DEVICES, SYSTEMS, AND METHODS FOR MONITORING AND TREATMENT OF INJURIES
Provided herein are medical devices, systems, and methods for monitoring and treating injuries, diseases, or other conditions in patients. The medical devices include body structures that comprise an imaging array, a stimulation array, and an electrode array. The medical devices are implantable in patients in some embodiments.
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This application claims priority to U.S. Provisional Patent Application Ser. No. 63/088,310, filed Oct. 6, 2020, the disclosure of which is incorporated herein by reference.
BACKGROUNDFew viable treatment options are available for patients who have suffered a traumatic injury, such as a spinal cord injury (SCI), brain injury, burn injury, or another type of serious injury. Spinal cord injury can be a devastating condition with lifelong complications. Spinal cord injury monitoring and interventions remain in their infancy compared with advances made for other types of injuries. For example, monitoring of intracranial pressure and tissue oxygenation are mainstays in the treatment of acute traumatic brain injury (TBI), and information gathered from this monitoring is also helpful in the prevention and mitigation of secondary injury. Similar to TBI, SCI leads to severed axons, glial scarring, and a global lack of innate regenerative capacity at the injury site during the acute phase. Secondary injury is common due to subsequent ischemia and inflammation, and it leads to further tissue destruction, prolonging recovery.
Disruption of the autonomic nervous system after severe SCI, particularly rostral to thoracic level 5, where sympathetic nervous system fibers exit the spinal cord and innervate the immune system, leads to dysregulated local and systemic inflammatory responses, impairment of immune function, and increased infection risk, all of which hinder recovery after SCI. Acute inflammation in the spinal cord exacerbates the primary SCI injury, triggers secondary injury, worsens ischemia and scarring, and inhibits recovery. Chronic SCI results in long-term systemic inflammation, which is clinically exacerbated by a state of chronic immunosuppression.
Spinal cord injury and other types of injury are not totally preventable. Prevention and mitigation of the pathophysiologic sequelae of an SCI devastating injury are critical to preserving spinal cord tissue and improving functional outcome after injury. In acute SCI, multimodal real-time and continuous monitoring of biomarkers such as perfusion pressure, pulsatility of the spinal cord, oxygenation, intrathecal pressure, temperature, and inflammatory markers does not exist. Interventions such as cerebrospinal fluid (CSF) drainage and maintaining mean arterial pressure (MAP) goals have shown great promise. Electrical stimulation has also been reported to influence inflammatory pathways. However, it is currently impossible to optimally titrate these therapies in real-time because there is no way to directly and continuously assess the spinal cord after SCI.
Loss of motor control is perhaps the most obvious sequela of SCI. However, multiple systems, including the functions of cardiovascular and bladder control, are affected after this injury. Urological complications after SCI require lifelong management. SCI also causes profound disruption of the cardiovascular (CV) system, particularly in motor-complete injuries in the cervical and upper thoracic levels. CV dysregulation leads to persistent hypotension, bradycardia, orthostatic hypotension, and episodes of autonomic dysreflexia, which drastically diminish quality of life by affecting overall health and preventing patients from engaging in activities of daily life. Ultimately, the simultaneous restoration of motor, CV, and urologic systems would allow patients with SCI and certain other injuries to fully participate in daily activities.
Accordingly, there is a need for devices, systems and methods for effective monitoring and treatment of spinal cord and other injuries.
SUMMARYThe present disclosure relates, in certain aspects, to methods, devices, systems, and computer readable media of use in monitoring of and treatment of an injury in a human or other mammal. In certain applications, for example, the injury may be a spinal cord injury. These and other aspects will be apparent upon a complete review of the present disclosure, including the accompanying figures.
In accordance with some aspects, the present disclosure provides a system, device or corresponding method for treatment of an injury in a human or other mammal. In some embodiments, the system may include an implantable device configured to be implanted into a human body, the implantable device having a sensing device and a treatment device, the sensing device configured to sense a first condition of the injury and to generate a signal corresponding to the sensed first condition, the treatment device configured to provide treatment to the injury, a wearable device configured to be wearable on an external portion of the human (or animal) body, the wearable device configured to sense a condition of the human (or animal) related to the injury, and a controller connected to the implantable device and to the wearable device, the controller configured to receive signals from the implantable device and the wearable device and to control the implantable device to selectively cause the treatment device to apply the treatment based on the signal corresponding to the sensed condition.
The medical devices or systems disclosed herein include numerous applications. In some embodiments, for example, the medical devices or systems are configured for imaging and neuromodulation/stimulation using ultrasound. In some exemplary embodiments, the medical devices or systems are configured for microflow sensing, remote ablation of selected tissue (e.g., tumor tissue), drug delivery, thermal energy delivery, deep tissue thermometry, and/or the like. In some embodiments, the medical devices, systems, or components thereof are configured as omnisonic wearables (e.g., patches, etc.). In some embodiments, the medical devices are configured to perform remote deep-tissue temperature sensing using ultrasound thermometry. The temperature can be determined based on how changes in temperature affect the speed of sound, and hence the propagation and time-of-flight of the ultrasonic waves.
In accordance with some aspects, the present disclosure provides a medical device that includes a body structure that comprises at least portions of at least three subassemblies, which subassemblies comprise at least one imaging array or device, at least one stimulation array or device, and at least one electrode array or device. In some embodiments, one or more of the subassemblies are configured to perform one or more diagnostic and/or therapeutic applications. The subassemblies are positionable within communication of at least one target location of a subject. The imaging array is structured to generate and/or capture images (e.g., still and/or video images) at least proximal to the target location of the subject when the imaging array is positioned within communication of the target location of the subject. Typically, the imaging array is configured with flow sensing capabilities, which enable, for example, slow flow (i.e. microcirculation) to be monitored (e.g., at one or more time points) in small micro-vasculature of the subject. The stimulation array is structured to administer at least a first therapy at least proximal to the target location of the subject when the stimulation array is positioned within communication of the target location of the subject. The electrode array is structured to administer at least a second therapy at least proximal to the target location of the subject when the electrode array is positioned within communication of the target location of the subject. In addition, the subassemblies are operably connected, or connectable, to at least one power source and/or at least one controller. In some embodiments, one or more of the subassemblies (e.g., transducer array elements) are configured to perform both imaging and therapeutic ultrasound. In some embodiments, a kit includes the medical device disclosed herein. In some embodiments, the medical devices disclosed herein, whether configured as wearable and/or implantable devices, comprise a photoacoustic transceiver that provides light pulses to the target location (e.g., a monitoring site and/or treatment site) and receives ultrasound energy from the target location. In some embodiments, the medical devices, whether configured as wearable and/or implantable devices, comprise a photothermal transmitter and a thermal camera in which the photothermal transmitter provides light pulses to the target location (e.g., a monitoring site and/or treatment site) and the thermal camera detects thermal changes at the target location. In some of these embodiments, for example, the medical devices are configured to perform deep-tissue temperature sensing.
