Vagus nerve stimulation system and method

Abstract

The system comprises a wearable sensor 1 for wearing against the skin of the subject and comprising a plurality of microneedles configured in use to traverse the epidermis corneum and further insert i

Description

Technical field 5 The present invention relates to a vagus nerve stimulation system and method and in particular to a closed loop system comprising a vagus nerve stimulator and a chemical / biomarker wearable sensor and associated method. Background 10 Vagus nerve stimulation (VNS) both excitatory and inhibitory, has been shown to be an effective therapy for various conditions, including drug-resistant epilepsy, appetite suppression, and early Alzheimer's disease, among others. [See Mariana Vargas-Caballero et al, “Vagus Nerve Stimulation as a Potential Therapy in Early Alzheimer’s 15 Disease: A Review”, Frontiers in Human Neuroscience. 2022; Vol 16: Art 866434.] Implantable vagus nerve stimulators may comprise a pulse generator that is surgically implanted under the skin of the chest and connected to the vagus nerve by electrodes (e.g. cuff electrode). The pulse generator delivers regular pulses of electrical energy to 20 the vagus nerve. However, implantable VNS devices pose risks such as pain, infection, and vocal cord paralysis. To address this, wearable VNS devices have been developed as a non-invasive alternative, including electrical auricular vagus nerve stimulators. Closed-loop systems offer a promising technology for the future, as they allow for the personalized and adaptable treatment of VNS. These systems use a controller to modify 25 the "dose," "duration," and "timing" of the stimulation in response to measured biomarker data of the patient. [An example of an implantable closed-loop nerve stimulation device is disclosed in the patent GB2528070. This device uses a sensor that measures the patient's physiological 30 response to the stimulation and adjusts the stimulation parameters accordingly. Another example is disclosed in the patent US2019 / 0358456A1, which relates to a closed-loop implantable vagus nerve stimulation system that uses a sensor to monitor the patient's heart rate variability (HRV) and adjusts the stimulation parameters to optimize the HRV.] 35 Summary 10 According to a first aspect of the present invention there is provided a closed-loop system for managing and / or treating a physiological condition and / or alleviating symptoms of a physiological condition in a human or animal subject. The system comprises a wearable sensor for wearing against the skin of the subject and comprising a plurality of microneedles configured in use to traverse the epidermis corneum and further insert into the viable epidermis. The sensor is configured to generate and transmit signals indicative of the presence of one or more biomarkers in dermal interstitial fluid. The system further comprises a wearable in-ear stimulator for providing wireless electrical stimulation to a portion of a vagus nerve of the subject, through the subject’s skin; and a controller configured to receive said signals and to provide control signals to the wearable in-ear stimulator based on said signals. 15 Optionally, said physiological condition is obesity or excess weight, and said one or more biomarkers are one or more of: ghrelin, leptin, insulin, GLP-1, neuropeptide Y, urea, creatinine, neural signals, pH, sodium, potassium, calcium, glucose, or other analyte. 20 Optionally, the wearable sensor is configured to transmit the signals wirelessly by Bluetooth. Optionally, the controller is a smart phone. 25 Optionally, the controller is further configured to receive additional biomarker data and / or activity data from at least one of a smart phone, smart watch, or fitness wristband, and wherein the control signals are based on the additional biomarker data and / or activity data in combination with said signals generated by the wearable sensor. 30 35 Optionally, the controller comprises a calculating means configured to receive said signals and, based on said signals, generate control signals if at least one biomarker is greater than a threshold level specific to that biomarker and / or at least one biomarker is less than a threshold level specific to that biomarker. Optionally, a pulse should be generated if the level of ghrelin is greater than a threshold G and / or the level of leptin is below a threshold L. 10 15 20 25 30 35 According to a second aspect of the present invention there is provided a method for managing and / or treating a physiological condition and / or alleviating symptoms of a physiological condition in a human or animal subject in a closed-loop system comprising a wearable sensor, a wearable in-ear stimulator and a controller, the method comprising: sensing, with the wearable sensor, the presence of one or more biomarkers in the dermal interstitial fluid of the subject; generating, with the wearable sensor, a signal indicative of the presence of the one or more biomarkers; receiving, with the controller, said signals; providing, with the controller, control signals to the wearable in-ear stimulator based on said signals; receiving, with the wearable in-ear stimulator, the control signals and providing, with the wearable in-ear stimulator, wireless stimulation to a portion of a vagus nerve of the subject, through the subject’s skin. The present invention provides a closed-loop system for managing and treating a physiological condition and / or alleviating symptoms of a physiological