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The field of bioelectronic medicine has advanced rapidly from rudimentary electrical therapies to cutting-edge closed-loop systems that integrate real-time physiological monitoring with adaptive neuromodulation. Early innovations, such as cardiac pacemakers and deep brain stimulation, paved the way for these sophisticated technologies. This review traces the historical and technological progression of bioelectronic medicine, culminating in the emerging potential of closed-loop devices for multiple disorders of the brain and body. We emphasize both invasive techniques, such as implantable devices for brain, spinal cord and autonomic regulation, while we introduce new prospects for non-invasive neuromodulation, including focused ultrasound and newly developed autonomic neurography enabling precise detection and titration of inflammatory immune responses. The case for closed-loop non-invasive autonomic neuromodulation (incorporating autonomic neurography and splenic focused ultrasound stimulation) is presented through its applications in conditions such as sepsis and chronic inflammation, illustrating its capacity to revolutionize personalized healthcare. Today, invasive or non-invasive closed-loop systems have yet to be developed that dynamically modulate autonomic nervous system function by responding to real-time physiological and molecular signals; it represents a transformative approach to therapeutic interventions and major opportunity by which the bioelectronic field may advance. Knowledge gaps remain and likely contribute to the lack of available closed loop autonomic neuromodulation systems, namely, (1) significant exogenous and endogenous noise that must be filtered out, (2) potential drift in the signal due to temporal change in disease severity and/or therapy induced neuroplasticity, and (3) confounding effects of exogenous therapies (e.g., concurrent medications that dysregulate autonomic nervous system functions). Leveraging continuous feedback and real-time adjustments may overcome many of these barriers, and these next generation systems have the potential to stand at the forefront of precision medicine, offering new avenues for individualized and adaptive treatment.

Abstract The field of bioelectronic medicine has advanced rapidly from rudimentary electrical therapies to cutting-edge closed-loop systems that integrate real-time physiological monitoring with adaptive neuromodulation. Early innovations, such as cardiac pacemakers and deep brain stimulation, paved the way for these sophisticated technologies. This review traces the historical and technological progression of bioelectronic medicine, culminating in the emerging potential of closed-loop devices for multiple disorders of the brain and body. We emphasize both invasive techniques, such as implantable devices for brain, spinal cord and autonomic regulation, while we introduce new prospects for non-invasive neuromodulation, including focused ultrasound and newly developed autonomic neurography enabling precise detection and titration of inflammatory immune responses. The case for closed-loop non-invasive autonomic neuromodulation (incorporating autonomic neurography and splenic focused ultrasound stimulation) is presented through its applications in conditions such as sepsis and chronic inflammation, illustrating its capacity to revolutionize personalized healthcare. Today, invasive or non-invasive closed-loop systems have yet to be developed that dynamically modulate autonomic nervous system function by responding to real-time physiological and molecular signals; it represents a transformative approach to therapeutic interventions and major opportunity by which the bioelectronic field may advance. Knowledge gaps remain and likely contribute to the lack of available closed loop autonomic neuromodulation systems, namely, (1) significant exogenous and endogenous noise that must be filtered out, (2) potential drift in the signal due to temporal change in disease severity and/or therapy induced neuroplasticity, and (3) confounding effects of exogenous therapies (e.g., concurrent medications that dysregulate autonomic nervous system functions). Leveraging continuous feedback and real-time adjustments may overcome many of these barriers, and these next generation systems have the potential to stand at the forefront of precision medicine, offering new avenues for individualized and adaptive treatment.

