SYSTEMS AND METHODS FOR ON-PERSON WEARABLE ELECTRONICS - Patent application

Abstract

A system and method for on-person wearable electronic devices for extended wear is provided. A matching agent can be provided made of a flexible, dehydration-resistant hydrogel-elastomer hybrid material. A bioadhesive can connect the matching agent, the electronic device, and the human. The matching agent can function as a configuration for coupling and transferring information to and from the electronic device.

Description

[Background technology]

[0001] Wearable devices that can non-invasively and continuously monitor human physiological states represent a central trend in precision and digital medicine. In particular, deep tissue physiology, including organ signals and dynamics, contains important information for health and disease. Although current wearable devices have been successful in recording physical and chemical signals from the skin, such as electrocardiogram data, sweat metabolites, and electrolytes, clinical-grade imaging of various internal organs remains a central issue and challenge in the field of wearable devices. Ultrasound imaging diagnostics with zero radiation allows clinicians to evaluate tissue and organ function and diagnose various diseases. If sampled frequently over days to months, ultrasound imaging diagnostics of internal organs may help clinicians monitor health status, observe disease progression, and assess disease risk, and may also lead to discoveries and better understanding in developmental biology.

[0002] Wearable ultrasound devices have the potential to provide continuous imaging of internal organs. Conventional wearable ultrasound imaging methods typically rely on the attachment of bulky ultrasound probes to the skin, either by robotic systems or mechanical fixation such as straps or tapes, which impede patient mobility and the convenience and comfort of the wearable. Furthermore, conventional wearable ultrasound imaging methods are only applicable to limited body parts, such as muscles, due to the thick ultrasound probes and the high pressure they create. For example, mechanically attaching a conventional ultrasound probe to the neck to image the carotid artery, jugular vein, or vagus nerve may cause choking.

[0003] Although stretchable ultrasound imaging devices have improved wearability, they still suffer from limitations including low image resolution, unstable image quality during body motion, short image duration (1 hour), and susceptibility to effects from device failure. These limitations are primarily due to the device design, which includes piezoelectric elements on a stretchable substrate. Although the stretchable substrate can conform and deform to the skin, it limits the density of the elements (156 per square centimeter) and is incompatible with backing and matching layers, leading to low image resolution. Furthermore, deformation of the substrate along with the skin under body motion causes the spatial and angular positions of the elements to change unpredictably, thus hindering the image stability of the device. Furthermore, existing wearable ultrasound devices rely mostly on hydrogel or elastomer couplants for acoustic transmission to the skin, both in terms of stiffness and stretchable shape factors. However, hydrogel couplants typically dehydrate or peel off from the skin over the course of several hours, and elastomer couplants are too attenuating to image deep organs.

[0004] Current rigid and stretchable ultrasound imaging devices have several additional drawbacks. First, because sound waves are directional, the position of the ultrasound probe needs to be adjusted on the fly (e.g., by tilting or rotating the probe on the patient) to obtain an optimized imaging direction. However, the position of a wearable ultrasound probe is fixed to the skin and cannot be adjusted during the procedure, significantly hindering its imaging performance. For example, because a stretchable ultrasound probe can only be paralleled to the skin that conforms to it, the resulting imaging direction is usually not optimized for imaging internal organs. Second, existing wearable ultrasound imaging diagnostic devices have only one imaging window and cannot simultaneously image multiple distant organs. However, in a routine manner, simultaneous imaging of multi-organ correlations may provide important information for disease diagnosis and monitoring and basic biological research.

[0005] Thus, there is a need for wearable electronic devices that can be positioned on the human body and worn for extended periods of time and that can obtain more information than can be obtained from superficial skin monitoring or optical monitoring from a piece of clothing or jewelry. There also remains a need for systems that are comfortable and do not distort the subject's body in adverse ways. Summary of the Invention

[0006] The present disclosure addresses the aforementioned shortcomings and provides a system and method for securing an electronic device directly on the human body for effective long-term data collection while facilitating long-term wear. In particular, an elastomeric membrane can be utilized and coupled to the electronic device. An electronically communicable or conductive material can be disposed within the elastomeric membrane. A bioadhesive layer can be coupled to the elastomeric membrane on an opposite side from the electronic device and configured to couple the elastomeric membrane to the subject.

[0007] In one non-limiting example, the wearable electronic device may include a high-resolution wearable ultrasound. In some configurations, a bioadhesive ultrasound (BAUS) device may be used, which includes a thin, rigid, high-resolution ultrasound probe firmly adhered onto the skin via a coupling layer made of a soft, tough, dehydration-resistant, bioadhesive hydrogel-elastomer hybrid. The thin, rigid BAUS probe provides high transducer density and stable transducer position under dynamic body movements, high probe reliability over long periods of use, etc. The BAUS probe assembled onto the BAUS couplant may include a thin, rigid ultrasound probe, a handheld ultrasound probe, a stretchable ultrasound probe, etc.

[0008] In one configuration, a system is provided for long term ultrasound imaging of a subject. The apparatus includes an ultrasound probe formed from a plurality of transducers arranged across a plane. The system also includes an elastomeric membrane extending across and coupled to the plane of the ultrasound probe. The system also includes an acoustically transparent material disposed within the elastomeric membrane. The system also includes a bioadhesive layer coupled to the elastomeric membrane opposite the ultrasound probe and configured to couple the elastomeric membrane to the subject.

[0009] In one configuration, a method is provided for forming a long-term ultrasound imaging system for a subject. The method includes forming an ultrasound probe from a plurality of transducers arranged across a plane. The method also includes stretching a coupled elastomeric membrane across the plane of the ultrasound probe. The method also includes disposing an acoustically transparent material within the elastomeric membrane and forming a bioadhesive layer coupled to the elastomeric membrane opposite the ultrasound probe and configured to couple the elastomeric membrane to the subject.

[0010] In one configuration, a system for securing an electronic circuit system to a subject over an extended period of time is provided. The system includes an electronic circuit substrate forming a planar surface having at least one electronic circuit formed thereon. The system also includes an elastomeric membrane extending across and coupled to the planar surface of the electronic circuit substrate, and a hydrogel disposed within the elastomeric membrane. The system also includes a bioadhesive layer coupled to the elastomeric membrane on a side of the electronic circuit substrate opposite the planar surface and configured to couple the elastomeric membrane to the subject.

[0011] In one configuration, a system is provided that includes an elastomeric membrane forming an enclosure around a void. The system also includes a hydrogel disposed within the void and encased by the elastomeric membrane. The system also includes a bioadhesive layer coupled to the elastomer for coupling the elastomeric membrane to a subject.

