BACKGROUND OF INVENTION

Surgical nerve damage where inadvertent damage is caused to nerves during surgery is a significant concern to medical professionals as it can lead to significant patient pain and, in some cases, loss of motor function. Intraoperative techniques have been developed to monitor nerve activity during surgery in attempts to avoid or reduce nerve damage. However, many conventional intraoperative techniques require that electrode leads be percutaneously placed inside of a patients muscle tissue and wired to a bench-top console, which causes patient discomfort and bleeding and requires additional surgery time and trained medical personnel, which increases costs. The increased cost of intraoperative monitoring has effectively limited its use to specific surgeries in which nerve damage is of high concern.

Nerve activity can be monitored using surface electromyography, removing the need for percutaneous electrode placement. Additionally, it has been suggested that wireless communication may be implemented to provide intraoperative monitoring of nerve activity, to provide medical practitioners critical feedback and help avoid nerve damage. For example, US Patent Publication No. 2006/0276702 describes the monitoring of nerve activity via electromyography using a wireless device. However, the described devices are relatively large and bulky, due to the requirement of additional components required for wireless transmission such as a transmitter, a battery, etc. The added size and rigidity of these components make them impractical for many surgeries as it is difficult to obtain or maintain conformal contact with tissue surface in order to provide accurate readings regarding nerve activity, and thus, their usefulness as an intraoperative monitoring system is limited.

It can be seen from the foregoing that there remains a need in the art for small, non-invasive, wireless sensors that are capable of conformal skin contact for intraoperative monitoring of surgical procedures to reduce nerve damage. Further, new microelectronic technologies may be implemented to reduce the number of components or reduce of the size of components, while increasing effectiveness.

SUMMARY OF THE INVENTION

The provided systems, methods and devices describe lightweight, wireless tissue monitoring devices that are capable of establishing conformal contact due to the flexibility or bendability of the device. The described systems and devices are useful, for example, for skin mounted intraoperative monitoring of nerve-muscle activity. The present systems and methods are versatile and may be used for a variety of tissues (e.g. skin, organs, muscles, nerves, etc.) to measure a variety of different parameters (e.g. electric signals, electric potentials, electromyography, movement, vibration, acoustic signals, response to various stimuli, etc.).

Advantageously, the present systems and methods take advantage of advances in microelectronics to reduce the size and rigidity of components allowing for soft, conformal devices. These devices may also be stretchable or bendable, without breaking or altering the functionality of the device. The described devices can be thin, soft and comfortable for the patient, while eliminating the need for wires which may be a nuisance for medical professionals during surgical procedures. The described devices may take advantage of various advancements in wireless technology such as Bluetooth and other near field communication techniques.

In an aspect, provided is a method of characterizing a neuromuscular property of a subject comprising: i) providing a conformable device comprising: a) a flexible or stretchable substrate; and b) a sensor supported by the flexible or stretchable substrate; the sensor comprising plurality of electrodes for measuring electric potentials of a tissue of the subject; wherein the flexible or stretchable substrate and sensor provide a net bending stiffness such that the device is capable of establishing conformal contact with a receiving surface of the tissue; ii) contacting the device with the receiving surface of the tissue, wherein contact results in the conformal contact of at least a portion of the device with the surface of the tissue; and iii) measuring a temporal profile of electric potentials of the tissue with the plurality of electrodes; thereby characterizing the neuromuscular property.

The described methods, systems and devices may provide a method or device for sensing, for example directly sensing, an electromyography signal or of the subject. The method may provide for sensing nerve conduction of the subject. The methods, systems, or devices may characterize various neuromuscular properties including, for example, threshold current to elicit an electromyography signal in response to electrical nerve stimulation and/or in a neuromuscular property is in response to electrical stimulation of the tissue, for example, direct electrical stimulation. The conformable devices may be capable of stretching, twisting or bending without altering functional operation and/or signal fidelity of the device.

The conformable device may comprise a plurality of sensors supported by the flexible or stretchable substrate, for example, each sensor independently comprising plurality of electrodes for measuring electric potentials of a tissue of the subject.

The neuromuscular property may be spontaneous muscle activity, for example activity corresponding to a level of anesthesia of the subject. This allows for the intraoperative monitoring of anesthesia to calculate the current level of anesthesia of a subject throughout an operation. The neuromuscular property may be depth of paralysis. Depth of paralysis may correspond to nerve or muscle activity of a tissue that has been treated with a paralytic agent.

