FUS+ on day 1, SEP under Sham on day 1. SEP under FUS+ on day 28, SEP under Sham on day 28, where significant difference was observed P27-N20 complex in SEP, and where observable differences in long latency complexes). (FIG. 6D) Suppression of early onset P27- N20 complex observed across C3, CPI, and CP5 in SEP by FUS shown within each group. No significant difference was observed across FUS groups in bioadhesive hydrogel (HG) when compared to the FUS group using commercial gel (CG). Significant decrease in P27- N20 complexes was observed when comparing within each day of the hydrogel, (n = 8 per group , Sidak multiple comparison One-way ANOVA, 8 male). All plots show mean ± s.e.m unless otherwise mentioned, *P < 0.05, **P < 0.01, and ***P < 0.001 (Table 5).

FIGs. 7A-7B provide data regarding representative SFAT-ACFAL acoustic characteristics in absolute pressure and intensity as described in the examples. (FIG. 7A) Axial and radial absolute peak pressure of Pristine PZT and SFAT-ACFAL in free-field. (FIG. 7B) Comparison of absolute spatial-temporal pulse average intensity (ISPPA) and absolute acoustic pressure with and without macaque skull in free-field.

FIG. 8 depicts the thermal heating effect of a representative SFAT-ACFAL as described in the examples. Infrared camera to measure thermal heating of MiniUlTra on macaque skull under varying stimulation conditions.

EIGs. 9A-9C depict and provide data regarding the surface thermal profile of a representative SEAT-ACEAL as described in the examples. (FIG. 9A) Surface thermal profile of SFAT-ACFAL under varying conditions when sonicated at 360ps ON and 640ps OFF with 0.5s pulse duration at 1 Hz pulse repetition frequency for 120 seconds. (FIG. 9B) Schematic of measurement points of surface thermal profile on transducer. (FIG. 9C) Demonstration of pre- stimulation and post-stimulation surface thermal profiles using infrared camera imaging.

FIGs. 10A-10B provide data regarding the acoustic characterization of a representative bioadhesive hydrogel as described in the examples. (FIG. 10A) Acoustic speed and impedance of the hydrogel for 7 days. (FIG. 10B) Transmission and reflection coefficient of with respect to the human skull.

FIGs. 11A-11B provide data regarding the effects of water retention properties of in a repsentative hydrogel through AMPS variation as described in the examples. (FIG. 11 A) Selling behavior of the hydrogels in distilled water over time (n = 4 per condition). (FIG. 11B) Weight change of hydrogels at 37°C over 6 days at low (RH 25%) and high (85%) humidity conditions (n = 4 per condition). FIG. 12 provides comparison photographs of the dehydration state between a representative bioadhesive hydrogel (left) and commercial gel (right) over 24 hours as described in the examples.

FIGs. 13A-13B provide comparison photographs of the dehydration state between (FIG. 13A) a representative bioadhesive hydrogel and (FIG. 13B) commercial gel over 14 days as described in the examples.

FIGs. 14A-14B depict and provide data regarding measuring the Young’s modulus of a representative acoustic hydrogel as described in the examples. (FIG. 14A) Experimental setup for measuring the adhesion force of the bioadhesive hydrogel. (FIG. 14B) strain-stress curve of the bioadhesive hydrogel.

FIG. 15 provides data regarding the time-frequency analysis of a representative MiniUlTra in neuromodulation of sensory-evoked potential (SEP). MiniUlTra’s application towards the S 1 region during median nerve stimulation indicated a decreased power of alpha and beta band baseline activity recorded from EEG sites C3 within 100 ms onset from stimulus when comparing the short time fourier transform (STFT) of sham (FUS-FES+, dashed line) and stimulation (FUS+FES+, solid line) conditions. Attenuation in the power of short-latency evoked gamma-band activity occurred also within 70 ms compared to sham.

FIGs. 16A-16B provide data regarding the electroencephalographic (EEG) evoked potential elicited by representative tFUS to the SI somatosensory cortex as described in the examples. (FIG. 16A) Suppression of SEP through tFUS to the contralateral SI. (FIG. 16B) Evaluation on effects of tFUS on SI without FES demonstrated similar baseline results indicating no noise, artifacts, and other evoked potentials were present.

FIGs. 17A-17D depict and provide data regarding the post ad-hoc analysis of questionnaire for representative MiniUlTra use as described in the examples. (FIG. 17A) Questionnaire on inquiry of subject’s comfortability, pain, sensitivity, and sensation. (FIG. 17B) Participants reporting their ability to differentiate sham and FUS trials. (FIG. 17C) Subject trial prediction response to randomized order of sham and FUS (Only three participants reported they are capable of differentiating trials), where subjects who reported capable of differentiating trials were less than 62.5% accurate. (FIG. 17D) Summary of sensation experienced during trials by subjects (n = 8) on a scale of 1-5.

FIG. 18A-18D depict a demonstration of a representative MiniUlTra’s wearability as described in the examples. (FIG. 18A) Optical image of MiniUlTra. (FIG. 18B) Demonstration of MiniUlTra at left SI on the scalp. (FIG. 18C) Demonstration of MiniUlTra applied to the temporal window. (FIG. 18D) Application of MiniUlTra for median nerve. Calibrated weight was applied to indicate bioadhesive strength in supporting 100g.

FIGs. 19A-19B depict and provide data regarding the design and simulation of a representative SFAT-ACFAL as described in the examples. (FIG. 19A) Comparison of simulated and measured results with pristine DL-47 PZT. Focal spot is more dispersed and lower intensity based on simulation, where measured result is highly scattered and beam profile shows no focality. (FIG. 19B) Comparison of designed SFAT-ACFAL on DL-47 PZT. Simulated and measured results show comparable similarities, with increased acoustic intensity and higher spatial resolution of focal spot at focal depth of 10 mm.

FIG. 20 provides a representative fabrication procedure of a representative MiniUlTra as described in the examples. (Panel A) Representative fabrication process of device without the need of traditional lithography, i) Transfer printing of laser etched copper tape pattern onto glass substrate to develop desired negative pattern, ii) Development of ACFAL using transfer printed mold with PDMS via sacrificial layer of Omnicoat, iii) Development of SFAT by O2 plasma treatment of ACFAL for reverse bonding, iv) Device integration of SFAT- ACFAL into housing and connectors encapsulated with PDMS and bioadhesive hydrogel coupling. (Panel B) Application of MiniUlTra towards somatosensory cortex (SI).

FIGs. 21A-21C depict and provide data regarding PDMS spin-coating calibration as described in the examples. (FIG. 21A) PDMS spin-coating calibration curve. (FIG. 21B) Microscope imaging of patterned ACFAL. (FIG. 21C) Profilometer measurements of samples.

FIG. 22 depicts acoustic field measurement as described in the examples via the experimental setup for measuring and characterizing a representative SFAT-ACFAL with and without macaque skull.

FIG. 23A -23B depict and provide data as described in the examples regarding (FIG. 23A) Ecoflex caps for filling of commercial and bioadhesive hydrogels from 0.5 to 2.5 mm, and (FIG. 23B) Effects on degassing and microbubbles on acoustic pressure.

FIG. 24 provides photographs of representative hydrogel samples for acoustic speed measurement for 7 days as described in the examples. The acoustic speed in hydrogel was measured with an Ecoflex frame. Between measurements, the Ecoflex frame was removed temporarily, and the hydrogel samples were stored in a room environment (humidity: -30%, temperature: ~23°C).

FIG. 25 depicts a representative experimental setup for estimating the acoustic speed of a bioadhesive hydrogel as described in the examples.

FIGs. 26A-26C depict and provide data regarding the long-term acoustic stability of a representative MiniUlTra as described in the examples. (FIG. 26 A) Measurement experimental setup for acoustic field stability measurement over 28 days. (FIG. 26B) Normalized axial and radial acoustic distribution over 28 days. (FIG. 26C) Normalized 2D acoustic field distribution with respect to Day 1 over 28 days.

FIG. 27 provides a schematic of a representative somatosensory evoked potential experimental setup as described in the examples. Arduino Uno was programmed with a stimulation paradigm and triggers ultrasound (BBBoq, Image Guided Therapy System), median nerve stimulation (RehaMove3 FES System) and EEG recording triggers (AntNeuro). Four channels (C3, CPI, P3, CP5) of EEG data were recorded and saved via LabStreamingLayer. Epochs were extracted to evaluate SEPs and short-latency complex features were obtained.

FIG. 28A-28D depict and provide data regarding the simultaneous EEG measurement and FUS neuromodulation artifacts as described in the examples. (FIG. 28A) Grand average epoch of EEG epochs and artifacts generated by FUS. Mitigation and suppression of artifacts were resolved with common grounding and shielding. (FIG. 28B) Grand average epoch comparison of baseline with FUS only and with FES only. (FIG. 28C) Power spectrum density of grand average epoch demonstrating suppression of harmonic electromagnetic interference from the piezoelectric using common grounding and shielding. (FIG. 28D) Schematic of experimental setup for common ground and shielding connections for artifact removal in EEG recording.

FIG. 29A-29B depict SI Targeting of SI using a representative MiniUlTra as described in the examples. (FIG. 29 A) Tl-weighted anatomical magnetic resonance imaging (MRI) overlaid with estimated positioning of MiniUlTra and acoustic field. (FIG. 29B) Schematic representation of targeting of SI by first using 10-20 EEG montage headcap to mark with medical markers. Subsequently, placement of MiniUlTra and EEG electrodes were performed. FIG. 30A-30B depict the statistical analysis of SEP complexes as described in the examples. (FIG. 30A) Normality test using Q-Q plot on SEP complexes to determine statistical test use. (FIG. 30B) Two-Way ANOVA to compare and evaluate the difference in change comparing sham (FUS-FES+) and stimulation (FUS+FES+) between commercial gel and hydrogel.

FIG. 31 provides data regarding the influence of varying potassium chloride (KC1) concentrations on the impedance of representative hydrogels as described in the examples.

FIG. 32 provides data regarding the influence of varying potassium chloride (KC1) concentrations on the phase angle of representative hydrogels as described in the examples.

FIG. 33 is an example computing device.

Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

As apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

Any recited method can be carried out in the order of events recited or any other order that is logically possible. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not explicitly state in the claims or descriptions that the steps are to be limited to a particular order, it is in no way intended that an order be inferred in any respect. This holds for any possible non-express basis for interpretation, including logic concerning an arrangement of steps or operational flow, meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

All publications mentioned herein are incorporated by reference to disclose and describe the methods or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure before the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

It is also to be understood that the terminology herein describes particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It can be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

As used herein, “comprising” is interpreted as specifying the presence of the stated features, integers, steps, or components but does not preclude the presence or addition of one or more features, integers, steps, components, or groups thereof. Moreover, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of’ and “consisting of.” Similarly, “consisting essentially of’ is intended to include examples encompassed by the term “consisting of.”

As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context dictates otherwise.

Ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. Further, the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. There are many values disclosed herein, and each value is also disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value and to “about” another particular value. Similarly, when values are expressed as approximations, using the antecedent “about,” the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed. When a range is expressed, a further aspect includes from the one particular value and to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g., ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x,’ ‘about y,’ and ‘about z’ as well as the ranges of ‘less than x,’ ‘less than y.’ and ‘less than z.’ Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x,’ ‘about y,’ and ‘about z’ as well as the ranges of ‘greater than x,’ greater than y,’ and ‘greater than z.’ In addition, the phrase “about ‘x’ to ‘y’,” where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’.”

Such a range format is used for convenience and brevity and, thus, should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5% but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact but may be approximate, larger or smaller, as desired, reflecting tolerances, conversion factors, rounding, measurement error, and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, as used herein, “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter, or other quantity or characteristic is “about,” “approximate,” or “at or about,” whether or not expressly stated to be such. Where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself unless expressly stated otherwise.

As used herein, “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur. The description includes instances where said event or circumstance occurs and those where it does not.

As used herein, “treating” and “treatment” generally refer to obtaining a desired pharmacological or physiological effect. The effect can be but does not necessarily have to be prophylactic in preventing or partially preventing a disease, symptom, or condition. The effect can be therapeutic regarding a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term “treatment” as used herein can include any treatment of a disorder in a subject, particularly a human. It can include any one or more of the following: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease or its symptoms or conditions. The term “treatment,” as used herein, can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (i.e., subjects in need thereof) can include those already with the disorder or those in which the disorder is to be prevented. As used herein, the term “treating” can include inhibiting the disease, disorder, or condition, e.g., impeding its progress, and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

The terms “coupled” and “associated” generally mean electrically, electromagnetically, and/or physically (e.g., mechanically or chemically) coupled or linked and do not exclude the presence of intermediate elements between the coupled or associated items.

It will be understood that when an element is referred to as being “connected” or “coupled” to another element, it can be directly connected or coupled to the other element, or intervening elements can be present. In contrast, when an element is referred to as being “directly connected” or “directly coupled” to another element, there are no intervening elements present. Other words used to describe the relationship between elements or layers should be interpreted in a like fashion (e.g., “between” versus “directly between,” “adjacent” versus “directly adjacent,” “on” versus “directly on”).

It will be understood that although the terms “first,” “second,” etc., can be used herein to describe various elements, components, regions, layers, and/or sections. These elements, components, regions, layers, and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. Thus, a first element, component, region, layer, or section discussed below could be termed a second element, component, region, layer, or section without departing from the teachings of example aspects.

Spatially relative terms, such as “beneath,” “below,” “lower,” “above,” “upper,” “upward,” “downward,” “top,” “bottom,” and the like, can be used herein for ease of description to describe one element or feature’s relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is turned over, elements described as “below” or “beneath” other elements or features would then be oriented “above” the other elements or features. Thus, the term “below” can encompass both an orientation of above and below. The device can be otherwise oriented (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein are interpreted accordingly.

Terms such as “proximal,” “distal,” “ radially outward,” “radially inward,” “outer,” “inner,” and “side” describe the orientation and/or location of portions of the components or elements within a consistent but arbitrary frame of reference which is made clear by reference to the text and the associated drawings describing the components or elements under discussion. Such terminology can include the words specifically mentioned above, derivatives thereof, and words of similar import. Similarly, the terms “first,” “second,” and other such numerical terms referring to structures neither imply a sequence nor order unless clearly indicated by the context. As used herein, the term “substantially” means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance generally, typically, or approximately occurs.

Still further, the term “substantially” can, in some aspects, refer to at least about 90 %, at least about 91 %, at least about 92 %, at least about 93 %, at least about 94 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about 98 %, at least about 99 %, or about 100 % of the stated property, component, composition, or other condition for which substantially is used to characterize or otherwise quantify an amount.

As used herein, the term “substantially,” in, for example, the context “substantially identical” or “substantially similar,” refers to a method or a system, or a component that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% by similar to the method, system, or the component it is compared to.

Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

As used herein, “treating” and “treatment” generally refer to obtaining a desired effect that affects the physical or psychological status of a patient. The effect can be but does not necessarily have to be prophylactic in preventing or partially preventing a disease, symptom, or condition. The effect can be therapeutic regarding a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term “treatment” as used herein can include any treatment of a disorder in a subject, particularly a human. It can include any one or more of the following: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease or its symptoms or conditions. The term “treatment,” as used herein, can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (i.e., subjects in need thereof) can include those already with the disorder or those in which the disorder is to be prevented. As used herein, the term “treating” can include inhibiting the disease, disorder, or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

Some aspects described herein relate to systems and methods. In certain aspects, the systems can comprise computers, processing devices, controllers, and the lake. In other aspects, the methods can be computer-implemented. That is, where the method or other events are described herein, it should be understood that they may be performed by a computing device having a processor and a memory. Memory of a computing device is also referred to as a non-transitory computer-readable medium, which can include instructions or computer code for performing various computer-implemented operations. The computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not include transitory propagating signals per se (e.g., a propagating electromagnetic wave carrying information on a transmission medium such as space or a cable). The media and computer code (also referred to as code) may be those designed and constructed for a specific purpose or purpose. Examples of non-transitory computer-readable media include but are not limited to magnetic storage media such as hard disks, floppy disks, and magnetic tape; optical storage media such as Compact Disc/Digital Video Discs (CD/DVDs), Compact Disc-Read Only Memories (CD-ROMs), and holographic devices; magneto-optical storage media such as optical disks; carrier wave signal processing modules, Read-Only Memory (ROM), Random- Access Memory (RAM) and/or the like. One or more processors can be communicatively coupled to the memory and operable to execute the code stored on the non-transitory processor-readable medium. Examples of processors include general purpose processors (e.g., CPUs), Graphical Processing Units, Field Programmable Gate Arrays (FPGAs), Application Specific Integrated Circuits (ASICs), Digital Signal Processor (DSPs), Programmable Logic Devices (PLDs), and the like. Examples of computer code include, but are not limited to, micro-code or micro-instructions, machine instructions, such as those produced by a compiler, code used to produce a web service, and files containing higher-level instructions that are executed by a computer using an interpreter. For example, aspects may be implemented using imperative programming languages (e.g., C, Fortran, etc.), functional programming languages (Haskell, Erlang, etc.), logical programming languages (e.g., Prolog), object-oriented programming languages (e.g., Java, C++, etc.) or other suitable programming languages and/or development tools. Additional examples of computer code include but are not limited to, control signals, encrypted code, and compressed code.

The compositions, devices, systems, and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions, devices, systems, and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions, devices, systems, and methods, in addition to those shown and described herein, are intended to fall within the scope of the appended claims. Further, while only certain representative compositions, devices, systems, and method steps disclosed herein are specifically described, other combinations of the compositions, devices, systems, and method steps are also intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

Hydrogels

In one aspect, the present disclosure provides a hydrogel. In some aspects, the hydrogel is formed from a first monomer comprising one or more ion-forming moieties. In some aspects, the hydrogel is further formed from a polyol. In some aspects, the hydrogel is further formed from water.

In some aspects, the first monomer and water have a ratio by weight from about 1:1 to about 1:4, for example, from about 1:1 to about 1:2, from about 1:1 to about 1:3, from about 1:2 to about 1:4, from about 1:2 to about 1:3, or from about 1:3 to about 1:4. In some aspects, the first monomer and water have a ratio by weight of about 1 : 1. In some aspects, the first monomer and water have a ratio by weight of about 1:2. In some aspects, the first monomer and water have a ratio by weight of about 1:3. In some aspects, the first monomer and water have a ratio by weight of about 1:4.

In some aspects, the polyol is present in an amount from about 10% to about 60% by weight based on the weight of the hydrogel, for example, from about 10% to about 55%, about 10% to about 50%, about 10% to about 45%, about 10% to about 40%, about 10% to about 35%, from about 10% to about 30%, from about 10% to about 25%, from about 10% to about 20%, from about 10% to about 15%, from about 15% to about 60%, about 15% to about 55%, about 15% to about 50%, about 15% to about 45%, about 15% to about 40%, for example, from about 15% to about 35%, from about 15% to about 30%, from about 15% to about 25%, from about 20% to about 30%, from about 20% to about 50%, from about 20% to about 60%, from about 20% to about 40%, for example, from about 20% to about 35%, from about 20% to about 30%, from about 20% to about 25%, from about 25% to about 60%, example from about 25% to about 50%, from about 25% to about 40%, from about 25% to about 35%, from about 25% to about 30%, from about 30% to about 60%, from about 30% to about 50%, from about 30% to about 40%, example from about 30% to about 35%, or from about 35% to about 40% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 10% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 15% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 20% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 25% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 30% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 35% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 40% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 50% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 60% by weight based on the weight of the hydrogel.

In some alternative aspects, the polyol is present in an amount from about 0% to about 60% by weight based on the weight of the hydrogel. In some alternative aspects, the polyol is present in an amount of about 60% by weight or more based on the weight of the hydrogel.

In some aspects, a hydrogel is formed from a) a first monomer comprising one or more ion-forming moieties; b) a polyol; and c) water; wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1 :4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

In some aspects, a hydrogel is formed from a) a first monomer comprising one or more ion-forming moieties; b) a polyol; and c) water; wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1 :4; and wherein the polyol is present in an amount from about 10% to about 60% by weight based on the weight of the hydrogel. In some aspects, the first monomer comprises one or more anion-forming moieties, one or more cation-forming moieties, or combinations thereof.

In some aspects, the first monomer comprises one or more anion-forming moieties. An “anion” is any molecule, portion of a molecule (e.g., zwitterion), a cluster of molecules, molecular complex, moiety, or atom that contains a net negative charge or that can be made to contain a net negative charge. The term “anion-forming moiety” is used herein to specifically refer to a moiety that can be converted to an anion via a chemical reaction (e.g., deprotonation). Representative examples of such first monomers include but are not limited to, vinyl sulfonic acid, styrene sulfonic acid, allyl sulfonic acid, ethyl acrylate sulfonic acid, butyl acrylate sulfonic acid, acryl sulfonic acid, methacryl sulfonic acid, 2-acrylamido-2- methylpropane sulfonic acid, vinyl carboxylic acid, styrene carboxylic acid, allyl carboxylic acid, acryl carboxylic acid, methacryl carboxylic acid, 2-acrylamido-2-methylpropane carboxylic acid, isoprene carboxylic acid, polyacrylic acid, salts thereof, or combinations thereof. In some particular aspects, the first monomer comprises 2-acrylamido-2- methylpropane sulfonic acid (AMPS) and/or a salt thereof.

In other aspects, the first monomer comprises one or more cation-forming moieties. A “cation” is any molecule, portion of a molecule (e.g., zwitterion), a cluster of molecules, molecular complex, moiety, or atom containing a net positive charge or that can be made to contain a net positive charge. The term “cation-forming moiety” is used herein to specifically refer to a moiety that can be converted to a cation via a chemical reaction (e.g., protonation or alkylation). Representative examples of such first monomers include but are not limited to, vinyl pyridine (such as 2-vinyl pyridine or 4- vinyl pyridine), an aminoethyl methacrylate (such a 2-aminoethyl methacrylate or 2-(dimethylamino)ethyl methacrylate), or 2, 2,6,6- tetramethyl-piperidenyloxyl-4-yl methacrylate, or any combination thereof.