condition in a human or animal subject. The system comprises a wearable sensor that is worn against the skin of the subject and comprises a plurality of microneedles configured to traverse the epidermis corneum and insert into the viable epidermis and is capable of generating and transmitting signals indicative of the presence of one or more biomarkers in dermal interstitial fluid. The system also includes a wearable in-ear stimulator that provides wireless electrical stimulation to a portion of a vagus nerve of the subject through the subject’s skin, and a controller that receives signals from the wearable sensor and provides control signals to the wearable in-ear stimulator based on the signals received. In an optional embodiment of the invention, the physiological condition being managed or treated is obesity or excess weight, and the one or more biomarkers include ghrelin, leptin, insulin, GLP-1, neuropeptide Y, urea, creatinine, neural signals, pH, sodium, potassium, calcium, glucose, or other analyte. The wearable sensor is capable of wirelessly transmitting signals by Bluetooth, and the controller may be a smart phone. The controller is also capable of receiving additional biomarker data and / or activity data from a smart phone, smart watch, or fitness wristband, and uses this data in combination with the signals generated by the wearable sensor to generate control signals. The controller includes a calculating means that generates control signals if at least one biomarker is greater than a threshold level specific to that biomarker and / or at least one 4 biomarker is less than a threshold level specific to that biomarker. In one optional embodiment, a pulse is generated if the level of ghrelin is greater than a threshold G and / or the level of leptin is below a threshold L. 5 The present invention also provides a method for managing and treating a physiological condition and / or alleviating symptoms of a physiological condition in a closed-loop system comprising a wearable sensor, a wearable in-ear stimulator, and a controller. The method includes sensing the presence of one or more biomarkers in the dermal interstitial fluid of the subject with the wearable sensor, generating a signal indicative of 10 the presence of the one or more biomarkers with the wearable sensor, receiving the signals with the controller, providing control signals to the wearable in-ear stimulator based on the received signals, and providing wireless stimulation to a portion of a vagus nerve of the subject through the subject’s skin with the wearable in-ear stimulator. 15 Brief Description of the Drawings C\J Figure 1 illustrates schematically a wearable closed-loop vagus nerve stimulation system; and Figure 2 is a flow diagram illustrating a closed-loop vagus nerve stimulation method. CD 20 Detailed Description By way of example a closed-loop system will now be described which may be suitable for achieving weight loss in a human or animal subject. Of course, the system and 25 associated method may be used to manage and / or treat other physiological conditions and / or alleviate symptoms of other physiological conditions including but not limited to: insomnia, high cholesterol, high blood pressure, diabetes, and Alzheimer’s. Figure 1 shows a closed-loop system 10 comprising a wearable sensor 1, a controller 2, and a wearable in-ear stimulator 3. 30 The wearable sensor 1 is a microneedle patch comprising a substrate layer supporting a plurality of microneedles. The microneedle patch may be any suitable type of microneedle patch for measuring various physiological parameters such as glucose, lactate, and electrolytes. In addition to this, the microneedle patch may also be suitable 35 for delivering drugs, vaccines, and other therapeutics through the skin. The plurality of 5 microneedles points away from a first side of the substrate layer. The substrate layer is interfaced with an electronic circuit, and the electronic circuit is connected to a wireless radio interface. The wearable sensor 1 further comprises a battery to power the electronic circuit and wireless radio interface. The substrate layer, electronic circuit, 5 wireless radio interface and battery are held within a housing that protects these components. The housing also positions the substrate layer such that the microneedles are exposed from one side of the housing. The wearable sensor 1 further comprises an adhesive layer for attaching the wearable sensor 1 to the skin. 10 15 The plurality of microneedles of the closed-loop system 10 is arranged in an array and is designed to reach the viable epidermis. The viable epidermis is the layer of the skin where the living cells are located. The length of each microneedle is between 300-1500pm, which is suitable for collecting physiological data from the patient's body. The microneedles have enzymes located on the tips of each of the plurality of microneedles that react with biomarkers to generate a current. The term “biomarker” is used to refer to any type of biological molecule or analyte that is suitable for monitoring a process, condition or disease of a subject. Each microneedle comprises a specific enzyme that reacts with a biomarker such as ghrelin, leptin, insulin, GLP-1, neuropeptide Y, urea, Creatinine, neural signals, pH, sodium, potassium, calcium, glucose or any other suitable analyte. These biomarkers are related to appetite, weight, and metabolism, and can provide insight into the patient's physiological state. The electronic circuit is