In accordance with some aspects, the present disclosure provides a system that includes a medical device comprising a body structure that comprises at least portions of at least three subassemblies, which subassemblies comprise at least one imaging array, at least one stimulation array, and at least one electrode array. The subassemblies of the medical device are positionable within communication of at least one target location of a subject. The imaging array of the medical device is structured to generate and/or capture images (e.g., still and/or video images) at least proximal to the target location of the subject when the imaging array is positioned within communication of the target location of the subject. The stimulation array of the medical device is structured to administer at least a first therapy at least proximal to the target location of the subject when the stimulation array is positioned within communication of the target location of the subject. The electrode array of the medical device is structured to administer at least a second therapy at least proximal to the target location of the subject when the electrode array is positioned within communication of the target location of the subject. In addition, the medical device includes at least one power source operably connected to the subassemblies. The system also includes at least one controller operably connected to the subassemblies, which controller comprises, or is capable of accessing, computer readable media comprising non-transitory computer executable instructions which, when executed by at least one electronic processor, perform at least: generating and/or capturing images at least proximal to a target location of a subject using the imaging array; administering at least a first therapy at least proximal to the target location of the subject using the stimulation array; and administering at least a second therapy at least proximal to the target location of the subject using the electrode array. In some applications, the therapies administered using devices and systems disclosed herein include photoacoustic, photothermal, and other fusion modalities, among other therapeutic applications. In some embodiments, the non-transitory computer executable instructions comprise one or more machine learning algorithms that effectuate generating and/or capturing the images and/or administering the first and/or second therapies. In some of these embodiments, the machine learning algorithms comprise one or more artificial neural networks. In some of these embodiments, the machine learning algorithms are used to automatically detect a targeted location in a subject (e.g., an anatomically relevant or curved structure, such as a spinal cord), track movement of the targeted location in the subject (e.g., while accounting for motion-related artifacts due, for example, to a cardiac cycle or respiratory effects), and the like. In some embodiments, the system further comprises one or more additional medical devices operably connected to the power source and to the controller, which additional medical devices are structured to monitor one or more additional physiological properties of the subject and/or to administer one or more additional therapies to the subject.
In accordance with some aspects, the present disclosure provides a computer readable media comprising non-transitory computer executable instruction which, when executed by an electronic processor perform at least: generating and/or capturing images at least proximal to a target location of a subject using at least one imaging array of a medical device that comprises a body structure that comprises at least portions of the imaging array; administering at least a first therapy at least proximal to the target location of the subject using at least one stimulation array of the medical device that comprises the body structure that comprises at least portions of the stimulation array; and administering at least a second therapy at least proximal to the target location of the subject using at least one electrode array of the medical device that comprises the body structure that comprises at least portions of the electrode array.
In accordance with some aspects, the present disclosure provides a method of providing medical care to a subject. The method includes generating and/or capturing images at least proximal to a target location of the subject using at least one imaging array of a medical device that comprises a body structure that comprises at least portions of the imaging array. The method also includes administering at least a first therapy at least proximal to the target location of the subject using at least one stimulation array of the medical device that comprises the body structure that comprises at least portions of the stimulation array. In addition, the method also includes administering at least a second therapy at least proximal to the target location of the subject using at least one electrode array of the medical device that comprises the body structure that comprises at least portions of the electrode array, thereby providing the medical care to the subject. In some embodiments, the method includes monitoring blood flow (e.g., slow microflow in small micro-vasculature, microflow detection, or microcirculation imaging) in the subject using the imaging array. In some embodiments, the imaging array comprises an ultrasound device and the method further comprises generating and/or capturing ultrasound images at least proximal to the target location of the subject. In some embodiments, the method includes monitoring one or more physiological properties (e.g., neural activity, pulsatility of the spinal cord, or the like) of the subject using the imaging array. In some of these embodiments, for example, the method includes continuously monitoring the target location (and pulsatility) of the subject over a selected period of time. In some embodiments, the method further includes positioning the medical device at least proximal to the target location of the subject using a gel (e.g., a shear-thinning material (STM) and/or shear-thinning biomaterial (STB)) and/or other attachment mechanism.
In accordance with some aspects, the present disclosure provides a method of positioning a medical device proximal to a target location of a subject. The method includes applying at least one shear-thinning material (STM) (e.g., a shear-thinning biomaterial (STB)) to the target location and/or to a portion of the medical device. The method also includes contacting the medical device with the target location of the subject such that the STM substantially retains the medical device at least proximal to the target location of the subject.
In some embodiments, the medical device is fabricated from one or more magnetic resonance imaging compatible (or MR-safe) materials. In some embodiments, the medical device is fabricated from one or more biodegradable, bioresorbable, and/or biocompatible materials. In some embodiments, the medical device is configured to continuously monitor perfusion, autoregulation, pulsatility of the spinal cord, temperature, flow, or pressure, at least proximal to the target location of the subject substantially in real-time when the subassemblies are positioned within communication of the target location of the subject. In some embodiments, the medical device includes pairs of the imaging arrays, the stimulation arrays, and the electrode arrays. In some of these embodiments, the pairs of the imaging arrays, the stimulation arrays, and the electrode arrays are positioned nested relative to one another in the body structure. In some embodiments, the medical device or system is configured to report substantially real-time values of spinal cord autoregulation. In some embodiments, the medical device further comprises a position tracking system that tracks angular and torsional deflection of one or more of the subassemblies when the subassemblies are positioned within communication of the target location of the subject. In some embodiments, the imaging array comprises an ultrasound device. In some embodiments, for example, the imaging array is configured to perform elastography (i.e., detecting vibration propagated through, or otherwise mapping the elasticity of, selected tissues of the subject using shear waves or the like). In some embodiments, ultrasound imaging arrays use a rectangular, square, or trapezoidal shaped region of interest (ROI) that is specified by a user. In some of these embodiments, the ROI is substantially static or fixed.