[0012] The foregoing and other aspects and advantages of the present disclosure will appear in the following description. In this specification, reference is made to the accompanying drawings, which form a part of this specification, illustrating a preferred embodiment. However, this embodiment does not necessarily represent the full scope of the invention, and therefore, reference is made to the claims and this specification to interpret the scope of the invention. In the following description, like reference numerals are used to refer to like parts in each figure. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 is a block diagram of a non-limiting example ultrasound system capable of implementing the methods described in this disclosure. [Diagram 2] FIG. 2 is a profile diagram of a non-limiting example wearable ultrasound system. [Diagram 3] 1 is a cross-section of a non-limiting example wearable ultrasound system. [Figure 4A] FIG. 2 is an exploded view of an ultrasound probe, by way of a non-limiting example. [Figure 4B] FIG. 2 is a diagram of a non-limiting example ultrasound probe placed on a flat tissue surface. [Diagram 5] 5A shows the adhesive performance of a non-limiting example wearable ultrasound system. FIG. 5A shows the interfacial toughness between the BAUS matching agent and porcine skin measured over 48 hours after adhesive formation. Error bars indicate the standard deviation (±sd) of the interfacial toughness (n=4 independent samples). FIG. 5B shows that a non-limiting example wearable ultrasound system adhered to skin can withstand high tensile forces and maintain a strong adhesion to the skin over 48 hours. [Figure 6]6A is a photograph of a non-limiting example of a wearable ultrasound system after peeling. FIG. 6A shows that the non-limiting example of a wearable ultrasound system can be removed at any time by peeling from one corner of the matching agent. FIG. 6B to FIG. 6C show the peeling process without leaving any residue on the skin after removal. [Figure 7] 7 shows the vibration isolation performance of a non-limiting example of a wearable ultrasound system. FIG. 7A shows a schematic diagram of the vibration isolation test setup and imaging results under vibration. The test apparatus consists of an orbital shaker with vibration frequencies of 0-3.5 Hz and an ultrasound phantom on top of the shaker. Images are performed by the non-limiting example of a wearable ultrasound system at different vibration frequencies on a mock vessel in the ultrasound phantom. FIG. 7B shows a quantitative analysis of the diameter of the mock vessel imaged by the non-limiting example of a wearable ultrasound device at various vibration frequencies. Error bars represent the mean deviation (±sd) (n=3 independent samples). [Figure 8] FIG. 8A illustrates the thermal characterization of a non-limiting example of a wearable ultrasound system under various operating voltages (0V, 15V, 30V, 45V, 60V, 75V, 90V). The figure shows the relationship of maximum temperature of the device to operating voltage. The error bars represent the mean deviation (±sd) of maximum temperature on the device surface (n=3 independent samples). FIG. 8B illustrates the thermal characterization of a non-limiting example of a wearable ultrasound system adhered to skin for 48 hours under an operating voltage of 90V. The figure shows the relationship of maximum temperature of the device to time. The error bars represent the mean deviation (±sd) of maximum temperature on the device surface (n=3 independent samples). [Figure 9] 1A-1D are schematic diagrams of non-limiting examples of wearable ultrasound systems at various locations on a subject's body for imaging corresponding organs. [Figure 10]10A-10D show non-limiting example results of high-resolution long-term continuous imaging of blood vessels using a wearable ultrasound system. FIG. 10A shows a schematic diagram of a non-limiting example of a wearable ultrasound system attached to a subject's neck to image the carotid artery and jugular vein. FIG. 10B shows that a non-limiting example of a wearable ultrasound system can stably image blood vessels under dynamic body movements such as head shaking at angles up to ±30 degrees (scale bar is 0.5 cm). FIG. 10C shows that the diameter of the jugular vein increases significantly from a sitting / standing position to a supine position. FIG. 10D shows color flow imaging of the carotid artery by a non-limiting example of a wearable ultrasound system. The diameter of the carotid artery and the blood flow velocity in the carotid artery increase significantly after 0.5 hours of physical exercise (scale bar is 0.5 cm). FIG. 10E shows the waveforms of the carotid artery blood pressure before and after 0.5 hours of physical exercise. Carotid systolic blood pressure increases significantly 0.5 hours after physical exercise. The drop in blood pressure from the systolic peak in each cardiac cycle is much steeper 0.5 hours after physical exercise. Figure 10F shows carotid systolic blood pressure measured from wearable ultrasound imaging over a 48-hour period. Systolic blood pressure is measured by calculating the mean and standard deviation of 15 consecutive systolic peaks every 0.5 hours. Error bars (n=15 independent samples) indicate the standard deviation (±sd) of the measured systolic pressure. [Figure 11] 11A-11C show non-limiting examples of high-resolution long-term continuous wearable ultrasound imaging of the lungs and diaphragm. In FIG. 11A, non-limiting example wearable ultrasound imaging shows smooth pleural lines and repetitive A-lines in the lungs. In FIG. 11B, non-limiting example wearable ultrasound imaging shows clear diaphragm morphology. In FIG. 11C, diaphragm motility increases significantly in amplitude and frequency 0.5 hours after physical exercise. [Figure 12] 12A-B show non-limiting examples of high-resolution long-term continuous wearable ultrasound imaging of the heart. In FIG. 12A, non-limiting example wearable ultrasound imaging showing the functional status of the four chambers of the heart. In FIG. 12B, the size of the left ventricle is shown to increase significantly after 0.5 hours of physical exercise. [Figure 13] 13A and 13B are diagrams showing non-limiting examples of wearable ultrasound imaging of stomach dynamics. [Figure 14] 1 is a flowchart of non-limiting example steps of a method for forming a long-term ultrasound imaging system. [Figure 15] 1 is a graph of energy release rate G as a function of layer thickness H of a matching agent, as a non-limiting example. [Figure 16] FIG. 1 is a schematic diagram of a non-limiting example of adjusting a wearable ultrasound system on a surface. The ultrasound system includes multiple thin ultrasound probes for wearable imaging of multiple organs and a reshapeable ultrasound matching agent for in situ tuning of the imaging direction. In the top view, the imaging direction of the wearable ultrasound probes is not optimized before adjustment. In the bottom view, the optimized imaging direction is obtained by reshaping the wearable ultrasound probes on the skin. [Figure 17] A non-limiting example of a matching agent material made of a thermoresponsive hydrogel consisting of κ-carrageenan-polyacrylamide (κ-CG-PAAm) interpenetrating polymer network and water. At 45° C., the hydrogel is able to reshape. At 35° C., the hydrogel is elastic and maintains its shape. [Figure 18]18A-18E are schematic diagrams and photographs showing non-limiting examples of the adjustable properties of the wearable ultrasound probe matching agent. FIG. 18A shows the shear modulus of κ-CG-PAAm hydrogels with different compositions (2 wt% κ-CG, 8 wt% PAAm; 3 wt% κ-CG, 7 wt% PAAm; 4 wt% κ-CG, 6 wt% PAAm) as they are cooled from 60° C. to 25° C. FIG. 18B shows the reshaping of κ-CG-PAAm hydrogel (3 wt% κ-CG, 7 wt% PAAm) to various shapes by heating it to 45° C. and then cooling it to 35° C. FIG. 18C-18E show the rocking (C), sweeping (D), and rotating (E) of the wearable ultrasound probe by reshaping the matching agent to obtain an optimized imaging direction. [Figure 19] 19A-19D show schematics, photographs, and ultrasound scans of non-limiting examples comparing the imaging performance of a wearable ultrasound system before and after calibration. Figures 19A-19D show wearable ultrasound imaging of a knuckle (A), heart (B), carotid artery (C), and bladder (D) before and after calibration. [Figure 20] 20A-20D are schematic diagrams, photographs, and ultrasound operations of a non-limiting example of multi-window simultaneous imaging of multi-organ correlation by a wearable ultrasound system. FIG. 20A shows a schematic diagram of the position of a wearable ultrasound probe on the skin. FIG. 20B shows the diaphragm-right atrium-jugular vein correlation when the subject lifts the diaphragm. FIG. 20C shows the stomach-bladder correlation when the subject drinks 500 ml of water. FIG. 20D shows the quantified cross-sectional area of ​​the stomach and bladder by segmenting the time series of wearable ultrasound imaging in FIG. 20C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present disclosure provides systems and methods for fastening electronic devices directly to the human body to facilitate long-term wear, proper positioning and adjustment of the electronic device, and effective, long-term data collection. In particular, an elastomeric membrane is available and can be coupled to the electronic device. An electronically communicable or conductive material can be disposed within the elastomeric membrane. A bioadhesive layer can be configured to couple to the elastomeric membrane on the side opposite the electronic device and to couple the elastomeric membrane to the subject.

[0015] In one non-limiting embodiment, the electronic device may be a sensor or a monitoring system. In yet another non-limiting example, the electronic device may be an ultrasound transducer or an array of ultrasound transducers. Additionally, the electronic device may include a processing unit and / or a communication component.

[0016] High-resolution ultrasound imaging with zero radiation is the most readily available tool for clinicians to assess tissue and organ function and diagnose various diseases. High-resolution ultrasound imaging of deep tissue physiology is difficult to understand, and existing ultrasound imaging devices predominantly used by clinicians have proven difficult to access for patients for routine continuous imaging and monitoring of deep physiology.

[0017] Conventional wearable ultrasound imaging typically relies on the attachment of a bulky ultrasound probe to the skin, either by a robotic system or by mechanical fasteners such as straps or tapes, which significantly impedes patient mobility and the convenience and comfort of wearing. Furthermore, conventional wearable ultrasound imaging is only applicable to limited body parts, such as muscles, due to the thick ultrasound probe itself and the high pressure caused by the probe. Furthermore, clothing typically cannot cover a thick probe when worn on the skin. For conventional wearable technology, subjects are expected to adapt and conform to the wearable system rather than the other way around.

[0018] Some have attempted to create stretchable ultrasound devices with improved wearability, but they still suffer from limitations such as low image resolution (2 mm), unstable image quality during body movement, short imaging times (2 hours), and a tendency to device failure. These limitations arise primarily from the device design, which patterns the imaging transducers on a stretchable substrate attached to the skin. Although the stretchable substrate can conform and deform to the skin, it effectively limits the areal density of the transducers (156 per square centimeter) and therefore the imaging resolution (2 mm).

[0019] Furthermore, as the substrate deforms with the skin under body movement, the spatial and angular position of the transducer changes unpredictably, which dramatically impedes the imaging stability of the device. Most importantly, existing wearable ultrasound devices, in both large, rigid and stretchable thin form factors, primarily rely on liquid matching agents for acoustic transmission to the skin. However, liquid matching agents can easily flow away under pressure applied by the probe and / or become dehydrated over the course of several minutes, limiting the continuous imaging time of the device to a few minutes.

[0020] As a specific, but non-limiting example, a system and method for high-resolution wearable ultrasound is provided. In some configurations, a bioadhesive ultrasound (BAUS) device can be used that includes a thin, rigid, high-resolution ultrasound probe that is firmly adhered onto a subject, such as the subject's skin, via a matching layer made of a soft, tough, dehydration-resistant, bioadhesive hydrogel-elastomer hybrid material. The thin, rigid probe provides high transducer density, stable transducer position under dynamic body movements, high probe reliability in long-term use, and the like. The probes that are matched onto the matching layer can include thin, rigid ultrasound probes, handheld ultrasound probes, and extendable ultrasound probes, and the like.

[0021] Referring to FIG. 1, one non-limiting example of an electronic or sensor device according to the present disclosure is provided. In this example, the electronic device is illustrated as an ultrasound system 100 capable of implementing the methods described in this disclosure. The ultrasound system 100 includes a transducer array 102 including a plurality of separately driven transducer elements 104. The transducer array 102 can include any suitable ultrasound transducer array, including a linear array, a curved array, an annular array, a phased array, and the like. Similarly, the transducer array 102 can include a 1D transducer, a 1.5D transducer, a 1.75D transducer, a 2D transducer, a 3D transducer, and the like.