In some aspects, the polyol can be a diol, a triol, or the like. Representative examples of suitable polyol include but are not limited to, glycerol, trimethylolpropane, pentaerythritol, ethylene glycol, 1,5-butanediol, 1,2,5-hexanetriol, diethylene glycol, triethylene glycol, maltitol, sorbitol, xylitol, erythritol, isomalt, malic acid, a polyalkylene glycol (such as polyethylene glycol or polypropylene glycol), polyvinyl alcohol, a polyether polyol, a polyester polyol, or combinations thereof. In some particular aspects, the polyol comprises glycerol. In some aspects, a hydrogel is formed from a) a first monomer comprising one or more ion-forming moieties; b) a polyol; and c) water; and further from: d) a crosslinker, wherein the first monomer and water have a ratio by weight from about 1:1 to about 1:4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

In some aspects, a hydrogel is formed from a) a first monomer comprising one or more ion-forming moieties; b) a polyol; and c) water; and further from: d) a crosslinker, wherein the first monomer and water have a ratio by weight from about 1:1 to about 1:4; and wherein the polyol is present in an amount from about 10% to about 60% by weight based on the weight of the hydrogel.

In some aspects, the hydrogel is substantially crosslinked. In further aspects, the hydrogel is crosslinked. Any known crosslinkers in the art can be utilized. For example, and without limitation, the crosslinker can include N,N-methylenebis(acrylamide), N,N- dimethylacrylamide (DMAA), or poly(ethylene glycol) diacrylate (PEGDA), or any combination thereof. However, it is further understood that any other crosslinkers suitable for the desired application can be used. In still further aspects, if the crosslinker is present, the crosslinking of the hydrogel can be achieved by any known and suitable for the desired application methods. For example, and without limitations, the crosslinking of the hydrogel can be achieved through thermal crosslinking, radiation-induced crosslinking, e-beam- induced crosslinking, and the like, or any combination thereof.

In some aspects, a hydrogel is formed from a) a first monomer comprising one or more ion-forming moieties; b) a polyol; c) water; and d) optionally a crosslinker; and further from e) an initiator, wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1 :4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

In some aspects, a hydrogel is formed from a) a first monomer comprising one or more ion-forming moieties; b) a polyol; c) water; and d) optionally a crosslinker; and further from e) an initiator, wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1 :4; and wherein the polyol is present in an amount from about 10% to about 60% by weight based on the weight of the hydrogel.

In some aspects, the initiator may comprise a photoinitiator. Any known photoinitiators in the art can be utilized. Representative examples of photoinitiators that can be used include but are not limited to 2-hydroxy-4’-(2-hydroxyethoxy)-2- methylpropiophenone, 4,4’-azo-bis(4-cyanopentanoic acid), or 40benzoylphenyl acrylate (4- ABP), or any combination thereof.

In some alternative aspects, the initiator may comprise a radical initiator. Any known radical initiators in the art and suitable for the desired application can be used. In some alternative aspects, the radical initiator can comprise an azo compound, an organic peroxide, an inorganic peroxide, or any combination thereof. Representative examples of radical initiators which can be used include but are not limited to, azobisisobutyronitrile (AIBN), l,l’-azobis(cyclohexanecarbonitrile) (ABCN), di-tert-butyl peroxide, benzoyl peroxide, methyl ethyl ketone peroxide, acetone peroxide, or a peroxydisulfate salt (such as sodium persulfate, potassium persulfate, or ammonium persulfate), or any combination thereof. In some alternative aspects, the radical initiator comprises ammonium persulfate.

In some alternative aspects, the radical initiator can be used in combination with a catalyst. For example, when ammonium persulfate is used as the radical initiator, tetramethylethylenediamine (TMEDA) may also be used as a catalyst.

In some alternative aspects, a hydrogel is formed from a) a first monomer comprising one or more ion-forming moieties; b) a polyol; c) water; d) optionally a crosslinker; and e) optionally an initiator, and further from: f) a salt; wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1 :4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

In some alternative aspects, a hydrogel is formed from a) a first monomer comprising one or more ion-forming moieties; b) a polyol; c) water; d) optionally a crosslinker; and e) optionally an initiator, and further from: f) a salt; wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1 :4; and wherein the polyol is present in an amount from about 10% to about 60% by weight based on the weight of the hydrogel.

In such exemplary and nonlimiting alternative aspects, any known in the art salts that can provide the desired result can be used. In certain alternative aspects, the salt comprises an inorganic salt of alkali or alkaline-earth metal. For example, the salt can be a salt of Li, K, Na, Cs, Rb, Ca, Mg, Ba, Sr, and the like. In yet still further alternative aspects, the salt can be nitrate, chloride, bromide, iodide, sulfate, carbonate, fluoride, and the like. In yet still further alternative aspects, the salt can be any reaction product of the strong acid and strong base. It is understood that in such aspects, the salt can fully dissociate with the ions and improve the conductivity of the composition. In some particular alternative aspects, the salt comprises a potassium halide salt, for example, potassium chloride, potassium bromide, or potassium iodide, more particularly potassium chloride. In some other further aspects, the salt may comprise an organic salt.

In some alternative aspects, the salt may be present in the hydrogel at a concentration from about 0 M to about 3 M, for example, about 0 M, 0.01 M, 0.05 M, 0.10 M, 0.15 M, 0.20 M, 0.25 M, 0.3 M, 0.35 M, 0.4 M, 0.45 M, 0.5 M, about 0.6 M, about 0.7 M, about 0.8 M, about 1 M, about 1.25 M, about 1.5 M, about 1.75 M, about 2 M, about 2.25 M, about 2.5 M, and about 3 M. In still further aspects, the salt can be present in any subrange formed from the above exemplary values. For example, it can be about 0 M to about 2.75 M, about 0 M to 2.5 M, about 0 M to about 2 M, 0 M to about 1.75 M, about 0 M to 1.5 M, about 0 M to about 1 M, 0 M to about 0.75 M, about 0 M to 0.5 M, about 0 M to about 0.1 M, about 0 M to about 0.05 M, or about 0.05 M to 3 M, about 0.1 M to about 3 M, about 0.5 M to about 3M, about 1 M to about 3 M, and so on. In still further aspects, the salet can be present in amounts of about 0 M to about 0.5 M, about 0 M to about 0.1 M, or about 0 M to about 0.05 M.

In an alternative aspect, a hydrogel is formed from a) a first monomer comprising one or more ion-forming moieties; b) a polyol; c) water; d) a crosslinker; e) an initiator; and f)a salt; wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1 :4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel. In still further aspects, the polyol is present in an amount from about 10% to about 60% by weight based on the weight of the hydrogel.

In another alternative aspect, a hydrogel is provided from a) 2-acrylamido-2- methylpropane sulfonic acid (AMPS) or a salt thereof; b) glycerol; c) water; d) N,N- methylenebis(acrylamide); e) ammonium persulfate (optionally in combination with methylethylenediamine (TMEDA)); and f) potassium chloride; wherein AMPS and water have a ratio by weight from about 1 : 1 to about 1 :4; and wherein glycerol is present in an amount from about 10% to about 60% by weight based on the weight of the hydrogel.

Any salt of AMPS can be used. For example, and without limitations, it can be 2- Acrylamido-2-methyl- 1 -propanesulfonic acid sodium salt. But again, it is understood that it can be a potassium salt, lithium salt, or any other suitable salt. In some aspects, the hydrogel is substantially adhesive. In other aspects, the hydrogel is adhesive. In still further aspects, the hydrogel has an adhesion force of about 1 N/m or greater as determined by ASTM D2861-87(1998) (August 1, 2017), for example of about 1 N/m or greater, 2 N/m or greater, 3 N/m or greater, 4 N/m or greater, or 5 N/m or greater. In some aspects, the hydrogel is adhesive to a biological tissue or organ (e.g., skin). A “biological tissue,” as used herein, refers to an assembly of similar cells and their extracellular matrix from the same embryonic origin that carry out a specific function. An “organ,” as used herein, refers to a collection of tissues joined in a structural unit to serve a common function. “Skin,” as used herein, refers to a flexible layer or layers of outer tissue covering the body of a vertebrate mammal. In humans, the skin comprises up to several layers of ectodermal tissue comprising the epidermis (comprising the stratum comeum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale), the dermis, and the hypodermis or subcutaneous tissue.

In some aspects, the hydrogel exhibits an attenuation of sound of about 10% or less, for example, of about 9% or less, of about 8% or less, of about 7% or less, of about 6% or less, of about 5% or less, of about 4% or less, of about 3% or less, of about 2% or less, or of about 1% or less.

In some aspects, the hydrogel exhibits substantially no swelling over a period of about 10 days, about 20 days, about 30 days, about 40 days, about 50 days, about 60 days, or about 100 days. It is understood that in other aspects, the hydrogel exhibits substantially no swelling over a period of about 30 days. In other aspects, the hydrogel exhibits substantially no swelling over a period of about 50 days.

In still further aspects, the hydrogel can be moldable to form any desired shape. In yet other aspects, any known in the art shapes can be formed. The shapes can be irregular or regular. In yet other aspects, the hydrogel can be 3D printed to form the desired shapes. In still further aspects, the desired shape can comprise circular, square, rectangular shape, microneedles, or micropillars shape.

In some alternative aspects, the hydrogel is a conductive hydrogel. In some further alternative aspects, the hydrogel is an electrode material.

In some alternative aspects, the hydrogel can exhibit an ionic conductivity of about 0.001 S/m to about 10 S/m, including exemplary values of about 0.005 S/m, about 0.01 S/m, about 0.05 S/m, about 0.1 S/m, about 0.25 S/m, about 0.5 S/m, about 0.75 S/m, about 1 S/m, about 1.25 S/m, about 1.5 S/m, about 2 S/m, about 3 S/m, about 4 S/m, about 5 S/m, about 6 S/m, about 7 S/m, about 8 S/m, and about 9 S/m. It is understood that the conductivity of the hydrogel can have any value that falls between any two foregoing values or within the range that is formed by any two foregoing values. For example, the hydrogel can have an ionic conductivity of about 0.001 S/m to about 9 S/m, about 0.001 S/m to about 5 S/m, about 0.001 S/m to about 1 S/m, about 0.001 S/m to about 0.05 S/m, or 0.005 S/m to about 10 S/m, 0.01 S/m to about 10 S/m, about 0.05 S/m to about 10 S/m, 0.1 S/m to about 10 S/m, 0.5 S/m to about 10 S/m, 1 S/m to about 10 S/m, 5 S/m to about 10 S/m, or so on.

In particular aspects, the hydrogel is provided as a film.

In still further aspects, disclosed herein are articles comprising any of the disclosed herein hydrogels. In still further aspects, disclosed herein is an electrode comprising any of the disclosed above hydrogels. In still further aspects, disclosed herein is a device comprising at least one electrode comprising any of the disclosed herein hydrogels.

In still further aspects, the hydrogel exhibits an impedance of less than about 100 kQ cm², less than about 90 k cm², less than about 80 kQ cm², less than about 70 kQ cm², less than about 60 kQ cm², less than about 50 kQ cm², or less than about 40 kQ cm² for at least about 8 days, for at least 10 days, for at least 14 days, or for at least a month when stored at ambient conditions. In still further aspects, disclosed herein are articles comprising any of the disclosed herein hydrogels. In still further aspects, disclosed herein is an electrode comprising any of the disclosed above hydrogels. In still further aspects, disclosed herein is a device comprising at least one electrode comprising any of the disclosed herein hydrogels.

Also disclosed herein are devices comprising a hydrogel-based electrode, wherein the hydrogel-based electrode is configured to exhibit an electrode- skin interfacial impedance of about 150 kQ cm² or less through about 4 weeks after fabrication. In such aspects, the hydrogel-based electrode can comprise any of the disclosed above compositions. In still further aspects, such an electrode can exhibit an electrode- skin interfacial impedance of about 150 kQ cm² or less, about 125 kQ cm² or less, about 100 kQ cm² or less, about 90 kQ cm² or less, about 80 kQ cm² or less, about 70 kQ cm² or less, about 60 kQ cm² or less, about 50 kQ cm² or less, or about 40 kQ cm² or less through about 4 weeks after fabrication.

In other aspects, a method is provided for manufacturing a hydrogel described herein. In some aspects, the method comprises mixing a first monomer as described herein and water to form a first mixture. In some aspects, the first monomer comprises one or more anion- forming moieties, one or more cation-forming moieties, or combinations thereof. In some aspects, the first monomer comprises one or more anion-forming moieties, for example, vinyl sulfonic acid, styrene sulfonic acid, allyl sulfonic acid, ethyl acrylate sulfonic acid, butyl acrylate sulfonic acid, acryl sulfonic acid, methacryl sulfonic acid, 2-acrylamido-2- methylpropane sulfonic acid, vinyl carboxylic acid, styrene carboxylic acid, allyl carboxylic acid, acryl carboxylic acid, methacryl carboxylic acid, 2-acrylamido-2-methylpropane carboxylic acid, isoprene carboxylic acid, polyacrylic acid, salts thereof, or combinations thereof. In some particular aspects, the first monomer comprises 2-acrylamido-2- methylpropane sulfonic acid (AMPS) and/or a salt thereof. In other aspects, the first monomer comprises one or more cation-forming moieties, for example, vinyl pyridine (such as 2- vinyl pyridine or 4- vinyl pyridine), an aminoethyl methacrylate (such a 2-aminoethyl methacrylate or 2-(dimethylamino)ethyl methacrylate), or 2,2,6,6-tetramethyl-piperidenyloxyl-4-yl methacrylate, or any combination thereof.

In some aspects, the first monomer and water have a ratio by weight from about 1:1 to about 1:4, for example, from about 1:1 to about 1:2, from about 1:1 to about 1:3, from about 1:2 to about 1:4, from about 1:2 to about 1:3, or from about 1:3 to about 1:4. In some aspects, the first monomer and water have a ratio by weight of about 1 : 1. In some aspects, the first monomer and water have a ratio by weight of about 1:2. In some aspects, the first monomer and water have a ratio by weight of about 1:3. In some aspects, the first monomer and water have a ratio by weight of about 1:4.

In some aspects, the method further comprises adding a polyol to the first mixture to form a second mixture. In some aspects, the polyol can be a diol, a triol, or the like. Representative examples of suitable polyol include but are not limited to, glycerol, trimethylolpropane, pentaerythritol, ethylene glycol, 1,5-butanediol, 1,2,5-hexanetriol, diethylene glycol, triethylene glycol, maltitol, sorbitol, xylitol, erythritol, isomalt, malic acid, a polyalkylene glycol (such as polyethylene glycol or polypropylene glycol), polyvinyl alcohol, a polyether polyol, a polyester polyol, or combinations thereof. In some particular aspects, the polyol comprises glycerol.

In some aspects, the polyol is present in an amount from about 10% to about 60% by weight based on the weight of the hydrogel, for example, from about 10% to about 55%, about 10% to about 50%, about 10% to about 45%, about 10% to about 40%, about 10% to about 35%, from about 10% to about 30%, from about 10% to about 25%, from about 10% to about 20%, from about 10% to about 15%, from about 15% to about 60%, about 15% to about 55%, about 15% to about 50%, about 15% to about 45%, about 15% to about 40%, for example, from about 15% to about 35%, from about 15% to about 30%, from about 15% to about 25%, from about 20% to about 30%, from about 20% to about 50%, from about 20% to about 60%, from about 20% to about 40%, for example, from about 20% to about 35%, from about 20% to about 30%, from about 20% to about 25%, from about 25% to about 60%, example from about 25% to about 50%, from about 25% to about 40%, from about 25% to about 35%, from about 25% to about 30%, from about 30% to about 60%, from about 30% to about 50%, from about 30% to about 40%, example from about 30% to about 35%, or from about 35% to about 40% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 10% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 15% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 20% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 25% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 30% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 35% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 40% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 50% by weight based on the weight of the hydrogel. In some aspects, the polyol is present in an amount of about 60% by weight based on the weight of the hydrogel.

In some aspects, the method further comprises crosslinking the second mixture to form the hydrogel. It is understood that crosslinking can be done by any known in the art methods that are suitable for the desired application. For example, in some aspects, the crosslinking is UV crosslinking. In yet other aspects, crosslinking can be done with IR radiation or using any other type of energy source. In still further aspects, the crosslinking is achieved chemically without applying any external energy sources. In some aspects, the crosslinking is achieved via a crosslinker, for example, N,N-methylenebis(acrylamide), N,N- dimethylacrylamide (DMAA), or poly(ethylene glycol) diacrylate (PEGDA), or any combination thereof.

In some alternative aspects, the above method can be performed in the presence of an initiator and, optionally, a catalyst, as described herein. In some further alternative aspects, the above method can be performed in the presence of a salt, as described herein. In still further aspects, the hydrogel can be molded, 3D printed, or formed as a thin film in the desired shape for the particular application, such as for a desired device.

Wearable Devices and Systems

In another aspect, a wearable device is also provided herein. In some aspects, the wearable device comprises a housing containing an acoustic lens and a hydrogel, as described herein. In some further aspects, the wearable device further comprises at least one electrical connector operatively coupled to the acoustic lens and hydrogel. In some aspects, the wearable device may be configured to be worn in proximity to a subject’s head.

In some aspects, the hydrogel comprises a coating on a surface of the acoustic lens. In some aspects, the acoustic lens comprises polydimethylsiloxane (PDMS). In some aspects, the wearable device comprises a self-focusing ultrasound transducer or ultrasound device.

In some aspects, the wearable device can be used for neuromodulation. In other aspects, the wearable device can be used for stimulation. In further aspects, the wearable device can be used for heating.

In some aspects, the wearable device can be used for the treatment of a disease or disorder. Representative examples of diseases or disorders that may be treated include but are not limited to, Parkinson’s disease, epilepsy, Alzheimer’s disease, stroke, traumatic brain injury, psychiatric disorders (e.g., depression, anxiety, obsessive-compulsive disorder), pain, (e.g., brain stimulation, spinal cord stimulation, or peripheral stimulation), peripheral chronic joint pain, overactive bladder syndrome, sleep disorders (e.g., sleep apnea, redness leg syndrome), carpal tunnel syndrome, visual prosthetics and/or blindness, or mood disorders.

In some aspects, the wearable device can be in electronic communication with at least one of a controller and an ultrasound generator. In some aspects, the controller can be configured via computer readable instructions or electronic circuitries, to provide control signals for controlling operations of the wearable device.

In another aspect, a system is provided. In some aspects, the system comprises at least one wearable device, as described herein. In some aspects, the system further comprises an ultrasound generator in electronic communication with the at least one wearable device. In some aspects, the system further comprises a controller operatively coupled to the ultrasound generator and the at least one wearable device. In another aspect, methods of manufacturing the wearable devices described herein are also provided. In some aspects, the method comprises preparing a substrate. In some aspects, the method further comprises preparing a mold that defines a pattern for the acoustic lens. In some aspects, the method further comprises disposing (e.g., pouring) an elastomer (e.g., PDMS) into at least a portion of the mold to form the acoustic lens. In some aspects, the method further comprises integrating the at least one electrical connector with the acoustic lens. In some aspects, the method further comprises integrating (e.g., applying) any of the disclosed herein hydrogels of with the acoustic lens.

In some aspects, the at least one electrical connector can comprise a piezoelectric material.

In some aspects, the method can further comprise positioning the mold within the housing prior to disposing the elastomer.

In some aspects, preparing the mold can comprise creating the pattern using a laser etching scheme. In some aspects, preparing the mold can comprise transfer printing the pattern unto the substrate to create the mold.

In still further aspects, the hydrogel can be incorporated into an electrode. In such aspects, the electrode can be configured to be placed on the skin of a subject. In certain aspects, the electrode can have a circular, square, or rectangular shape. It should be understood that the shapes described here are only provided as examples. This disclosure contemplates providing hydrogel-based electrodes having other shapes. Additionally, the hydrogel-based electrode optionally has a surface area of about 2 cm². It should be understood that the surface area described here is only provided as an example. This disclosure contemplates providing hydrogel-based electrodes having other surface areas. Alternatively or additionally, the device optionally further includes a controller operably coupled to the hydrogel-based electrode or electrodes, for example, using a communication link. This disclosure contemplates the communication link is any suitable communication link. For example, a communication link may be implemented by any medium that facilitates signal or energy exchange between the controller and hydrogel-based electrode, including, but not limited to, wired or wireless links. The controller can include at least a processor and memory. The controller can be configured to receive an electroencephalography (EEG) signal recorded by the hydrogel-based electrode. Alternatively or additionally, the controller can further be configured to analyze the EEG signal. Optionally, the EEG signal comprises oscillatory rhythms. Optionally, the oscillatory rhythms comprise sensori-motor rhythm (SMR) or motor imagery (MI) rhythm. Optionally, the EEG signal includes an event-related potential, such as an error-related potential (ErRP). In still further aspects, the disclosed herein hydrogel-based electrodes can be used to record EEG signals.

Additionally, as described herein, this disclosure contemplates using a device including one or more hydrogel-based electrodes and a controller, the device being configured to record EEG signals to generate and send control signals to an external device, where such control signals are responsive to the analyzed EEG signal. The external device can be a robot, a drone, a wheelchair, a neuroprosthesis, or an assistive device. It should be understood that the devices above are provided only as examples. This disclosure contemplates using a hydrogel-based electrode in other devices. An example application is devices for EEG-based BCI devices. For example, the disclosed herein hydrogels can be used in functional electrical stimulation (FES) devices. Yet, in other aspects, the disclosed herein hydrogels can be used in electromyography (EMG) devices. Yet, in other aspects, the hydrogels disclosed herein can be used in transcutaneous electrical nerve stimulation devices (TENS) or neuromuscular electrical stimulation devices (NMES). Yet in other aspects, the hydrogels disclosed herein can be used in electrocardiography (ECG) related devices. Yet in other aspects, the hydrogels disclosed herein can be used in electrooculogram (EOG) devices. Yet in other aspects, the hydrogels disclosed herein can be used in an electrogastrogram (EGG) device.