In some embodiments, the body structure comprises at least one substantially rigid section and at least one substantially flexible section. In some of these embodiments, the substantially rigid section comprises at least one of the subassemblies. In some embodiments, the body structure comprises a length of less than about 100 millimeters, a width of less than about 10 millimeters, and a depth of less than about 5 millimeters.
In some embodiments, the body structure is implantable in the subject. In some embodiments, the body structure is non-implantable in the subject. In some of these embodiments, a wearable device comprises the non-implantable body structure. In some embodiments, at least a first device component (e.g., one or more of the subassemblies) that is implantable and at least a second device component (e.g., one or more of the subassemblies) that is non-implantable. Exemplary wearable devices include smart watches, smart clothing or textiles, virtual reality headsets, or the like.
In some embodiments, the subassemblies are operably connectable to the power source and/or to the controller via a wired connection. In some embodiments, the subassemblies are operably connectable to the power source and/or to the controller via a wireless connection. In some of these embodiments, the body structure comprises at least a portion of the power source and/or the controller.
In some embodiments, the medical device includes at least two imaging arrays in which at least a first imaging array is configured to be positioned within communication of an uninjured site of the subject and at least a second imaging array is configured to be positioned within communication of an injured site of the subject. In some embodiments, the medical device includes at least two stimulation arrays. In some embodiments, the medical device includes at least two electrode arrays. In some embodiments, the imaging array comprises at least one transmit (Tx) electrode and/or at least one receive (Rx) electrode. In some embodiments, for example, the imaging comprises an Rx electrode that is used to monitor the pulsatility of a spinal cord, liver, or other tissue of the subject.
In some embodiments, the medical device includes at least one wearable device comprising at least one breakout box that is operably connected, or connectable, to the medical device at least when the subassemblies are positioned within communication of the target location of the subject. The breakout box is configured to receive data from the medical device and/or to transmit data to the medical device. In some embodiments the wearable device comprises a belt.
In some embodiments, the imaging array is configured to image a cross section of the target location of the subject in at least one plane (e.g., two planes, three planes, etc.) when the imaging array is positioned within communication of the target location of the subject. In some of these embodiments, for example, the imaging array is configured to provide planar ultrasound images of micro-vasculature of a spinal cord or other tissue of the subject. In some embodiments, the imaging array comprises a lens, an imaging stack, a flexible circuit, and an acoustic impedance backing material. In some embodiments, the imaging array comprises at least about 64 elements. In some embodiments, the imaging array comprises of 1024 by 1024 array elements on a flexible surface. In some embodiments, the imaging array comprises only a single element, whereas in other embodiments the imaging array comprises, for example, a 1D, 1.5D, 2D, 2.5D, 3D, 3.5D, 4D, or other array configuration.
In some embodiments, the stimulation array is configured to administer focused ultrasound (FUS) and/or flashlight therapeutic ultrasound at least proximal to the target location of the subject when the stimulation array is positioned within communication of the target location of the subject. In some embodiments, the stimulation array is structured to administer ultrasonic stimulation at least proximal to the target location of the subject and the electrode array is structured to administer electrical stimulation at least proximal to the target location of the subject when the stimulation array and the electrode array are positioned within communication of the target location of the subject. In some embodiments, the stimulation array comprises an air backed array, at least eight element stack, a matching layer, and a dielectric layer. In some embodiments, the stimulation array comprises only a single element, whereas in other embodiments the stimulation array comprises, for example, a 1D, 1.5D, 2D, 2.5D, 3D, 3.5D, 4D, or other array configuration. In some embodiments, the stimulation array comprises a piezo-ceramic (e.g., PZT), polymer (e.g., PVDF or PLLA), micro-electromechanical system (MEMS) based capacitive micromachined ultrasonic transducers (CMUT) and/or composite material.
In some embodiments, the electrode array is further configured to effect data recording at least proximal to the target location of the subject when the electrode array is positioned within communication of the target location of the subject. In some embodiments, the electrode array comprises a titanium nitride electrode surface conductor. In some embodiments, the electrode array comprises a multi-layer polyimide/copper circuit having independent layers for transmit and receive modalities.
In some embodiments, the target location comprises at least a portion of a spinal cord of the subject. In some embodiments, the target location comprises at least a portion an organ system of the subject selected from the group consisting of: an integumentary system, a skeletal system, a muscular system, a lymphatic system, a respiratory system, a digestive system, a nervous system, an endocrine system, a cardiovascular system, a urinary system, and a reproductive system. In some embodiments, the subject is a human or other mammalian subject. In some embodiments, for example, the organ system comprises a brain of the subject, whereas in other embodiments, the organ system comprises a liver of the subject.
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain embodiments, and together with the written description, serve to explain certain principles of the methods, devices, kits, systems, and related computer readable media disclosed herein. The description provided herein is better understood when read in conjunction with the accompanying drawings which are included by way of example and not by way of limitation. It will be understood that like reference numerals identify like components throughout the drawings, unless the context indicates otherwise. It will also be understood that some or all of the figures may be schematic representations for purposes of illustration and do not necessarily depict the actual relative sizes or locations of the elements shown.
In order for the present disclosure to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms may be set forth through the specification. If a definition of a term set forth below is inconsistent with a definition in an application or patent that is incorporated by reference, the definition set forth in this application should be used to understand the meaning of the term.
As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Further, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In describing and claiming the methods, computer readable media, devices, systems, and component parts, the following terminology, and grammatical variants thereof, will be used in accordance with the definitions set forth below.
About: As used herein, “about” or “approximately” as applied to one or more values or elements of interest, refers to a value or element that is similar to a stated reference value or element. In certain embodiments, the term “about” or “approximately” refers to a range of values or elements that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value or element unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value or element).