[0022] When energized by the transmitter 106, a given transducer element 104 generates a burst of ultrasonic waves. Ultrasound waves (e.g., echoes) reflected from the object or object under study to the transducer array 102 are converted by each transducer element 104 into electrical signals (e.g., echo signals) that can be individually applied to the receiver 108 through a set of switches 110. The transmitter 106, receiver 108, and switch 110 operate under the control of a controller 112, which can include one or more processors. As an example, the controller 112 can include a computer system. In a non-limiting example, the controller 112 may be wirelessly connected to the transmitter 106, receiver 108, and switch 110. Alternatively, the controller 112 can be connected to the transmitter 106, receiver 108, and switch 110 via a wired connection. In a non-limiting example, the controller 112 may be portable.

[0023] The transmitter 106 can be programmed to transmit unfocused or focused ultrasound. In some configurations, the transmitter 106 can also be programmed to transmit branching waves, spherical waves, cylindrical waves, plane waves, or combinations thereof. Additionally, the transmitter 106 can be programmed to transmit spatially or temporally encoded pulses.

[0024] In some configurations, beam steering can be used, which can be achieved by energizing each transducer element 104, or a subset of the transducer elements, in a specified sequence to steer an ultrasound beam along a path R to a target point P at an angle θ from the axis of the transducer array 102.

[0025] The receiver 108 can be programmed to implement a detection sequence appropriate for the imaging task at hand, in some embodiments the detection sequence can include one or more of line-by-line scanning, compound plane wave imaging, synthetic aperture imaging, and compound divergent beam imaging.

[0026] In some configurations, the transmitter 106 and receiver 108 can be programmed to implement a high frame rate, for example a frame rate associated with an acquisition pulse repetition frequency (PRF) of at least 100 Hertz. In some configurations, the ultrasound system 100 can sample and store at least 100 populations of echo signals in time.

[0027] The controller 112 can be programmed to design the imaging sequence using techniques described in this disclosure or as otherwise known in the art. In some embodiments, the controller 112 receives user input that defines various factors used in the design of the imaging sequence.

[0028] A scan may be performed by setting the switches 110 to their transmit positions, thereby directing the transmitters 106 to momentarily turn on to energize the transducer elements 104 for a single transmit event according to a designed imaging sequence. The switches 110 may then be set to their receive positions, and subsequent echo signals generated by the transducer elements 104 in response to one or more detected echoes are measured and applied to the receiver 108. The separate echo signals from the transducer elements 104 may combine in the receiver 108 to generate a single echo signal.

[0029] The echo signals are communicated to a processing unit 114, which is implemented by a hardware programmer and memory to process the echo signals or images generated from the echo signals. As an example, the processing unit 114 can process images from the wearable system using methods described in this disclosure. Images generated from the echo signals by the processing unit 114 can be displayed on a display system 116.

[0030] Referring to FIG. 2, a non-limiting example of a wearable system 200 on a human body is shown. Again, in this non-limiting embodiment, the electronic device or sensor is an ultrasound probe 202. The ultrasound probe 202 can include an array of transducer elements 204. In some configurations, the ultrasound probe 202 can be a thin, rigid or flexible ultrasound probe by including a substrate 205, for example, a circuit board or other such structure. The wearable system 200 can include a matching agent 206. In some non-limiting examples, the matching agent 206 can be a hydrogel-elastomer hybrid with a bioadhesive layer. While conventional systems require the skin to deform to match the rigidity of the ultrasound array or for the ultrasound array to bend to conform to the skin, the matching agent 206 can be used to conform to the skin surface 208 without the need to deform the skin surface 208 or bend or deform the ultrasound probe 202.

[0031] In some configurations of hydrogel-elastomer hybrids, the hydrogel may include hydrophilic polymers or copolymers with good acoustic transparency. In non-limiting examples, the hydrogel may include materials such as polyacrylate, polyacrylamide, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyethylene glycol, polyurethane, casein, albumin, gelatin, chitosan, hyaluronic acid, alginate, oxidized alginate, cellulose, oxidized cellulose, kappa-carrageenan, sulfonated polysaccharides, and the like. In some configurations, the hydrogel may contain chemical or physical crosslinkers (e.g., gelatin methacrylate, hyaluronic acid methacrylate, oxidized methacrylate alginate, polycaprolactone diacrylate, N,N'-bis(acryloyl)cystamine, N,N'-methylene bis(acrylamide), polyvinyl alcohol, acrylate cyclodextrin (CD), and adamantane triacrylate, t-butyl acrylate, polyethylene glycol diacrylate, polyethylene glycol dimethacrylate) in single, double, or multiple networks.

[0032] Elastomers may include one or more elastic polymers or rubbers that have high elasticity. Non-limiting example elastomeric materials include natural rubber, styrene-butadiene block copolymers, polyisoprene, polybutadiene, ethylene-propylene rubber, ethylene propylene diene rubber, silicone elastomers, fluoroelastomers, polyurethane elastomers, nitrile rubber, and the like.

[0033] The bioadhesive layer may comprise one or more adhesive polymers capable of adhering to skin without corrosion. Non-limiting example bioadhesive layer materials include animal glue, casein glue, starch, dextrin, agar, algin, gum arabic, epoxy resin, nitrocellulose, polyvinyl acetate, vinyl acetate-ethylene copolymer, polyethylene, polypropylene, polyamide, polyester, acrylic, cyanoacrylic, natural rubber, butyl rubber, butadiene rubber, styrene-butadiene rubber, nitrile rubber, silicone, neoprene, and the like.

[0034] In non-limiting examples, hydrogel-elastomer matching agents include polyacrylamide (PAAm) and chitosan interpenetrating hydrogels, polypropylene elastomers, and poly(2-ethylhexylacrylate-co-acrylic acid) bioadhesives.

[0035] In another non-limiting example, the hydrogel-elastomer matching agent includes polyacrylamide (PAAm) and kappa-carrageenan interpenetrating hydrogels, and a polyurethane bioadhesive elastomer.

[0036] Referring to Figure 3, a cross-section of a non-limiting example of a wearable ultrasound system is shown. A thin, rigid ultrasound probe 302 can be coupled to a matching agent 303 via an upper bioadhesive layer 304. The matching agent 303 can include elastomeric membranes 306, 310 that encapsulate a hydrogel 308. A lower bioadhesive layer 312 can be used to provide a removable, fixed coupling to a skin surface 314. Ultrasound transmission 316 can be transmitted from the probe 302 through the skin 314, and ultrasound can be detected from the skin 314 by detection.

[0037] The matching agent 303 may also include a hydrogel 308 designed for transmission of electronic signals or sensing of sensor information from the skin 314 and tissues or organs beneath the skin 314. In a non-limiting embodiment, the hydrogel 308 may be 95% water by weight, encapsulated by an elastomeric membrane 308, 310, and further coated with a thin bioadhesive layer having an upper bioadhesive layer 304 and a lower bioadhesive layer 312. The matching agent 303 may maintain a strong adhesion between the ultrasound probe 302 or the probe and the skin 314 for an extended period of time, and may exclude the ultrasound probe 302 from skin deformation during dynamic body movements. For example, the system may be designed to be worn for multiple days, such as 48 hours or more.

[0038] The matching agent 303 may provide a set of properties and functions that typical ultrasound matching agents cannot provide. The elastomeric membranes 306, 310 may be used to prevent dehydration of the encapsulating hydrogel contained therein and ensure a strong and comfortable adhesion of the probe on the skin for extended periods such as over 48 hours. In some configurations, the matching agent 303 may be a strong matching agent that is flexible, maintains elasticity, and is stable at high pressures. The matching agent 303 may also shield the probe from skin deformation.

[0039] The acoustic transparency of the matching agent 303 can maintain high transparency over an extended period of time. In a non-limiting example, the acoustic transparency is greater than 97% transparent to degassed water over an extended period of time. In some configurations, the matching agent 303 can easily adhere a thin probe of various commercially available ultrasound devices to the skin over an extended period of time. In some configurations, the matching agent 303 can be composed entirely of common chemicals that can be mass-produced as a low-cost pharmaceutical product, facilitating widespread use of the device. In a non-limiting example, the total thickness of the elastomeric membrane and bioadhesive layer can be less than ¼ of the ultrasound wavelength.

[0040] The wearable ultrasound system may also optionally include a heater 320 for providing thermal energy 322 to the hydrogel 308. The heater 320 may be removably coupled to the wearable ultrasound system. The thermal energy 322 may heat the hydrogel 308 of the adjustable BAUS matching agent 303 from normal skin temperature (e.g., 35° C.) to an elevated, but skin-tolerable temperature (e.g., 50° C.) for in situ adjustment of the position of the adjustable BAUS probe on the skin.

[0041] 4A, an exploded view is shown of a non-limiting example ultrasonic probe 400. The ultrasonic probe 400 can include a high density matrix of high performance piezoelectric transducers 406 that can be controlled by a top circuit 404 and a bottom circuit 408. The top circuit 404 and the bottom circuit 408 can be covered by an acoustic backing layer 402 and a matching layer 410, respectively. In a non-limiting example, the high density matrix of transducers 406 includes 2500 or more elements per square centimeter.