The described methods, systems and devices are versatile and may incorporate a variety of sensors and sensing technologies. The described sensors can be electrical, thermal, mechanical or chemical in nature, for example, capable of measuring electric parameters, temperature, blood pressure, acoustics and various other sensing modalities. Further, the described devices may be useful with a variety of components and materials.

The present methods, systems and devices may measure a temporal profile of electric potentials to provide measurement of an electromyography (EMG) waveform. The methods, systems and devices may analyze the EMG waveforms. The temporal profile of electric potentials may provide a surface electromyography (s-EMG) measurement. The described electrodes may comprise at least a pair of Ag/AgCl electrodes or ENIG/AU electrodes. The sensor of the conformal device may be a multimodal sensor, providing for the sensing of a plurality of tissue properties. The present method may further comprise measuring one or more properties selected from the group consisting of tissue position, tissue movement, blood flow, blood pressure, a temperature, hydration state, tissue stiffness, mechano-acoustic signatures, and swelling.

The described sensor of the conformal device may further comprise a motion detector supported by the substrate, providing for measuring a temporal profile of the position, movement or both of the tissue. The motion detector may comprise an accelerometer, a gyroscope or both. The accelerometer or gyroscope may further characterize the neuromuscular property.

The described methods may further comprise: providing a stimulating conformable device comprising: a) a second flexible or stretchable substrate; b) an actuator for electrically stimulating the tissue of the subject, supported by the second flexible or stretchable substrate; and wherein the second flexible or stretchable substrate and the actuator provide a net bending stiffness such that the device is capable of establishing conformal contact with the receiving surface of the tissue; contacting the stimulating conformal device with the receiving surface of the tissue, wherein contact results in the conformal contact of at least a portion of the stimulating conformal device with the surface of the tissue; and stimulating the tissue using the actuator and simultaneously measuring a temporal profile of electric potentials of the tissue with the plurality of electrodes in response to the stimulation.

The methods and systems of stimulation described herein may occur internally (e.g. physically contacting a nerve within the tissue directly) or externally (e.g. stimulation through tissue, including skin, to stimulate underlying nerves.

The conformal device may comprise an actuator, which may provide stimulation of the tissue of the subject and the neuromuscular property may be in response to the stimulation, for example, electrical stimulation. The described methods may further comprise electrically stimulating the subject using the actuator and simultaneously measuring a temporal profile of electric potentials of the tissue with the plurality of electrodes in response to the electrical stimulation. The characterization of the neuromuscular property may be time-synced to the stimulation. The actuation may be electrical actuation, thermal actuation, acoustic actuation or any combination of these. The conformal device may further comprise a thermal actuator, which may provide thermal stimulation of the tissue of the subject.

The characterization of the neuromuscular property may trigger a downstream clinical response. The characterization of the neuromuscular property may provide a real-time clinical metric.

The sensor of the conformable device may have a stretchable or flexible island interconnect geometry. The stretchable or flexible island interconnect geometry may be characterized by a plurality of functional device components electrically interconnected via filamentary serpentine traces.

The provided methods, systems and devices eliminate the need for wires between the sensing device and console or data processing device. Additionally, wireless charging may reduce the size of the battery on the conformal device that is applied to the patient.

The described device may further comprise a one-way or two-way wireless component supported by the substrate and operationally connected to the sensor. The wireless component may be a wireless transmitter supported by the substrate, which may provide for outputting signals corresponding to the temporal profile of electric potentials. The wireless component may be a wireless receiver supported by the substrate; which may provide for receiving a signal from a user, a monitor or a device, for example, an additional conformable device as described herein or another separate device.

The device may further comprise a rechargeable battery providing power to the conformable device. The method may further comprise providing a monitor in wireless communication with one or more of the conformable devices. The method may further comprise displaying or audibly reporting the characteristic of the neuromuscular property, for example, to a doctor or medical professional. The monitor may be a smartphone, a laptop computer, a desktop computer, a tablet, a speaker, a wearable electronic or a console, which may establish a closed-loop feedback system for the doctor or medical professional to monitor nerve activity and adjust therapy accordingly.

One or more hydrogel layers may be provided between the tissue and the conformal device. The hydrogel may be a conductive gel. The described tissue may be an external tissue, for example, skin. The described tissue may be an internal tissue, for example, nervous system tissue. The tissue may be peripheral nerves, muscle, or spinal cord. A plurality of the conformal devices may be provided to a variety of receiving surface corresponding to tissues of the subject, which may provide for measuring a plurality of temporal profiles of electric potentials of the tissues, thereby characterizing the neuromuscular property.