Communicate: As used herein, “communicate” refers to the direct or indirect transfer or transmission, and/or capability of directly or indirectly transferring or transmitting, something at least from one thing to one or more other things or between or among those things. In some embodiments, for example, a device imaging array transmits acoustic waves to a target location (e.g., a spinal cord) of a subject and receives acoustic waves that echo back from that target location, such that the imaging array and the target location “acoustically communicate” with one another. A device stimulation array also acoustically communicates with a target location of a subject when it transmits acoustic waves to that location. To further illustrate, in some embodiments, an electrode array of a device transmits electrical current to a target location of a subject and receives electrical signal from that location, such that the electrode array and the target location “electrically communicate” with one another.
Subject: As used herein, “subject” refers to an animal, such as a mammalian species (e.g., human) or avian (e.g., bird) species. More specifically, a subject can be a vertebrate, e.g., a mammal such as a mouse, a primate, a simian or a human. Animals include farm animals (e.g., production cattle, dairy cattle, poultry, horses, pigs, and the like), sport animals, and companion animals (e.g., pets or support animals). A subject can be a healthy individual, an individual that has or is suspected of having a disease or a predisposition to the disease, or an individual that is in need of therapy or suspected of needing therapy. The terms “individual” or “patient” are intended to be interchangeable with “subject.”
System: As used herein, “system” in the context of medical instrumentation refers a group of objects and/or devices that form a network for performing a desired objective.
DETAILED DESCRIPTIONThe present disclosure relates, in certain aspects, to medical systems, devices and methods for the monitoring and treatment of injuries, disease, or other conditions in humans or other mammals. In some embodiments, the present disclosure relates, in certain aspects, to medical systems, devices and methods for the monitoring and treatment of spinal cord injuries in patients, although the system may be used for other types of injuries such as brain injuries, burn injuries, etc.
Embodiments disclosed herein provide a system and corresponding methods that can provide continuous monitoring and stimulation of the spinal cord or area of an injury by utilizing an implantable device implantable near the injury. The implantable device may include a sensor to sense/image the injury and a first condition of the human (or animal) related to the injury. The implantable device may also include a treatment device for treatment of the injury.
The system may also include a wearable device configured to be worn by the human or animal. The wearable device may be configured to sense a second condition of the human related to the injury.
The system may further include a control device separate from the wearable device and the implantable device. The control device may receive signals from the wearable device and from the implantable device based on the sensed first and second conditions. In response to the signals, the control device may be configured to control the treatment device.
In some embodiments, the system is configured to monitor and treat spinal cord injuries (SCI), although other types of injuries could be monitored and treated. The implantable device may be configured to be implanted near or proximal to the spinal cord injury or other type of injury to sense conditions of and treat the spinal cord injury or other injury.
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The wearable device 104 may be one wearable device or a plurality of wearable devices. The wearable device 104 is configured to be wearable on or in proximity to the patient's or subject's body. For example, the wearable device 104 may be attached by a strap or other means to a portion of the patient's body such as to an arm, a leg, a waist, a neck, groin, etc. In alternative embodiments, the wearable device may be configured to be attached in proximity to a particular portion of the patient's body. For example, the wearable device 104 may be configured to be attached to clothes worn by a person. The wearable device 104 may also be integrated into or attached to another device worn by a person. For example, the wearable device 104 could be configured to attach to a watch, to a belt, to jewelry, to glasses, to undergarment, etc.
The system 100 may additionally include a software application running on a device such as an Android tablet with an SCI-specific interface for both a physician and a patient that includes an API, allowing peripherals to use the application to change device settings to support closed-loop control of the therapy.
The sensing device 108 may be any type of sensing device configured to sense a condition of the patient's body related to the injury or other condition. In some embodiments, the sensing device may be an imaging device, an ultrasound device, a temperature sensing device, an electromyography (EMG) sensor with accelerometers, etc.
The wearable device 104 is some embodiments may include a treatment device 112, although other wearable devices 104 may omit the treatment device. The treatment device 112 may be configured to apply a treatment related to the injury. In some embodiments described herein the treatment device may be configured to apply an electrical stimulation or some other type of treatment, as further described herein.
The wearable device 104 may include a communications interface 110 for sending signals to the control device 102 and for receiving signals from the control device 102. The communications interface in some embodiments may be a wireless interface configured to send and receive signals to and from the control device 102. The signals may be indicative of the sensed conditions of the body related to the injury or other condition.
The control device 102 is configured to send and receive signals to the communications interface to control the sensing device 108 of the wearable device 104 and/or to control the treatment device 112. For example, the control device can be configured to cause the sensing device 108 to be activated to sense conditions and to cause the treatment device 112 to apply treatment to the patient's body.
The sensing device 116 may be configured to sense conditions of or related to an injury to a human. For example, the sensing device 116 may be an imaging device, a sensor or another type of sensing device. In some embodiments the sensing device may be an imaging device such as an ultrasound imaging device or other type of imaging device, such as an optical imaging device, a thermal imaging device, of the like. In some embodiments, the sensing device 116 may be a sensor configured to sense conditions of a body related to an injury or other condition, such as a pressure sensor, a temperature sensor, a biomarker sensor (such as oxygenation, lactate, etc.), an EMG sensor, etc.
Exemplary program product or machine readable medium 406 is optionally in the form of microcode, programs, cloud computing format, routines, and/or symbolic languages that provide one or more sets of ordered operations that control the functioning of the hardware and direct its operation. Program product 406, according to an exemplary aspect, also need not reside in its entirety in volatile memory, but can be selectively loaded, as necessary, according to various methodologies.
The term “computer-readable medium” or “machine-readable medium” refers to any medium that participates in providing instructions to a processor for execution. To illustrate, the term “computer-readable medium” or “machine-readable medium” encompasses distribution media, cloud computing formats, intermediate storage media, execution memory of a computer, and any other medium or device capable of storing program product 406 implementing the functionality or processes of various aspects of the present disclosure, for example, for reading by a computer. A “computer-readable medium” or “machine-readable medium” may take many forms, including but not limited to, non-volatile media, volatile media, and transmission media. Non-volatile media includes, for example, optical or magnetic disks. Volatile media includes dynamic memory, such as the main memory of a given system. Transmission media includes coaxial cables, copper wire and fiber optics, including the wires that comprise a bus. Transmission media can also take the form of acoustic or light waves, such as those generated during radio wave and infrared data communications, among others. Exemplary forms of computer-readable media include a floppy disk, a flexible disk, hard disk, magnetic tape, a flash drive, or any other magnetic medium, a CD-ROM, any other optical medium, punch cards, paper tape, any other physical medium with patterns of holes, a RAM, a PROM, and EPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wave, or any other medium from which a computer can read.