[0042] 4B, a non-limiting example of an ultrasound probe 450 positioned on a flat tissue surface 452 is shown. An object of interest 454 can be imaged by ultrasound transmitted by a transmitter 456 and detected by a receiver 458. The transmitter 456 (x i , y i ) and receiver 458(x j , y j ) is on a flat geometry, the spatial location of the object of interest P(x,y) can be accurately calculated based on the received signals. This is in contrast to extensible systems, which, among other challenges, can introduce errors when attempting to image the object of interest 454 by deforming into a surface as the transmitter and receiver are no longer flat and at the same distance from the target.

[0043] On-person wearable ultrasound systems can provide high resolution (up to 200 μm), long duration (greater than 48 hours), and continuous imaging of various internal tissues and organs including blood vessels, muscles, heart, gastrointestinal tract, diaphragm, etc. The systems can also provide diagnosis and / or treatment of various diseases including high / low blood pressure, neuromuscular disorders, cardiac disease, gastrointestinal disorders, COVID-19, etc.

[0044] In some configurations, the ultrasound probe includes a piezoelectric transducer with a center frequency in the range of 2 MHz to 10 MHz. The center frequency of the transducer determines the imaging resolution and penetration depth, with a resolution of 200 μm for penetration depths of less than 6 cm and a resolution of 600 μm for penetration depths up to 18 cm. Each transducer can be controlled by circuitry above and below the ultrasound probe.

[0045] The ultrasonic circuit can be fabricated using any suitable technique, such as three-dimensional (3D) printing, laser etching, photolithography, etc. In some configurations, circuit-line resolutions of 100 μm, 10 μm, and 1 μm can be achieved for each method. The bottom circuit may be covered by an acoustic matching layer to enhance acoustic transparency to the skin. The top circuit may be covered by an acoustic backing layer to quench any resonant effects.

[0046] In some configurations, the ultrasound probe may be sealed with an epoxy layer for high stability and reliability over long periods of use. To connect the ultrasound probe to the imaging system, a wireless connection may be used, or a "plug-and-play" input / output (I / O) may be used to instantly transmit the probe's data. In a non-limiting example, the I / O may include a flexible flat wire to form the connection.

[0047] The ultrasound probe may be sized for use on a subject. In a non-limiting example, the probe may have a thickness of 3 mm, and a length and width ranging from 2 cm to 4 cm. The ultrasound probe may be much smaller in size and lighter in weight (e.g., 10-40 g) than conventional ultrasound imaging probes. The bottom surface (i.e., the matching layer side) of the ultrasound probe may be firmly adhered to the skin via a bioadhesive matching agent.

[0048] The matching agent can include a soft but tough hydrogel composed of chitosan-polyacrylamide (PA-Am) interpenetrating polymer network (e.g., 10 wt%) and water (e.g., 90 wt%). The hydrogel can be encapsulated by a thin elastomeric membrane, such as polyurethane less than 40 μm thick, to prevent dehydration of the hydrogel and allow the skin to comfortably contact the dry matching agent surface instead of the wet hydrogel for extended periods of time (more than 48 hours). The polyurethane can be grafted with poly(acrylic acid) conjugated with N-hydroxysuccinimide ester (NHS ester) to form a strong bond between the elastomeric membrane and the hydrogel. The hydrogel-elastomer hybrid can be further coated by a thin bioadhesive layer (e.g., less than 10 μm thick) synthesized by copolymerizing poly(ethylene glycol) diacrylate, 2-ethylhexyl acrylate, and acrylic acid.

[0049] Carboxylic acid, ethyl, and hexyl groups in the bioadhesive layer may form physical bonds, such as hydrogen bonds and electrostatic interactions, with the skin and probe surface, resulting in instant, stable, noncorrosive adhesion over long periods of time. NHS ester groups that form covalent bonds with the skin may be further coupled to the bioadhesive layer to enhance adhesion of the matching agent on the skin in moist environments such as sweating or immersion in water. The total thickness of the elastomeric membrane and bioadhesive layer may be selected to be less than 1 / 4 of the acoustic wavelength, and therefore not affect the acoustic transparency of the matching agent. In a non-limiting example, the transmission may be selected to be greater than 97% for degassed water over 48 hours.

[0050] When a rigid device is attached to the skin via a matching agent, the interface toughness is 100 Jm2 over long periods of time in both air and water. -2 , and maintains strong adhesion of the device on the skin for any thickness of matching agent.

[0051] Non-Limiting Exemplary Adhesion Tests To evaluate the adhesive performance of the device to skin, a standard 90° peel test (according to ASTM D2861) was performed to measure the interfacial toughness of the elastomeric membrane adhered to porcine skin via a bioadhesive layer. Pig skin was chosen as a model tissue to evaluate the adhesive performance due to its similarity to human skin. The elastomeric membrane can immediately establish a strong adhesion upon contact with porcine skin. The interfacial toughness between the elastomeric membrane and porcine skin, adhered via a bioadhesive layer with or without NHS ester groups, was consistently 800 Jm -2 When the bonded samples were stored in air (relative humidity 30-50%, temperature 24°C), the interfacial toughness showed only a relatively small decrease (less than 5%) over 48 hours. When the bonded samples were stored in water to simulate a humid environment, the interfacial toughness of samples bonded via bioadhesive layers without and with NHS ester groups increased by 575 Jm over 48 hours, respectively. -2 and 280 Jm -2These results, as shown in Figure 5, indicate that the device is expected to maintain strong adhesion on the skin over a 48 hour period in both dry and humid environments.

[0052] The bioadhesive layer with NHS ester groups can provide more stable adhesion in a moist environment. The device can be peeled off from the skin by peeling off one end of the matching agent without leaving any residue, as shown in Figure 6.

[0053] A study was conducted to evaluate an example of the above-mentioned system forming the BAUS device. To evaluate the comfort of wearing the device on the skin, a set of matching agents was applied to various body locations including the arms, neck, chest, and lower back of five subjects for 48 hours. All BAUS matching agents maintained robust adhesion to the subjects over 48 hours. Most subjects did not experience any positive reactions (i.e., itching, irritation, dryness, redness) at any location. As a control sample, a silicone patch and liquid matching agent were mechanically wrapped around the arms of five subjects for 48 hours. Positive reactions were observed in two subjects wearing the silicone patch and in all five subjects wearing the liquid matching agent. These results demonstrated the excellent wearing comfort and skin compatibility of the BAUS matching agent.

[0054] To evaluate the acoustic performance of the BAUS device, the relative acoustic transmittance of the BAUS matching agent was measured. The measured relative acoustic transmittance was consistently above 97% over 48 hours (compared to degassed water), demonstrating the high stability and acoustic transparency of the BAUS matching agent during long-term imaging. The BAUS device was bonded onto a soft tissue vascular phantom at various vibration frequencies (0 Hz to 3.5 Hz with an amplitude of 2 cm) to evaluate the acoustic performance under dynamic body motion. The BAUS device could continuously and stably image the long axis of the blood vessel under severe vibration of various frequencies (see Figure 7), demonstrating stable imaging quality under dynamic body motion.

[0055] The temperature of the BAUS device was measured while it was continuously operated with different levels of operating voltage (0V-90V) for 48 hours, as shown in Figures 8 and 9. Given the low operating power and thin heat dissipation, the BAUS device maintained a constant temperature (24°C) while continuously taking images for 48 hours, further verifying the image stability in long-term applications.

[0056] (High-resolution, long-term continuous imaging of various organs) In some configurations, a wearable imaging platform is provided that is capable of high-resolution, long-term continuous imaging of human organs including blood vessels and heart, muscles and diaphragm, stomach, and lungs (see FIG. 9). The organs represent the cardiovascular, muscular, digestive, and respiratory systems, respectively. To image organs less than 6 cm below the skin (i.e., jugular vein, carotid artery, and biceps), an ultrasound probe with a center frequency of 6-10 MHz can be configured and a synthetic aperture imaging method can be used. To image organs deeper than 6 cm below the skin (i.e., heart, stomach, diaphragm, and lungs), an ultrasound probe with a center frequency of 2-5 MHz can be used with a phased array imaging method. The probes can be adhered to various locations on the subject's skin via a BAUS matching agent such that continuous imaging of the corresponding organs can be performed over a selected period of time, such as, for example, 48 hours, or continuously.

[0057] Dynamic body movements such as neck rotation can cause vascular deviation and skin deformation, which dramatically deteriorates the imaging quality and stability of conventional wearable ultrasound devices, as shown in Figure 10. In contrast, the BAUS device can provide high-resolution (200 μm) continuous imaging of structures such as the jugular vein and carotid artery (see Figure 10A) under dynamic body movements such as neck rotation at angles up to ±30 degrees (see Figure 10B). The robust attachment of the BAUS device to the neck, the high imaging resolution of the BAUS probe, and the large acoustic window afforded by the BAUS probe aperture (e.g., 2 cm × 2 cm aperture) can mitigate the effects of dynamic movements.