Optionally, in some implementations, the device further includes a wireless transceiver. The wireless transceiver is configured to transmit the control signal to the external device.

In some alternative aspects, an article is provided comprising a hydrogel as described herein. In some aspects, the article can be a device. Representative examples of suitable articles include but are not limited to, an electroencephalography (EEG) recording device, a functional electrical stimulation (FES) device, an electromyography (EMG) device, a transcutaneous electrical nerve stimulation (TENS) device, a neuromuscular electrical stimulation (NMES) device, an electrocardiography (ECG) device, an electrooculogram (EOG) device, or an electrogastrogram (EGG) device.

In some alternative aspects, a device is provided comprising one or more electrodes comprising a hydrogel as described herein. In some aspects, the electrode is configured to be placed on the skin of a subject. In some aspects, the device can further comprise a controller operably coupled to the one or more electrodes. In some aspects, the controller can be in wired or wireless electronic communication with the one or more electrodes. In some aspects, the controller can be configured, via computer readable instructions or electronic circuitries, to provide control signals for operating the device. In some aspects, the controller can be configured to receive an electrical signal recorded by the one or more electrodes. In some aspects, the controller can be configured to analyze an electrical signal recorded by the one or more electrodes. The electrical signal may comprise in some aspects any suitable biologically or therapeutically derived electrical signal. In some aspects, the electrical signal can comprise an electroencephalography (EEG), electrocardiomyography (ECG), electrooculogram (EOG), or electrogastrogram (EGG) signal. In some aspects, the controller can be configured to transmit a control signal to cause the one or more electrodes to deliver an electrical current. In some aspects, the electrical current can delivered to target site of the one or more electrodes. In some particular aspects, the electrical current can be delivered to induce a therapeutic effect at a target site.

In some alternative aspects, a system is provided comprising a device in accordance with any aspects described herein; and a controller or processor; and a memory.

In view of the described compounds, compositions, articles, devices, and methods, hereinbelow are described certain more particular aspects of the disclosure. These particularly recited aspects should not, however, be interpreted to have any limiting effect on any different claims containing different or more general teachings described herein or that the “particular” aspects are somehow limited in some way other than the inherent meanings of the language and formulae literally used therein.

Exemplary Aspects

Example Al. A hydrogel is formed from: a) a first monomer comprising one or more ionforming moieties; b) a polyol; and c) water; wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1 :4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

Example A2. The hydrogel of example Al, wherein the first monomer comprises one or more anion-forming moieties, one or more cation-forming moieties, or combinations thereof.

Example A3. The hydrogel of example Al or example A2, wherein the first monomer comprises one or more anion-forming moieties. Example A4. The hydrogel of example A3, wherein the first monomer comprises vinyl sulfonic acid, styrene sulfonic acid, allyl sulfonic acid, ethyl acrylate sulfonic acid, butyl acrylate sulfonic acid, acryl sulfonic acid, methacryl sulfonic acid, 2-acrylamido-2- methylpropane sulfonic acid, vinyl carboxylic acid, styrene carboxylic acid, allyl carboxylic acid, acryl carboxylic acid, methacryl carboxylic acid, 2-acrylamido-2-methylpropane carboxylic acid, isoprene carboxylic acid, polyacrylic acid, salts thereof, or combinations thereof.

Example A5. The hydrogel of example A4, wherein the first monomer comprises 2- acrylamido-2-methylpropane sulfonic acid (AMPS) or a salt thereof.

Example A6. The hydrogel of example Al or example A2, wherein the first monomer comprises one or more cation-forming moieties.

Example A7. The hydrogel of example A6, wherein the first monomer comprises vinyl pyridine (such as 2-vinyl pyridine or 4-vinyl pyridine), an aminoethyl methacrylate (such a 2-aminoethyl methacrylate or 2-(dimethylamino)ethyl methacrylate), or 2,2,6,6-tetramethyl- piperidenyloxyl-4-yl methacrylate, or a combination thereof.

Example A8. The hydrogel of any one of examples A1-A7, wherein the polyol comprises glycerol, trimethylolpropane, pentaerythritol, ethylene glycol, 1,5-butanediol, 1,2,5- hexanetriol, diethylene glycol, triethylene glycol, maltitol, sorbitol, xylitol, erythritol, isomalt, malic acid, a polyalkylene glycol (such as polyethylene glycol or polypropylene glycol), polyvinyl alcohol, a polyether polyol, a polyester polyol, or combinations thereof.

Example A9. The hydrogel of example A8, wherein the polyol comprises glycerol.

Example A10. The hydrogel of any one of examples A1-A9, wherein the hydrogel is formed from a), b), and c), and further from: d) a crosslinker.

Example All. The hydrogel of example A10, wherein the crosslinker comprises N,N- methylenebis(acrylamide), N,N-dimethylacrylamide (DMAA), or poly(ethylene glycol) diacrylate (PEGDA), or a combination thereof.

Example A12. The hydrogel of example A10 or example All, wherein the hydrogel is substantially crosslinked.

Example A13. The hydrogel of any one of examples Al -A 12, wherein the hydrogel is formed from a), b), and c), optionally d), and further from: e) an initiator.

Example A14. The hydrogel of example A13, wherein the initiator is a photoinitiator. Example A15. The hydrogel of example A 14, wherein the photoinitiator comprises 2- hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, 4,4'-azo-bis(4-cyanopentanoic acid), or 4-benzoylphenyl acrylate (4-ABP), or a combination thereof.

Example A 16. The hydrogel of example A 13, wherein the initiator is a radical initiator.

Example A17. The hydrogel of example A16, wherein the radical initiator comprises an azo compound, an organic peroxide, an inorganic peroxide, or a combination thereof.

Example Al 8. The hydrogel of example A16 or example A 17, wherein the radical initiator comprises azobisisobutyronitrile (AIBN), l,l'-azobis(cyclohexanecarbonitrile) (ABCN), di- tert-butyl peroxide, benzoyl peroxide, methyl ethyl ketone peroxide, acetone peroxide, a peroxydisulfate salt (such as ammonium persulfate), or a combination thereof.

Example A 19. The hydrogel of any one of examples A 16-Al 8, wherein the radical initiator is ammonium persulfate.

Example A20. The hydrogel of any one of examples A16-A19, wherein the radical initiator is used in combination with a catalyst.

Example A21. The hydrogel of example A20, wherein the catalyst comprises tetramethylethylenediamine (TMED A) .

Example A22. The hydrogel of any one of examples A1-A21, wherein the hydrogel is formed from a), b), c), optionally d), optionally e), and further from: f) a salt.

Example A23. The hydrogel of example A22, wherein the salt is a salt of an alkali or alkaline- earth metal.

Example A24. The hydrogel of example A22 or example A23, wherein the salt is a salt of Li, K, Na, Cs, Rb, Ca, Mg, Ba, Sr, or a combination thereof.

Example A25. The hydrogel of any one of examples A22-A24, wherein the salt is a nitrate, chloride, bromide, iodide, sulfate, carbonate, fluoride salt, or a combination thereof.

Example A26. The hydrogel of any one of examples A22-A25, wherein the salt is potassium chloride.

Example A27. The hydrogel of example A22, wherein the salt is an organic salt.

Example A28. A hydrogel formed from: a) a first monomer comprising one or more ionforming moieties; b) a polyol; c) water; d) a crosslinker; e) a radical initiator; and f) a salt; wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1 :4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

Example A29. The hydrogel of example A28, wherein the first monomer comprising one or more ion-forming moieties comprises 2-acrylamido-2-methylpropane sulfonic acid (AMPS) and/or a salt thereof.

Example A30. The hydrogel of example A28 or example A29, wherein the polyol comprises glycerol.

Example A31. The hydrogel of any one of examples A28-A30, wherein the crosslinker comprises N,N-methylenebis(acrylamide).

Example A32. The hydrogel of any one of examples A28-A31, wherein the radical initiator comprises ammonium persulfate.

Example A33. The hydrogel of example A32, wherein the radical initiator is used in combination with a catalyst.

Example A34. The hydrogel of example A33, wherein the catalyst comprises tetramethylethylenediamine (TMED A) .

Example A35. The hydrogel of any one of examples A28-A34, wherein the salt comprises potassium chloride.

Example A36. The hydrogel of any one of examples A1-A35, wherein the hydrogel is adhesive.

Example A37. The hydrogel of any one of examples A1-A36, wherein the hydrogel is a conductive hydrogel.

Example A38. The hydrogel of any one of examples A1-A37, wherein the hydrogel is an electrode material.

Example A39. The hydrogel of any one of examples A36-A38, wherein the hydrogel is adhesive to a biological tissue or organ, for example, skin.

Example A40. The hydrogel of any one of examples A37-A39, wherein the hydrogel has an adhesion force of about 1 N/m or greater as determined by ASTM D2861-87(1998) (August 1, 2017).

Example A41. The hydrogel any one of examples A1-A40, wherein the hydrogel exhibits an attenuation of sound of about 10% or less. Example A42. The hydrogel of any one of examples A1-A41, wherein the hydrogel exhibits substantially no swelling over a period of about 30 days.

Example A43. The hydrogel of any one of examples A1-A42, wherein the hydrogel exhibits an ionic conductivity of about 0.05 S/m to about 1.5 S/m.

Example A44. The hydrogel of any one of examples A1-A43, wherein the hydrogel is moldable.

Example A45. The hydrogel of any one of examples A1-A44, wherein the hydrogel is provided as a film.

Example A46. An article comprising the hydrogel of any one of examples A1-A45.

Example A47. The article of example A46, wherein the article is a wearable device.

Example A48. The article of example A46 or A47, wherein the article is a focus ultrasound device (FUS).

Example A49. The article of example A46 or A47, wherein the article is an electroencephalography (EEG) recording device.

Example A50. The article of example A46 or A47, wherein the article is a functional electrical stimulation (FES) device.

Example A51. The article of example A46 or A47, wherein the article is an electromyography (EMG) recording device.

Example A52. A method of manufacturing a hydrogel of any one of examples A1-A45 comprising: mixing a first monomer comprising one or more ion-forming moieties and water to form a first mixture, wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1 :4; adding a polyol to the first mixture to form a second mixture, wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel; and crosslinking the second mixture to form the hydrogel.

Example A53. The method of example A52, wherein the method is performed in the presence of an initiator and optionally a catalyst.

Example A54. The method of example A52 or example A53, wherein the method is performed in the presence of a salt.

Example A55. A wearable device comprising: a housing containing an acoustic lens and the hydrogel of any one of examples A1-A45; and at least one electrical connector operatively coupled to the acoustic lens and hydrogel, wherein the wearable device is configured to be worn in proximity to a subject's head.

Example A56. The wearable device of example A55, wherein the hydrogel comprises a coating on a surface of the acoustic lens.

Example A57. The wearable device of example A55 or A56, wherein the acoustic lens comprises polydimethylsiloxane (PDMS).

Example A58. The wearable device of any one of examples A55-A57, wherein the wearable device comprises a self-focusing ultrasound transducer or ultrasound device, or a combination thereof.

Example A59. The wearable device of any one of examples A55-A58, wherein the wearable device is used for at least one of neuromodulation, stimulation, or heating, or a combination thereof.

Example A60. The wearable device of any one of examples A55-A59, wherein the wearable device is used for treatment of at least one of: Parkinson's disease, epilepsy, Alzheimer's disease, stroke, traumatic brain injury, psychiatric disorders (e.g., depression, anxiety, obsessive-compulsive disorder), pain, (e.g., brain stimulation, spinal cord stimulation, or peripheral stimulation), peripheral chronic joint pain, overactive bladder syndrome, sleep disorders (e.g., sleep apnea, redness leg syndrome), carpal tunnel syndrome, visual prosthetics and/or blindness, or mood disorders, or any combination thereof.

Example A61. The wearable device of any one of examples A55-A60, wherein the wearable device is in electronic communication with at least one of a controller and an ultrasound generator.

Example A62. The wearable device of example A61, wherein the controller is configured via computer readable instructions or electronic circuitries, to provide control signals for controlling operations of the wearable device.

Example A63. A system comprising: at least one wearable device according to any one of examples A55-A62; an ultrasound generator in electronic communication with the at least one wearable device; and a controller operatively coupled to the ultrasound generator and the at least one wearable device.

Example A64. A method of manufacturing the wearable device of any one of examples A55- A62, the method comprising: preparing a substrate; preparing a mold that defines a pattern for the acoustic lens, disposing (e.g., pouring) an elastomer (e.g., PDMS) into at least a portion of the mold to form the acoustic lens; integrating the at least one electrical connector with the acoustic lens; and integrating (e.g., applying) the hydrogel of any one of claims 1-45 with the acoustic lens.

Example A65. The method of example A64, wherein the at least one electrical connector comprises a piezoelectric material.

Example A66. The method of example A64 or A65, further comprising: positioning the mold within the housing prior to disposing the elastomer.

Example A67. The method of any one of examples A64-A66, wherein preparing the mold comprises: creating the pattern using a laser etching scheme, and transfer printing the pattern onto the substrate to create the mold.

Further Exemplary Aspects

Example Bl. A hydrogel formed from: a) a first monomer comprising one or more ion-forming moieties; b) a polyol; and c) water; wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1:4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

Example B2. The hydrogel of example Bl, wherein the first monomer comprises one or more anion-forming moieties, one or more cation-forming moieties, or combinations thereof.

Example B3. The hydrogel of example Bl or example B2, wherein the first monomer comprises one or more anion-forming moieties.

Example B4. The hydrogel of example B3, wherein the first monomer comprises vinyl sulfonic acid, styrene sulfonic acid, allyl sulfonic acid, ethyl acrylate sulfonic acid, butyl acrylate sulfonic acid, acryl sulfonic acid, methacryl sulfonic acid, 2-acrylamido-2- methylpropane sulfonic acid, vinyl carboxylic acid, styrene carboxylic acid, allyl carboxylic acid, acryl carboxylic acid, methacryl carboxylic acid, 2-acrylamido-2-methylpropane carboxylic acid, isoprene carboxylic acid, polyacrylic acid, salts thereof, or combinations thereof.

Example B5. The hydrogel of example B4, wherein the first monomer comprises 2- acrylamido-2-methylpropane sulfonic acid (AMPS) or a salt thereof.

Example B6. The hydrogel of example Bl or example B2, wherein the first monomer comprises one or more cation-forming moieties.

Example B7. The hydrogel of example B6, wherein the first monomer comprises vinyl pyridine (such as 2-vinyl pyridine or 4-vinyl pyridine), an aminoethyl methacrylate (such a 2-aminoethyl methacrylate or 2-(dimethylamino)ethyl methacrylate), or 2,2,6,6-tetramethyl- piperidenyloxyl-4-yl methacrylate, or a combination thereof.

Example B8. The hydrogel of any one of examples B1-B7, wherein the polyol comprises glycerol, trimethylolpropane, pentaerythritol, ethylene glycol, 1,5-butanediol, 1,2,5- hexanetriol, diethylene glycol, triethylene glycol, maltitol, sorbitol, xylitol, erythritol, isomalt, malic acid, a polyalkylene glycol (such as polyethylene glycol or polypropylene glycol), a polyvinyl alcohol, a polyether polyol, a polyester polyol, or combinations thereof.

Example B9. The hydrogel of example B8, wherein the polyol comprises glycerol.

Example BIO. The hydrogel of any one of examples B1-B9, wherein the hydrogel is formed from a), b), and c), and further from: d) a crosslinker.

Example B 11. The hydrogel of example BIO, wherein the crosslinker comprises N,N- methylenebis(acrylamide), N,N-dimethylacrylamide (DMAA), or poly(ethylene glycol) diacrylate (PEGDA), or a combination thereof.

Example B 12. The hydrogel of example BIO or example Bl l, wherein the hydrogel is substantially crosslinked.

Example B13. The hydrogel of any one of examples B1-B12, wherein the hydrogel is formed from a), b), and c), optionally d), and further from: e) an initiator.

Example B14. The hydrogel of example B13, wherein the initiator is a photoinitiator. Example Bl 5. The hydrogel of example B14, wherein the photoinitiator comprises 2- hydroxy-4’-(2-hydroxyethoxy)-2-methylpropiophenone, 4,4’-azo-bis(4-cyanopentanoic acid), or 4-benzoylphenyl acrylate (4-ABP), or a combination thereof.

Example B16. The hydrogel of example B13, wherein the initiator is a radical initiator.

Example B17. The hydrogel of example B16, wherein the radical initiator comprises an azo compound, an organic peroxide, an inorganic peroxide, or a combination thereof.

Example Bl 8. The hydrogel of example B16 or example B17, wherein the radical initiator comprises azobisisobutyronitrile (AIBN), l,l’-azobis(cyclohexanecarbonitrile) (ABCN), di- tert-butyl peroxide, benzoyl peroxide, methyl ethyl ketone peroxide, acetone peroxide, a peroxydisulfate salt (such as ammonium persulfate), or a combination thereof.

Example B19. The hydrogel of any one of examples B16-B18, wherein the radical initiator is ammonium persulfate.

Example B20. The hydrogel of any one of examples B16-B19, wherein the radical initiator is used in combination with a catalyst.

Example B21. The hydrogel of example B20, wherein the catalyst comprises tetramethylethylenediamine (TMED A) .

Example B22. The hydrogel of any one of examples B1-B21, wherein the hydrogel is adhesive.

Example B23. The hydrogel of example B22, wherein the hydrogel is adhesive to a biological tissue or organ, for example, skin.

Example B24. The hydrogel of example B22 or B23, wherein the hydrogel has an adhesion force of about 1 N/m or greater as determined by ASTM D2861-87(1998) (August 1, 2017).

Example B25. The hydrogel any one of examples B1-B24, wherein the hydrogel exhibits an attenuation of sound of about 10% or less.

Example B26. The hydrogel of any one of examples B1-B25, wherein the hydrogel exhibits substantially no swelling over a period of about 30 days.

Example B27. The hydrogel of any one of examples B1-B26, wherein the hydrogel is moldable.

Example B28. The hydrogel of any one of examples B1-B27, wherein the hydrogel is provided as a film. Example B29. An article comprising the hydrogel of any one of examples B1-B28.

Example B30. The article of example B29, wherein the article is a wearable device. Example B31. The article of example B29 or B30, wherein the article is a focused ultrasound device (FUS).

Example B32. A method of manufacturing a hydrogel of any one of examples B1-B28 comprising: mixing a first monomer comprising one or more ion-forming moieties and water to form a first mixture, wherein the first monomer and water have a ratio by weight from about 1:1 to about 1:4; adding a polyol to the first mixture to form a second mixture, wherein the polyol is present in an amount from about 10% to about 60% by weight based on the weight of the hydrogel; and crosslinking the second mixture to form the hydrogel.

Example B33. The method of example B32, wherein the method is performed in the presence of an initiator and optionally a catalyst.

Example B34. A wearable device comprising: a housing containing an acoustic lens and the hydrogel of any one of examples Bl- B28; and at least one electrical connector operatively coupled to the acoustic lens and hydrogel, wherein the wearable device is configured to be worn in proximity to a subject’s head.

Example B35. The wearable device of example B34, wherein the hydrogel comprises a coating on a surface of the acoustic lens.

Example B36. The wearable device of example B34 or B35, wherein the acoustic lens comprises polydimethylsiloxane (PDMS).

Example B37. The wearable device of any one of examples B34-B36, wherein the wearable device comprises a self-focusing ultrasound transducer or ultrasound device, or a combination thereof.

Example B38. The wearable device of any one of examples B34-B37, wherein the wearable device is used for at least one of neuromodulation, stimulation, or heating, or a combination thereof.

Example B39. The wearable device of any one of examples B34-B38, wherein the wearable device is used for treatment of at least one of: Parkinson’s disease, epilepsy, Alzheimer’s disease, stroke, traumatic brain injury, psychiatric disorders (e.g., depression, anxiety, obsessive-compulsive disorder), pain, (e.g., brain stimulation, spinal cord stimulation, or peripheral stimulation), peripheral chronic joint pain, overactive bladder syndrome, sleep disorders (e.g., sleep apnea, redness leg syndrome), carpal tunnel syndrome, visual prosthetics and/or blindness, or mood disorders, or any combination thereof.

Example B40. The wearable device of any one of examples B34-B39, wherein the wearable device is in electronic communication with at least one of a controller and an ultrasound generator.

Example B41. The wearable device of example B40, wherein the controller is configured, via computer readable instructions or electronic circuitries, to provide control signals for controlling operations of the wearable device.

Example B42. A system comprising: at least one wearable device according to any one of examples B34-B41; an ultrasound generator in electronic communication with the at least one wearable device; and a controller operatively coupled to the ultrasound generator and the at least one wearable device.

Example B43. A method of manufacturing the wearable device of any one of examples B34-B41, the method comprising: preparing a substrate; preparing a mold that defines a pattern for the acoustic lens, disposing (e.g., pouring) an elastomer (e.g., PDMS) into at least a portion of the mold to form the acoustic lens; integrating the at least one electrical connector with the acoustic lens; and integrating (e.g., applying) the hydrogel of any one of examples B1-B45 with the acoustic lens.

Example B44. The method of example B43, wherein the at least one electrical connector comprises a piezoelectric material.

Example B45. The method of example B43 or B44, further comprising: positioning the mold within the housing prior to disposing the elastomer.

Example B46. The method of any one of examples B43-B45, wherein preparing the mold comprises: creating the pattern using a laser etching scheme, and transfer printing the pattern onto the substrate to create the mold.

Example B47. A hydrogel formed from: a) a first monomer comprising one or more ion-forming moieties; b) a polyol; c) a salt; and d) water; wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1:4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

Example B48. The hydrogel of example B47, wherein the first monomer comprises one or more anion-forming moieties, one or more cation-forming moieties, or combinations thereof.