In some aspects, program product 406 includes non-transitory computer-executable instructions which, when executed by electronic processor 402 perform at least: monitoring and treatment of injuries, diseases, or other conditions in a subject by controlling the implantable device 106 and/or the wearable device 104. The systems and methods disclosed herein may include machine learning such that the systems can adapt by learning. For example, the system 100 can monitor how a patient reacts to various treatments applied by the implantable device 106 and/or the wearable device 104 and learn how to better apply the treatments to various sensed conditions.
The wearable device 508 may be a wearable device configured to sense a blood pressure of a human wearing the wearable device. In
The wearable device 510 may be a wearable device configured to sense a bladder volume and or bladder pressure of a subject wearing the wearable device. In
The wearable device 512 may be an EMG wearable device configured to sense/detect motor functions of a subject wearing the wearable device. In
In some embodiments, a plurality of the wearable devices 512 may be utilized. For example, in some embodiments, a wearable device could be wearable on each arm and each leg, so that the system could monitor motor function of each arm and leg.
In some embodiments, the wearable device may include one or a plurality of accelerometers. In some embodiments, the accelerometers may be configured to generate signals indicative of a limb's motion in real time. The wearable device may be configured to send such signals to the control device 102.
The implantable device 504 may be a multi-function spinal cord implant (MUSIC). The multi-function spinal cord implant 504 may include one or more imaging or sensing devices and one or more treatment devices. In one embodiment, the imaging devices may include an ultrasound imaging array or arrays to generate three-dimensional images of the spinal cord at an injury or other target location and an electrical array or arrays for electrical recording, although other types of imaging or sensing devices could be used. The treatment devices may include an electrical stimulation device or devices for applying electrical stimulation and a focused ultra-sound (FUS) device or devices for applying focused ultra-sound treatment, although other types of treatment devices may be used.
The multi-function spinal cord implant 504 may be a multimodal, conformal, wireless epidural implant device for use in patients with acute or chronic SCI. The multi-function spinal cord implant 504 may be configured to: (a) produce three-dimensional, real-time, high-resolution imaging at the injury site or other target location to monitor and prevent secondary injury; (b) evaluate and assess the reestablishment of autoregulation to optimize acute intervention; (c) continuously monitoring the perfusion or pulsatility of the spinal cord, as a surrogate for its tissue health; (d) measure biomarkers using aptamers; (e) enhance blood flow and potential neural regeneration as a result of acoustic neuromodulation/focused ultrasound (FUS) at the site of injury; (f) actuate release of encapsulated pharmacotherapeutic agents; (g) measure temperature of spinal cord, using ultrasound thermometry; (h) measure electrical conductivity above and below the site of injury; (i) stimulate and record neurophysiological data with electrodes; and/or the like. In some embodiments, the multi-function spinal cord implant 504 may conform to the dorsal spinal cord while displacing a volume of only about 50 mm3.
In some embodiments, the multi-function spinal cord implant 504 may be wirelessly powered from an external “relay station” attached outside the body at the implant site. This facilitates higher power levels without bulky battery implants. In some embodiments, the multi-function spinal cord implant 504 communicates with the relay station via a custom ultra-wide-band networking protocol that may support 200 Mbps uplink and 100 Mbps downlink. The relay station may be an 802.11 device that communicates wirelessly with the control device 102.
In some embodiments, the multi-function spinal cord implant (MUSIC) 504 may be configured to interface with custom-designed encapsulating hydrogel scaffolds that can be stimulated with focused ultrasound (FUS) to deliver pharmacotherapeutic agents. FUS may also be used to enhance blood flow at the site of the injury or other condition. In some embodiments, the multi-function spinal cord implant 504 may be a biocompatible, biodegradable, and/or bioresorbable permanently implantable wireless device.
In some embodiments, the multi-function spinal cord implant (MUSIC) 504 may be configured to interface with custom-designed hydrogel that can be used to adhere the device to the tissue of interest. The hydrogel may be photocrosslinkable via application of UV light to effect solidification. In some embodiments, the multi-function spinal cord implant (MUSIC) 504 may be configured to interface with custom-designed shear-thinning hydrogel that can be used to adhere the device to the tissue of interest, upon application of force to attach to or remove from the tissue of interest.
In some embodiments, the medical devices disclosed herein (e.g., multi-function spinal cord implant (MUSIC) 504, implantable device 506, wearable devices 508, 510, and 512, and/or the like) are included as part of a larger system, such as system 500. In other exemplary embodiments, one or more of these individual medical devices are included as part of a smaller stand-alone system.
In some embodiments, the purpose of the MUSIC device is to continuously monitor both healthy and injured spinal cord tissue, and provide stimulation in a multi-modality, semi-flexible device the size of a BAND-AID®. Continuously monitoring is generally achieved through ultrasonic, photoacoustic or photothermal imaging arrays along the length of the device, two poised near the injury site, and one at an uninjured site in some embodiment. These are used for real-time and continuous perfusion quantification, monitoring the pulsatility of the spinal cord, and imaging at the injury site. Stimulation is achieved through both ultrasonic and electrical modalities. Ultrasonic stimulation is achieved through two transmit-only arrays located around the injury site. These arrays allow for steering the ultrasonic energy deep inside the tissue of the spinal cord injury site. Electrical stimulation and recording is achieved through electrodes placed along the length of the device in these exemplary embodiments.
In some embodiments, the MUSIC device includes a body structure that comprises at least portions of at least three subassemblies. The subassemblies include at least one imaging array or device (e.g., used to record biological response), at least one stimulation array or device (e.g., used to provide ultrasound stimulation), and at least one electrode array or device (e.g., used to provide SCS based stimulation and recording). The subassemblies are positionable within communication of a spinal injury of a subject. The imaging array is structured to generate and/or capture images (e.g., still, HD live images, and/or video images) proximal to the target location of the subject when the imaging array is positioned within communication of the spinal injury of the subject. The stimulation array is structured to administer a first therapy (e.g., FUS, etc.) proximal to the spinal injury of the subject when the stimulation array is positioned within communication of the spinal injury of the subject. The electrode array (e.g., electrical stimulation and recording electrodes) is structured to administer a second therapy (e.g., electrical current, etc.) proximal to the spinal injury of the subject when the electrode array is positioned within communication of the spinal injury of the subject. In addition, the subassemblies are operably connected, or connectable, to at least one power source and/or at least one controller (e.g., as part of a stand-alone system or as part of a larger system, such as system 500).