[0058] In a non-limiting example, a wearable ultrasound system was used to obtain image results of the jugular vein and carotid artery. A 10MHz BAUS device was attached to the right cervical region. The results showed that the diameter of the subject's jugular vein increased significantly on a daily basis from the sitting / standing to supine positions. The change in jugular vein diameter was strongly correlated with the right atrial pressure, and can therefore be used to diagnose cardiac diseases such as heart failure and pulmonary hypertension. In addition, 48-hour continuous blood flow velocity and carotid artery blood pressure waveforms were obtained. Dramatic increases in the subject's vascular diameter (from 0.5cm to 1.75cm), blood flow velocity (from 65cm / sec to 117cm / sec), and carotid artery systolic blood pressure (from 115mmHg to 168mmHg) were observed before and after 0.5 hours of physical exercise (see Figure 10C). From the blood pressure waveforms after physical exercise, a steeper drop in blood pressure from the systolic peak in each cardiac cycle test was observed than before exercise, which was probably due to exercise-induced vasodilation of the carotid artery. Such long-term continuous monitoring of real-time changes in blood flow velocity and blood pressure waveforms can provide unprecedented information about one's cardiovascular status and enable new powerful means for the diagnosis and prognosis of cardiovascular disease (see Figure 10D-10F).

[0059] In a non-limiting example, imaging of the biceps muscle was obtained with a 7 MHz BAUS device attached to the subject's upper arm. The BAUS system can provide high resolution (300 μm) continuous imaging of the biceps muscle. Increased blood perfusion and echogenicity at the muscle-tendon interface was observed 2 hours after a 1-hour weightlifting training session, with increased vascularity 10 hours after training. Such long-term continuous imaging of the musculoskeletal system may facilitate advances in sports medicine.

[0060] In a non-limiting example, as shown in FIG. 11A, lung imaging results were obtained by a 4 MHz BAUS phased array device attached to the right thorax (longitudinal orientation) of a subject. It can continuously image key lung features including pleural lines, A-lines, and B-lines at high resolution (500 μm). BAUS imaging showed smooth pleural lines and recurrent A-lines in the subject over a 48-hour period, indicating healthy aerated lungs. Lung ultrasound has proven to be an effective tool in the diagnosis and treatment of COVID-19 patients, but in most cases, it is available in hospitals for rare and non-continuous lung imaging diagnostics. The wearable BAUS system could continuously monitor symptoms of COVID-19 patients who may be infected at home, providing important real-time information on the patient's health status and disease progression.

[0061] In a non-limiting example, imaging of diaphragmatic movement was obtained with a 4 MHz BAUS phased array device attached to the right anterior subcostal area of ​​a subject before and after 0.5 hours of physical exercise, as shown in Figures 11B-11C. The BAUS images showed that diaphragmatic motility after training was more dramatic in amplitude and frequency compared to pre-training quiet breathing.

[0062] In a non-limiting example, cardiac imaging results were obtained by a 4 MHz BAUS phased array attached to the subject's left chest (imaging via apical 4-chamber view), as shown in FIG. 12. The BAUS system can give high-resolution (600 μm) continuous images of the dynamics of the four cardiac chambers, including the right ventricle, right atrium, left ventricle, and left atrium (see FIG. 12, A). The size of the left ventricle was observed to increase significantly 0.5 hours after physical exercise. The continuous images of the cardiac chambers can be further processed to calculate the dynamics of cardiac loading, a critical parameter that may indicate cardiomyopathy (see FIG. 12, B). Cardiovascular diseases are usually weakly symptomatic in the early stages with random attacks, and are infrequent, but are difficult to catch even in routine health screening. The wearable BAUS platform can provide high-resolution continuous imaging of cardiac dynamics over several days, allowing for early detection and diagnosis of various cardiovascular diseases.

[0063] In a non-limiting example, gastric imaging results were obtained with a 4.5 MHz BAUS phased array device attached to the subject's upper abdominal skin (see FIG. 13A). The BAUS imaging system provided high-resolution (500 μm) 48-hour continuous imaging of gastric antrum cross-sections. When the subject drank 450 ml of juice, gastric antrum expansion was observed. Over the next 2 hours, gastric emptying led to a gradual decrease in gastric antrum cross-sectional area (see FIG. 13B). Gastrointestinal motility may indicate systematic digestion, which affects systematic nutritional intake and metabolism. The BAUS imaging system can provide high-resolution continuous imaging of gastrointestinal motility by attaching the BAUS device to various locations on the abdominal skin.

[0064] With its high-resolution, long-term imaging capability, the BAUS imaging platform may be used in other human organ systems to provide information for precision medicine and digital medicine. It may be possible to image the development of various tissues and organs, such as embryos, tumors, and brains, at high resolution and long-term in a non-invasive procedure. The high-quality, long-term time series images of various tissues and organs obtained by the BAUS imaging platform may be useful for training deep learning models for future clinical and biological applications.

[0065] In a non-limiting example, a bioadhesive focused ultrasound (BAFUS) device can be used for high-resolution, long-term, on-demand stimulation of various tissues and organs of the body. The BAFUS stimulation can be guided by a BAUS imaging system to synergistically achieve closed-loop diagnosis and therapy.

[0066] Conventional epidermal device designs include making the device thin and stretchable to allow for conformal attachment to the skin. Thin and stretchable form factors often compromise device reliability and functionality, but do not necessarily ensure stable adhesion of the device to the skin. Ultrasound devices in accordance with the present disclosure can be used to firmly adhere thin, rigid devices to the skin via a soft, durable, bioadhesive matching layer that effectively transmits acoustic waves, isolates the device from skin deformation, and maintains a strong, comfortable adhesion to the skin over time. The bioadhesive matching layer allows electrical, optical, and chemical contact with the skin.

[0067] 14, a flow chart is provided including non-limiting example steps of a method for forming an enhanced ultrasound imaging system. An ultrasound probe having a plurality of transducers arranged across a plane may be formed in step 1402. An elastomeric membrane may be stretched across the plane of the ultrasound probe and bonded in step 1404. An acoustically transparent material may be disposed within the elastomeric membrane in step 1406. In step 1408, a bioadhesive layer may be formed and bonded to the elastomeric membrane opposite the ultrasound probe and configured to bond the elastomeric membrane to a subject.

[0068] In forming a matching agent by way of non-limiting example, chemicals for synthesizing a strong hydrogel include acrylamide (AAm), acetic acid (AAc), α-ketoglutaric acid, chitosan (high molecular weight), N,N ’Chemicals for synthesizing the elastomeric membrane may include hydrophilic polyurethane (Advansource Biomaterials), hydrophobic polyurethane (Advansource Biomaterials), acrylic acid (AAc), benzophenone, α-ketoglutaric acid, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and N-hydroxysuccinimide (NHS). Chemicals for synthesizing the bioadhesive layer may include acrylic acid (AAc), acrylic acid N-acryloxysuccinimide (AAc-NHS ester), 2-hydroxy-4-methyl-2-propanediol (2-methyl-2-propanediol), 2 ... ’ -(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959), polycaprolactone polyurethane, 2-ethylhexyl acrylate (EHA), poly(ethylene glycol) diacrylate (average Mn 560, PEGDA), ethanol, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and N-hydroxysuccinimide (NHS).

[0069] In a non-limiting example, to make a PAAm-chitosan rigid hydrogel, 3% (w / w) high molecular weight chitosan, 12% (w / w) acrylamide, 0.15% (w / w) N,N ’ -methylenebisacrylamide, 0.3% (w / w) α-ketoglutaric acid can be dissolved in 1% acetic acid solution. The mixture can be centrifuged, for example, at 6000 rpm, and poured into a glass mold with a transparent cover. The solution can then be cured in an ultraviolet (UV) chamber, for example, at 364 nm, 10 W power, for 60 minutes. The resulting hydrogel can then be immersed in a 1M CaCl2 solution for a period of time, such as 24 hours, to reach equilibrium.

[0070] Non-Limiting Examples To make a PU elastomeric membrane, 30% poly(acrylic acid) can be attached onto hydrophilic PU by UV-initiated reaction at 364 nm wavelength and 10 W power in the presence of 1.5 w / v% benzophenone and 0.3 w / v% α-ketoglutaric acid for, for example, 120 minutes. After the reaction, the mixture can be dialyzed (cutoff Mn 3000 Da) against ethanol for a period such as 3 days and against water for 3 days to obtain pure adhesive PU. The purified adhesive PU can be washed with water and thoroughly dried. On clean glass, a thin layer of hydrophobic PU (30% w / w) can be spin-coated onto the glass at 1500 rpm. After the hydrophobic PU is completely dried, a thin layer of hydrophilic PU (30% w / w) can be spin-coated onto the hydrophobic PU layer at 1500 rpm. A thin layer of adhesive PU with EDC and NHS (30% w / w adhesive PU, 5% w / w EDC, and 5% w / w NHS) can be spin-coated at 1500 rpm onto the hydrophilic PU layer. After the membrane is completely dried in airflow for a period such as 4 hours, a PU elastomeric membrane can be obtained.

[0071] To prepare a non-limiting example bioadhesive layer, 0.5% (w / w) Irgacure 2959, 0.05% (w / w) PEGDA, 12% (w / w) AAc, 35% (w / w) EHA can be dissolved in nitrogen-purged ethanol. The mixture can then be poured into a glass mold with spacers. An adhesive film is obtained after curing the mixture under ultraviolet (UV) light, such as 10 W power at a wavelength of 364 nm, for a time such as 40 minutes.

[0072] To form the hydrogel-elastomer hybrid, the hydrogel may be cut to the desired shape and size, and then the adhesive polyurethane side of the elastomer membrane may be adhered onto the gel with light pressing to eliminate any air bubbles. The hydrophobic side of the PU may be adhered to a bioadhesive layer. The edges of the elastomer and the bioadhesive capsule may be cut and sealed by laser sintering. The outer layer of the elastomer membrane may be a bioadhesive layer, which may be firmly adhered to the skin and device with light pressing.