Bioelectronic Medicine stands as an emerging field that rapidly evolves and offers distinctive clinical benefits, alongside unique challenges. It consists of the modulation of the nervous system by precise delivery of electrical current for the treatment of clinical conditions, such as post-stroke movement recovery or drug-resistant disorders. The unquestionable clinical impact of Bioelectronic Medicine is underscored by the successful translation to humans in the last decades, and the long list of preclinical studies. Given the emergency of accelerating the progress in new neuromodulation treatments (i.e., drug-resistant hypertension, autoimmune and degenerative diseases), collaboration between multiple fields is imperative. This work intends to foster multidisciplinary work and bring together different fields to provide the fundamental basis underlying Bioelectronic Medicine. In this review we will go from the biophysics of the cell membrane, which we consider the inner core of neuromodulation, to patient care. We will discuss the recently discovered mechanism of neurotransmission switching and how it will impact neuromodulation design, and we will provide an update on neuronal and glial basis in health and disease. The advances in biomedical technology have facilitated the collection of large amounts of data, thereby introducing new challenges in data analysis. We will discuss the current approaches and challenges in high throughput data analysis, encompassing big data, networks, artificial intelligence, and internet of things. Emphasis will be placed on understanding the electrochemical properties of neural interfaces, along with the integration of biocompatible and reliable materials and compliance with biomedical regulations for translational applications. Preclinical validation is foundational to the translational process, and we will discuss the critical aspects of such animal studies. Finally, we will focus on the patient point-of-care and challenges in neuromodulation as the ultimate goal of bioelectronic medicine. This review is a call to scientists from different fields to work together with a common endeavor: accelerate the decoding and modulation of the nervous system in a new era of therapeutic possibilities.

Abstract Bioelectronic Medicine (BEM), which uses implantable electronic medical devices to interface with electrically active tissues, aspires to revolutionize the way we understand and fight disease. By leveraging knowledge from microelectronics, materials science, information technology, neuroscience and medicine, BEM promises to offer novel solutions that address unmet clinical needs and change the concept of therapeutics. This perspective communicates our vision for the future of BEM and presents the necessary steps that need to be taken and the challenges that need to be faced before this new technology can flourish.

Bioelectronic Medicine (BEM), which uses implantable electronic medical devices to interface with electrically active tissues, aspires to revolutionize the way we understand and fight disease. By leveraging knowledge from microelectronics, materials science, information technology, neuroscience and medicine, BEM promises to offer novel solutions that address unmet clinical needs and change the concept of therapeutics. This perspective communicates our vision for the future of BEM and presents the necessary steps that need to be taken and the challenges that need to be faced before this new technology can flourish. [ABSTRACT FROM AUTHOR]

Abstract Electrical stimulation of spinal neurons has emerged as a valuable tool to enhance rehabilitation after spinal cord injury. In separate parameterizations, it has shown promise for improving voluntary movement, reducing symptoms of autonomic dysreflexia, improving functions mediated by muscles of the pelvic floor (e.g., bowel, bladder, and sexual function), reducing spasms and spasticity, and decreasing neuropathic pain, among others. This diverse set of actions is related both to the density of sensorimotor neural networks in the spinal cord and to the intrinsic ability of electrical stimulation to modulate neural transmission in multiple spinal networks simultaneously. It also suggests that certain spinal stimulation parameterizations may be capable of providing multi-modal therapeutic benefits, which would directly address the complex, multi-faceted rehabilitation goals of people living with spinal cord injury. This review is intended to identify and characterize reports of spinal stimulation-based therapies specifically designed to provide multi-modal benefits and those that report relevant unintended effects of spinal stimulation paradigms parameterized to enhance a single consequence of spinal cord injury.

Electrical stimulation of spinal neurons has emerged as a valuable tool to enhance rehabilitation after spinal cord injury. In separate parameterizations, it has shown promise for improving voluntary movement, reducing symptoms of autonomic dysreflexia, improving functions mediated by muscles of the pelvic floor (e.g., bowel, bladder, and sexual function), reducing spasms and spasticity, and decreasing neuropathic pain, among others. This diverse set of actions is related both to the density of sensorimotor neural networks in the spinal cord and to the intrinsic ability of electrical stimulation to modulate neural transmission in multiple spinal networks simultaneously. It also suggests that certain spinal stimulation parameterizations may be capable of providing multi-modal therapeutic benefits, which would directly address the complex, multi-faceted rehabilitation goals of people living with spinal cord injury. This review is intended to identify and characterize reports of spinal stimulation-based therapies specifically designed to provide multi-modal benefits and those that report relevant unintended effects of spinal stimulation paradigms parameterized to enhance a single consequence of spinal cord injury. [ABSTRACT FROM AUTHOR]