Example B49. The hydrogel of example B47 or example B48, wherein the first monomer comprises one or more anion-forming moieties.

Example B50. The hydrogel of example B49, wherein the first monomer comprises vinyl sulfonic acid, styrene sulfonic acid, allyl sulfonic acid, ethyl acrylate sulfonic acid, butyl acrylate sulfonic acid, acryl sulfonic acid, methacryl sulfonic acid, 2-acrylamido-2- methylpropane sulfonic acid, vinyl carboxylic acid, styrene carboxylic acid, allyl carboxylic acid, acryl carboxylic acid, methacryl carboxylic acid, 2-acrylamido-2-methylpropane carboxylic acid, isoprene carboxylic acid, polyacrylic acid, salts thereof, or combinations thereof.

Example B 51. The hydrogel of example B50, wherein the first monomer comprises 2- acrylamido-2-methylpropane sulfonic acid (AMPS) or a salt thereof.

Example B52. The hydrogel of example B47 or example B48, wherein the first monomer comprises one or more cation-forming moieties.

Example B53. The hydrogel of example B52, wherein the first monomer comprises vinyl pyridine (such as 2-vinyl pyridine or 4-vinyl pyridine), an aminoethyl methacrylate (such a 2-aminoethyl methacrylate or 2-(dimethylamino)ethyl methacrylate), or 2,2,6,6-tetramethyl- piperidenyloxyl-4-yl methacrylate, or a combination thereof. Example B54. The hydrogel of any one of examples B47-B53, wherein the polyol comprises glycerol, trimethylolpropane, pentaerythritol, ethylene glycol, 1,5-butanediol, 1,2,5- hexanetriol, diethylene glycol, triethylene glycol, maltitol, sorbitol, xylitol, erythritol, isomalt, malic acid, a polyalkylene glycol (such as polyethylene glycol or polypropylene glycol), a polyvinyl alcohol, a polyether polyol, a polyester polyol, or combinations thereof.

Example B55. The hydrogel of example B54, wherein the polyol comprises glycerol.

Example B56. The hydrogel of any one of examples B47-B55, wherein the salt is a salt of an alkali or alkaline-earth metal.

Example B57. The hydrogel of example B56, wherein the salt is a salt of Li, K, Na, Cs, Rb, Ca, Mg, Ba, Sr, or a combination thereof.

Example B58. The hydrogel of any one of examples B56 or B57, wherein the salt is a nitrate, chloride, bromide, iodide, sulfate, carbonate, fluoride salt, or a combination thereof.

Example B59. The hydrogel of any one of examples B56-B58, wherein the salt is potassium chloride.

Example B60. The hydrogel of any one of examples B47-B55, wherein the salt is an organic salt.

Example B61. The hydrogel of any one of examples B47-B60, wherein the hydrogel is formed from a), b), and c), and further from: d) a crosslinker.

Example B 62. The hydrogel of example B61, wherein the crosslinker comprises N,N- methylenebis(acrylamide), N,N-dimethylacrylamide (DMAA), or poly(ethylene glycol) diacrylate (PEGDA), or a combination thereof.

Example B63. The hydrogel of example B61 or example B62, wherein the hydrogel is substantially crosslinked.

B64. The hydrogel of any one of examples B47-B63, wherein the hydrogel is formed from a), b), and c), optionally d), and further from: e) an initiator.

Example B65. The hydrogel of example B64, wherein the initiator is a photoinitiator. Example B66. The hydrogel of example B65, wherein the photoinitiator comprises 2- hydroxy-4’-(2-hydroxyethoxy)-2-methylpropiophenone, 4,4’-azo-bis(4-cyanopentanoic acid), or 4-benzoylphenyl acrylate (4-ABP), or a combination thereof.

Example B67. The hydrogel of example B64, wherein the initiator is a radical initiator.

Example B68. The hydrogel of example B67, wherein the radical initiator comprises an azo compound, an organic peroxide, an inorganic peroxide, or a combination thereof.

Example B69. The hydrogel of example B67 or example B68, wherein the radical initiator comprises azobisisobutyronitrile (AIBN), l,l’-azobis(cyclohexanecarbonitrile) (ABCN), di- tert-butyl peroxide, benzoyl peroxide, methyl ethyl ketone peroxide, acetone peroxide, a peroxydisulfate salt (such as ammonium persulfate), or a combination thereof.

Example B70. The hydrogel of any one of examples B67-B69, wherein the radical initiator is ammonium persulfate.

Example B71. The hydrogel of any one of examples B67-B70, wherein the radical initiator is used in combination with a catalyst.

Example B72. The hydrogel of example B71, wherein the catalyst comprises tetramethylethylenediamine (TMED A) .

Example B73. A hydrogel formed from: a) a first monomer comprising one or more ion-forming moieties; b) a polyol; c) water; d) a crosslinker; e) a radical initiator; and f) a salt; wherein the first monomer and water have a ratio by weight from about 1:1 to about 1:4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

Example B74. The hydrogel of example B73, wherein the first monomer comprising one or more ion-forming moieties comprises 2-acrylamido-2-methylpropane sulfonic acid (AMPS) and/or a salt thereof.

Example B75. The hydrogel of example B73 or example B74, wherein the polyol comprises glycerol. Example B76. The hydrogel of any one of examples B73-B75, wherein the crosslinker comprises N,N-methylenebis(acrylamide).

Example B77. The hydrogel of any one of examples B73-B76, wherein the radical initiator comprises ammonium persulfate.

Example B78. The hydrogel of any one of examples B73-B77, wherein the radical initiator is used in combination with a catalyst.

Example B79. The hydrogel of example B78, wherein the catalyst comprises tetramethylethylenediamine (TMED A) .

Example B80. The hydrogel of any one of examples B73-B79, wherein the salt comprises potassium chloride.

Example B81. The hydrogel of any one of examples B47-B80, wherein the hydrogel is adhesive.

Example B82. The hydrogel of any one of examples B47-B81, wherein the hydrogel is a conductive hydrogel.

Example B83. The hydrogel of any one of examples B47-B82, wherein the hydrogel is an electrode material.

Example B84. The hydrogel of any one of examples B81-B83, wherein the hydrogel is adhesive to a biological tissue or organ, for example, skin.

Example B85. The hydrogel of any one of examples B81-B84, wherein the hydrogel has an adhesion force of about 1 N/m or greater as determined by ASTM D2861-87(1998) (August 1, 2017).

Example B86. The hydrogel of any one of examples B47-B85, wherein the hydrogel exhibits substantially no swelling over a period of about 30 days.

Example B87. The hydrogel of any one of examples B47-B86, wherein the hydrogel exhibits an ionic conductivity of about 0.001 S/m to about 10 S/m.

Example B88. The hydrogel of any one of examples B47-B87, wherein the hydrogel is moldable.

Example B89. The hydrogel of any one of examples B47-B88, wherein the hydrogel is provided as a film.

Example B90. A method of manufacturing a hydrogel of any one of examples B47-B89 comprising: mixing a first monomer comprising one or more ion-forming moieties and water to form a first mixture, wherein the first monomer and water have a ratio by weight from about 1:1 to about 1:4; adding a polyol to the first mixture to form a second mixture, wherein the polyol is present in an amount from about 10% to about 60% by weight based on the weight of the hydrogel; and crosslinking the second mixture to form the hydrogel, wherein the method is performed in the presence of a salt.

Example B91. The method of example B90, wherein the method is performed in the presence of an initiator and optionally a catalyst.

Example B92. An article comprising the hydrogel of any one of examples B47-B89.

Example B93. The article of example B92, wherein the article is a device.

Example B94. The article of example B92 or B93, wherein the article is an electroencephalography (EEG) recording device, a functional electrical stimulation (FES) device, an electromyography (EMG) device, a transcutaneous electrical nerve stimulation (TENS) device, a neuromuscular electrical stimulation (NMES) device, an electrocardiography (ECG) device, an electrooculogram (EOG) device, or an electrogastrogram (EGG) device.

Example B95. A device comprising: one or more electrodes comprising a hydrogel of any one of examples B47-B89.

Example B96. The device of example B95, wherein the electrode is configured to be placed on the skin of a subject.

Example B97. The device of example B95 or B96, further comprising a controller operably coupled to the one or more electrodes.

Example B98. The device of example B97, wherein the controller is in wired or wireless electronic communication with the one or more electrodes.

Example B99. The device of example B97 or B98, wherein the controller is configured, via computer readable instructions or electronic circuitries, to provide control signals for operating the device.

Example B100. The device of any one of examples B97 to B99, wherein the controller is configured to receive an electrical signal recorded by the one or more electrodes.

Example B101. The device of any one of examples B97 to B100, wherein the controller is configured to analyze an electrical signal recorded by the one or more electrodes. Example B102. The device of example B100 or B101, wherein the electrical signal comprises an electroencephalography (EEG), electrocardiomyography (ECG), electrooculogram (EOG), or electrogastrogram (EGG) signal.

Example B103. The device of any one of examples B97 to B102, wherein the controller is configured to transmit a control signal to cause the one or more electrodes to deliver an electrical current.

Example B104. The device of example B103, wherein the electrical current is delivered to target site of the one or more electrodes.

Example B 105. A system comprising: a device in accordance with any one of examples B95-B104; and a controller or processor; and a memory.

A number of aspects of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other aspects are within the scope of the following claims.

By way of non-limiting illustration, examples of certain aspects of the present disclosure are given below.

EXAMPLES

The following examples are set forth below to illustrate the compounds, compositions, articles, devices, and methods claimed herein, along with associated methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present disclosure, which are apparent to one skilled in the art.

Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.

Bioadhesive Hydrogel- Coupled and Miniaturized Ultrasound Transducer System for Long-Term, Wearable Neuromodulation

Transcranial focused ultrasound has become a promising non-invasive approach for neuromodulation applications, particularly for neurodegenerative diseases and psychiatric illnesses. However, its implementation in wearable neuromodulation has thus far been limited due to the devices’ large size, which needs external supporting systems for the neuromodulation process. Furthermore, the need for ultrasound gel for acoustic coupling between the device and skin limits the viability for long-term use, due to its inherent susceptibility to dehydration and lack of adhesiveness to form a stable interface. In this example, we report a representative wearable miniaturized ultrasound device with size comparable to standard EEG/ECG electrodes integrated with a representative bioadhesive hydrogel to achieve efficient acoustic intensity upon ultrasound stimulation for long-term, wearable primary somatosensory cortical stimulation. Specifically, air-cavity Fresnel lens (ACFAL) based self-focusing acoustic transducer (SFAT) was fabricated using a lithography- free microfabrication process. The representative transducer was able to achieve an acoustic intensity of up to 30.7 W/cm² (1.92 MPa) in free-field with a focal depth of 10 mm. The representative bioadhesive hydrogel was developed to address the need for long-term stability of acoustic couplant for ultrasound application. The hydrogel demonstrated less than 13% attenuation in acoustic intensity and stable adhesion force of 0.961 N/cm across 35 days. Leveraging the described representative bioadhesive hydrogel-integrated wearable ultrasound transducer, we were able to suppress somatosensory evoked potentials elicited by median nerve stimulation via functional electrical stimulation over 28 days, demonstrating the efficacy of the representative transducer for long-term, wearable neuromodulation in the brain.

Introduction

The increase in brain diseases amongst the general population has motivated significant research in therapeutic treatment approaches. With 1 million people in the US diagnosed with Parkinson’s disease and a projected increase of 78% annually, the socioeconomic burden on individuals, families, and the healthcare system is significant^1,2. Deep brain stimulation (DBS) has been clinically approved in treating Parkinson’s disease^{3 7}, essential tremor^8-12, epilepsy^13-16, dystonia^17-19 and obsessive-compulsive disorder^4,20. Despite being a very effective method, it requires invasive implanted electrodes with complications involving hematoma, lead fractures, and glial response rendering electrodes ineffective^21,22. Alternatively, non-invasive brain stimulation devices provide an opportunity for treatments for a multitude of psychiatric, mental, and neurodegenerative diseases in a substantial number of patients as a non-invasive intervention. Transcranial magnetic stimulation (TMS) are currently effective and clinically approved treatment methods for mental health disorders such as obsessive-compulsive disorders and depression²³. It has also shown promising improvements in sleep disorders, Parkinson’s²⁴, Alzheimer’s²⁵ and potentially several other neuropsychiatric disorders²⁶. However, TMS stimulates large brain areas due to its low spatial resolution, making it difficult to achieve the most effective treatment without causing adverse off-targeting effects^27-30. Since TMS generally requires a 3-6 weeks treatment period and DBS require continuous stimulation upon implantation, there is a strong need for non-invasive and high- spatial resolution neuromodulation approach with long-term wearability^6,25,31-33.

Transcranial focused ultrasound (tFUS) provides an alternative non-invasive strategy for highly precise targeting of subcortical and deep brain stimulation with high spatial- temporal resolution³⁴. It has shown improvement in neurological diseases such as tremor associated with Parkinson’s disease^35,36, cognitive and memory impairments in Alzheimer’s disease^{37 4 I}, epilepsy^{42 44}, and chronic mental health disorders⁴⁵. However, the current tFUS systems are typically bulky and are not in wearable format for long-term neuromodulation. To develop an effective wearable ultrasound neuromodulation system requires: 1) miniaturized transducer with effective acoustic intensity and focality for tFUS⁴⁶, 2) stable fixation to the skin during neuromodulation⁴⁷, and 3) acoustic impedance match between the ultrasound transducer and tissue⁴⁸. Currently, the commercial ultrasound gel has been commonly used as a medium to match the acoustic impedance during ultrasound stimulation by eliminating air gaps in promoting the efficiency of ultrasound transmission⁴⁹. Yet, its limitations of non-adhesive properties for ultrasound transducer fixation to the skin and dehydration susceptibility prevents long-term use in continuous neuromodulation treatment of brain disorders over several weeks⁵⁰. Current approaches in developing bioadhesive hydrogel for wearable ultrasound imaging application has shown to be effective for ultrasound applications, however its efficacy diminishes drastically after 72 hours^51,52. Therefore, a wearable ultrasound device integrated with an acoustically compatible medium that provides robust device-to-skin adhesion for long-term application is desired.

In this example, we developed a strategy to address the current limitations of ultrasound devices to enable long-term cortical neuromodulation. Specifically, we have developed representative self-focusing acoustic transducers (SFAT) that leverages geometrical patterning of acoustic lens in altering wave propagation to achieve acoustic focusing through the use of air-cavity fresnel acoustic lens (ACFAL), allowing an increase in acoustic intensity of the focal depth limit originally constrained by the geometrical diameter of the transducer (FIGs. 2A-2C)⁵³. In addition, we have designed a representative bioadhesive hydrogel, consisting of 2-acrylamido-2-methyl-l -propanesulfonic acid (AMPS) and glycerol, to have high water absorption and rehydration properties over a month and strong adhesion to the skin (FIG. 2D). Through integration of the representative bioadhesive hydrogel to the representative SFAT transducer, the representative Miniaturized and Bioadhesive-coupled Ultrasound Transducer (MiniUlTra) weighs 8.5 grams and can be easily attached to the target skin for an extended period, allowing ease of use for long-term applications (FIG. 2E-2H). We evaluated the efficacy of MiniUlTra in its effectiveness in suppressing somatosensory evoked potential elicited by median nerve stimulation via functional electrical stimulation over 28 days, demonstrating MiniUlTra’s efficacy in longterm cortical neuromodulation as a wearable ultrasound device.

Results

Development and Characterization of Representative Miniaturized Ultrasound Transducer

Acoustic frequencies used for ultrasound stimulation with ideal transcranial transmission and brain absorption has been reported to be less than 650 kHz^54,55, where clinical demonstration of using ultrasound stimulation at 210 kHz and 500 kHz frequency in humans has shown effective suppression evoked potential and enhanced sensory functions^56,57. In this example, we used 650 kHz based on previous observations and studies demonstrating effective neuromodulation with improved spatial focality under the constraint of a miniaturized single-element transducer. Thus, we developed a custom miniaturized 650 kHz ultrasound transducer (similar size to standard EEG electrode leads, OD = 18 mm) with microfabrication techniques to create a self-focusing acoustic transducer (SFAT) using air cavity Fresnel acoustic lens (ACFAL) coupled with a representative highly adhesive and conformable bioadhesive hydrogel for long-term applications. Characterization of acoustic pressure fields emitted from the representative SFAT-ACFAL was done using a calibrated hydrophone (FIG. 3A) on a motorized 3-axis system submerged in a degassed distilled water bath. Comparison of acoustic field distribution with and without the ACFAL formed by PDMS (Pristine PZT vs. SFAT-ACFAL) showed less scattering and higher focusing on the desired focal point in the transducer with ACFAL (FIG. 3B). Recording of acoustic waveforms pulsed and transmitted was performed in free-field and with a macaque skull, where measurements indicate a spatial focality of 3.5 mm axially and 8 mm laterally (FIG. 4C-4D). The focal depth was measured to be at 10 mm, at the expected and designed specification. To determine the acoustic intensity and biosafety of the devices for ultrasound neuromodulation, a calibration curve was performed with the representative ultrasound system (Image Guided Therapy System) used to drive the SFAT-ACFAL to evaluate the linearity of acoustic intensity and pressure when driving amplitude was increased. The measurements revealed a spatial-peak pulse-average intensity (ISPPA) in the free field to be less than 30.7 W/cm² (1.92 MPa) (FIG. 3E). To validate efficacious acoustic transmission of the device, initial peak pressure of SFAT-ACFAL measured in free-field with and without the macaque skull resulted in a decrease from 1.31 MPa to 1.01 MPa corresponding to 36.9% (1.79 dB, FIGs. 7A-7B), which is similar to that of attenuation reported in macaque skull at frequency ranges 300-800kHz (0.85 - 2.06 dB)⁵⁸. Adjustment of initial peak pressure using reported attenuation coefficient (5.21 - 11.29 dB) in human skull with thickness at parietal section (-5.8 mm) resulted in the estimated attenuated peak pressure of 0.104 MPa⁵⁹. To compare, a study has demonstrated free-field acoustic intensity of 23.9 W/cm² has shown to be effective when transmitting through the human skull with a four-fold drop in intensity to 5.9 W/cm^{2 56}. Therefore, all stimulation paradigms performed in healthy volunteers using the representative device were performed at 23.1 W/cm² (1.66MPa), to necessitate sufficient acoustic intensity threshold in suppression of sensory evoked potentials⁵⁶. The effect of transcranial skull transmission effectively attenuates the amplitude of the acoustic pulse waveform (FIG. 3F) and increases the spatial resolution resulting in a smaller focal spot. This is possibly due to the inhomogeneity of skull and tissue interfaced between the boundary conditions resulting in time-reversible wave propagation, commonly used for imaging⁶⁰. The shift in axial peak of the focal spot (FIG. 3D) was due to the curvature of the macaque skull and its’ difficulty in positioning between the hydrophone and device to prevent collision. To ensure thermal biosafety, the device during ultrasound stimulation should not exceed an increase of 2°C ⁶¹. We then characterized the thermal biosafety of the device by performing the stimulation paradigm used by Legon et al.⁵⁶ in comparison with higher duty cycle and pulse duration through the macaque skull and monitoring the temperature of the stimulation site using an infrared camera (FIGs. 3G, 8, 9A-9C). Results indicated that with 10 min of continuous stimulation, the paradigm of 360 ps ON and 640 ps OFF ⁵⁶ had no thermal increase. Similarly, when the duty cycle was increased to 50% (500 ps ON and 500 ps OFF) there was no significant temperature increase. However, when the pulse duration increased to 50 ms ON and 50 ms OFF, dramatic temperature increase was observed beyond the 5 min mark. This demonstrates the device’s safety regime for human applications. Electrical characterization of the device was performed using an impedance spectrum analyzer to determine the impedance and phase response of SFAT-ACFAL. The impedance was then used to determine harmonic frequencies where the lowest impedance (-174Q) represents the center frequency (~653kHz) of choice used in designing of SFAT-ACFAL and also for impedance matching purposes⁶² (FIG. 3H). Given the multiple resonances in impedance spectrum is present, further optimization is required. As a result, potential surface heating of the transducer may induce further thermal biosafety concerns. Thus, additional performance details of SFAT-ACFAL surface thermal profile were measured from 5 points on the surface for 120 seconds (1 pulse/sec) without commercial gel, with commercial gel, and with the representative bioadhesive hydrogel (FIG. 8). Results demonstrate an overall increase of less than ~7°C across all conditions and no more than 43°C, where burn and necrosis in subcutaneous tissues begin to occur under FDA guidelines beyond 43°C ⁶³. Furthermore, the skin and skull dissipate the heat as demonstrated previously (FIG. 3G).

Development and Characterization of Representative Bioadhesive Hydrogel

To ensure long-term neuromodulation viability, the need for an acoustic couplant to sustain stable acoustic properties over time is needed to be integrated with the SFAT-ACFAL. Specifically, it should sustain hydration, effectively transmit ultrasound, adhere conformally to the skin with a low modulus to minimize air gaps, and maintain high adhesion force over time^51,52. The bioadhesive hydrogel used in this study includes two primary materials: 1) 2- acrylamido-2-methylpropane sulfonic acid (AMPS) and 2) glycerol (FIG. 2D). Poly AMPS is an ionic polymer with a hydrophilic sulfonic group resulting in it being inherently negatively charged, which allows for strong ionic interaction with water molecules⁶⁴. Thus, it enables high water absorption rate^{65 67} , allowing sustained hydrated state through absorption of ambient moisture⁶⁸. In addition to its high water content and retention, Poly AMPS provides modulus similar to that of biological tissues⁶⁹, and is suitable as a longterm substitute of commercially available ultrasound gel that tends to dehydrate within hours. Furthermore, the addition of glycerol containing hydroxyl groups, which forms hydrogen bonds with water molecules, provides water retention capacity and enhanced adhesion to the skin by offering a hydrating effect on the stratum comeum ^65,70,71.