[0073] 15, a non-limiting example graph 1500 of energy release rate G is shown as a function of matching layer thickness H. As shown, a rigid device physically attached to the skin can peel off and a rigid device attached to the skin via a liquid hydrogel matching agent can form an unstable bond due to the matching agent running off and dehydration, whereas a rigid device attached to the skin via a matching agent according to the present disclosure can form a stable bond.

[0074] (Acoustic simulation of phased array probe) The phased array directivity, penetration, and strength of the transducers may be determined using computer simulation. The center frequency and geometry of all transducers in the array can be set to be identical. The excitation voltage (40V), single-cycle pulse, and electromechanical correlation coefficient (0.6) of all transducers can be set to be the same. The attenuation coefficient of the medium is set to 0.75 dBcm to mimic the acoustic properties of human tissue. -1 MHz -1 can be selected as.

[0075] (Measurement of interface toughness) The interfacial toughness of the elastomeric membrane may be determined. In a non-limiting example, the elastomeric membrane was adhered to porcine skin via the bioadhesive layer and measured using a standard 90° peel test (per ASTM D 2861) using a mechanical tester (20 N load cell; Z2.5 by Zwick / Roell) and a 90° peel fixture (G50 by Test Resources). All tests were performed either in ambient air or in water at room temperature. A width of 2.5 cmW and a length of 7.5 cmL of the elastomer (40 μm thick) and the bioadhesive layer (10 μm thick) were prepared. A polycarbonate membrane was adhered to the backside of the elastomer as a rigid backing for the elastomeric membrane. The resulting samples were then subjected to a 50 mm min -1 The samples were tested in a standard 90° peel test at a constant peel rate of 0.05 mm. The measured peel force reached a plateau (with slight oscillations) as the peel process entered a steady state. The interfacial toughness G was determined by dividing the plateau force F by the width of the sample W.

[0076] (Formation of backing layer) The backing layer of the BAUS probe can provide mechanical support to the transducer that may generate high frequency vibrations within the probe. The backing layer may also be selected to have strong attenuation to ultrasound to effectively shorten the pulse duration and therefore increase the imaging resolution. The backing design can be optimized by constructing transducers with backing layers of various compositions of epoxy (EPO-TEK301) with tungsten powder (particle size 1um, Sigma-Aldrich) and performing comparisons. In a non-limiting example, an 8:1 composition (epoxy to tungsten powder, weight ratio) provided optimized acoustic properties. A BAUS probe with an optimized backing layer with shorter pulse length and higher signal-to-noise ratio can provide improved signal quality.

[0077] (Formation of matching layer) In a non-limiting example, a matching layer for a BAUS probe can be constructed by doping epoxy (EPO-TEK301) with cerium dioxide nanoparticles (e.g., 10 nm particle size) in ethanol (0% to 80% cerium dioxide by weight in epoxy). The matching layer can provide the required acoustic impedance gradient, which allows the acoustic energy from the transducer to penetrate smoothly into the body tissue and for the reflected acoustic waves (return echoes) to return smoothly to the transducer for imaging.

[0078] Non-Limiting Exemplary Data Acquisition and Image Processing The radio frequency signals received by the ultrasound probe may be post-processed. Synthetic aperture imaging algorithms may be used to image organs within 6 cm below the skin, including muscles, carotid arteries, and jugular veins. For applications requiring a relatively high frame rate, such as blood pressure measurement, a plane wave imaging mode may be used to increase the frame rate. A plane wave may be generated by applying a flat delay to all elements of the ultrasound probe. The generated wave may inactivate the entire region of interest. Plane wave imaging allows the acquisition of one complete ultrasound image from a single shot.

[0079] Phased array harmonic imaging and spatial compounding algorithms can be used to image organs deeper than 6 cm below the skin, including the heart, lungs, diaphragm, and stomach. Imaging algorithms may be adapted from algorithm packages of commercial or research systems.

[0080] (Blood Pressure Calculation) In some configurations, systems and methods according to the present disclosure may determine blood pressure for a subject. By recording successive cross-sectional images of a blood vessel, its diameter can be determined and the blood pressure waveform calculated. The arterial blood pressure waveform p(t) is given by:

number

[0081] Here, p d is the expansion pressure, and A d is the expansion tract cross section, A(t) is a function of time t, α is the stiffness coefficient, and t is time. Assuming that the artery is rotationally symmetric, A(t) can be determined as follows:

number

[0082] Assuming that human blood vessels are elastic and that viscoelasticity is negligible, the pressure-diameter curve can have moderate hysteresis, less than 0.2%, which is considered appropriate for subjects with normal local vascular status, or only slight local atherosclerosis. The blood vessel diameter does not lag behind the pressure waveform, and an accurate blood pressure waveform can be reconstructed from the blood vessel diameter waveform using the above equation.

[0083] The stiffness coefficient α is expressed as follows:

number

[0084] Statistical analysis can be used to assess the statistical significance of all comparisons. For all parametric tests, data distribution may be assumed to be normal. For statistical analysis for comparisons between multiple samples, one-way ANOVA followed by Tukey's multiple comparison test can be performed. In non-limiting examples, the thresholds for statistical analysis can be *p≦0.05, **p≦0.01, and ***p≦0.001. For statistical analysis between two groups of data, a two-sample Student's t-test can be used, with significance thresholds of *p≦0.05, **p≦0.01, and ***p≦0.001.

[0085] (Non-limiting examples of adjustable BAUS) The adjustable BAUS includes multiple thin ultrasound probes for wearable imaging of multiple organs simultaneously and adjustable matching agents for instantaneous adjustment and optimization of imaging direction. The adjustable BAUS matching agent is realized by a durable hydrogel with thermo-responsive, remolding ability, which can rigidly maintain its shape at normal skin temperature and can be remolded at elevated but skin-tolerant temperatures (see Fig. 16-18). The hydrogel is encapsulated by a bioadhesive elastomer that adheres to the skin and prevents dehydration of the adjustable BAUS matching agent. Through the adjustable BAUS matching agent, multiple thin, rigid, and adjustable BAUS probes are adhered to various positions on the skin, and each probe is adjusted toward the optimized imaging direction by the instantaneous remolding of the adjustable BAUS matching agent on the skin. The adjustable BAUS probes are controlled by connecting to an adjustable portable BAUS controller. The adjustable BAUS system realizes multi-organ correlation optimization, multi-direction, and multi-window imaging in daily activities.

[0086] In a non-limiting example, the tunable BAUS matching agent comprises a thermo-responsive, reshapeable, and tough hydrogel composed of a first polymer network, a second polymer network, and water. The first polymer network is a polymer network with thermal transition properties and may comprise κ-carrageenan (κ-CG), agarose, or gelatin. The second polymer network is a general hydrophilic polymer including polyacrylamide (PAAm), polyvinyl alcohol, polyethylene glycol, poly(acrylic acid), poly(2-hydroxyethyl methacrylate), silicone, and poly(N-isopropylacrylamide). In a non-limiting embodiment, the tunable BAUS matching agent comprises a thermo-responsive and reshapeable tough hydrogel composed of a κ-CG-PAAm interpenetrating polymer network (10 wt%) and water (90 wt%), as shown in FIG. 17. The hydrogel is encapsulated by a thin bioadhesive elastomeric membrane (less than 40 mm thick) of polyurethane, which prevents hydrogel dehydration and provides comfortable and stable adhesion to the skin (see Figure 18A-18C). The hydrogel utilizes the thermal transition properties of κ-CG. At normal skin temperature (28°C-37°C), the hydrogel is in an elastic solid state and is stable on the skin and maintains its shape. At elevated but skin-tolerant temperatures (37°C-50°C), the thermoresponsive hydrogel transitions to a remoldable state. This allows adjustment of the adjustable BAUS probe position and imaging orientation by remolding the heated adjustable BAUS matching agent on the skin. Once the optimized probe position and imaging orientation are determined, the adjustable BAUS matching agent cools down to the normal skin temperature and maintains its shape.

[0087] In a non-limiting example, the adjustable BAUS probe integrates a thin, rigid, high performance ultrasonic probe with an electric heater. The ultrasonic probe has 96 piezoelectric elements with a center frequency of 4 or 10 MHz. The integrated electric heater can heat the adjustable BAUS matching agent from normal skin temperature (e.g., 35°C) to an elevated but skin tolerable temperature (e.g., 50°C) within 6 seconds for fast and immediate adjustment of the adjustable BAUS probe's position on the skin. The adjustable BAUS probe has dimensions of 30mm x 10mm x 3mm and a weight of 54g, and can be comfortably adhered to various positions on the skin via the adjustable BAUS matching agent.