Bioelectronic medicine are an emerging class of treatments aiming to modulate body nervous activity to correct pathological conditions and restore health. Recently, it was shown that the high frequency electrical neuromodulation of the carotid sinus nerve (CSN), a small branch of the glossopharyngeal nerve that connects the carotid body (CB) to the brain, restores metabolic function in type 2 diabetes (T2D) animal models highlighting its potential as a new therapeutic modality to treat metabolic diseases in humans. In this manuscript, we review the current knowledge supporting the use of neuromodulation of the CSN to treat T2D and discuss the future perspectives for its clinical application. Firstly, we review in a concise manner the role of CB chemoreceptors and of CSN in the pathogenesis of metabolic diseases. Secondly, we describe the findings supporting the potential therapeutic use of the neuromodulation of CSN to treat T2D, as well as the feasibility and reversibility of this approach. A third section is devoted to point up the advances in the neural decoding of CSN activity, in particular in metabolic disease states, that will allow the development of closedloop approaches to deliver personalized and adjustable treatments with minimal side effects. And finally, we discuss the findings supporting the assessment of CB activity in metabolic disease patients to screen the individuals that will benefit therapeutically from this bioelectronic approach in the future. [ABSTRACT FROM AUTHOR]

Bioelectronic Medicine stands as an emerging field that rapidly evolves and offers distinctive clinical benefits, alongside unique challenges. It consists of the modulation of the nervous system by precise delivery of electrical current for the treatment of clinical conditions, such as post-stroke movement recovery or drug-resistant disorders. The unquestionable clinical impact of Bioelectronic Medicine is underscored by the successful translation to humans in the last decades, and the long list of preclinical studies. Given the emergency of accelerating the progress in new neuromodulation treatments (i.e., drug-resistant hypertension, autoimmune and degenerative diseases), collaboration between multiple fields is imperative. This work intends to foster multidisciplinary work and bring together different fields to provide the fundamental basis underlying Bioelectronic Medicine. In this review we will go from the biophysics of the cell membrane, which we consider the inner core of neuromodulation, to patient care. We will discuss the recently discovered mechanism of neurotransmission switching and how it will impact neuromodulation design, and we will provide an update on neuronal and glial basis in health and disease. The advances in biomedical technology have facilitated the collection of large amounts of data, thereby introducing new challenges in data analysis. We will discuss the current approaches and challenges in high throughput data analysis, encompassing big data, networks, artificial intelligence, and internet of things. Emphasis will be placed on understanding the electrochemical properties of neural interfaces, along with the integration of biocompatible and reliable materials and compliance with biomedical regulations for translational applications. Preclinical validation is foundational to the translational process, and we will discuss the critical aspects of such animal studies. Finally, we will focus on the patient point-of-care and challenges in neuromodulation as the ultimate goal of bioelectronic medicine. This review is a call to scientists from different fields to work together with a common endeavor: accelerate the decoding and modulation of the nervous system in a new era of therapeutic possibilities. [ABSTRACT FROM AUTHOR]

Bioelectronic medicine are an emerging class of treatments aiming to modulate body nervous activity to correct pathological conditions and restore health. Recently, it was shown that the high frequency electrical neuromodulation of the carotid sinus nerve (CSN), a small branch of the glossopharyngeal nerve that connects the carotid body (CB) to the brain, restores metabolic function in type 2 diabetes (T2D) animal models highlighting its potential as a new therapeutic modality to treat metabolic diseases in humans. In this manuscript, we review the current knowledge supporting the use of neuromodulation of the CSN to treat T2D and discuss the future perspectives for its clinical application. Firstly, we review in a concise manner the role of CB chemoreceptors and of CSN in the pathogenesis of metabolic diseases. Secondly, we describe the findings supporting the potential therapeutic use of the neuromodulation of CSN to treat T2D, as well as the feasibility and reversibility of this approach. A third section is devoted to point up the advances in the neural decoding of CSN activity, in particular in metabolic disease states, that will allow the development of closed-loop approaches to deliver personalized and adjustable treatments with minimal side effects. And finally, we discuss the findings supporting the assessment of CB activity in metabolic disease patients to screen the individuals that will benefit therapeutically from this bioelectronic approach in the future.