We characterized the acoustic attenuation rate of the representative bioadhesive hydrogel at different thickness in comparison to commercial gel. As a result, we observe that the ultrasound power attenuation of the bioadhesive hydrogel is comparable to that of commercial gel at thicknesses of 0.5 mm and 1 mm (FIG. 4A). With ultrasound as a mechanical acoustic wave, the mismatch in impedance when propagated between mediums with varying acoustic impedances inevitably leads to partial transmission and reflection at the boundary layers. By minimizing the mismatch in impedance, reduction of reflected and maximizing transmitted waves provides higher acoustic intensity deposition to the target site. Therefore, the need for minimizing the impedance mismatch between the representative device and the skin using the representative bioadhesive hydrogel is necessary⁵¹. As acoustic speed in a material is directly related to its elastic properties and density, the acoustic impedance could be derived directly from the acoustic speed and density^72,73. We experimentally characterize and measure the acoustic speed of the representative hydrogel. Firstly, with the acoustic speed of water being 1500 m/s and the distance between PZT and hydrophone positioned 20 mm apart in the water tank, the time required for an acoustic pulse (time-of-flight, ToF) to travel from the transducer to the hydrogel theoretically will be 13.3 ps in free-field. Upon measurement of ToF with the hydrogel, comparison of to the free-field measurement allows us to determine the time difference and the acoustic speed through the hydrogel (FIG. 4B). With the measured density of the hydrogel being 1166.7 kg/m³, the derived acoustic impedance of the hydrogel yielded 2.13 ± 0.11 MRayl and 2.17 ± 0.13 MRayl, with estimated acoustic speed of 1816 ± 76.36 m/s and 1864 ± 113.7 m/s on day 0 and day 7 respectively (FIGs. 3C, 10A-10B). Overall, the acoustic impedance of the bioadhesive hydrogel remained stable across 7 days, with an average hydrogel impedance of 2.17 MRayl. Compared to the acoustic impedance of 1.99 MRayl for skin⁵², the representative bioadhesive hydrogel exhibits a much more similar impedance to human skin^{74 77} , indicating minimum acoustic loss of the representative hydrogel in addition to its’ long-term stability with minimal mismatch between the hydrogel and skin (1.99 MRayl) when evaluating acoustic transmission efficiency. Results show an overall higher transmission and reduced reflection coefficient when compared to commercial gels (Konix: 1.45 MRayl, Aquasonic 100: 1.60 MRayl), water, and skin^48,51,78,79 (FIGs. 10A-10B). Therefore, indicating minimum acoustic loss of the representative hydrogel in addition to its’ long-term stability.

The water retention capacity of bioadhesive hydrogels as a function of AMPS ratio for long-term neuromodulation applications was investigated. We prepared bioadhesive hydrogels with 24.4 w/w%, 32.3 w/w%, 38.9 w/w%, and 44.3 w/w% of AMPS ratio, respectively. The swelling ratios of the hydrogels (with 24.4 w/w%, 32.3 w/w%, 38.9 w/w%, and 44.3 w/w% AMPS ratio) after 3h were 7696.5%, 5749.8%, 4855.9%, and 4451.0%, respectively, where the hydrogel with the lowest AMPS ratio showing the highest swelling ratio due to the large pore size of hydrogels with crosslink ratio resulting increased swelling ratio (FIG. 11A)⁸⁰. To evaluate the dehydration and rehydration characteristics of the hydrogels as an effect of the AMPS amount in the air condition, the hydrogels for each AMPS ratio were stored at 37°C degrees at low humidity (RH 25%) for the first three days and at high humidity (RH 85%) for the next three days, thus showing the dehydration and rehydration characteristics of the hydrogels. During the first three days at low humidity, the hydrogels exhibited dehydration rates of 69.9%, 79.0%, 82.5%, and 83.3%, with the hydrogel containing the lowest AMPS ratio dehydrated more. In the high-humidity phase from days 3 to 6, rehydration ratios for the hydrogels were 156.6%, 151.4%, 150.5%, and 151.2%, indicating comparable water retention across different AMPS ratios, though those with lower AMPS ratios showed slightly higher rehydration. By day 6, the hydrogel with 24.4% AMPS had the lowest absolute weight, demonstrating higher dehydration and less stability than those with higher AMPS ratios (FIG. 11B). The water retention ability of a hydrogel can be evaluated by comparing the dehydration rate of the hydrogel over time, and with a dehydration rate of 82.5% over 3 days, the water retention ability of the representative bioadhesive hydrogel (with 38.9 w/w% of AMPS) is comparable to other wearable hydrogel applications^{81 83}. Overall, hydrogels with AMPS ratios of 32.3 w/w% or higher exhibited relatively lower dehydration and higher rehydration rates.

Further investigation of the long-term stability of the hydrogel in acoustic attenuation was performed under low and high humidity conditions at room and body temperatures. Low humidity of 25-30% mimicked a typical indoor room environment and 75-85% reflects high humidity outdoor conditions, which was emulated by a sealed humidity controlled container storage where the hydrogel was stored in a controlled temperature incubator^84,85. Here, the representative hydrogel had an attenuation of up to -9% and less than -5% when stored in humidity conditions of -25% and -85% respectively over 35 days (FIGs. 4D-4E). Additionally, weight change test was also performed for both the representative hydrogel and a commercial gel stored in these two humidity conditions (FIGs. 12, 13A-13B). Under low humidity (~ 25%), the representative hydrogel exhibited a slow dehydration rate, retaining 79.6% of its weight and remained stable post 7 days. Conversely, the weight of the commercial gel decreased significantly with only 0.2% weight retention on day 7 (FIG. 4F), indicating that it was completely dried. Under high humidity (RH 75%), the representative hydrogel had a significant and consistent increase in weight of approximately 121% after 35 days (FIG. 4G). The only time the weight of the hydrogel in the high humidity condition increased to 133% in week 2 was because the humidity in the incubator increased from 85% to 95% at that time. It then stabilized again as the humidity was maintained at 85% later.

To ensure long-term robustness in wearability, sufficient adhesion between SFAT- ACFAL and the skin is necessary. Additionally, strong adhesion between the hydrogel and the PDMS-based ACFAL is required aside from the interface between hydrogel and the skin to prevent detachment. The robust integration between ACFAL and hydrogel was achieved by using the photografting agent for the hydrogel. Treating PDMS with benzophenone (BZP), a type II photoinitiator, extracts hydrogen from the grafted surface of PDMS and generates radicals allowing the PDMS and hydrogel to form a polymeric bond under UV irradiation⁸⁶ (FIG. 4H). As a result, the adhesion of BZP-treated PDMS to the hydrogel was 2.09 N/cm, which was 13 times higher than the adhesion of non-treated PDMS to the hydrogel (0.1513 N/cm) (FIG. 41). Optimization of the representative hydrogel’s adhesiveness to the skin was achieved by tuning the loading of glycerol and was determined via measurement of adhesion force through 90° T-Peel test. As the glycerol loading increases, the adhesion force of the hydrogel improves and plateaus when glycerol loading exceeds 10 wt% (FIG. 4J). In this example, glycerol was loaded at 20 wt% to maintain high water retention properties, allowing an adhesion force of -0.941 N/cm, comparable with other wearable hydrogel applications and sufficient for attachment to the skin^{87 89}. Skin adhesion cycling was performed subsequently to determine the adhesive reusability, where adhesion force remained stable over 20 cycles with a mean adhesion force of 0.961 N/cm (FIG. 4K). Modulus compliance of hydrogel with skin was investigated, where the modulus of the hydrogel is -31.4 kPa, similar to that of skin tissues. As a result, the minimal mechanical mismatch demonstrates suitability of skin-device interface for long-term use (FIGs. 14A-14B)⁹⁰ . These results further indicate that the bioadhesive hydrogel could provide an alternative to long-term ultrasound applications.

Representative SFAT-ACFAL Enables Suppresention of Somatosensory Evoked Potentials at SI Targeting

Studies in SEP by median nerve (MN) stimulation have been explored and researched greatly. Well-defined characteristic morphology of EEG signals of SEP are distinguished into waveform peaks assigned by their polarity (positive P or negative N) and its corresponding post-stimulus latency (in ms)⁹¹. The changes in latency and amplitudes of these waveform peaks are often interpreted as dynamical alterations in neural activity as a result of combination from peripheral and central nervous system to external stimulus. Specifically, early SEP peaks or “short latency” SEPs occurring within 40 ms post-stimuli are of great importance as they have the least variability in response to peripheral external stimulation whereas long latency responses are susceptible to cognitive factors and higher ordered complex neural processing of the sensory pathways⁹¹. Thus, waveform peaks of N20, P27, N33, P50, N70, P100 and N140 were examined. In brief, each of these peaks serve as a biomarker with implications of tactile information processing. However, of most great interest corresponds to N20 (or commonly known as P27-N20 complex) has been highly known for its relevance to the sensory input of dorsal column-medial lemniscal pathway and acts as a primary evoked response in response to peripheral stimuli to the lateral portion hand area of somatosensory cortex extended posteriorly over to supramarginal gyrus⁹².

Recently, transcranial focused ultrasound stimulation at the somatosensory cortex has been shown to suppress somatosensory evoked potential (SEP) via the elicitation of sensory stimuli. The suppression in SEP effectively resulted in higher subjects’ ability to discriminate fine differences in two points through sensory perception at the epidermis of distal phalanges⁵⁶. To demonstrate the efficacy of the representative SFAT-ACFAL, we applied the representative device in targeting the left SI through transmission of tFUS into the cortex at the CP3 site (FIG. 5A). Electroencephalographic (EEG) electrodes using commercial Ag/AgCl was applied at the scalp of electrode sites CPI, C3, P3, and CP5 in the 10-20 EEG configuration as a means to study the influence of tFUS short-to-late onset evoked brain activity through understanding of changes in peak-to-peak amplitudes of SEP complexes and spectral changes in power elicited by the contralateral (right) MN stimulation with functional electrical stimulation (FES) (FIG. 5B). To determine the efficacy in SEP suppression of the representative miniaturized transducer, we first applied commercially available ultrasound gel coupled between the SFAT- ACFAL with the scalp at the 10-20 EEG electrode site CP3. 650 kHz tFUS beams were pulsated to the target region (n = 5) with a pulse of 360 ps ON and 640 ps OFF at a pulse repetition frequency (PRF) of 1 kHz for 500 ms. The stimulation paradigm chosen has been demonstrated experimentally in humans to suppress SEP⁵⁶ whilst ensuring minimal thermal heating effects with the representative device due to the short pulse time (FIG. 3G). MN stimulation occurred for 200 ps at 100 ms after the beginning of tFUS transmission. Sham and tFUS treatment conditions were performed identically apart from the device being turned off in the sham group. Some subjects reported auditory chirping noises initially at the beginning of each trial produced by the device during stimulation. However, the chirping noises quickly subsided within a few seconds reported by subjects. Additionally, subjects did not report any discomfort, heating, or abnormal sensations at the site of tFUS treatment between sham and tFUS treatments.

With the representative device for tFUS treatment, we demonstrated a significant decrease in short latency peaks (P27-N20 complex) across electrode sites at C3 (sham, 0.425 ± 0.175 pV s.e.m. ; tFUS 0.119 ± 0.082 pV s.e.m), P3 (sham, 1.752 ± 0.186 pV s.e.m. ; tFUS 1.324 ± 0.301 pV s.e.m), CPI (sham, 0.888 ± 0.355 pV s.e.m. ; tFUS 0.355 ± 0.191 pV s.e.m), and CP5 (sham, 0.280 ± 0.103 pV s.e.m. ; tFUS 0.128 ± 0.076 pV s.e.m) compared to the sham. tFUS using SFAT-ACFAE did not produce any significant changes in long- latency peaks (FIG. 5C-5D, Tables 1-4) but late potential (>140 ms) showed general attenuation across all electrodes in late-onset SEP complexes.

Spectral decomposition of EEG signals enables understanding of spatial-temporal changes in dynamics regarding excitation and inhibition of cortex in response to information processing^93,94. Therefore, spectral analysis was performed on the grand averaged epochs of SEP to evaluate the effects of tFUS using SFAT-ACFAE. By taking the difference between the spectral decomposition of FUS and sham, a significant short latency decrease in alpha (7- 12 Hz) and beta (13-30 Hz) band power of -6 dB was observed within 100 ms of MN stimuli. Additionally, a short period of low gamma band (30-50 Hz) power decrease was observed around 100 ms post MN stimuli (FIG. 15).

Long-term Wearability and Neuromodulation of Representative MiniUlTra The ability for the representative device to stimulate the SI region long-term was tested within the same experimental protocols that target the characteristic pattern of SEP with MN stimuli. Particularly, SEP suppression via tFUS tests were conducted in 3 sessions (Day 1, 7, and 28) throughout 28 days (FIG. 6A) to investigate the efficacy of neuromodulation using the representative MiniUlTra device (bioadhesive hydrogel incorporated) on healthy volunteers (n = 8). The length of the experimental protocol was chosen to investigate the extreme longitudinal conditions of the representative MiniUlTra device over a month period, where the representative bioadhesive hydrogel remains stable compared to commercial gel over 28 days (FIG. 6B). To ensure tFUS did not generate noise, artifacts, or off-targeted evoked potentials, comparison of baseline (FUS-FES-) and stimulation (FUS+FES-) indicated no difference suggesting the representative device and FUS did not induce artifacts or off-targeted effects (FIG. 16A-16B). When MiniUlTra was used on day 1, significant suppression of SEP was observed compared to the sham group across all electrode channels. Furthermore, there was no significant difference between the treatment group when the representative bioadhesive hydrogel was used compared to commercial gel, validating the acoustic characteristics of the bioadhesive hydrogel in ultrasound transmission has similar performance to commercially available ultrasound gel (FIG. 6D). Additional sessions were performed on day 7 and day 28, which also showed significant suppression against the sham condition across all channels except for CPI on day 7. We also observe a significant decrease in the P27-N20 complex over time (Table 5). Overall, the SEP amplitude across the epoch was observed with clear decreases in short (P27- N20 complex) and long latency (>70 ms) biomarkers (FIG. 6C). However, long latency biomarkers are more complex in its relation with median nerve stimuli due to its association with indirect somatosensory pathways involving cognitive and motor processes⁹⁵. Hence, the P27-N20 complex was focused due to its prominent and well established association to contralateral stimuli at the SI region^96,97. Results indicated significant reduction in amplitude at the corresponding P27-N20 complexes across all electrode channels over 28 days (FIG. 6D), demonstrating robustness in ultrasound neuromodulation over long time stimulation with the representative MiniUlTra.

Discussion

We have demonstrated a representative bioadhesive hydrogel coupled and miniaturized wearable ultrasound transducer that offers long-term brain neuromodulation capability without the need of handheld operators and fixtures. The device utilizes an alternative simplified microfabrication approach without the need of standard lithography techniques for SFAT-ACFAL patterning to achieve higher focality, acoustic intensity, and miniaturization. Additionally, development of the described hydrogel provides mechanical compliance, bioadhesion and stable acoustic coupling between the representative device and skin interface. The described representative hydrogel has shown acoustic and adhesive stability for more than a month compared to current state-of-the-art bioadhesive hydrogel’s stability of 72 hours. By integrating the two components, the described representative device MiniUlTra can be used to perform noninvasive focused ultrasound stimulation delivered into the cortical region over 28 days with robust performance and clinical applications. Biosafety of the device was demonstrated to achieve spatial pulsed averaged intensity and acoustic pressure within the safety limits suggested by FDA guidelines and literature. Thus, the described representative system provides a promising platform for non-invasive long-term wearable ultrasound applications.

Targeting via neuro-navigation and other modalities can be difficult due to the variances in anatomical dimensions and structures across subjects. Furthermore, the cranial thickness variation can be even more crucial when considering tFUS. In the present example, we delivered tFUS beams to the SI using 10-20 EEG montage for navigation as the approach for targeting. The projection of the measured acoustic field beam alongside the targeting method was consistent with the physiological response of tFUS in suppression of SEP specifically for the P27-N20 complex. The validity of tFUS targeting via SEP amplitude change has been demonstrated whereby off-targeting of the SI Brodmann areas 3B/1 of 1 cm posterior and anterior resulted in diminished effects of SEP suppression of tFUS elicited by MN stimulation⁵⁶. It should be noted that MiniUlTra’ s focal resolution of 10 mm in depth and ~8mm width covers a large section of the SI provided within 1 cm of off-targeting.

To evaluate whether if FUS was successful in suppressing SEP, it is essential to determine whether FUS alone (FUS+/FES-) would generate any evoked potentials. As demonstrated in other works where FUS elicited auditory and visual evoked potentials at the auditory and visual cortex respectively^57,98. As such, FUS alone was compared to baseline epochs (FUS+/FES- vs. FUS-/FES-) and demonstrated potential elicitation of FUS evoked- potentials in the C3 and P3 channel (FIGs. 16A-16B), which may align with results previously demonstrating FUS-evoked potential in somatosensory evoked potential⁹⁹.

All tFUS stimulation parameters used on the SI cortex located at CP3 through 10-20 montage localization were maintained in brief exposures (3 min per trial, 120 pulses per trial, 360ps ON 640ps OFF, 0.5ms pulse duration, 1Hz PRF), with total duty cycle of each trial at 36%. This led to negligible measured temperature increase (< 0.2°C) at the base of a macaque skull where the SI cortex is expected (FIGs. 8, 9A-9C). Additionally, the mechanical index (MI) measured in-vitro at the targeted brain area (f = 10 mm) through the macaque skull was less than 0.125, lower than the FDA guideline (< 1.9). The low MI suggests unlikely brain tissue cavitation for neuromodulation¹⁰⁰’¹⁰¹.

In this examples, the acoustic characterization of the representative SFAT-ACFAL used in MiniUlTra were performed with a fragment of the parietal section of a macaque skull. Whilst tFUS offers high spatial resolution compared to other non-invasive techniques, the presence of other factors involving standing waves, diffraction and resonance due to the enclosed structure of a realistic human skull was not taken into consideration⁵⁸. In particular, the inhomogeneity structure of the skull both geometrically and composition can result in off- targeting and unintended beam structures when targeting the SI region. Thus, why we performed axial and radial acoustic field characterization of the representative device with the macaque skull and resulted in a broader full-width half maximum and shifted focal depth (FIGs. 3C-3D). Ideally, conducting volumetric pressure mapping from the base of macaque skull like that of FIG. 3B would provide greater insight on the effects of acoustic transmission. However, due to the geometrical curvature of the skull and the need to prevent collision of the hydrophone with the skull, we opted to perform 1-D measurement for in-vitro characterization.

A potential confounding factor to the above experiments was the lack of randomization of tFUS and sham ultrasound conditions across subjects. Specifically, all subjects received the same combination of stimuli groups (FUS-FES-, FUS-FES+, FUS+FES-, FUS+FES+) without knowing the specific sequence or order as a form of singleblinded approach to help mitigate placebo and bias. However, the thermal heating and mechanical vibration of the transducer may potentially remove the single-blinded nature of FUS conditions by subjects (FIGs. 9A-9C). As such, post-ad hoc analysis of questionnaire given to subjects indicated self-report of 5 out of 8 subjects were unaware when they were receiving FUS- or FUS+ conditions (FIGs. 17A-17C).

Regarding the number of electrode channels for recording SEP, source localization using high-density EEG recordings and analysis offers high spatial-temporal resolution, enabling observation of detailed effects of SEP based on tFUS targeting^{102 105}. However, many prior studies assessing tFUS effects on visual evoked potentials (VEP)^98,99 and sensory evoked potentials (SEP)^{56 106} employed 2-4 EEG electrodes positioned in corresponding cortical regions using the 10-20 electrode montage. In these studies, electrode placement and tFUS targeting were determined by the international 10-20 EEG system, and placement accuracy was validated through VEP and SEP spikes observed in EEG recordings. For example, the comparison between sham (FUS-FES+) and stimulation (FUS+FES+) conditions confirms successful SEP elicitation via contralateral median nerve stimulation (FIGs. 16A-16B). Additionally, comparing baseline (FUS-FES-) to tFUS (FUS+FES-) reveals no unintended effects or evoked potentials due to ultrasound stimulation. Together, these results confirm effective EEG electrode placement around the pre- and post-central gyrus of SI, with strong SEP signals, and successful targeting and suppression of SEP using MiniUlTra.

In conclusion, wearable ultrasound stimulation devices hold significant promise for the long-term treatment of chronic diseases like Parkinson's disease, essential tremor, epilepsy and depression (FIGS. 18A-18D). These devices offer non-invasive, spatiotemporal targeted modulation of neural activity, potentially improving disease symptoms without the drawbacks of medications or surgery. Their non-invasive nature and wearability also suggest the potential for home-based therapy, although continued research is essential to optimize treatment protocols and ensure long-term safety and efficacy across diverse patient populations.