[0088] (Non-limiting example of changing the adjustable BAUS position) To evaluate the tunability of the tunable BAUS matching agent, the shear modulus of κ-CG-PAAm hydrogel with optimized composition (3 wt% κ-CG, 7 wt% PAAm) was measured as it was cooled from 60°C to 27°C. When the temperature of the hydrogel is increased but at skin tolerable temperature (45°C-50°C), the shear modulus of the hydrogel is less than 1 kPa (see FIG. 18A), which allows the hydrogel to reshape in various shapes (see FIG. 18B). When the temperature of the hydrogel is decreased to normal skin temperature (27°C-37°C), the hydrogel is frozen in the reshape (see FIG. 18B) and the shear modulus of the hydrogel increases to more than 10 kPa (see FIG. 18A). At normal skin temperature (27°C-37°C), the hydrogel is also able to elastically recover its shape after large deformation. The adjustable BAUS matching agent with the optimized composition allows for instant adjustment of the ultrasound imaging direction by rocking, sweeping, and / or rotating the adjustable BAUS probe, which reshapes the adjustable BAUS matching agent at an elevated but skin-tolerable temperature (see FIG. 18C-18E). Once the optimized imaging direction is determined, the reshapeable adjustable BAUS matching agent is cooled to skin temperature and frozen in its adjusted shape.

[0089] (Non-limiting example of evaluating the acoustic performance of adjustable BAUS) To evaluate the acoustic performance of the tunable BAUS matching material, the attenuation coefficient of the tunable BAUS matching material was measured before and after reshaping using a transmission through method (e.g., by uniaxially stretching the matching material twice). In the frequency range of 1-10 MHz, the attenuation coefficient of the tunable BAUS matching material before and after reshaping was measured to be between 0.064-0.133 dB / mm and 0.066-0.116 dB / mm, respectively. The acoustic impedance of the tunable BAUS matching material was further measured to be 1.59 MRayl, which matches the acoustic impedance of the skin. In comparison, typical liquid and solid hydrogel matching materials have attenuation coefficients similar to those of the tunable BAUS matching material, i.e., 0.057-0.120 dB / mm and 0.102-0.173 dB / mm in the frequency range of 1-10 MHz. However, the attenuation coefficient of typical elastomeric matching agents is several times higher than that of tunable BAUS matching agents at the same frequency. Furthermore, typical solid hydrogel and elastomeric matching agents cannot reshape on the skin, and typical liquid hydrogel matching agents cannot maintain their shape under pressure from an ultrasound probe.

[0090] (Non-limiting examples of adjustable BAUS imaging directions) To demonstrate the ability of the adjustable BAUS matching agent to provide an optimized imaging direction, the adjustable BAUS probe was adhered to various positions on the body via a flat, adjustable BAUS matching agent. As a result, the adjustable BAUS probe was initially parallel to the skin. The unadjusted imaging direction is usually not optimized because most biological interfaces, such as organ walls, are not parallel to the skin (see FIG. 16). Therefore, before adjusting the imaging direction, ultrasound images of various tissues and organs, such as finger joints, heart, carotid artery, bladder, liver, muscle, stomach, lungs, and kidneys, were blurred and lacking details (see FIG. 19). Once the adjustable BAUS probe was adjusted to achieve an optimized imaging direction by reshaping the adjustable BAUS matching agent, the ultrasound images obtained by the same system were dramatically enhanced. For example, the adjustable BAUS matching agent was reshaped around the finger joints after adjustment to give substantially improved image quality (see FIG. 19B). The adjustable thoracic BAUS probe was tilted by an angle of 30° to 60° after adjustment to give an optimized imaging orientation for the two-chamber view of the heart (see FIG. 19C). The cervical adjustable BAUS probe was tilted by an angle of 15° after adjustment to achieve an optimized orientation for imaging the carotid artery (see FIG. 19D).

[0091] (Non-Limiting Example of Tunable BAUS Simultaneous Multi-Window Imaging) The multi-window simultaneous imaging capability of multi-organ correlations of the adjustable BAUS system was demonstrated, including diaphragm-heart-jugular vein, stomach-bladder, and muscle-brachial artery correlations during daily activities (see Figure 20). The adjustable BAUS probe was attached to multiple positions on the skin via the adjustable BAUS matching agent, and then the probe position was instantly adjusted to achieve the optimized imaging direction.

[0092] Figure 20A-20C show the correlation between the diaphragm, heart, and blood vessels. Using the adjustable BAUS system, the subject's diaphragm, right atrium, and jugular vein were imaged simultaneously. In the baseline condition, the subject's diaphragm, right atrium, and jugular vein were all observed to function normally (see Figure 20B). The subject then suddenly lifted the diaphragm and compressed the right atrium. The adjustable BAUS system spontaneously imaged a drop in the right atrial volume and a dilated area of ​​the jugular vein, as the compressed right atrium caused an increase in blood pressure flowing into the pulmonary artery, followed by an increase in blood pressure flowing into the jugular vein. The increase in jugular vein pressure led to the dilated area of ​​the jugular vein observed in the BAUS images. These findings provide valuable information for understanding the mechanical interactions between the diaphragm, heart, and blood vessels, and have significant implications for the diagnosis and monitoring of respiratory and cardiovascular diseases.

[0093] FIG. 20C and FIG. 20D provide correlations between the stomach and bladder imaged simultaneously by the adjustable BAUS system over several hours. At 0 hours, both the stomach and bladder were in baseline state. After the subject ingested 500 ml of water at 0.5 hours, the stomach immediately expanded and then gradually reduced the stomach volume to baseline over the next 2 hours by absorbing and passing water. Correspondingly, the bladder gradually filled with urine and its volume increased. After 2.5 hours, the subject urinated and the bladder returned to the baseline state. In a non-limiting example, the deep learning algorithm MOSNet further segmented the time-series ultrasound images of the stomach and bladder to quantify their cross-sectional areas (see FIG. 20D). The quantification results (see FIG. 20D) are consistent with the ultrasound images of the stomach-bladder correlation (see FIG. 20C). This finding demonstrates the ability of the adjustable BAUS system to capture the physiological relationship between the stomach and bladder, providing valuable insights into the human digestive and urinary systems.

[0094] The human body is a complex system with multiple organs that interact with each other over time. Existing portable and wearable ultrasound devices mostly perform short-term imaging of an individual organ at a time via a single ultrasound probe. A portable adjustable BAUS system can simultaneously image most organs (correctable to ultrasound imaging) in a freely moving subject over several days via multiple adjustable BAUS probes. Each adjustable BAUS probe is further adjusted to an optimized imaging orientation for high wearable imaging performance. The obtained multi-organ correlated long-term time-series imaging data could provide new system-level insights into human physiology. The adjustable BAUS system could also provide multi-window imaging, monitoring, and diagnostic tools for various diseases.

[0095] This disclosure has described one or more preferred embodiments, and it should be recognized that, except as expressly stated, many equivalents, alternatives, variations, and modifications are possible and are within the scope of the invention.

Claims

1. 1. A system for long term ultrasound imaging of a subject, comprising: an ultrasonic probe formed from a plurality of transducers arranged across a plane; an elastomeric membrane extending across and coupled to the plane of the ultrasonic probe; an acoustically transparent material disposed within the elastomeric membrane; and a bioadhesive layer configured to couple to the elastomeric membrane opposite the ultrasound probe and to couple the elastomeric membrane to the subject; A system comprising:

2. The plane has rigidity; the elastomeric membrane is configured to deform away from the ultrasound probe and bond to the elastomeric membrane using the bioadhesive layer, and to bond the elastomeric membrane to the subject. The system of claim 1 .

3. The system of claim 1 , wherein the acoustically transparent material comprises a rigid hydrogel matching agent.

4. 4. The system of claim 3, wherein the hydrogel is a polymer network saturated with water and comprises at least one of the following materials: polyacrylic acid and its derivatives, polymethacrylic acid and its derivatives, polyacrylamide and its derivatives, polyvinyl alcohol and its derivatives, polyethylene glycol and its derivatives, polyurethane and its derivatives, latex and its derivatives, natural rubber, polydimethylsiloxane and its derivatives, casein and its derivatives, albumin and its derivatives, gelatin and its derivatives, collagen and its derivatives, chitosan and its derivatives, hyaluronic acid and its derivatives, alginate and its derivatives, fibrin and its derivatives, agarose and its derivatives, oxidized alginate and its derivatives, cellulose and its derivatives, oxidized cellulose and its derivatives, and κ-carrageenan and its derivatives.

5. The system of claim 4 , wherein the hydrogel comprises at least one chemical or physical crosslinker.

6. The chemical crosslinking agent may be selected from the group consisting of gelatin methacrylate, gelatin acrylate, gelatin N-hydroxysuccinimide, gelatin maleimide, hyaluronic acid methacrylate, hyaluronic acid acrylate, hyaluronic acid N-hydroxysuccinimide, hyaluronic acid maleimide, oxidized methacrylic alginate, oxidized acrylic alginate, alginic acid N-hydroxysuccinimide, alginic acid maleimide, polycaprolactone dimethacrylate, fibrin methacrylate, fibrin acrylate, fibrin N-hydroxysuccinimide, fibrin maleimide, collagen methacrylate, collagen acrylate, collagen N-hydroxysuccinimide, collagen maleimide, agarose methacrylate, agarose acrylate, agarose N-hydroxysuccinimide, agarose maleimide, cellulose methacrylate, cellulose acrylate, cellulose N-hydroxysuccinimide , cellulose maleimide, chitosan methacrylate, chitosan acrylate, chitosan N-hydroxysuccinimide, chitosan maleimide, polycaprolactone diacrylate, polycaprolactone dimethacrylate, polycaprolactone di-N-hydroxysuccinimide, polycaprolactone dimaleimide, dipic acid dihydrazide, N,N'-bis(acryloyl)cystamine, N,N'-methylene bis(acrylamide), polyvinyl alcohol, genipin, glutaraldehyde, glyoxal, ethylene glycol dimethacrylate, N,O-bismethacryloylethanolamine, divinylbenzene, trimethylolpropane trimethacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, 1,3-diisopropenylbenzene, glycidyl methacrylate, 2,6-bisacryloylamidopyridine, 3,5-bis(acryloamido)benzoic acid, 1,6. The system of claim 5, comprising at least one of 4-diacryloylpiperazine, acrylic cyclodextrin (CD), methacrylic cyclodextrin (CD), acrylic cucurbit[n]uril, methacrylic cucurbit[n]uril, polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, polyethylene glycol di-N-hydroxysuccinimide, polyethylene glycol dimaleimide, multi-arm polyethylene glycol acrylate, multi-arm polyethylene glycol methacrylate, multi-arm polyethylene glycol N-hydroxysuccinimide, or multi-arm polyethylene glycol maleimide.