Nearly 5 decades ago, the effect of trigeminal nerve stimulation (TNS) on cerebral blood flow was observed for the first time. This implication directly led to further investigations and TNS' success as a therapeutic intervention. Possessing unique connections with key brain and brainstem regions, TNS has been observed to modulate cerebral vasodilation, brain metabolism, cerebral autoregulation, cerebral and systemic inflammation, and the autonomic nervous system. The unique range of effects make it a prime therapeutic modality and have led to its clinical usage in chronic conditions such as migraine, prolonged disorders of consciousness, and depression. This review aims to present a comprehensive overview of TNS research and its broader therapeutic potentialities. For the purpose of this review, PubMed and Google Scholar were searched from inception to August 28, 2023 to identify a total of 89 relevant studies, both clinical and pre-clinical. TNS harnesses the release of vasoactive neuropeptides, modulation of neurotransmission, and direct action upon the autonomic nervous system to generate a suite of powerful multitarget therapeutic effects. While TNS has been applied clinically to chronic pathological conditions, these powerful effects have recently shown great potential in a number of acute/traumatic pathologies. However, there are still key mechanistic and methodologic knowledge gaps to be solved to make TNS a viable therapeutic option in wider clinical settings. These include bimodal or paradoxical effects and mechanisms, questions regarding its safety in acute/traumatic conditions, the development of more selective stimulation methods to avoid potential maladaptive effects, and its connection to the diving reflex, a trigeminally-mediated protective endogenous reflex. The address of these questions could overcome the current limitations and allow TNS to be applied therapeutically to an innumerable number of pathologies, such that it now stands at the precipice of becoming a ground-breaking therapeutic modality. [ABSTRACT FROM AUTHOR]

Bioelectronic Medicine stands as an emerging field that rapidly evolves and offers distinctive clinical benefits, alongside unique challenges. It consists of the modulation of the nervous system by precise delivery of electrical current for the treatment of clinical conditions, such as post-stroke movement recovery or drug-resistant disorders. The unquestionable clinical impact of Bioelectronic Medicine is underscored by the successful translation to humans in the last decades, and the long list of preclinical studies. Given the emergency of accelerating the progress in new neuromodulation treatments (i.e., drug-resistant hypertension, autoimmune and degenerative diseases), collaboration between multiple fields is imperative. This work intends to foster multidisciplinary work and bring together different fields to provide the fundamental basis underlying Bioelectronic Medicine. In this review we will go from the biophysics of the cell membrane, which we consider the inner core of neuromodulation, to patient care. We will discuss the recently discovered mechanism of neurotransmission switching and how it will impact neuromodulation design, and we will provide an update on neuronal and glial basis in health and disease. The advances in biomedical technology have facilitated the collection of large amounts of data, thereby introducing new challenges in data analysis. We will discuss the current approaches and challenges in high throughput data analysis, encompassing big data, networks, artificial intelligence, and internet of things. Emphasis will be placed on understanding the electrochemical properties of neural interfaces, along with the integration of biocompatible and reliable materials and compliance with biomedical regulations for translational applications. Preclinical validation is foundational to the translational process, and we will discuss the critical aspects of such animal studies. Finally, we will focus on the patient point-of-care and challenges in neuromodulation as the ultimate goal of bioelectronic medicine. This review is a call to scientists from different fields to work together with a common endeavor: accelerate the decoding and modulation of the nervous system in a new era of therapeutic possibilities.

This document is an editorial titled "Women in neuroscience of Bioelectronic Medicine" published in the journal Frontiers in Integrative Neuroscience. The editorial discusses the emerging field of Bioelectronic Medicine, which combines pharmacological treatments with electrical stimulation to restore organ function. The editorial emphasizes the multidisciplinary nature of this field and the need for collaboration. It also highlights the importance of women's participation in science and features research on various topics related to Bioelectronic Medicine, including retinal function, inflammation prevention, and neuromodulation. The editorial aims to promote the integration of neurosciences with other disciplines and increase women's participation in the field. [Extracted from the article]

Gastrointestinal (GI) disorders, which extend from the esophagus to the anus, are the most common diseases of the GI tract. Among these disorders, pain, encompassing both abdominal and visceral pain, is a predominant feature, affecting the patients' quality of life and imposing a substantial financial burden on society. Pain signals originating from the gut intricately shape brain dynamics. In response, the brain sends appropriate descending signals to respond to pain through neuronal inhibition. However, due to the heterogeneous nature of the disease and its limited pathophysiological understanding, treatment options are minimal and often controversial. Consequently, many patients with GI disorders use complementary and alternative therapies such as neuromodulation to treat visceral pain. Neuromodulation intervenes in the central, peripheral, or autonomic nervous system by alternating or modulating nerve activity using electrical, electromagnetic, chemical, or optogenetic methodologies. Here, we review a few emerging noninvasive neuromodulation approaches with promising potential for alleviating pain associated with functional dyspepsia, gastroparesis, irritable bowel syndrome, inflammatory bowel disease, and non-cardiac chest pain. Moreover, we address critical aspects, including the efficacy, safety, and feasibility of these noninvasive neuromodulation methods, elucidate their mechanisms of action, and outline future research directions. In conclusion, the emerging field of noninvasive neuromodulation appears as a viable alternative therapeutic avenue for effectively managing visceral pain in GI disorders. [ABSTRACT FROM AUTHOR]