Methods

Fabrication of Representative SFAT-ACFAL

Geometric shape and radius of the ACFAL was determined first by selection of 10 mm focal depth according to the equations governed by Fresnel lens¹¹⁶, which was then implemented into finite element analysis software for simulation (COMSOL Multiphysics 6.0, COMSOL Inc.) to determine acoustic field distribution (FIGs. 19A-19B, Table 6-7). Optimization of PDMS and air-cavity thickness was performed with reference to previous feasibility of microfabrication (FIGs. 19A-19B)

Mold glass substrates were initially patterned by first laminating 36 um thick copper tape (1125, 3M) onto adhesive interlayer (Ultra 582U, TransferRite), which was then laminated onto an adhesive backing layer (GXF341, DigiClear Plus). The laminated copper tape was then negatively patterned using laser etching (LPKF, U4 Laser) and transferred printed onto the glass substrate (FIG. 20, panel i). Patterned mold glass substrates were cleaned and prepared by first submerging into a beaker filled with acetone and sonicated to remove particulates for 5 min. Substrates were then removed, rinsed with distilled water and submerged in methanol for 5 min of sonication. The substrates were then rinsed with distilled water before blow dried with purified nitrogen gas. Substrate was spin-coated with a sacrificial layer (Omnicoat, Kayaku Advanced Materials) for 30s at 1000 RPM and 3 min of planarization before soft-baking at 200°C on a hotplate. The parameters were determined empirically through patterning and measurement of thickness using profilometer (FIGs. 21A-21C) Subsequently, substrates were then spin- coated with 5 ml of PDMS (Sylgard 184); prepared by mixing 1 : 10 of curing agent with base elastomer and desiccated for 1 hour at 500 RPM to achieve ~200pm thickness and cured on a hotplate at 90°C for 35 mins. Substrates were then placed in acetone filled beakers and sonicated for 5 min each to release the patterned PDMS mold (FIG. 20, panel ii). Using tweezers, the patterned PDMS layer was carefully removed and placed onto a temporary glass substrate, which was then trimmed with medical scalpel. Similarly, the PZT (DL-47, Del Piezo) was subjected to the same substrate cleaning process mentioned previously. 2 ml of prepared PDMS was spin-coated onto the surface of PZT at 2000 RPM for 30s to achieve a thickness of 40pm; cured at 90°C for 30 min (FIG. 20, panel iii).

Next, the released patterned PDMS layer and coated-PDMS PZT was treated with Reactive Ion Etching (RIE) O2 plasma treatment for 25 s (30W @ 30% O2, 30 SCCM) to remove organic hydrocarbons on the surface and create silanol (SiOH) functional groups, effectively increasing the wettability and rendering surface more hydrophilic¹¹⁷. The patterned PDMS layer was then reversely bonded onto the coated-PDMS PZT by attachment and applying 1 kg weight simultaneously on a 120°C hotplate for 5 min (FIG. 20, panel iv).

Acoustic Field Mapping of Representative SFAT-ACFAL

Mapping. The SFAT-ACFAL device was mounted on a submersible stand in a degassed distilled glass water tank. Acoustic intensity and waveform were measured using a calibrated capsule hydrophone (HGL-0200, Onda) mounted on a three-axis stage system, which was connected to an oscilloscope (SDS 1204-XE, Siglent) via a signal preamplifier (AG-2010, Onda) interfaced to a custom MATLAB program for automated 3D scanning and signal processing (FIG. 22). The device was controlled and actuated by a commercially available ultrasound system (BBBoq, Image Guided Therapy Systems). Acoustic field scans without macaque skulls were first performed at 500 pm increments (0 - 40 mm from transducer in a 40 mm x 40 mm grid workspace). Focal depth and spatial peak locations were obtained from the acquired acoustic field scans axially and radially. Subsequently, the macaque skull (3-mm thick macaque cortical bone, rehydrated for 24h in phosphate buffer solution) was inserted in between the transducer and hydrophone using the same scan procedures. Due to the curvature and inhomogeneous geometry, acoustic field scans were performed at 500pm increments (-10 - 40 mm from the transducer in a 40 mm x 40 mm grid workspace) to avoid collision between transducer, skull, and hydrophone. tFUS Waveform. Generation of tFUS profile from SFAT-ACFAL was performed using a 40- W high-voltage biphasic ultrasound function generator system (BBBoq, Image Guided Therapy System) controlled and pulsed by an external Arduino trigger. Briefly, the function generator was set to deliver individual pulses at 360 ps ON and 640 ps OFF with center frequency of 650 kHz (FIG. 3E). The Arduino was then programmed to trigger the function generator at a pulse repetition frequency (PRF) of 1 kHz and pulse duration of 500 ms ON and 500 ms OFF.

Electrical Characteristics. SFAT-ACFAL was connected to an impedance spectrum analyzer (SP300, BioLogic) using a two-electrode connection configuration. Impedance of the device was measured from 0-lMHz to validate resonant frequencies. Fundamental harmonics and phases were identified in addition to the desired 650kHz (FIG. 3H).

Thermal Heating. SFAT-ACFAL was placed facing upwards on a 3D-printed mounted stand, where the superficial side of the macaque skull was placed in contact with the transducer using ultrasound coupling gel (Aquasonic 100, Parker). Three stimulation paradigms with varying duty cycle and pulse duration were used (360ps ON/640ps OFF, 500ps ON/500ps OFF, 50ms ON/50ms OFF) for 10 mins to compare and observe the thermal heating effects from tFUS (FIG. 3F). An infrared camera (One Edge, FLIR) was used to record three points in a triangular configuration surrounding the targeting area on the inferior side of the macaque skull (FIGs. 8, 9A-9C).

Synthesis and Integration of Representative Bioadhesive Hydrogel to SFAT

Materials and. fabrication of bioadhesive hydrogel: The preparation of the bioadhesive hydrogel started with mixing the hydrogel solution. First, AMPS (Sigma-Aldrich) was dissolved in deionized (DI) water at a 1:1 ratio using a vortex mixer for 30s. Subsequently, glycerol (Alfa Aesar) with 20 wt% was added to the AMPS/DI water mixture using a vortex mixer for 30s. N, N’-Methylenebis(acrylamide) (MBAA crosslinker, Sigma- Aldrich) with~0.16 wt% was then added and mixed for 60s. Irgacure 2959 (2-Hydroxy-4’-(2- hydroxyethoxy)-2-methylpropiophenone 98%, Sigma-Aldrich) with -0.59 wt%, serving as the photoinitiator, was mixed for 30s. The solution was stirred additionally for 30 minutes. To improve adhesion force between PDMS and hydrogel, the PDMS-based ACFAL integrated with SFAT was treated with benzophenone (BZP) by first mixing 10% w/w BZP with acetone for 60s via vortexing followed by 60s of sonication to ensure complete incorporation of BZP in solvent. Subsequently, the solution was pipetted onto the surface of PDMS and exposed to air for solution to evaporate for 10 min. Upon complete evaporation, the PDMS surface was washed gently with DI water three times to remove excess BZP crystalline solids formed and dried with O2 air gun before depositing the bioadhesive hydrogel for curing. Lastly, bioadhesive hydrogel was integrated with SFAT- ACFAL by cross-linking the hydrogel solution under UV light for 15 minutes (-4.21 J).

Characterization of Representative Bioadhesive Hydrogel

Adhesion strength of bioadhesive hydrogel with skin and PDMS: The adhesion strength of the bioadhesive hydrogel was evaluated modified ASTM F2255-05 and ASTM F2256-05 methods through custom-developed and integrated testing machine (FB5, Torbal) with 90°- peeling off test. The samples were prepared with dimensions of 20 x 50 x 2 mm (width x length x thickness), and the backside of each sample was affixed with Kapton film (7413D, 3M) to prevent stretching during peeling. To measure the adhesion between the skin and bioadhesive hydrogel, the samples were gently attached onto a skin, and then peeled off at a 90° angle from the skin at a speed of 68 mm/min. To measure the adhesion between PDMS and bioadhesive hydrogel, PDMS was initially deposited and cured on a glass substrate mold (width: 50 mm, length: 76 mm). Then, a BZP treatment process was conducted. Using a similar 90°-peeling off test, the substrate was mounted and performed to compare adhesion force with and without BZP-treatment between the hydrogel and PDMS (FIG. 41).

Weight Loss. To measure the dehydration characteristics of the hydrogel, a weight loss test was conducted. A circular- shaped bioadhesive hydrogel and a commercial gel (Aquasonic 100, Parker) sample were prepared (diameter: 19mm, thickness: 1mm). The weight of each was measured over time both in a typical room environment (-41%, ~23°C) and inside a container with high humidity (-65%, ~23°C) (FIGs. 11A-11B, 12, 13A-13B). The weight loss of the samples (Wi) was calculated using the equation Wi (%) = (Wt - Wi)/ Wi x 100, where Wi and Wt denote, respectively, the initial weight of the sample and the weight of the sample at different times. Acoustic attenuation of hydrogel. To prevent the bioadhesive hydrogel and commercial gel from swelling and dissipating in the water during ultrasound measurement, a thin Ecoflex cap was fabricated with a mold to wrap around hydrogel/gel (FIGs. 23A-23B). The internal thickness of the Ecoflex cap was adjustable to control the thickness of bioadhesive hydrogel or commercial gel (0.5 - 2.5 mm thick). The Ecoflex cap was then filled with the hydrogel or commercial gel and attached to a pristine PZT (DL-47, Del Piezo) and mounted on a submersible stand in a degassed distilled water tank. Acoustic intensity and waveforms were measured using a calibrated capsule hydrophone (HGL-0200, Onda) mounted a three-axis stage system at a fixed distance of 10 mm from the PZT uniaxially in the water tank.

Acoustic Impedance and Speed of hydrogel. Acoustic properties of the bioadhesive hydrogel were characterized by measuring and estimating the acoustic time-of-flight difference of ultrasound transmission through water, PET, and hydrogel between transducer and hydrophone. A single cycle sine wave pulse was generated using a 3-level beamformer transmitter circuit (TX7316, Texas Instrument) with a supplied driving voltage of ± 20V. To measure the acoustic time-of-flight of the hydrogel, a 3-mm thick hydrogel was prepared with a mold consisting of PET film and Ecoflex frame (FIGs. 24, 25) and measurements were performed over a period of 7 days. The purpose of the Ecoflex frame was to maintain the thickness of the hydrogel and to prevent the penetration of the water into the hydrogel when measuring in the water tank. Between measurements, the Ecoflex frame was removed temporarily, and the hydrogel samples were stored in a room environment (humidity: -30%, temperature: ~23°C). Then, when measurements were taken again, the Ecoflex frame was placed around the hydrogel again to prevent water from entering the hydrogel. The acoustic time-of-flight was measured by placing the hydrogel samples between transducer and hydrophone in a water tank. The acoustic speed of the hydrogel was estimated by following equations :

Where Tuydrogei is the thickness of the bioadhesive hydrogel, TPET is the thickness of the PET film, cwater is the speed of sound in water (1500 m/s), CPET is the speed of sound in PET film (polyethylene, high density: 2430 m/s, ¹¹⁸), ATPET is ToF difference between with and without PET film, ATpET+Hydrogei is ToF difference between with and without hydrogel samples. Where Znydrogei is the acoustic impedance of the bioadhesive hydrogel, pi i_ydn>gei is the density of the hydrogel, CHydrogei is the speed of sound of the hydrogel.

Long-term acoustic stability: To assess the long-term acoustic stability of the bioadhesive hydrogel, the ultrasound intensity of the bioadhesive hydrogel integrated SFAT was measured over time. The number of circular- shaped hydrogels were prepared and stored in a container with high humidity (-65%, ~23°C). At specific time intervals, each bioadhesive hydrogels were taken out of the container and attached to a bare PZT transducer. All measurements were conducted under the deionized water. To prevent rapid swelling of the AMPS-based bioadhesive hydrogel upon contact with water, bioadhesive on the bare PZT transducer was covered with a thin Ecoflex cap (thickness: 0.5 mm). Then, the attenuation of ultrasound intensity due to the bioadhesive hydrogel over time was measured using a custom setup 3- axis hydrophone acoustic scanning system.

Device Integration of Representative MiniUlTra

Fabricated SFAT-ACFAL was connected via low temperature solder (NP510-LT HRL1, Kester) to a BNC cable and housed in a custom-designed 3D printed casing (PLA Galaxy, Prusa), which was lined with copper shielding (1181, 3M) and grounded to the BNC shielding layer for electromagnetic shielding purposes. To integrate SFAT-ACFAL with the bioadhesive hydrogel, the hydrogel solution was then poured to a thickness of 1 mm. Subsequently, the bioadhesive hydrogel on the SFAT-ACFAL was cross-linked under UV light for 15 minutes. Finally, the integrated device was completed by removing the mold (FIG. 20, panel v).

Long-term Stability of Representative MiniUlTra

Fabricated MiniUlTra was covered with Ecoflex cap (FIG. 23) and cured to seal and protect the bioadhesive hydrogel grafted on the transducer from swelling. The device was then submerged into a degassed distilled water tank (FIG. 23) and free-field (without macaque skull) measurement were performed across 28 days (Day 1, 3, 5, 7, 14, and 28) to demonstrate beam-focusing and focal depth stability of MiniUlTra (FIGs. 26A-26C).

Characterization of tFUS on Sensory-evoked Potentials in SI using Representative SFAT-ACFAL

Participants . Five healthy volunteers (4 male, 1 female, aged 24-36 with a mean age of 27.4 ± 5.1 years) provided written informed consent to participate in the study. Volunteers were screened for contraindications and neurological impairment and all subjects were right-hand dominant.

Experimental setup. Participants were positioned and seated in an adjustable height chair, where their right forearm is fully extended and supported in supination. Four 10-20 EEG electrode sites (C3, CPI, P3, CP5) were connected for recording somatosensory evoked potentials. During testing, subjects were initially stimulated by FES with varying currents (8- 25mA, 200ps) to obtain the minimum threshold necessary to elicit muscle contraction of the right contralateral side. The SFAT-ACFAL was applied topically to CP3 manually with administration of ultrasound gel (Aquasonic 100, Parker) as interface to the scalp, which was then held in place using medical tape. Additionally, three electrical stimulation electrodes (2” Round, Reserv) were placed on the right contralateral arm (ground electrode on elbow, bipolar electrodes axially paired on the wrist via palpation of median nerve). The electrodes were connected to a functional electrical stimulation (FES) system (RehaMove3, Hasomed) for median nerve stimulation (MN), which was controlled externally by custom Python software. tFUS treatment condition stimulation occurring 100ms before MN stimuli (360ps ON and 640ps OFF, PRF 1kHz, Pulse Duration 500ms ON 500ms OFF) was controlled by programming of microcontroller (Uno, Arduino), which was connected to trigger the ultrasound generator (BBBoq, Image Guided Therapy System), FES system (MN stimuli), and EEG amplifier for time-locked epoch events during somatosensory evoked potentials (SEP) (FIG. 27). Custom Python code was developed to integrate all systems together in addition to use of LabStreamingLayer (LSL) to stream and log EEG data into dataframe with external data including trigger and metadata. Subjects were then subjected to three blocks of trials, where each block consisted of four trials (FUS-/FES-, FUS-/FES+, FUS+/FES-, FUS+/FES+) and each trial lasted 3 mins. Within each trial, 30s of baseline recording occurs before 120s of sham/FUS followed by 30s of rest recording to ensure sufficient buffered data for post-recording cleaning. Total recording session time was approximately 1 h.

EEG placement and artifact mitigation. Subjects recruited were invited to a dedicated EEG recording room with minimal electronics for minimizing electromagnetic interferences. Tape ruler was used to measure the distance between nasion-to-inion and left-right preauricular points to determine electrode positioning according to the 10-20 system for EEG recording. Marker was used to indicate the position of C3, CPI, P3, CP5 for EEG and CP3 for tFUS targeting (FIG. 5B). Subsequently, rubbing alcohol was applied carefully at the sites before conductive hydrogel electrodes (H124SG, Kendall) were applied carefully to the scalp to ensure minimal obstruction of hair. Impedance per electrode was measured using commercial amplifier (eego MyLab, AntNeuro) to ensure it is less than lOkQ. EEG data were digitized at 512 Hz and stored for offline analysis. To ensure artifacts from electromagnetic interference generated by piezoelectric in MiniUlTra, common grounding connecting the microcontroller, EEG amplifier, and ultrasound generator was performed. Furthermore, the copper shielding on MiniUlTra was also connected to the same ground to ensure complete grounding of the device and mitigating leakage current path through the body (FIGs. 28A-28D).

Statistical analysis of somatosensory evoked, potentials. Digitized EEG data were analyzed offline by first filtering using a third-order butterworth bandpass filter (2-90Hz) followed by a first-order butterworth bandstop filter (59-61Hz) to remove DC offsets, mains interference, and high frequency noises^{1 19 l 22}. A total of 120 epochs per trial recorded was then extracted using custom MATLAB code using triggered signals as markers. Briefly, data were epoched around median nerve stimulus trigger, 200 ms prior up to 500 ms after the trigger was extracted as a single epoch for analysis. Subsequently, the data was baseline corrected by subtracting the mean values from = -200 ms to 0 ms. For each epoch, inspection of artifacts using rejection criteria of absolute peak-to-peak amplitude threshold greater than 75pV will be removed. Grand averaged epochs across 5 subjects and 15 trials were obtained to determine the effects of sham and FUS in SEP using SFAT-ACFAL elicited by MN stimuli. EEG biomarkers N20, P27, N33, P50, N70, P100, and N140 were extracted by obtaining the mean amplitude ± 2 ms the desired biomarker time event due to the difficulty to reliably identify SEP peaks accurately per trial. Statistical analyses were performed on mean peak-to- peak amplitudes for the N20/P27, N33/P27, P50/N33, N70/P50, P100/N70, N140/P100 and long potential (LP) components (Tables 1-4). These data were averaged across all trials and subjects and presented as mean ± s.e.m for different group conditions. Non-parametric statistical test using Wilcoxon signed-rank test was applied for SEP complexes to determine significance of treatment conditions.

Time-frequency analysis of short-latency somatosensory evoked potentials. Time frequency analysis was performed (MATLAB R2021a, The Math Works) to decompose effects and changes in frequency spectrum due to SI targeting using tFUS with SFAT-ACFAL as a function of time¹²³. Short-time Fourier transform (STFT) was used with a window size of 4.8 ms and 2.3 ms overlap through Hamming window approach. Power of spectral data was then converted into power (dB). Comparison between treatment groups was performed by comparing spectral epochs to observe dynamic changes in power with respect to frequency bands (FIG. 15).

Long-term Demonstration of tFUS Neuromodulation of Representative MiniUlTra

Participants . Eight healthy volunteers (8 male, aged 26-37 with a mean age of 32.2 ± 3.6 years) provided written informed consent to participate in the study. Volunteers were screened for contraindications and neurological impairment and all subjects were right-hand dominant.

Experimental setup. Subjects were invited to SI targeted tFUS stimulation using MiniUlTra (SFAT-ACFAL integrated with bioadhesive hydrogel) for long-term study (Day 1, 7, and 28). For each session, subjects were pre-screened for contraindications before beginning the experiment. Four 10-20 EEG electrode sites (C3, CPI, P3, CP5) were connected for recording somatosensory evoked potentials (FIG. 5B). Minimum threshold for right contralateral hand movement due to MN stimulation was performed to obtain the minimum threshold necessary to elicit muscle contraction of the right contralateral side. The MiniUlTra was applied to CP3 and held in place independently by its adhesive nature (FIGs. 29A-29B). For EEG recording stability, additional medical tape was used to fix EEG electrodes and transducers to prevent motion artifacts. Three electrical stimulation electrodes (2” Round, Reserv) were placed on the right contralateral arm similarly to the previous experiment for SI targeting mentioned before. The electrodes were connected to a functional electrical stimulation (FES) system (RehaMove3, Hasomed) for MN stimulation. tFUS treatment and sham conditions performed identically where subjects were subjected to five blocks of trial, where each block consisted of four trials (FUS-/FES+; Sham, FUS+/FES+; Treatment, FUS-FES-; Negative Control, FUS+FES-; Positive Control) and each trial lasted 3 mins. Total recording session time was approximately 1 h.

Long-term effects and post ad-hoc analysis. Questionnaires were provided to subjects to examine the comfortability, pain, sensitivity, and sensation of FUS neuromodulation using MiniUlTra (FIG. 17A). Furthermore, subjects were asked per session to identify which trials they believe were the FUS+ trials to determine if sensations reported were due to placebo (FIGs. 17C-17D).

Statistical analysis of somatosensory evoked potentials. A total of 120 epochs per trial recorded was then extracted using custom MATLAB code using triggered signals as markers. Grand averaged epochs across 8 subjects and 20 trials were obtained to determine the effects of sham and FUS in SEP using MiniUlTra elicited by MN stimuli. EEG biomarkers N20 and P27 were extracted by obtaining the mean amplitude ± 2 ms the desired biomarker time event due to the difficulty to reliably identify SEP peaks accurately per trial. Statistical analyses were performed on mean peak-to-peak amplitudes for the N20/P27 (Table 5). These data were averaged across all trials and subjects and presented as mean ± s.e.m for different group conditions. Sidak multiple comparison One-way ANOVA was applied for SEP complexes to determine effects of sham (FUS-FES+) and stimulation (FUS+FES+) groups across multiple sessions compared to the use of commercial gel over long-term¹²⁴. Additional comparison using Two-way ANOVA was applied to evaluate treatment conditions across days with treatment (hydrogel) and with control (commercial gel) in comparison to sham (no FUS) conditions within groups (FIGs. 30A-30B).

Table. 1. SEP Complexes in C3 channel. Mean amplitudes of SEP complexes recorded from C3.

Table. 2. SEP Complexes in P3 channel. Mean amplitudes of SEP complexes recorded from P3.

recorded from CPI. Table. 4. SEP Complexes in CP5 channel. Mean amplitudes of SEP complexes recorded from CP5.

Table. 5. Long-term suppression of P27-N20 SEP Complex using MiniUlTra

Table. 6. ACFAL parameters. Boundary radii dimensions for air-cavity Fresnel lens Table. 7. Acoustic simulation parameters. Electrical and mechanical properties of SFAT-ACFAL simulation. Device Design of SFAT-ACFAL. Air-cavity dimensions were determined using the annular rings formed into Fresnel half-wavelength bands (FHWB) to create a phase difference no greater than 180°/ The radii of the lens were determined such that the path-length from the desired focal depth (F_z) of 10 mm to any radii is no greater than integer half wavelength multiples of F_z. This is defined by the equation below:

Given the diameter of the representative PZT to be 18 mm, the number of boundary rings bounded would be n = 3, resulting in a single channel air-cavity. The boundary radii metrics are provided in Table 6.