The described method may use multiple devices to monitor muscle activities from multiple parts of a patient's body, including synchronized monitoring where the devices are time-synched to external or internal electrical stimulation, for example of peripheral nerves to promote recovery after surgery, or relevant surgical system. The methods described herein may further comprise a plurality of conformable devices, wherein the step contacting independently contacts each of the devices with one or more receiving surfaces of one or more tissues. The plurality of conformable devices may comprise: a) a conformable device capable of measuring an electrocardiogram; b) a conformable device capable of measuring an electrooculogram; and c) a conformable device capable of measuring an electromyogram. The plurality of conformable devices may be time-synched and may form a closed loop system.

The described systems, methods and devices may be capable of sensing very early signs of muscle reinnervation, for example, after a subject has undergone a surgical operation. The systems and methods described herein may detect muscle reinnervation or recovery at a very early stage, for example, prior to traditional methods of clinical detection such as muscle contraction.

In an aspect, provided is a conformable device comprising: i) a flexible or stretchable substrate; ii) a sensor supported by the flexible or stretchable substrate; the sensor comprising plurality of electrodes for measuring electric potentials of a tissue of the subject; and iii) a multilayer encapsulant at least partially encapsulating the sensor; the multilayer encapsulant comprising a lower modulus core layer at least partially embedding the sensor and a higher modulus shell at least partially surrounding the a first lower modulus core layer and sensor; wherein the lower modulus core layer has a Young's modulus at least 10 times lower than that of the higher modulus shell; wherein the flexible or stretchable substrate, sensor and multilayer encapsulant provide a net bending stiffness such that the device is capable of establishing conformal contact with a receiving surface of a tissue of a subject.

The device may be for measuring a temporal profile of electric potentials of the tissue; thereby characterizing a neuromuscular property of the subject. The lower modulus core layer may be characterized by an average Young's modulus equal to or less than 100 kPa, equal to or less than 50 kPa, or optionally, equal to or less than 10 kPa. The lower modulus core layer may be characterized by an average Young's modulus selected over the range of 1 kPa-100 kPa, selected over the range of 0.1 kPa-10 kPa, or optionally, selected over the range of 2 kPa-50 kPa. The lower modulus core layer may have an average thickness selected over the range of 2 microns to 2 millimeters, selected over the range of 2 microns to 1 millimeter, or optionally, selected over the range of 2 microns to 500 microns. The one or more hydrogel layers may contain pharmaceutical agents that are delivered upon skin contact, for example, delivered transdermally.

The higher modulus shell may be characterized by an average Young's modulus equal to or less than 2 MPa, equal to or less than 1 MPa, or optionally, equal to or less than 500 kPa. The higher modulus shell may be characterized by an average Young's modulus selected over the range of 50 kPa-2 MPa, selected over the range of 50 kPa-1 MPa, or optionally, selected over the range of 10 kPa-1 MPa. The higher modulus core layer may have an average thickness selected over the range of 10 microns to 2 millimeters, selected over the range of 10 microns to 1 millimeter, or optionally, selected over the range of 10 microns to 500 microns.

The lower modulus core layer may comprise a silicone composition. The higher modulus core layer may comprise a silicone composition. The lower modulus core layer and the higher modulus shell may combine to provide an effective modulus of the conformal device of less than or equal to 2 MPa, less than or equal to 1 MPa, or optionally, less than or equal to 500 kPa.

The described sensor may be a multimodal sensor. The sensor may further comprise one or more additional components for measuring one or more properties selected from the group consisting of tissue position, tissue movement, blood flow, blood pressure, a temperature, hydration state, tissue stiffness, mechano-acoustic signatures, and swelling. The sensor may further comprise a motion detector for measuring a temporal profile of the position, movement or both of the tissue. The motion detector may comprise an accelerometer, a gyroscope or both. The described electrodes may comprise at least a pair of Ag/AgCl electrodes or ENIG/AU electrodes.

The conformal device may further comprise an actuator for providing a stimulation of the tissue of the subject. The described stimulation may be electrical actuation, thermal actuation, acoustic actuation or any combination of these. The sensor of the conformable device may have a stretchable or flexible island interconnect geometry. The stretchable or flexible island interconnect geometry may be characterized by a plurality of functional device components electrically interconnected via filamentary serpentine traces.