In some embodiments, the stimulation arrays 808 have a spatial frequency of half lambda. This allows the beam to radiate with very little directivity within the sagittal plane, which allows for the focus to move throughout a large volume in front of the arrays through applying time delay or phasing to the signals. In some embodiments, there is effectively a 1 to 1 relationship from the radiating surface to the focal zone of the device. In some embodiments, the beam can then be swept around to cover the volume in front of the arrays with a collimating beam if subsequent focal positions are time averaged. Typically, the stimulation arrays 808 provide coverage from about 4 mm to about 12 mm in depth.
In some embodiments, the MUSIC device is inserted through the skin of a patient and is positioned alongside the spine. In these embodiments, the implanted end of the device is typically encapsulated, providing a smooth gap free surface to minimize tissue response of the device. In some embodiments, an over-mold extends outside of the surgical incision before transitioning to a bare flex circuit. The flex circuit is typically a multi-layer assembly. In some embodiments, the entire length of flex circuit is over-molded, whereas a disposable sleeve is used in other embodiments. In some embodiments, one or more components of the MUSIC device are fabricated from, for example, a conformal coating (e.g., parylene), an elastic epoxy, a rigid epoxy/urethane, silicone (e.g., stimulation lens), ULTEM® 1000 resin (e.g., imaging lens), polyimide (PI), and the like.
Typically, the geometry of the imaging array subassembly (e.g., a 13 MHz imaging array in some exemplary embodiments) maximizes the total number of elements while maintaining acoustic imaging characteristics. A width in elevation of about 2.000 mm provides a balance of sensitivity and acoustic performance in some embodiments. In addition, an aspect ratio (width/thickness) of the individual beam-mode elements of about 0.87 is used to minimize mode structures in the piezoceramic. In some embodiments, a pitch of about 135 microns and kerf width of 24 microns is used for the dicing parameters. After the array is machined, the kerfs cuts are filled with a specialized epoxy that aids in minimizing the effects of cross-talk between adjacent elements in some of these embodiments.
To further illustrate,
To further illustrate,
The implantable device 506 (referenced, for example, in
In some embodiments, ACMI 506 may include one or a plurality of sensors. The sensors may be configured to sense/detect temperature, pressure, and biomarkers. In some embodiments, the ACMI 506 may be configured to include optical sensors for measuring intrathecal pressure and temperature. In some embodiments, ACMI 506 may include sensors such as a fiber-optic, spectroscopy system that monitors spinal cord oxygenation by providing nearly continuous CSF concentration measurements of oxygenation indicators, such as lactate.
In some embodiments, ACMI 506 may include a drainage catheter to remove spinal fluid to adjust intraspinal pressure. In some embodiments, ACMI 506 measuring and managing CSF pressure throughout the acute phase of neurological injury.
Another implantable device may be utilized with the system 500, an epidural spinal stimulator (ESS) device. In some embodiments, the ESS device may be a biocompatible epidural implant. The ESS implantable device may be placed at the lumbosacral level (L1-S2), in the post-acute period of injury.
In some embodiments, the ESS device may be configured with electrodes configured to apply electrical stimulation of the spinal cord, particularly of the dorsal lumbosacral spinal cord. Dorsal epidural electrical stimulation does not induce movement by directly activating motor pools. Instead, it enables motor function by (1) stimulating medium- and large-diameter afferent fibers in lumbar and upper sacral posterior roots that transmit proprioceptive information from muscle spindle primary endings in the legs to the spinal cord and trans-synaptically engaging interneurons that integrate the proprioceptive inputs and central pattern generator networks. Epidural electrical stimulation modulates spinal circuits into a physiological state that allows for task-specific sensory input derived from movements to serve as a source of motor control.
In certain embodiments, motor outputs of the stimulation provided by the ESS device can be monitored and characterized by an accelerometer as well as by EMG potentials in target muscles. The EMG wearable device 512 may be used in conjunction with the ESS device in a manner that when the ESS device applies electrical stimulation, the EMG device monitors and generates signals indicative of the movement of the limbs of a human.
In some embodiments, properties of the signals generated by the EMG wearable device, such as latencies and peak-to-peak amplitudes, will be fed back to the epidural stimulation console to provide real-time information on locomotor output that are used to dynamically modulate and optimize stimulation parameters.
The ESS device may be configured to provide extremely fine temporal resolution (i.e., time resolution of 10 μs), increased independent rate options for programs providing therapy simultaneously, and independent amplitude control on each active electrode. The control device 102 may be configured with an ESS application programming interface (API), may be configured to wirelessly adjust the stimulation provided by the ESS device, at a rate of, for example, up to six times per second. In conjunction with intent information decoded from the individual's neural activity (the MUSIC device), posture and muscle-firing information (wearable EMG and accelerometer), bladder and cardiovascular (CV) parameters (wearable sensors), and machine learning algorithms for closed-loop neuromodulation, the ESS device is configured to be used to restore complex motor, bladder, and CV control.
In some embodiments, the ESS device is configured to be used to along with the other elements of the system 100 to restore complex motor, bladder, and CV control to an individual with a SCI. For example, when electrical stimulation is provided by the ESS device, the control device can receive signals from the sensor devices to continuously monitor motor, bladder, and CV control in response thereto.
In some embodiments, the ESS device can using a MICS band/Bluetooth relay, with USB or Bluetooth connection to the control device 102. MICS band communication will allow the control device to be several feet away from the patient while still providing therapy in a closed-loop manner through distance telemetry.
In some embodiments, the ESS device is configured to be implanted subcutaneously in the abdomen, flank, or upper buttock area, but could be implanted elsewhere. consists of a hermetic titanium enclosure housing stimulation and telemetry electronics with a battery. In some embodiments, the ESS device is configured to be used to stimulate the lumbar area of the spinal cord to provide SCI therapy.
In some embodiments, the system 100, 500 may be used to treat and monitor an individual with a SCI. For example, an individual with a SCI, such as a severe thoracic SCI, can have the ACMI device 506 implanted at subarachnoid space, and the MUSIC device 504 implanted epidurally at the site of the injury.