Acoustic simulation parameters. Using the dimensions provided in Table 6, geometrical shape of SFAT-ACFAL was designed in COMSOL 6.0 Multiphysics. Firstly, a circular piston disk of 18mm in diameter of 3.1mm (aligned with measured PZT) was patterned with Fresnel lens, where air cavities were implemented. Acoustic and mechanical properties of material of PDMS and PZT was imported according to Table 7. Using electrical properties of a driving voltage of ±40V at center frequency of 650kHz, a frequency domain simulation was performed across the mesh of 40x40mm of varying medium including water and brain.

PDMS Spin-coat Calibration. Control of layer thickness when fabricating ACFAL for the SFAT was done by developing a calibration curve. Utilizing the same fabrication process, glass substrates were initially patterned with 36 um thick copper tape using laser etching (LPKF, U4 Laser) via transfer printing method (FIGs. 9A-9C). Glass substrates were cleaned and prepared by first submerging into a lOOOmL beaker filled with acetone and sonicated in an ultrasonic sonicator to remove particulates for 5 min. Substrates were then removed, rinsed with distilled water and submerged in methanol for 5 min of sonication. The substrates were then rinsed with distilled water before blow dried with purified nitrogen gas. Substrate was spin-coated with a sacrificial layer (Omnicoat, Kayaku Advanced Materials) for 30s at 1000 RPM and 3 min of planarization before soft-baking at 200°C on a hotplate. Subsequently substrates were then spin-coated with 5 mL of PDMS (Sylgard 184); prepared by mixing 1 : 10 of curing agent with base elastomer and desiccated for 1 hour; at varying speeds (500-4000 RPM at 500 RPM increments) and cured on a hotplate at 90°C for 40 mins. Substrates were then placed in acetone filled beakers, for which it was sonicated for 5 min each to release the patterned PDMS mold. The PDMS mold was then reversely placed on a separate glass substrate for measurement. Each patterned mold substrate was then imaged (Axioscope 2 MAT, Zeiss) and measured using a profilometer (Dektak 150, Veeco) and layer thicknesses were determined accordingly (FIGs. 11A-11B).

Ultrasound peak pressure calibration. Measurement of peak pressure of the fabricated SFAT-ACFAL was performed by submerging the device into a degassed distilled water tank with hydrophone (Onda, Corporation, HGE-0200) connected to a preamplifier (Onda Corporation, AG-2010) with an amplification gain of 20dB. The hydrophone was aligned perpendicular to the face of the transducer. The water tank walls were lined with acoustic absorbing material (Precision Acoustic, Aptflex F28) to prevent acoustic reflections by absorption to reduce artifact and noise during measurement. Transducer was tested experimentally following sonication protocol used in the stimulation paradigm (340us ON and 640us OFF) at 650kHz with varying amplitudes of 0-100% (FIG. 3E). Measured voltage signals from hydrophone were connected and recorded by an oscilloscope (Siglent Technologies, SDS1202X-E), which was converted to pressure by calibration equation provided by the hydrophone manufacturer below.

Vmeasured'- Voltage measured in oscilloscope via hydrophone and preamplifier

G(f) Gain of preamplifier (Onda Corporation AG-2010, G = 10 at 650kHz)

M_c(f) End of cable nominal sensitivity of hydrophone (Onda Corporation HGE-0200, M_c = 45nV/Pa at 650kHz)

CH'- Input capacitance of hydrophone (Onda Corporation HGE-0200, CH = 13pF at 650kHz)

Cc'. Capacitance of right-angle connector between hydrophone and pre-amplifier (Cc = 1.6 pF)

CA'. Input capacitance of pre-amplifier (Onda Corporation AGL-2010, CA = 6.3 pF at 650kHz)

Further Representative Wearable Device

FIG. 1A is a schematic diagram showing an example wearable device 100 configured to be worn in proximity to a subject’s head. The wearable device 100 can be used for at least one of neuromodulation, stimulation, or heating. The wearable device 100 can be or comprise an SFAT-ACFAL or ultrasound device configured to focus acoustic waves generated from an acoustic source at a focal point. In various implementations, the wearable device 100 can be embodied as a wearable patch, wearable film, fabric (e.g., hat, scarf), combinations thereof, and/or the like. A system or clinical device can include multiple wearable devices in accordance with the aspects described herein.

With reference to FIG. 1A, the wearable device 100 comprises a plurality of layers, including a PZT layer 105, an acoustic lens 118 (e.g., PDMS layer), and a hydrogel 120. In some aspects, at least some of the layers or components of the wearable device 100 are at least partially disposed within a housing. In the example shown in FIG. 1A, the PZT layer 105 defines a bottom portion of the device 100 and is positioned between two electrodes (as shown, nickel electrodes 110A, HOB) operatively coupled to the PZT layer 105. The wearable device 100 includes an acoustic lens 118 (e.g., PDMS layer) defining a middle portion of the device 100 (i.e., disposed between the PZT layer 105 and the hydrogel 120). As noted above, the wearable device 100 comprises a hydrogel 120 (e.g., bioadhesive hydrogel) that defines a top surface of the device 100. In some implementations, the hydrogel 120 is a coating on an outer surface of the acoustic lens 118. In some implementations, the acoustic lens 118 (e.g., PDMS layer) comprises one or more individual components. The acoustic lens 118 can include one or more air-cavity Fresnel acoustic lenses (ACFCLs 125A, 125B).

FIG. IB is a schematic diagram showing another view of a wearable device 100 designed for somatosensory cortical stimulation. As illustrated, the wearable device 100 comprises a housing 101 containing an acoustic lens 118 (e.g., PDMS layer) surrounded by a PZT layer 105. Said differently, the acoustic lens 118 defines a central portion of the wearable device 100. In the example shown in FIG. IB, the wearable device 100 is in wired connection/electronic communication with a controller and/or acoustic source (e.g., ultrasound generator) via one or more connectors 130, through which the wearable device 100 receives control signals for controlling operations of the wearable device 100. The one or more connectors 130 can include a piezoelectric material.

FIG. 1C is a schematic diagram showing another view of a wearable device 100. As depicted, the wearable device 100 comprises an SFAT-ACFCL and includes a plurality of polymer-based electrodes 111A, 11 IB, 111C, HID, each located at a respective comer of the polygonal wearable device 100. Additionally, the wearable device 100 includes an anisotropic conductive film connector 130A. FIG. ID illustrates an example method 200 for fabricating an example wearable device. At step (i), method 200 includes screen printing a substrate (EcoFlex substrate). At step (ii), the method 200 includes transfer printing EEG electrode interconnects. At step (iii), method 200 includes performing EEG interconnect encapsulation. At step (iv), method 200 includes injection and curing of PEDOT:PSS EEG electrode and bioadhesive hydrogel encapsulation. At step (v), method 200 includes performing PZT bonding (SEAT). At step (vi), method 200 includes SEAT encapsulation and screen printing of PEDOT:PSS electrode mold.

Representative System

FIG. IE is a schematic diagram showing an example system 150 in accordance with certain aspects described herein. In some implementations, the wearable device can include at least some of the components of the system 150.

As shown, the system 150 includes a recording and stimulation component 155, a control and signal processing component 160, a power source 165, and a computing device 170. The recording and stimulation component 155 includes a PoLITAG and a wearable device (SEAT). As further illustrated, the control and signal processing component 160 is operatively coupled to the recording and stimulation component 155 and includes an amplifier(s), a bandpass filter, an analog to digital converter (ADC), a field-programmable gate array (FPGA) for control, and an ultrasound wave generation circuit for providing acoustic signals to the wearable device. The power source 165 is operatively coupled to the control and signal processing component 160 and includes a lithium-ion battery and/or AC power supply, a voltage step-up, and a voltage regulator.

The computing device 170 can include a user interface to facilitate user interaction with computing device 170. The user interface may include a display screen and/or user input devices. For example, a user interface may include a light-emitting diode (LED) or liquid crystal display (LCD) screen for displaying data, images, graphics, and the like. In addition, in some implementations, the user interface includes a user input device such as a keyboard, a joystick, buttons, a mouse, etc. In some implementations, the user interface is a touchscreen. In some implementations, the user interface can display alerts to a user. Said alerts may be audio and/or visual alerts, such as noises, speech, videos, lights, graphics, and the like.

System 150 can include a communications interface that facilitates communications between the computing device 170, the wearable device (e.g., wearable device 100), and any external components or devices. Accordingly, a communications interface can be or can include a wired or wireless communications interface (e.g., jacks, antennas, transmitters, receivers, transceivers, wire terminals, etc.) for conducting data communications or a combination of wired and wireless communication interfaces. In some aspects, communications via communications interface are direct (e.g., local wired or wireless communications) or via a network (e.g., a WAN, the Internet, a cellular network, etc.). For example, a communications interface may include one or more Ethernet ports for communicably coupling computing devices 170 to a network (e.g., the Internet). In another example, a communications interface can include a Wi-Fi transceiver for communicating via a wireless communications network. In yet another example, communications interfaces may include cellular or mobile phone communications transceivers. In some implementations, the computing device 170 captures data from the wearable device and/or one or more additional sensors and provides at least some of the data for display or transfers at least some of the data to a remote device for processing and/or display. Therefore, it should be understood that the description of computing device 170 and the functions thereof are not limited to a single computing device.

Representative Computing Device

Referring to FIG. 33, an example computing device 400 upon which the methods described herein may be implemented is illustrated. It should be understood that the example computing device 400 is only one example of a suitable computing environment upon which the methods described herein may be implemented. Optionally, the computing device 400 can be a well-known computing system including, but not limited to, personal computers, servers, handheld or laptop devices, multiprocessor systems, microprocessor-based systems, network personal computers (PCs), minicomputers, mainframe computers, embedded systems, and/or distributed computing environments including a plurality of any of the above systems or devices. Distributed computing environments enable remote computing devices, which are connected to a communication network or other data transmission medium, to perform various tasks. In the distributed computing environment, the program modules, applications, and other data may be stored on local and/or remote computer storage media.

In its most basic configuration, computing device 400 typically includes at least one processing unit 406 and system memory 404. Depending on the exact configuration and type of computing device, system memory 404 may be volatile (such as random-access memory (RAM)), non-volatile (such as read-only memory (ROM), flash memory, etc.), or some combination of the two. This most basic configuration is illustrated in FIG. 12 by dashed line 402. The processing unit 406 may be a standard programmable processor that performs arithmetic and logic operations necessary for the operation of the computing device 400. The computing device 400 may also include a bus or other communication mechanism for communicating information among various components of the computing device 400.

Computing device 400 may have additional features/functionality. For example, computing device 400 may include additional storage such as removable storage 408 and nonremovable storage 410, including, but not limited to magnetic or optical disks or tapes. Computing device 400 may also contain network connection(s) 416 that allow the device to communicate with other devices. Computing device 400 may also have input device(s) 414, such as a keyboard, mouse, touch screen, etc. Output device(s) 412, such as a display, speakers, printer, etc., may also be included. The additional devices may be connected to the bus in order to facilitate the communication of data among the components of the computing device 400. All these devices are well-known in the art and need not be discussed at length here.

The processing unit 406 may be configured to execute program code encoded in tangible, computer-readable media. Tangible, computer-readable media refers to any media that is capable of providing data that causes the computing device 400 (i.e., a machine) to operate in a particular fashion. Various computer-readable media may be utilized to provide instructions to the processing unit 406 for execution. Examples of tangible, computer- readable media may include, but are not limited to, volatile media, non-volatile media, removable media, and non-removable media implemented in any method or technology for storage of information such as computer-readable instructions, data structures, program modules, or other data. System memory 404, removable storage 408, and non-removable storage 410 are all examples of tangible computer storage media. Examples of tangible, computer-readable recording media include but are not limited to, an integrated circuit (e.g., field-programmable gate array or application-specific IC), a hard disk, an optical disk, a magneto-optical disk, a floppy disk, a magnetic tape, a holographic storage medium, a solid- state device, RAM, ROM, electrically erasable program read-only memory (EEPROM), flash memory or other memory technology, CD-ROM, digital versatile disks (DVD) or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices. In an example implementation, the processing unit 406 may execute program code stored in the system memory 404. For example, the bus may carry data to the system memory 404, from which the processing unit 406 receives and executes instructions. The data received by the system memory 404 may optionally be stored on the removable storage 408 or the nonremovable storage 410 before or after execution by the processing unit 406.

It should be understood that the various techniques described herein may be implemented in connection with hardware or software or, where appropriate, with a combination thereof. Thus, the methods and apparatuses of the presently disclosed subject matter, or certain aspects or portions thereof, may take the form of program code (i.e., instructions) embodied in tangible media, such as floppy diskettes, CD-ROMs, hard drives, or any other machine-readable storage medium where, when the program code is loaded into and executed by a machine, such as a computing device, the machine becomes an apparatus for practicing the presently disclosed subject matter. In the case of program code execution on programmable computers, the computing device generally includes a processor, a storage medium readable by the processor (including volatile and non-volatile memory and/or storage elements), at least one input device, and at least one output device. One or more programs may implement or utilize the processes described in connection with the presently disclosed subject matter, e.g., through the use of an application programming interface (API), reusable controls, or the like. Such programs may be implemented in a high-level procedural or object- oriented programming language to communicate with a computer system. However, the program(s) can be implemented in assembly or machine language if desired. In any case, the language may be a compiled or interpreted language, and it may be combined with hardware implementations .

Representative Alternative Hydrogel

A further representative hydrogel was formed from the following components:

Hydrogel monomer:

(AMPSNa) 2-Acrylamido-2-methyl- 1 -propanesulfonic acid sodium salt solution (50 wt% in H₂O)

Already in solution form, water and hydrogel monomer have equivalent concentrations of:

H2O: 33.8 wt%

AMPSNa: 33.8 wt% Radical initiator:

Ammonium persulfate (0.5 wt%)

Catalyst:

A,A,A',A'-Tetramethylethylenediamine (with this can react faster, but it is optional)

Salt:

KC1 (0 M ~ 0.5 M concentration) in the hydrogel

Other:

Glycerol (I am using 25.4 wt%, but can be anywhere from 0 wt%~ 50 wt% or even higher)

Crosslinker:

A,A'-Methylenebis(acrylamide) (range from 0.005 wt% ~ 0.15 wt%)

Analysis of Alternative Hydrogel

This example studies the influence of varying potassium chloride (KC1) concentrations on the electrical properties of the proposed hydrogel. The EIS results are presented as Bode plots of impedance and phase angle over the frequency range of interest in FIG. 31 and FIG. 32.

Experimental Conditions

Additive. Potassium chloride or (KC1).

Conditions measured and compared: 0 wt% (control)) 0.29 wt%\ 0.58 wt%\ 0.88 wt% (wt% = total weight percentage)

Frequency range of interest: 1 Hz to 5 kHz.

Sample size (per condition): 4

Results

Impedance

Impedance was found to decrease with increasing KC1 concentration. The hydrogel without KC1 (0 wt%) exhibits the highest impedance, while the hydrogel with 0.88 wt% KC1 shows the lowest impedance. While not wishing to be bound by any particular theory, adding KC1 introduces mobile ions, increasing the ionic conductivity of the hydrogel. At low frequencies, ionic polarization dominates, resulting in a more significant reduction in impedance for hydrogels with higher KC1 concentrations. At high frequencies, the capacitive effects from the hydrogel matrix and double-layer formation at electrode interfaces become prominent, explaining the impedance convergence.

Phase Angle

The phase angle is more negative at low frequencies for the hydrogel without KC1. As the KC1 concentration increases, the phase angle is less negative. While not wishing to be bound by any particular theory, a more negative phase angle corresponds to a capacitive response, typical of systems with high resistive impedance and lower ion mobility. Adding KC1 reduces the capacitive nature of the hydrogel due to improved ionic conductivity and reduced resistive impedance. Increasing KC1 concentration reduces the capacitive behavior, as shown by a less negative phase angle at intermediate frequencies. At high frequencies, the system transitions to a resistive behavior as capacitive contributions from the double-layer capacitance at the electrode -hydrogel interface dominate as all samples tend to approach a phase angle closer to 0°.

References for Examples

1. Marras, C. et al. Prevalence of Parkinson’s disease across North America, npj Parkinson’s Disease 4, 1-7 (2018).

2. Matthews, K. A. et al. Racial and ethnic estimates of Alzheimer’s disease and related dementias in the United States (2015-2060) in adults aged >65 years. Alzheimer s. Dement. 15, 17-24 (2019).

3. Visser- Vandewalle, V. et al. Deep brain stimulation for obsessive-compulsive disorder: a crisis of access. Nat. Med. 28, 1529-1532 (2022).

4. Mar-Barrutia, L. et al. Deep brain stimulation for obsessive-compulsive disorder: A systematic review of worldwide experience after 20 years. World J Psychiatry 11, 659-680 (2021).

5. Volkmann, J. Deep brain stimulation for the treatment of Parkinson’s disease. J. Clin. Neurophysiol. 21, 6-17 (2004).

6. Benabid, A. L. Deep brain stimulation for Parkinson’s disease. Curr. Opin. Neurobiol. 13, 696-706 (2003).

7. Deuschi, G. et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N. Engl. J. Med. 355, 896-908 (2006). 8. Flora, E. D., Perera, C. L., Cameron, A. L. & Maddern, G. J. Deep brain stimulation for essential tremor: a systematic review. Mov. Disord. 25, 1550-1559 (2010).

9. Blomstedt, P., Hariz, G.-M., Hariz, M. I. & Koskinen, L.-O. D. Thalamic deep brain stimulation in the treatment of essential tremor: a long-term follow-up. Br J. Neurosurg. (2007) doi: 10.1080/02688690701552278.

10. Baizabal-Carvallo, J. F., Kagnoff, M. N., Jimenez- Shahed, J., Fekete, R. & Jankovic, J. The safety and efficacy of thalamic deep brain stimulation in essential tremor: 10 years and beyond. J. Neurol. Neurosurg. Psychiatry 85, 567-572 (2014).

11. Hubble, J. P. et al. Deep brain stimulation for essential tremor. Neurology 46, 1 ISO- 1153 (1996).

12. Koller, W. C., Lyons, K. E., Wilkinson, S. B., Troster, A. I. & Pahwa, R. Long-term safety and efficacy of unilateral deep brain stimulation of the thalamus in essential tremor. Mov. Disord. 16, 464-468 (2001).

13. Li, M. C. H. & Cook, M. J. Deep brain stimulation for drug -resistant epilepsy. Epilepsia 59, 273-290 (2018).

14. Loddenkemper, T. et al. Deep brain stimulation in epilepsy. J. Clin. Neurophysiol. 18, 514-532 (2001).

15. Boon, P. et al. Deep Brain Stimulation in Patients with Refractory Temporal Lobe Epilepsy. Epilepsia 48, 1551-1560 (2007).

16. Theodore, W. H. & Eisher, R. S. Brain stimulation for epilepsy. Eancet Neurol. 3, 111- 118 (2004).

17. Cury, R. G. et al. Thalamic deep brain stimulation for tremor in Parkinson disease, essential tremor, and dystonia. Neurology 89, 1416-1423 (2017).

18. Vercueil, L. et al. Deep brain stimulation in the treatment of severe dystonia. J. Neurol. 248, 695-700 (2001).

19. Vidailhet, M. et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N. Engl. J. Med. 352, 459-467 (2005).

20. Denys, D. et al. Deep brain stimulation of the nucleus accumbens for treatmentrefractory obsessive-compulsive disorder. Arch. Gen. Psychiatry 67, 1061-1068 (2010). 21. Hariz, M. I. Complications of deep brain stimulation surgery. Mov. Disord. 17 Suppl 3, SI 62-6 (2002).

22. Salatino, J. W., Ludwig, K. A., Kozai, T. D. Y. & Purcell, E. K. Glial responses to implanted electrodes in the brain. Nat Biomed Eng 1, 862-877 (2017).

23. A visual and narrative timeline of US FDA milestones for Transcranial Magnetic Stimulation (TMS) devices. Brain Stimul. 15, 73-75 (2022).

24. Elahi, B., Elahi, B. & Chen, R. Effect of transcranial magnetic stimulation on Parkinson motor function — Systematic review of controlled clinical trials. Mov. Disord. 24, 357-363 (2009).

25. Noninvasive brain stimulation in Alzheimer’s disease: Systematic review and perspectives for the future. Exp. Gerontol. 46, 611-627 (2011).

26. McNamara, B., Ray, J. L., Arthurs, O. J. & Boniface, S. Transcranial magnetic stimulation for depression and other psychiatric disorders. Psychol. Med. 31, 1141-1146 (2001).

27. Richter, L. Robotized Transcranial Magnetic Stimulation. (Springer Science & Business Media, 2014).

28. Toschi, N., Welt, T., Guerrisi, M. & Keck, M. E. A reconstruction of the conductive phenomena elicited by transcranial magnetic stimulation in heterogeneous brain tissue. Phys. Med. 24, 80-86 (2008).

29. Ravazzani, P, Ruohonen, J., Grandori, F. & Tognola, G. Magnetic stimulation of the nervous system: induced electric field in unbounded, semi-infinite, spherical, and cylindrical media. Ann. Biomed. Eng. 24, 606-616 (1996).

30. Thielscher, A. & Kammer, T. Linking physics with physiology in TMS: a sphere field model to determine the cortical stimulation site in TMS. Neuroimage 17, 1117-1130 (2002).

31. Fregni, F., Simon, D. K., Wu, A. & Pascual-Leone, A. Non-invasive brain stimulation for Parkinson’s disease: a systematic review and meta-analysis of the literature. J. Neurol. Neurosurg. Psychiatry 76. 1614—1623 (2005).

32. Hamid, P, Malik, B. H. & Hussain, M. L. Noninvasive Transcranial Magnetic Stimulation (TMS) in Chronic Refractory Pain: A Systematic Review. Cureus 11, e6019 (2019). 33. Deep Brain Stimulation for the Treatment of Alzheimer Disease and Dementias . World Neurosurg. 80, S28.el-S28.e8 (2013).