During type 1 diabetes, an autoimmune attack destroys pancreatic b-cells leading to the inability to maintain glucose homeostasis. These b-cells are neuroresponsive endocrine cells which normally secrete insulin partially in response to input from the vagus nerve. This neural pathway can be utilized as a point of therapeutic intervention by delivering exogenous stimulation to drive increased insulin secretion. In this study, a cuff electrode was implanted on the pancreatic branch of the vagus nerve just prior to pancreatic insertion in rats, and a continuous glucose meter was implanted into the descending aorta. Streptozotocin (STZ) was used to induce a diabetic state, and changes in blood glucose were assessed using various stimulation parameters. Stimulation driven changes in hormone secretion, pancreatic blood flow, and islet cell populations were assessed. We found increased changes in the rate of blood glucose change during stimulation which subsided after stimulation ended paired with increased concentration of circulating insulin. We did not observe increased pancreatic perfusion, which suggests that the modulation of blood glucose was due to the activation of b-cells rather than changes in the extra-organ transport of insulin. Pancreatic neuromodulation showed potentially protective effects by reducing deficits in islet diameter, and ameliorating insulin loss after STZ treatment. [ABSTRACT FROM AUTHOR]

During type 1 diabetes, an autoimmune attack destroys pancreatic β-cells leading to the inability to maintain glucose homeostasis. These β-cells are neuroresponsive endocrine cells which normally secrete insulin partially in response to input from the vagus nerve. This neural pathway can be utilized as a point of therapeutic intervention by delivering exogenous stimulation to drive increased insulin secretion. In this study, a cuff electrode was implanted on the pancreatic branch of the vagus nerve just prior to pancreatic insertion in rats, and a continuous glucose meter was implanted into the descending aorta. Streptozotocin (STZ) was used to induce a diabetic state, and changes in blood glucose were assessed using various stimulation parameters. Stimulation driven changes in hormone secretion, pancreatic blood flow, and islet cell populations were assessed. We found increased changes in the rate of blood glucose change during stimulation which subsided after stimulation ended paired with increased concentration of circulating insulin. We did not observe increased pancreatic perfusion, which suggests that the modulation of blood glucose was due to the activation of b-cells rather than changes in the extra-organ transport of insulin. Pancreatic neuromodulation showed potentially protective effects by reducing deficits in islet diameter, and ameliorating insulin loss after STZ treatment.

Healing of wounds is delayed in Type 2 Diabetes Mellitus (T2DM), and new treatment approaches are urgently needed. Our earlier work showed that splenic pulsed focused ultrasound (pFUS) alters inflammatory cytokines in models of acute endotoxemia and pneumonia via modulation of the cholinergic anti-inflammatory pathway (CAP) (ref below). Based on these earlier results, we hypothesized that daily splenic exposure to pFUS during wound healing would accelerate closure rate via altered systemic cytokine titers. In this study, we applied non-invasive ultrasound directed to the spleen of a rodent model [Zucker Diabetic Sprague Dawley (ZDSD) rats] of T2DM with full thickness cutaneous excisional wounds in an attempt to accelerate wound healing via normalization of T2DM-driven aberrant cytokine expression. Daily (1x/day, Monday-Friday) pFUS pulses were targeted externally to the spleen area for 3 min over the course of 15 days. Wound diameter was measured daily, and levels of cytokines were evaluated in spleen and wound bed lysates. Non-invasive splenic pFUS accelerated wound closure by up to 4.5 days vs. sham controls. The time to heal in all treated groups was comparable to that of healthy rats from previously published studies (ref below), suggesting that the pFUS treatment restored a normal wound healing phenotype to the ZDSD rats. IL-6 was lower in stimulated spleen (-2.24 ± 0.81 Log2FC, p = 0.02) while L-selectin was higher in the wound bed of stimulated rodents (2.53 ± 0.72 Log2FC, p = 0.003). In summary, splenic pFUS accelerates healing in a T2DM rat model, demonstrating the potential of the method to provide a novel, non-invasive approach for wound care in diabetes. [ABSTRACT FROM AUTHOR]