The ACMI device 506 is used for selectively draining CSF based on sensed feedback from its sensors. For example, the sensors the ACMI device may be configured to sense intrathecal pressure, oxygenation, lactate, and temperature, and feed signals indicative of the sensed conditions to the control device 102. The control device can control the ACMI device 506 to then selectively draining CSF based on analyzing the signals.
As described herein, the MUSIC device 504 utilizes its ultrasound and/or electrical imaging sensors to generate three-dimensional, real-time, high-resolution imaging at the injury site to continuously monitor and prevent secondary injury, and to selectively provide acoustic neuromodulation and/or focused ultrasound (FUS) at the site of injury or other condition. The MUSIC device 504 may be configured to generate signals/images based on conditions sensed by its sensors, and to send those signals to the control device 102. The control device 102 may be configures to selectively provide acoustic neuromodulation and/or focused ultrasound based on analyzing the received signals.
In a post-acute period, the ESS device may be implanted, and the wearable devices 104 may be worn and utilized with the system 100, 500. The ESS device may be configured to selectively apply electrical stimulation of the dorsal lumbosacral spinal cord based on sensed conditions from any of the wearable devices 104 or the implantable devices 106.
The system 100, 500 includes software programs (algorithms) as program product 406 that include a machine-learning modelling framework. All sensed data may be loaded to a persistent datastore. The data in the datastore is used with a real-time implementation of a multimodal time-series classification network built on efficient implementations of deep convolutional neural networks for processing multi-scale spatiotemporal representations. The networks are trained to predict optimal interventions (e.g., stimulation with electrodes, ultrasound, and drug delivery) based on simultaneous analysis of the MUSIC implant's electrode array, ultrasound measurements, and ACMI biomarker inputs, for example. Regression models based on deep features extracted from ultrasound using convolutional neural networks, can be used to estimate bladder state and blood pressure. As the amount of chronic data in the datastore increases and more functionality is demanded from the system, the algorithms are trained and deployed to predict improved stimulation patterns from multimodal inputs.
The present disclosure also provides various systems and computer program products or machine readable media. In some aspects, for example, the methods described herein are optionally performed or facilitated at least in part using systems, distributed computing hardware and applications (e.g., cloud computing services), electronic communication networks, communication interfaces, computer program products, machine readable media, electronic storage media, software (e.g., machine-executable code or logic instructions) and/or the like.
As understood by those of ordinary skill in the art, memory 404 of the control device 400 optionally includes volatile and/or nonvolatile memory including, for example, RAM, ROM, and magnetic or optical disks, among others. It is also understood by those of ordinary skill in the art that although illustrated as a control device, the illustrated configuration of control device 400 is given only by way of example and that other types of servers or computers configured according to various other methodologies or architectures can also be used. As also understood by those of ordinary skill in the art, the control device 400, for example, can be a laptop, desktop, tablet, personal digital assistant (PDA), cell phone, server, or other types of computers.
As further understood by those of ordinary skill in the art, exemplary program product or machine readable medium 406 is optionally in the form of microcode, programs, cloud computing format, routines, and/or symbolic languages that provide one or more sets of ordered operations that control the functioning of the hardware and direct its operation. Program product 406, according to an exemplary aspect, also need not reside in its entirety in volatile memory, but can be selectively loaded, as necessary, according to various methodologies as known and understood by those of ordinary skill in the art.
Program product 406 is optionally copied from the computer-readable medium to a hard disk or a similar intermediate storage medium. When program product 406, or portions thereof, are to be run, it is optionally loaded from their distribution medium, their intermediate storage medium, or the like into the execution memory of one or more computers, configuring the computer(s) to act in accordance with the functionality or method of various aspects. All such operations are well known to those of ordinary skill in the art of, for example, computer systems.
To further illustrate, in certain aspects, this application provides systems that include one or more processors, and one or more memory components in communication with the processor. The memory component typically includes one or more instructions that, when executed, cause the processor to provide information that causes at least one result, data, and/or the like to be displayed or otherwise indicated (e.g., via a result indicator of control device 400) and/or receive information from other system components and/or from a system user (e.g., via communication interface 408 or the like).
In some aspects, program product 406 includes non-transitory computer-executable instructions which, when executed by electronic processor 402 perform at least execution of algorithms contained in the computer program product 406 configured to perform the functionality described herein. In the case of the MUSIC device 504, for example, an exemplary computer readable media includes non-transitory computer executable instruction which, when executed by an electronic processor perform at least: generating and/or capturing images proximal to a target location (e.g., a spinal cord injury) of a subject using an imaging array of the MUSIC device 504 that comprises a body structure that comprises the imaging/sensing array; administering a first therapy (e.g., FUS) proximal to the target location of the subject using a stimulation array of the MUSIC device 504; and administering a second therapy (e.g., an electrical current) proximal to the target location of the subject using an electrode array of MUSIC device 504.
To further illustrate,
In some embodiments of the devices and systems disclosed herein, whether implantable or wearables, the device is placed on a sticky gel that due its stickiness allows for proper contact and retention between the tissue (e.g., skin, etc.) and the device (e.g., via negative pressure). In some embodiments, this gel is made out of both biocompatible and sonolucent materials. The materials have acoustic properties (e.g. speed of sound and attenuation) that allow for passage of ultrasonic waves without production of non-desirable echoes. In some embodiments, for example, this gel can be a hydrogel (e.g., a photocrosslinkable gel). In some of these embodiments, light (e.g., UV light) is used to increase viscosity or solidify the gel such that the device maintains proper contact with the body of a patient. In other embodiments, this gel can be a shear-thinning material (STM) and/or shear-thinning biomaterial (STB). In some applications, for example, an STM/STB is placed on the spinal cord dura mater (or the skin, in the case of the wearables) and when the device is pressed into place, the STM/STB liquefies just enough to accommodate the device and establish appropriate contact with the body, after which point, the gel solidifies and the device maintains its intended placement. In the case of an implantable MUSIC device, it can be held in place, through commercial or customized surgical toolkits or attachment mechanisms, such as the use of sutures, screws, rods, cages, rails or other metal (or non-metal) implants that can provide the positive pressure to ensure the device is properly placed on and in contact with the body of a patient.