7. 10. The system of claim 1, wherein the elastomeric membrane comprises at least one of the following materials: natural rubber, latex, styrene-butadiene block copolymer, polyisoprene, isoprene, polybutadiene, ethylene-propylene rubber, ethylene propylene diene rubber, silicone elastomer, fluoroelastomer, polyurethane elastomer, polyurethane, isobutylene isoprene, chloroprene, nitrile butadiene, or nitrile rubber.

8. The system of claim 1 , wherein the elastomeric membrane maintains a hydration level of the hydrogel.

9. The system of claim 1 , wherein the elastomer and the hydrogel are bonded together such that there are no delaminations, gaps, or air bubbles between them under deformation and force.

10. The system of claim 1 , wherein at least one of the elastomeric membrane, the acoustically transparent material, or the bioadhesive layer is configured to facilitate penetration of ultrasound energy into the subject.

11. 11. The system of claim 10, wherein the bioadhesive layer comprises a material that is at least one of animal glue, casein glue, starch, dextrin, agar, algin, gum arabic, epoxy resin, nitrocellulose, polyvinyl acetate, vinyl acetate-ethylene copolymer, polyethylene, polypropylene, polyamide, polyester, polyacrylic, polycyanoacrylic, polyethyleneimine, natural rubber, butyl rubber, butadiene rubber, styrene-butadiene rubber, nitrile rubber, silicone, or neoprene.

12. The system of claim 1 , wherein the ultrasonic probe comprises a heater configured to heat the acoustically transparent material to adjust a position of the probe.

13. 13. The system of claim 12, wherein the position of the ultrasound probe is adjusted by any of rocking, sliding, and twisting to improve ultrasound imaging of a target structure of the subject.

14. another ultrasonic probe formed from a plurality of transducers arranged across a plane; another elastomeric membrane traversing and bonded to the plane of the ultrasonic probe; another acoustically transparent material disposed within the elastomeric membrane; and another bioadhesive layer configured to couple to the elastomeric membrane opposite the ultrasound probe and to couple the elastomeric membrane to the subject; 13. The system of claim 1, further comprising: a first input / output port for receiving a first signal from a first receiving port;

15. 1. A method for long term ultrasound imaging of a subject, comprising: forming an ultrasonic probe having a plurality of transducers disposed across a plane; stretching the coupled elastomeric membrane across the plane of the ultrasonic probe; disposing an acoustically transparent material within the elastomeric membrane; forming a bioadhesive layer attached to the elastomeric membrane opposite the ultrasound probe and configured to attach the elastomeric membrane to the subject.

16. The plane has rigidity; the elastomeric membrane is configured to deform away from the ultrasound probe and bond to the elastomeric membrane using the bioadhesive layer, and to bond the elastomeric membrane to the subject. The method of claim 15.

17. The method of claim 15 , wherein the acoustically transparent material comprises a rigid hydrogel matching agent.

18. 18. The method of claim 17, wherein the hydrogel is a polymer network saturated with water and has materials comprising at least one of polyacrylic acid and its derivatives, polymethacrylic acid and its derivatives, polyacrylamide and its derivatives, polyvinyl alcohol and its derivatives, polyethylene glycol and its derivatives, polyurethane and its derivatives, latex and its derivatives, natural rubber, polydimethylsiloxane and its derivatives, casein and its derivatives, albumin and its derivatives, gelatin and its derivatives, collagen and its derivatives, chitosan and its derivatives, hyaluronic acid and its derivatives, alginate and its derivatives, fibrin and its derivatives, agarose and its derivatives, oxidized alginate and its derivatives, cellulose and its derivatives, oxidized cellulose and its derivatives, and kappa-carrageenan and its derivatives.

19. The method of claim 18 , wherein the hydrogel comprises at least one chemical or physical crosslinker.

20. The chemical crosslinking agent may be selected from the group consisting of gelatin methacrylate, gelatin acrylate, gelatin N-hydroxysuccinimide, gelatin maleimide, hyaluronic acid methacrylate, hyaluronic acid acrylate, hyaluronic acid N-hydroxysuccinimide, hyaluronic acid maleimide, oxidized methacrylic alginate, oxidized acrylic alginate, alginic acid N-hydroxysuccinimide, alginic acid maleimide, polycaprolactone dimethacrylate, fibrin methacrylate, fibrin acrylate, fibrin N-hydroxysuccinimide, fibrin maleimide, collagen methacrylate, collagen acrylate, collagen N-hydroxysuccinimide, collagen maleimide, agarose methacrylate, agarose acrylate, agarose N-hydroxysuccinimide, agarose maleimide, cellulose methacrylate, cellulose acrylate, cellulose N-hydroxysuccinimide , cellulose maleimide, chitosan methacrylate, chitosan acrylate, chitosan N-hydroxysuccinimide, chitosan maleimide, polycaprolactone diacrylate, polycaprolactone dimethacrylate, polycaprolactone di-N-hydroxysuccinimide, polycaprolactone dimaleimide, dipic acid dihydrazide, N,N'-bis(acryloyl)cystamine, N,N'-methylene bis(acrylamide), polyvinyl alcohol, genipin, glutaraldehyde, glyoxal, ethylene glycol dimethacrylate, N,O-bismethacryloylethanolamine, divinylbenzene, trimethylolpropane trimethacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, 1,3-diisopropenylbenzene, glycidyl methacrylate, 2,6-bisacryloylamidopyridine, 3,5-bis(acryloamido)benzoic acid, 1,20. The method of claim 19, comprising at least one of 4-diacryloylpiperazine, acrylic cyclodextrin (CD), methacrylic cyclodextrin (CD), acrylic cucurbit[n]uril, methacrylic cucurbit[n]uril, polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, polyethylene glycol di-N-hydroxysuccinimide, polyethylene glycol dimaleimide, multi-arm polyethylene glycol acrylate, multi-arm polyethylene glycol methacrylate, multi-arm polyethylene glycol N-hydroxysuccinimide, or multi-arm polyethylene glycol maleimide.

21. 16. The method of claim 15, wherein the elastomeric membrane comprises at least one material selected from the group consisting of natural rubber, latex, styrene-butadiene block copolymer, polyisoprene, isoprene, polybutadiene, ethylene-propylene rubber, ethylene propylene diene rubber, silicone elastomer, fluoroelastomer, polyurethane elastomer, polyurethane, isobutylene isoprene, chloroprene, nitrile butadiene, or nitrile rubber.

22. The method of claim 15 , wherein the elastomeric membrane maintains the hydration level of the hydrogel.

23. 16. The method of claim 15, further comprising bonding the elastomer and the hydrogel under deformation and force without delamination, gaps, or air bubbles therebetween.

24. 16. The method of claim 15, wherein at least one of the elastomeric membrane, the acoustically transparent material, or the bioadhesive layer is configured to facilitate penetration of ultrasound energy into the subject.

25. 16. The method of claim 15, wherein the bioadhesive layer comprises a material that is at least one of animal glue, casein glue, starch, dextrin, agar, algin, gum arabic, epoxy resin, nitrocellulose, polyvinyl acetate, vinyl acetate-ethylene copolymer, polyethylene, polypropylene, polyamide, polyester, polyacrylic, polycyanoacrylic, polyethyleneimine, natural rubber, butyl rubber, butadiene rubber, styrene-butadiene rubber, nitrile rubber, silicone, or neoprene.

26. The method of claim 15 , wherein the ultrasonic probe comprises a heater configured to heat the acoustically transparent material to adjust the position of the probe.

27. 27. The method of claim 26, wherein the position of the ultrasound probe is adjusted by any of rocking, sliding, and twisting to improve ultrasound imaging of a target structure of the subject.

28. 1. A system for immobilizing an electronic system on a subject for an extended period of time, comprising: an electronic substrate having a planar surface on which at least one electrical circuit is formed; an elastomeric membrane traversing and bonded to the planar surface of the electronic substrate; a hydrogel disposed within the elastomeric membrane; and a bioadhesive layer configured to bond to the elastomeric membrane opposite the electronic substrate and to bond the elastomeric membrane to the subject; A system comprising:

29. an elastomeric membrane forming an enclosure around the void; a hydrogel disposed within the void and encapsulated by and adhered to the elastomeric membrane; a bioadhesive layer coupled to the elastomeric membrane so as to couple the elastomeric membrane to a subject; A system comprising:

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