configured to generate signals indicative of the quantities of the biomarkers. The wireless radio interface, which in this case is a Bluetooth™ transmitter, 25 is used to transmit the signals wirelessly to the controller 2. It is important to note that transmission protocols other than Bluetooth™ may be utilized, depending on the specific needs of the system and the environment in which it is used. The controller 2 comprises a wireless radio interface and a calculating means configured 30 to determine a control signal for controlling the wearable in-ear stimulator 3. The controller 2 further comprises a port for transmitting the control signal to the wearable in-ear stimulator by a wired connection. The wireless radio interface includes a Bluetooth™ receiver for receiving the biomarker signals. The calculating means is configured to take the biomarker signals as input to determine: 35 a) if pulse generation is necessary, and if so 6 b) the pulse parameters to be generated by the wearable in-ear stimulator. In one example, the calculating means determines that pulse (train) generation is necessary if at least one biomarker is greater than a threshold level specific to that biomarker and / or at least one biomarker is less than a threshold level specific to that 5 biomarker. For example, the calculating means may determine that pulse generation is necessary if the level of ghrelin is greater than a threshold G and / or the level of leptin is below a threshold L. Ghrelin is a hormone that stimulates appetite, and leptin is a hormone that suppresses appetite. 10 If it is determined that pulse generation is necessary, the calculation means is further configured to calculate the parameters, or characteristics, of the pulse to be generated, based on the levels of the at least one biomarker. The pulse characteristics include pulse intensity, pulse width, pulse frequency, and the on / off duty cycle. The calculation means is further configured to determine the control signals to be sent to the wearable in-ear 15 stimulator, based on the pulse characteristics. CM The wearable in-ear stimulator 3 comprises a housing connected to a support member configured to allow the wearable in-ear stimulator to be removably secured to the ear. The support member comprises an ear bud configured to fit the inner ear and / or an ear 20 hook configured to fit the outer ear. The housing contains an input (and optionally an output) interface for receiving control signals. The input interface includes a port for receiving a cable. The housing further contains a pulse generator for generating a pulse based on the control signals and supplying the pulse to at least one electrode. The control signals specify the electrical charge (mA), pulse width (pm), pulse frequency (Hz) 25 and duty cycle (in seconds or minutes) of the pulse. The at least one electrode is arranged to deliver the electrical pulses to a suitable part of the ear, such as at least one of the cymba conchae, cavum and ear lobe. The housing further contains a battery to power the components of the in-ear stimulator. The wearable in-ear stimulator 3 further comprises an on and off switch arranged on the outer surface of the housing. 30 Turing to Figure 2, the closed loop system 10 is described in use. The subject wears the wearable sensor 1 against their skin by attaching the wearable sensor 1 with the adhesive layer. The plurality of microneedles traverses the epidermis corneum and further inserts into the viable epidermis. The microneedles sense biomarkers such as 35 ghrelin, leptin, insulin, neuropeptide Y, and glucose in the dermal interstitial fluid. These 7 biomarkers are related to appetite, weight, and metabolism, and can provide insight into the patient's physiological state. The electronic circuit generates signals indicative of the quantities of the at least one 5 biomarker. The electronic circuit outputs the signals to the Bluetooth transmitter. The Bluetooth transmitter periodically transmits the signals to controller 2. The controller 2 receives the signals by the Bluetooth receiver. The controller 2 uses the data from the signals to adjust the pulse parameters, or stimulation parameters, delivered 10 by the in-ear stimulator 3. This allows the system to adjust the stimulation in real-time, based on the patient's physiological state, to achieve weight loss or other therapeutic effects. At regular time intervals, the calculating means takes the biomarker data as an input and 15 determines if pulse generation is necessary, and if so, the pulse parameters that are required. The calculating means determines that pulse generation is necessary when the level of ghrelin is greater than a threshold G and / or the level of leptin is below a threshold L. By monitoring the levels of these hormones, the system can determine if the patient is hungry or full and adjust the stimulation accordingly. CD 20 The calculating means then determines the control signals based on the pulse parameters. The control signals are transmitted to the wearable in-ear stimulator 3 via cable 4. The controller 2 provides power to the wearable in-ear stimulator 1 via cable 4. 