34. Bowary, P. & Greenberg, B. D. Noninvasive Focused Ultrasound for Neuromodulation: A Review. Psychiatr. Clin. North Am. 41, 505-514 (2018).

35. Lipsman, N. et al. MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study. Lancet Neurol. 12, 462-468 (2013).

36. Martin, E., Jeanmonod, D., Morel, A., Zadicario, E. & Werner, B. High-intensity focused ultrasound for noninvasive functional neurosurgery. Ann. Neurol. 66, 858-861 (2009).

37. Resting state functional connectivity changes after MR-guided focused ultrasound mediated blood-brain barrier opening in patients with Alzheimer’s disease. Neuroimage 200, 275-280 (2019).

38. Nicodemus, N. E. et al. Focused transcranial ultrasound for treatment of neurodegenerative dementia. Alzheimer’s & Dementia: Translational Research & Clinical Interventions 5, 374-381 (2019).

39. Jeong, H. et al. A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer’s disease. Ultrasonography 40, 512-519 (2021).

40. Beisteiner, R. et al. Transcranial Pulse Stimulation with Ultrasound in Alzheimer’s Disease — A New Navigated Focal Brain Therapy. Adv. Sci. Lett. 7, 1902583 (2020).

41. Dori, G., Matt, E. & Beisteiner, R. Functional Specificity of TPS Brain Stimulation Effects in Patients with Alzheimer’s Disease: A Follow-up fMRI Analysis. Neurology and Therapy 11, 1391-1398 (2022).

42. Transcranial ultrasound neuromodulation for epilepsy: A pilot safety trial. Brain Stimul. 17, 7-9 (2024).

43. Lee, C.-C. et al. Pilot study of focused ultrasound for drug-resistant epilepsy. Epilepsia 63, 162-175 (2022).

44. Safety of focused ultrasound neuromodulation in humans with temporal lobe epilepsy. Brain Stimul. 14, 1022-1031 (2021). 45. A systematic review of preclinical and clinical transcranial ultrasound neuromodulation and opportunities for functional connectomics. Brain Stimul. 17, 734—751 (2024).

46. La, T.-G. & Le, L. H. Flexible and Wearable Ultrasound Device for Medical Applications: A Review on Materials, Structural Designs, and Current Challenges. Advanced Materials Technologies 7, 2100798 (2022).

47. Pang, C., Lee, C. & Suh, K.-Y. Recent advances in flexible sensors for wearable and implantable devices. J. Appl. Polym. Sci. 130, 1429-1441 (2013).

48. Rathod, V. T. A Review of Acoustic Impedance Matching Techniques for Piezoelectric Sensors and Transducers. Sensors 20, 4051 (2020).

49. Afzal, S. et al. Preparation and Evaluation of Polymer-Based Ultrasound Gel and Its Application in Ultrasonography. Gels 8, (2022).

50. Hu, Y.-Y. et al. Transcranial low-intensity ultrasound stimulation for treating central nervous system disorders: A promising therapeutic application. Front. Neurol. 14, 1117188 (2023).

51. Wang, C. et al. Bioadhesive ultrasound for long-term continuous imaging of diverse organs. Science 377, 517-523 (2022).

52. Lee, S.-M. et al. Calcium-Modified Silk Patch as a Next-Generation Ultrasound Coupling Medium. ACS Appl. Mater. Interfaces 13, 55827-55839 (2021).

53. Molerdn, M., Serra-Garcia, M. & Daraio, C. Acoustic Fresnel lenses with extraordinary transmission. Appl. Phys. Lett. 105, 114109 (2014).

54. White, P. J., Clement, G. T. & Hynynen, K. Local frequency dependence in transcranial ultrasound transmission. Phys. Med. Biol. 51, 2293-2305 (2006).

55. Hayner, M. & Hynynen, K. Numerical analysis of ultrasonic transmission and absorption of oblique plane waves through the human skull. J. Acoust. Soc. Am. 110, 3319— 3330 (2001).

56. Legon, W. et al. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat. Neurosci. 17, 322-329 (2014). 57. Kim, H.-C., Lee, W., Weisholtz, D. S. & Yoo, S.-S. Transcranial focused ultrasound stimulation of cortical and thalamic somatosensory areas in human. PLoS One 18, e0288654 (2023).

58. Deffieux, T. & Konofagou, E. E. Numerical study of a simple transcranial focused ultrasound system applied to blood-brain barrier opening. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57, 2637-2653 (2010).

59. Murty, O. Variability in thickness of skull bones and sternum. Journal of Forensic Medicine and Toxicology (2009).

60. Gateau, J. et al. Transcranial ultrasonic therapy based on time reversal of acoustically induced cavitation bubble signature. IEEE Trans. Biomed. Eng. 57, 134-144 (2010).

61. Lee, W., Weisholtz, D. S., Strangman, G. E. & Yoo, S.-S. Safety Review and Perspectives of Transcranial Focused Ultrasound Brain Stimulation. Brain Neurorehabil 14, e4 (2021).

62. Rahnama, R. Analyzing the piezoelectric rings resonance modes for bandwidth ultrasonic transducers. Micro sy st. Technol. 26, 1925-1929 (2020).

63. Ye, H. & De, S. Thermal injury of skin and subcutaneous tissues: A review of experimental approaches and numerical models. Bums 43, 909-932 (2017).

64. Luo, H. et al. Forward osmosis with electro-responsive P(AMPS-co-AM) hydrogels as draw agents for desalination. J. Memb. Sci. 593, 117406 (2020).

65. Hsieh, J.-C. et al. Design of an injectable, self-adhesive, and highly stable hydrogel electrode for sleep recording. Device 0, (2023).

66. Hsieh, J.-C. et al. A highly stable electrode with low electrode- skin impedance for wearable brain-computer interface. Biosens. Bioelectron. 218, 114756 (2022).

67. Lee, C.-J. et al. Ionic Conductivity of Polyelectrolyte Hydrogels. ACS Appl. Mater. Interfaces 10, 5845-5852 (2018).

68. Ashkani, M., Bouhendi, H., Kabiri, K. & Rostami, M. R. Synthesis of poly (2- acrylamido-2-methyl propane sulfonic acid) with high water absorbency and absorption under load (AUL) as concrete grade superabsorbent and its performance. Construction and Building Materials 206, 540-551 (2019). 69. Sekizkardes, B., Su, E. & Okay, O. Mechanically Strong Superabsorbent Terpolymer Hydrogels Based on AMPS via Hydrogen-Bonding Interactions. ACS Applied Polymer Materials (2023) doi:10.1021/acsapm.2c02085.

70. Chen, H. J. et al. Moisture retention of glycerin solutions with various concentrations: a comparative study. Sci. Rep. 12, 10232 (2022).

71. Shen, G. et al. A novel flexible hydrogel electrode with a strong moisturizing ability for long-term EEG recording. J. Neural Eng. 18, (2021).

72. Zhang, K. et al. Metagel with Broadband Tunable Acoustic Properties Over Air- Water-Solid Ranges. Adv. Funct. Mater. 29, 1903699 (2019).

73. Laugier, P. & Haiat, G. Introduction to the Physics of Ultrasound. Bone Quantitative Ultrasound 29-45 (2011).

74. Lee, S.-M. Calcium-Modified Silk Patch as a Next-Generation Ultrasound Coupling Medium. ACS Appl. Mater. Interfaces 13, 55827-55839 (2021).

75. Prokop, A. F. Polyacrylamide gel as an acoustic coupling medium for focused ultrasound therapy. Ultrasound Med. Biol 29, 1351-1358 (2003).

76. Bloomfield, P. E., Lo, W. J. & Lewin, P. A. Experimental study of the acoustical properties of polymers utilized to construct PVDF ultrasonic transducers and the acoustoelectric properties of PVDF and P(VDF/TrFE) films. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 47, 1397-1405 (2000).

77. Carlson, J. E., Van Deventer, J., Scolan, A. & Carlander, C. Frequency and temperature dependence of acoustic properties of polymers used in pulse-echo systems, in IEEE Symposium on Ultrasonics vol. 1 885-888 (IEEE, 2003).

78. Herman, I. P. Physics of the Human Body. (Springer International Publishing, Cham, 2016).

79. Gupta, S., Haiat, G., Laporte, C. & Belanger, P. Effect of the acoustic impedance mismatch at the bone-soft tissue interface as a function of frequency in transcranial ultrasound: A simulation and in vitro experimental study. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 68, 1653-1663 (2021). 80. Jeong, J. Hybrid neural interfacing devices based on Au wires with nanogranular Au shell and hydrogel layer for anti-inflammatory and bi-directional neural communications. Chem. Eng. J 465, (2023).

81. Wu, S. et al. Spider- silk- inspired strong and tough hydrogel fibers with anti-freezing and water retention properties. Nat. Commun. 15, (2024).

82. Wang, H. et al. Super stretchability and satisfactory water retention capacity via a dual-crosslinked hydrogel electrolyte for wide-temperature flexible zinc-air batteries. Chem. Eng. J. 498, 155539 (2024).

83. Wang, Y, Liu, H., Xie, H. & Zhou, S. An autofluorescent hydrogel with waterdependent emission for dehydration-visualizable smart wearable electronics. Adv. Funct. Mater. 33, (2023).

84. Nguyen, J. L., Schwartz, J. & Dockery, D. W. The relationship between indoor and outdoor temperature, apparent temperature, relative humidity, and absolute humidity. Indoor Air 24, 103-112 (2014).

85. Domenici, F. Long-term physical evolution of an elastomeric ultrasound contrast microbubble. J. Colloid Interface Sci 540, 185-196 (2019).

86. Leigh, B. L. et al. Antifouling Photograftable Zwitterionic Coatings on PDMS Substrates. Langmuir 35, 1100-1110 (2019).

87. Jung, H., Kim, M. K., Lee, J. Y, Choi, S. W. & Kim, J. Adhesive hydrogel patch with enhanced strength and adhesiveness to skin for transdermal drug delivery. Adv. Funct. Mater.

30, (2020).

88. Wang, S. et al. Wearable stretchable dry and self-adhesive strain sensors with conformal contact to skin for high-quality motion monitoring. Adv. Funct. Mater. 31, (2021).

89. Zhang, L. et al. Fully organic compliant dry electrodes self-adhesive to skin for longterm motion-robust epidermal biopotential monitoring. Nat. Commun. 11, (2020).

90. Kim, D.-H. et al. Epidermal electronics. Science 333, 838-843 (2011).

91. Rossetti, A. O. & Laureys, S. Clinical Neurophysiology in Disorders of Consciousness: Brain Function Monitoring in the ICU and Beyond. (Springer, 2015). 92. Allison, T. et al. Human cortical potentials evoked by stimulation of the median nerve. II. Cytoarchitectonic areas generating short-latency activity. J. Neurophysiol. (1989) doi: 10.1152/jn.1989.62.3.694.

93. Buzsaki, G. & Draguhn, A. Neuronal oscillations in cortical networks. Science 304, 1926-1929 (2004).

94. Makeig, S., Debener, S., Onton, J. & Delorme, A. Mining event-related brain dynamics. Trends Cogn. Sci. 8, 204-210 (2004).

95. Yamada, T., Kimura, J., Wilkinson, J. T. & Kayamori, R. Short- and long-latency median somatosensory evoked potentials. Findings in patients with localized neurological lesions. Arch. Neurol. 40, 215-220 (1983).

96. Poomima, S., Ali, S. S., Balaji, P. A., Shankar, V. & Kutty, K. Median nerve somatosensory evoked potentials in medical students: Normative data. Adv. Biomed. Res. 2, 56 (2013).

97. Hlushchuk, Y. & Hari, R. Transient suppression of ipsilateral primary somatosensory cortex during tactile finger stimulation. J. Neurosci. 26, 5819-5824 (2006).

98. Lee, W. et al. Transcranial focused ultrasound stimulation of human primary visual cortex. Sci. Rep. 6, (2016).

99. Lee, W. et al. Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Sci. Rep. 5, 8743 (2015).

100. Duck, F. A. Medical and non-medical protection standards for ultrasound and infrasound. Prog. Biophys. Mol. Biol. 93, 176-191 (2007).

101. Fda, U. S. Health and Human Services) (Center for Devices and Radiological Health). (2019).

102. Akhtari, M. et al. Somatosensory evoked response source localization using actual cortical surface as the spatial constraint. Brain Topogr. 7, 63-69 (1994).

103. Michel, C. M. & He, B. EEG source localization. Handb. Clin. Neurol. 160, 85-101 (2019).

104. Asadzadeh, S., Yousefi Rezaii, T., Beheshti, S., Delpak, A. & Meshgini, S. A systematic review of EEG source localization techniques and their applications on diagnosis of brain abnormalities. J. Neurosci. Methods 339, 108740 (2020). 105. Koles, Z. J. & Soong, A. C. EEG source localization: implementing the spatiotemporal decomposition approach. Electroencephalogr Clin. Neurophysiol. 107, 343-352 (1998).

106. Legon, W., Bansal, P., Tyshynsky, R., Ai, L. & Mueller, J. K. Transcranial focused ultrasound neuromodulation of the human primary motor cortex. Sci. Rep. 8, 10007 (2018).

107. Cools, R. & Arnsten, A. F. T. Neuromodulation of prefrontal cortex cognitive function in primates: the powerful roles of monoamines and acetylcholine. Neuropsychopharmacology 47, 309-328 (2022).

108. Yi, S.-S. et al. Ultrasound stimulation of prefrontal cortex improves lipopolysaccharide-induced depressive-like behaviors in mice. Front. Psychiatry 13, 864481 (2022).

109. Sanguinetti, J. L. et al. Transcranial focused ultrasound to the right prefrontal cortex improves mood and alters functional connectivity in humans. Front. Hum. Neurosci. 14, 52 (2020).

110. Folloni, D. et al. Ultrasound modulation of macaque prefrontal cortex selectively alters credit assignment-related activity and behavior. Sci. Adv. 7, eabg7700 (2021).

111. De Ridder, D., De Mulder, G., Verstraeten, E., Sunaert, S. & Moller, A. Somatosensory cortex stimulation for deafferentation pain. Acta Neurochir. Suppl. 97, 67-74 (2007).

112. Strohman, A., Payne, B., In, A., Stebbins, K. & Legon, W. Low-intensity focused ultrasound to the human dorsal anterior cingulate attenuates acute pain perception and autonomic responses. J. Neurosci. 44, (2024).

113. Kim, M. G. et al. Low-intensity transcranial focused ultrasound suppresses pain by modulating pain processing brain circuits. bioRxiv (2022) doi:10.1101/2022.12.07.519518.

114. Xia, X. et al. Effects of the motor cortical theta-burst transcranial-focused ultrasound stimulation on the contralateral motor cortex. J. Physiol. 602, 2931-2943 (2024).

115. Heimbuch, I. S. et al. Ultrasound stimulation of the motor cortex during tonic muscle contraction. PFoS One 17, e0267268 (2022).

116. Tang, Y. & Kim, E. S. Simple Sacri Fi Cial-Fayer-Free Microfabrication Processes for Air- Cavity Fresnel Acoustic Fenses ( ACFAFs ) with Improved Focusing Performance. (2022). 117. Bhattacharya, S., Datta, A., Berg, J. M. & Gangopadhyay, S. Studies on surface wettability of poly(dimethyl) siloxane (PDMS) and glass under oxygen-plasma treatment and correlation with bond strength. J. Microelectromech. Syst. 14, 590-597 (2005).

118. Lee, B. W., Ryeom, J., Ko, Y. H., Kim, K. J. & Ko, J.-H. Acoustic anisotropy of oriented polyethylene terephthalate films studied through Brillouin light scattering. J. Soc. Inf. Disp. 15, 201-205 (2014).

119. Rossini, P. M., Cracco, R. Q., Cracco, J. B. & House, W. J. Short latency somatosensory evoked potentials to peroneal nerve stimulation: scalp topography and the effect of different frequency filters. Electroencephalogr. Clin. Neurophysiol. 52, 540-552 (1981).

120. Zhang, Z.-G., Yang, J.-L., Chan, S.-C., Luk, K. D.-K. & Hu, Y. Time-frequency component analysis of somatosensory evoked potentials in rats. Biomed. Eng. Online 8, 4 (2009).

121. Wang, Y, Li, G., Luk, K. D. K. & Hu, Y. Component analysis of somatosensory evoked potentials for identifying spinal cord injury location. Sci. Rep. 7, 2351 (2017).

122. Cui, H.-Y, Wu, Y.-X., Li, R., Li, G.-S. & Hu, Y. A translational study of somatosensory evoked potential time-frequency components in rats, goats, and humans. Neural Regen. Res. 16, 2269-2275 (2021).

123. Auditory event-related dynamics of the EEG spectrum and effects of exposure to tones. Electroencephalogr. Clin. Neurophysiol. 86, 283-293 (1993).

124. Lee, S. & Lee, D. K. What is the proper way to apply the multiple comparison test? Korean J. Anesthesiol. 71, 353-360 (2018).

Claims

WHAT IS CLAIMED IS:

1. A hydrogel formed from: a) a first monomer comprising one or more ion-forming moieties; b) a polyol; and c) water; wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1:4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

2. The hydrogel of claim 1, wherein the first monomer comprises one or more anion- forming moieties, one or more cation-forming moieties, or combinations thereof, more particularly wherein the first monomer comprises one or more anion-forming moieties, even more particularly wherein the first monomer comprises vinyl sulfonic acid, styrene sulfonic acid, allyl sulfonic acid, ethyl acrylate sulfonic acid, butyl acrylate sulfonic acid, acryl sulfonic acid, methacryl sulfonic acid, 2-acrylamido-2-methylpropane sulfonic acid, vinyl carboxylic acid, styrene carboxylic acid, allyl carboxylic acid, acryl carboxylic acid, methacryl carboxylic acid, 2-acrylamido-2-methylpropane carboxylic acid, isoprene carboxylic acid, polyacrylic acid, salts thereof, or combinations thereof, even more particularly wherein the first monomer comprises 2-acrylamido-2-methylpropane sulfonic acid (AMPS) or a salt thereof.

3. The hydrogel of any one of claim 1 or claim 2, wherein the polyol comprises glycerol, trimethylolpropane, pentaerythritol, ethylene glycol, 1,5-butanediol, 1,2,5-hexanetriol, diethylene glycol, triethylene glycol, maltitol, sorbitol, xylitol, erythritol, isomalt, malic acid, a polyalkylene glycol (such as polyethylene glycol or polypropylene glycol), a polyvinyl alcohol, a polyether polyol, a polyester polyol, or combinations thereof, more particularly wherein the polyol comprises glycerol.

4. An article comprising the hydrogel of any one of claims 1-3.

5. The article of claim 4, wherein the article is a wearable device, more particularly wherein the article is a focused ultrasound device (FUS).

6. A wearable device comprising: a housing containing an acoustic lens and the hydrogel of any one of claims 1-3; and at least one electrical connector operatively coupled to the acoustic lens and hydrogel, wherein the wearable device is configured to be worn in proximity to a subject’s head.

7. A system comprising: at least one wearable device according to claim 6; an ultrasound generator in electronic communication with the at least one wearable device; and a controller operatively coupled to the ultrasound generator and the at least one wearable device.

8. A hydrogel formed from: a) a first monomer comprising one or more ion-forming moieties; b) a polyol; c) a salt; and d) water; wherein the first monomer and water have a ratio by weight from about 1 : 1 to about 1:4; and wherein the polyol is present in an amount from about 10% to about 40% by weight based on the weight of the hydrogel.

9. The hydrogel of claim 8, wherein the first monomer comprises one or more anion- forming moieties, one or more cation-forming moieties, or combinations thereof, more particularly wherein the first monomer comprises one or more anion-forming moieties, even more particularly wherein the first monomer comprises vinyl sulfonic acid, styrene sulfonic acid, allyl sulfonic acid, ethyl acrylate sulfonic acid, butyl acrylate sulfonic acid, acryl sulfonic acid, methacryl sulfonic acid, 2-acrylamido-2-methylpropane sulfonic acid, vinyl carboxylic acid, styrene carboxylic acid, allyl carboxylic acid, acryl carboxylic acid, methacryl carboxylic acid, 2-acrylamido-2-methylpropane carboxylic acid, isoprene carboxylic acid, polyacrylic acid, salts thereof, or combinations thereof, even more particularly wherein the first monomer comprises 2-acrylamido-2-methylpropane sulfonic acid (AMPS) or a salt thereof.

10. The hydrogel of claim 8 or claim 9, wherein the polyol comprises glycerol, trimethylolpropane, pentaerythritol, ethylene glycol, 1,5-butanediol, 1,2,5-hexanetriol, diethylene glycol, triethylene glycol, maltitol, sorbitol, xylitol, erythritol, isomalt, malic acid, a polyalkylene glycol (such as polyethylene glycol or polypropylene glycol), a polyvinyl alcohol, a polyether polyol, a polyester polyol, or combinations thereof, more particularly wherein the polyol comprises glycerol.

11. The hydrogel of any one of claims 8-10, wherein the salt is a salt of an alkali or alkaline-earth metal, more particularly wherein the salt is a salt of Li, K, Na, Cs, Rb, Ca, Mg, Ba, Sr, or a combination thereof, more particularly wherein the salt is a nitrate, chloride, bromide, iodide, sulfate, carbonate, fluoride salt, or a combination thereof, even more particularly wherein the salt is potassium chloride.

12. An article comprising the hydrogel of any one of claims 8-11.

13. The article of claim 12, wherein the article is a device, more particularly wherein the article is an electroencephalography (EEG) recording device, a functional electrical stimulation (FES) device, an electromyography (EMG) device, a transcutaneous electrical nerve stimulation (TENS) device, a neuromuscular electrical stimulation (NMES) device, an electrocardiography (ECG) device, an electrooculogram (EOG) device, or an electrogastrogram (EGG) device.

14. A device comprising: one or more electrodes comprising a hydrogel of any one of claims 8-11.

15. A system comprising: a device in accordance with claim 14; and a controller or processor; and a memory.