The device may further comprise a one-way or two-way wireless component supported by the substrate and operationally connected to the sensor. The wireless component may be a wireless transmitter supported by the substrate for outputting signals corresponding to the temporal profile of electric potentials. The wireless component may be a wireless receiver supported by the substrate for receiving a signal from a user. The wireless component may be both a wireless transmitter and a wireless receiver.

The device may comprise one or more hydrogel layers, which may further comprise a conductive gel. The one or more hydrogel layers may characterized by an average thickness selected from the range of 0.1 millimeters to 2 millimeters, selected from the range of 0.1 millimeters to 1 millimeters, or optionally, selected from the range of 1 millimeters to 2 millimeters. The one or more hydrogel layers may be characterized by an average Young's modulus selected from the range of 1 kPa to 100 kPa, selected from the range of 1 kPa to 50 kPa, or optionally, selected from the range of 1 kPa to 250 kPa. The one or more hydrogel layers may be characterized by an electrical conductivity selected from the range of 0.1 S/m to 0.8 S/m, selected from the range of 0.3 S/m to 0.8 S/m, or optionally, selected from the range of 0.2 S/m to 1.0 S/m.

The devices, systems and methods may be used in an outpatient setting to help patients rehabilitate by sensing very early signs of muscle reinnervation, for example, after a surgical operation. This sensing may detect muscle reinnervation before obvious clinical signs of muscle contraction, providing biofeedback indicating subclinical signs of muscle reinnervation. The devices, systems and methods may perform studies similar to a convention EMG study.

In an aspect, provided is a system for characterizing a neuromuscular property of a subject comprising: i) one or more conformable devices each comprising: a) a flexible or stretchable substrate; b) a sensor supported by the flexible or stretchable substrate; the sensor comprising plurality of electrodes for measuring electric potentials of a tissue of the subject; and c) a multilayer encapsulant at least partially encapsulating the sensor; the multilayer encapsulant comprising a lower modulus core layer at least partially embedding the sensor and a higher modulus shell at least partially surrounding the a first lower modulus core layer and sensor; wherein the lower modulus core layer has a Young's modulus at least 10 times lower than that of the higher modulus shell; wherein the flexible or stretchable substrate, sensor and multilayer encapsulant provide a net bending stiffness such that the device is capable of establishing conformal contact with a receiving surface of a tissue of a subject; and ii) a monitor in wireless communication with the one or more conformable devices, wherein the receives data corresponding to the neuromuscular property of the subject from the one or more sensors and displays or audibly reports the neuromuscular property or changes in the neuromuscular property.

The system may comprise a plurality of conformable devices. The plurality of conformable devices comprise: a) a conformable device capable of measuring an electrocardiogram; b) a conformable device capable of measuring an electrooculogram; and c) a conformable device capable of measuring an electromyogram. The plurality of conformable devices may be time-synched and may form a closed-loop system.

The monitor may further comprise a processor and the monitor may analyze the data from one or more sensors. The monitor may be a smartphone, a laptop computer, a desktop computer, a tablet, a speaker, a wearable electronic or a console. The monitor may be in two-way communication with the one or more conformable devices to signal an actuator in the one more conformable devices.

The monitor may display the neuromuscular property, thereby providing a real-time clinical metric. The real-time clinical metric may trigger a downstream clinical response.

In an aspect, provided is a method of monitoring a level of anesthesia of a subject comprising: i) providing a conformable device comprising: a) a flexible or stretchable substrate; and b) a sensor supported by the flexible or stretchable substrate; the sensor comprising plurality of electrodes for measuring electric potentials of a tissue of the subject; wherein the flexible or stretchable substrate and sensor provide a net bending stiffness such that the device is capable of establishing conformal contact with a receiving surface of the tissue; ii) contacting the device with the receiving surface of the tissue, wherein contact results in the conformal contact of at least a portion of the device with the surface of the tissue; iii) measuring a temporal profile of electric potentials of the tissue with the plurality of electrodes corresponding to spontaneous muscle activity; and iv) monitoring the spontaneous muscle activity in real time during an operation, wherein the spontaneous muscle activity corresponds to the level of anesthesia of the subject.

Monitoring the level of anesthesia of the subject may comprise treating the subject with a paralytic agent to prevent spontaneous movement of the tissue; wherein the step of monitoring spontaneous muscle activity further comprises monitoring a depth of a paralysis of the tissue.

Monitoring the spontaneous muscle activity or the level of anesthesia may provide a real-time clinical metric. The real-time clinical metric may trigger a downstream clinical response.