25 The subject wears the wearable-in ear stimulator 3 by securing the support member to the ear. The input interface receives the control signals via cable 4. The control signals are output to the pulse generator, which generates a pulse with the pulse parameters. The electrical pulse conducted by the at least one electrode stimulates the auricular branch of the vagus nerve, which has an inhibitory effect on the efferent fibers of the 30 vagus nerve. This leads to reduced gastric tone and contractile activity in the upper gastrointestinal tract of the subject. When the efferent fibers of the vagus nerve are inhibited, it leads to a decrease in the activity of the digestive system and a reduction in hunger signals sent to the brain, resulting in the subject feeling satiated. This reduction in hunger signals and the feeling of satiety can help to reduce the subject's appetite and 35 food intake, which can lead to weight loss. Advantageously, the use of a wearable sensor allows for the physiological state of the patient to be quantified in real time before, during and after the vagus nerve is stimulated. The physiological parameters may relate to at least one of the neural, metabolic or 5 cardiovascular state of the patient. The use of a wearable in-ear stimulator allows the vagus nerve can be stimulated non-invasively, which overcomes the disadvantages associated with an implantable vagus nerve stimulator. 10 A closed-loop control system allows the dose and timing of the signal to be modulated in response to the current physiological state of the patient. This enables the intervention to be tailored to the individual. In addition to the above, or alternatively, the signal may also be arranged to be sent to the electrode without being based on any of the processed 15 at least one physiological parameter. C\J It is envisaged that in some embodiments, the wearable sensor 1 may comprise only one microneedle which is sensitive to single biomarker, for example a microneedle sensitive to glucose. CD 20 In further embodiments, the wearable sensor 1 may be configured to deliver drugs to the subject, such as weight-loss drugs to treat obesity. In further embodiments, the wearable sensor 1 may, in addition to, or as alternative, to 25 the microneedle patch, be a non-invasive sensor configured to detect metabolites from the sweat on the surface of the skin. The controller 2 may be a smartphone. The port can be a USC / Lightning port. 30 In further embodiments, communication between the controller 2 and the in-ear stimulator 3 may also be achieved wirelessly by Bluetooth™ or other wireless, radio protocol. The wireless radio interface of the controller 2 may further comprise a Bluetooth™ transmitter for transmitting the control signals. The input interface of the in-ear stimulator 3 may further comprise a Bluetooth™ receiver for receiving the control 35 signals. In further embodiments, the wearable in-ear stimulator 3 may further comprise a driver to generate sound waves. The input interface may be further configured to receive audio signals by Bluetooth and / or a wired connection, which are output to the driver. The 5 wearable in-ear stimulator 3 can therefore also be used as headphones. In further embodiments, the wireless radio interface of the controller 2 may also be configured to receive additional biomarker data and / or activity data from at least one of a smart phone, smart watch, or fitness wristband. The further biomarker data may include 10 pulse rate and body temperature. The activity data may include the number of steps completed in a certain time period or the number of hours of sleep the previous night. The calculating means may consider the additional biomarker data and / or activity data when deciding if a pulse should be generated. The calculating means may consider the additional biomarker data and / or activity data when determining the pulse 15 characteristics. C\J The present invention relates to a wearable closed-loop system that utilizes microneedle-based sensors and in-ear stimulators to provide personalized and adaptable treatment for a range of physiological conditions. CD 20 The present invention employs wearable closed-loop systems that use microneedlebased sensors to measure various analytes in the interstitial fluid and wearable in-ear stimulators to provide electrical stimulation to a portion of the vagus nerve of the subject, through the skin, based on the measured analyte levels. This technology can be applied 25 to a wide range of physiological conditions, including obesity or excess weight, hormonal imbalances, metabolic disorders, pain management, and various neurological conditions. The microneedle-based sensors are capable of measuring a range of analytes in the 30 interstitial fluid, such as ghrelin, leptin, insulin, GLP-1, neuropeptide Y, urea, creatinine, pH, sodium, potassium, calcium, glucose, and other analytes. The wearable in-ear stimulator provides wireless electrical stimulation to a portion of the vagus nerve of the subject through the subject's skin and is controlled by a controller that receives signals from the microneedle-based sensors. The controller can also receive additional 35 biomarker data and / or activity data from other wearable devices, such as a smart phone, 10 smart watch, or fitness wristband, and generate control signals based on a combination of these data and the signals generated by the microneedle-based sensors. This closed-loop system provides a more personalized and adaptable approach to VNS 5 treatment, allowing for real-time adjustment of the electrical stimulation of the vagus nerve based on the measured analyte levels, thus providing a more personalized and adaptive treatment approach. The invention offers significant advantages over current VNS technologies and holds great potential for improving the treatment of a range of physiological conditions. 19 06 24