While the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be clear to one of ordinary skill in the art from a reading of this disclosure that various changes in form and detail can be made without departing from the true scope of the disclosure and may be practiced within the scope of the appended claims. For example, all the methods, devices, systems, computer readable media, and/or component parts or other aspects thereof can be used in various combinations. All patents, patent applications, websites, other publications or documents, and the like cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual item were specifically and individually indicated to be so incorporated by reference.
Claims
1. A medical device, comprising:
- a body structure that comprises at least portions of at least three subassemblies, which subassemblies comprise at least one imaging array, at least one stimulation array, and at least one electrode array;
- wherein the subassemblies are positionable within communication of at least one target location of a subject;
- wherein the imaging array is structured to generate and/or capture images at least proximal to the target location of the subject when the imaging array is positioned within communication of the target location of the subject;
- wherein the stimulation array is structured to administer at least a first therapy at least proximal to the target location of the subject when the stimulation array is positioned within communication of the target location of the subject;
- wherein the electrode array is structured to administer at least a second therapy at least proximal to the target location of the subject when the electrode array is positioned within communication of the target location of the subject; and,
- wherein the subassemblies are operably connected, or connectable, to at least one power source and/or at least one controller.
2. The medical device of claim 1, wherein the body structure comprises at least one substantially rigid section and at least one substantially flexible section.
3. The medical device of claim 2, wherein the substantially rigid section comprises at least one of the subassemblies.
4. The medical device of claim 1, comprising at least two imaging arrays, wherein at least a first imaging array is configured to be positioned within communication of an uninjured site of the subject and at least a second imaging array is configured to be positioned within communication of an injured site of the subject.
5-18. (canceled)
19. The medical device of claim 1, wherein the target location comprises at least a portion of a spinal cord of the subject.
20-25. (canceled)
26. The medical device of claim 1, further comprising a position tracking system that tracks angular and torsional deflection of one or more of the subassemblies when the subassemblies are positioned within communication of the target location of the subject.
27-34. (canceled)
35. The medical device of claim 1, wherein the electrode array comprises a multi-layer polyimide/copper circuit having independent layers for transmit and receive modalities.
36-38. (canceled)
39. A system, comprising:
- a medical device, comprising: a body structure that comprises at least portions of at least three subassemblies, which subassemblies comprise at least one imaging array, at least one stimulation array, and at least one electrode array; wherein the subassemblies are positionable within communication of at least one target location of a subject; wherein the imaging array is structured to generate and/or capture images at least proximal to the target location of the subject when the imaging array is positioned within communication of the target location of the subject; wherein the stimulation array is structured to administer at least a first therapy at least proximal to the target location of the subject when the stimulation array is positioned within communication of the target location of the subject; and, wherein the electrode array is structured to administer at least a second therapy at least proximal to the target location of the subject when the electrode array is positioned within communication of the target location of the subject;
- at least one power source operably connected to the subassemblies; and,
- at least one controller operably connected to the subassemblies, which controller comprises, or is capable of accessing, computer readable media comprising non-transitory computer executable instructions which, when executed by at least one electronic processor, perform at least: generating and/or capturing images at least proximal to a target location of a subject using the imaging array; administering at least a first therapy at least proximal to the target location of the subject using the stimulation array; and, administering at least a second therapy at least proximal to the target location of the subject using the electrode array.
40. The system of claim 39, wherein the non-transitory computer executable instructions comprise one or more machine learning algorithms that effectuate generating and/or capturing the images and/or administering the first and/or second therapies.
41-44. (canceled)
45. The system of claim 39, wherein the body structure comprises at least one substantially rigid section and at least one substantially flexible section.
46. The system of claim 45, wherein the substantially rigid section comprises at least one of the subassemblies.
47-50. (canceled)
51. The system of claim 39, wherein the medical device comprises at least one wearable device comprising at least one breakout box that is operably connected, or connectable, to the medical device at least when the subassemblies are positioned within communication of the target location of the subject, wherein the breakout box is configured to receive data from the medical device and/or to transmit data to the medical device.
52-73. (canceled)
74. The system of claim 39, wherein the electrode array comprises a titanium nitride electrode surface conductor.
75. The system of claim 39, wherein the electrode array comprises a multi-layer polyimide/copper circuit having independent layers for transmit and receive modalities.
76. (canceled)
77. (canceled)
78. A computer readable media comprising non-transitory computer executable instruction which, when executed by an electronic processor perform at least:
- generating and/or capturing images at least proximal to a target location of a subject using at least one imaging array of a medical device that comprises a body structure that comprises at least portions of the imaging array;
- administering at least a first therapy at least proximal to the target location of the subject using at least one stimulation array of the medical device that comprises the body structure that comprises at least portions of the stimulation array; and,
- administering at least a second therapy at least proximal to the target location of the subject using at least one electrode array of the medical device that comprises the body structure that comprises at least portions of the electrode array.
79. A method of providing medical care to a subject, the method comprising;
- generating and/or capturing images at least proximal to a target location of the subject using at least one imaging array of a medical device that comprises a body structure that comprises at least portions of the imaging array;
- administering at least a first therapy at least proximal to the target location of the subject using at least one stimulation array of the medical device that comprises the body structure that comprises at least portions of the stimulation array; and,
- administering at least a second therapy at least proximal to the target location of the subject using at least one electrode array of the medical device that comprises the body structure that comprises at least portions of the electrode array, thereby providing the medical care to the subject.
80. The method of claim 79, wherein the body structure of the medical device comprises at least one substantially rigid section and at least one substantially flexible section.
81. The method of claim 80, wherein the substantially rigid section comprises at least one of the subassemblies.
82-86. (canceled)
87. The method of claim 79, wherein the medical device comprises a belt that is worn by the subject.
88. The method of claim 79, wherein the body structure is implantable in the subject.
89-121. (canceled)
Type: Application
Filed: Oct 6, 2021
Publication Date: Nov 23, 2023
Applicant: THE JOHNS HOPKINS UNIVERSITY (Baltimore, MD)
Inventors: Amir MANBACHI (Baltimore, MD), Nicholas THEODORE (Ruxton, MD), George L. COLES (Baltimore, MD), Ana M. AINECHI (Roslyn Heights, NY), Sandeep KAMBHAMPATI (Irvine, CA)
Application Number: 18/247,759