In an aspect, provided is a method of promoting nerve recovery of a subject comprising: i) providing a sensing conformable device comprising: a) a flexible or stretchable substrate; b) a sensor supported by the flexible or stretchable substrate; the sensor comprising plurality of electrodes for measuring electric potentials of a tissue of the subject; and wherein the flexible or stretchable substrate and sensor provide a net bending stiffness such that the device is capable of establishing conformal contact with a receiving surface of the tissue; ii) providing a stimulating conformable device comprising: a) a second flexible or stretchable substrate; an actuator for stimulating the tissue of the subject, supported by the second flexible or stretchable substrate; and wherein the second flexible or stretchable substrate and the actuator provide a net bending stiffness such that the device is capable of establishing conformal contact with the receiving surface of the tissue; iii) contacting the flexible device and the stimulating conformal device with the receiving surface of the tissue, wherein contact results in the conformal contact of at least a portion of the flexible device and the stimulating conformal device with the surface of the tissue; and iv) stimulating the tissue using the actuator and simultaneously measuring a neuromuscular property is in response to the stimulation, wherein stimulation of the tissue promotes nerve recovery in the tissue.

Nerve recovery may be axonal regeneration, inhibition of demyelination, promotion of remyelination, secretion of trophic factors or a combination thereof. Actuation may be, for example, electrical actuation, thermal actuation, acoustic actuation or any combination of these.

In an aspect, the invention provides methods or systems for intraoperative monitoring, therapy or both. In an aspect, the invention provides methods or systems for postoperative monitoring, therapy or both. In an aspect, the invention provides methods or systems for preoperative monitoring, therapy or both.

In an aspect provided is a method of characterizing a neuromuscular property of a subject comprising: i) providing a conformable device comprising: a flexible or stretchable substrate; at least one actuator for providing electrical stimulation; and a sensor supported by the flexible or stretchable substrate; the sensor comprising plurality of electrodes; wherein the flexible or stretchable substrate and sensor provide a net bending stiffness such that the device is capable of establishing conformal contact with a receiving surface of a tissue of the subject; ii) contacting the device with the receiving surface of the tissue, wherein contact results in the conformal contact of at least a portion of the device with the surface of the tissue; iii) establishing electrical communication between the actuator and a nerve of the subject, wherein the contact is established by internal contact of the actuator with the nerve of the subject, by external contact of the actuator with the tissue of the subject or a combination thereof; and iv) stimulating the nerve via the actuator and measuring a temporal profile of electric potentials of the tissue or the nerve with the plurality of electrodes; thereby characterizing the neuromuscular property. Any of described methods and devices may be use for monitoring and confirming effective electrical stimulation of the tissue or the nerve.

In an aspect, provided is a method of detecting muscle reinnervation of a subject comprising: i) providing a conformable device comprising: a flexible or stretchable substrate; and a sensor supported by the flexible or stretchable substrate; the sensor comprising plurality of electrodes for measuring electric potentials of a tissue of the subject; wherein the flexible or stretchable substrate and sensor provide a net bending stiffness such that the device is capable of establishing conformal contact with a receiving surface of the tissue; ii) contacting the device with the receiving surface of the tissue, wherein contact results in the conformal contact of at least a portion of the device with the surface of the tissue; and iii) measuring a temporal profile of electric potentials of the tissue with the plurality of electrodes; thereby characterizing the muscle reinnervation.

Any of the conformable devices described herein may be capable of detecting muscle reinnervation prior to clinical detection and/or prior to muscle contraction. The described methods and systems may be post-operative.

As described herein and applied any of the described methods, system and devices, conformal contact may involve direct physical contact between one or more contact surfaces of the device and said receiving surface of the tissue. Conformal contact may involve indirect contact between one or more contact surfaces of the device and said receiving surface of the tissue. Conformal contact may involves direct physical contact or indirect contact between one or more contact surfaces of the device and said receiving surface of a surface of a skin of a subject. Conformal contact may involve direct physical contact or indirect contact between one or more contact surfaces of the device and said receiving surface of an internal tissue of a subject, for example, internal tissue may be peripheral nerves, muscle, or spinal cord tissue.

Without wishing to be bound by any particular theory, there may be discussion herein of beliefs or understandings of underlying principles relating to the devices and methods disclosed herein. It is recognized that regardless of the ultimate correctness of any mechanistic explanation or hypothesis, an embodiment of the invention can nonetheless be operative and useful.