Claims

1. A closed-loop system for managing and / or treating a physiological condition and / or alleviating symptoms of a physiological condition in a human or animal subject, the system comprising:a wearable sensor for wearing against the skin of the subject and comprising a plurality of microneedles configured in use to traverse the epidermis corneum and further insert into the viable epidermis, the sensor being configured to generate and transmit signals indicative of the presence of one or more biomarkers in dermal interstitial fluid;a wearable in-ear stimulator for providing wireless electrical stimulation to a portion of a vagus nerve of the subject, through the subject’s skin; anda controller configured to receive said signals and to provide control signals to the wearable in-ear stimulator based on said signals.

2. A system according to claim 1, where said physiological condition is obesity or excess weight, and said one or more biomarkers are one or more of: ghrelin, leptin, insulin, GLP-1, neuropeptide Y, urea, creatinine, neural signals, pH, sodium , potassium, calcium, glucose, or other analyte.

3. A system according to any preceding claim, wherein the wearable sensor is configured to transmit the signals wirelessly by Bluetooth.

4. A system according to any preceding claim, wherein the controller is a smart phone.

5. A system according to any preceding claim, wherein the controller is further configured to receive additional biomarker data and / or activity data from at least one of a smart phone, smart watch, or fitness wristband, and wherein the control signals are based on the additional biomarker data and / or activity data in combination with said signals generated by the wearable sensor.

6. A system according to any preceding claim, wherein the controller comprises a calculating means configured to receive said signals and, based on said signals, generate control signals if at least one biomarker is greater than a threshold level specificto that biomarker and / or at least one biomarker is less than a threshold level specific to that biomarker.

7. A system according to claim 6, wherein control signals are generated if the level of ghrelin is greater than a threshold G and / or the level of leptin is below a threshold L.

8. A method for managing and / or treating a physiological condition and / or alleviating symptoms of a physiological condition in a human or animal subject in a closed-loop system comprising a wearable sensor, a wearable in-ear stimulator and a controller, the method comprising:sensing, with the wearable sensor, the presence of one or more biomarkers in the dermal interstitial fluid of the subject;generating, with the wearable sensor, a signal indicative of the presence of the one or more biomarkers;receiving, with the controller, said signals;providing, with the controller, control signals to the wearable in-ear stimulator based on said signals;receiving, with the wearable in-ear stimulator, the control signals andproviding, with the wearable in-ear stimulator, wireless stimulation to a portion of a vagus nerve of the subject, through the subject’s skin.

Images