Healing of wounds is delayed in Type 2 Diabetes Mellitus (T2DM), and new treatment approaches are urgently needed. Our earlier work showed that splenic pulsed focused ultrasound (pFUS) alters inflammatory cytokines in models of acute endotoxemia and pneumonia via modulation of the cholinergic anti-inflammatory pathway (CAP) (ref below). Based on these earlier results, we hypothesized that daily splenic exposure to pFUS during wound healing would accelerate closure rate via altered systemic cytokine titers. In this study, we applied non-invasive ultrasound directed to the spleen of a rodent model [Zucker Diabetic Sprague Dawley (ZDSD) rats] of T2DM with full thickness cutaneous excisional wounds in an attempt to accelerate wound healing via normalization of T2DM-driven aberrant cytokine expression. Daily (1x/day, Monday-Friday) pFUS pulses were targeted externally to the spleen area for 3 min over the course of 15 days. Wound diameter was measured daily, and levels of cytokines were evaluated in spleen and wound bed lysates. Non-invasive splenic pFUS accelerated wound closure by up to 4.5 days vs. sham controls. The time to heal in all treated groups was comparable to that of healthy rats from previously published studies (ref below), suggesting that the pFUS treatment restored a normal wound healing phenotype to the ZDSD rats. IL-6 was lower in stimulated spleen (-2.24 ± 0.81 Log2FC, p = 0.02) while L-selectin was higher in the wound bed of stimulated rodents (2.53 ± 0.72 Log2FC, p = 0.003). In summary, splenic pFUS accelerates healing in a T2DM rat model, demonstrating the potential of the method to provide a novel, non-invasive approach for wound care in diabetes.

Abstract Mouse models have been of tremendous benefit to medical science for the better part of a century, yet bioelectronic medicine research using mice has been limited to mostly acute studies because of a lack of tools for chronic stimulation and sensing. A wireless neuromodulation platform small enough for implantation in mice will significantly increase the utility of mouse models in bioelectronic medicine. This perspective examines the necessary functionality of such a system and the technical challenges needed to be overcome for its development. Recent progress is examined and the outlook for the future of implantable devices for mice is discussed.

Bioelectronic medicine (BEM) is a relatively recent strategy towards discovering novel neuromodulation therapeutics for diseases that have traditionally been addressed with pharmaceuticals. Bioelectronic therapies are conceived as programmable implants that use closed-loop (CL) activation of neurons that regulate autonomic processes to address damaged autonomic responses. Such technologies are intended to track markers of the intended activity and, if a malfunction is detected, send modulatory signals to the embedded system of nerves to restore the activity to standard. The peripheral nerve system (PNS) has a great deal of potential for therapeutic treatment and regaining bodily functioning. Autonomic nerves have recently gained much attention because they govern a wide range of processes engaged in organ homeostasis and chronic condition, and they look tractable to specific regulation of single nerve unit. Ongoing pre-clinical researches have eliminated current constraints by identifying the anatomical targets, discovering novel neural technology and devising effective signal processing algorithms. In this way, the most significant clinical outcomes have been achieved by various BEM methods and the challenges of neuro-modulatory treatments have shown promising results. The existing state of knowledge and future prospects for clinical uses of neural decoding and ANS stimulation are summarized below in this study. Additionally, how the advances got translated into clinical settings have been investigated from retrospective studies and presented herewith. [ABSTRACT FROM AUTHOR]

Neuromodulation is a multi-interdisciplinary field of neuroscience, neural engineering, and medicine in a complex, but a way of understanding. Recently, the interest and researches in this field have been attracted due to its promising applications such as bionic limbs and bioelectronic medicine. For easier entry into this field, in this review, we approach the basic mechanism, methods, and applications of peripheral neuromodulation sequentially. Firstly, the overall structure and functions of the human nervous system are introduced, especially in the peripheral nervous system (PNS). Specifically, the fundamental neurophysiology regarding action potentials and neural signals is introduced to understand the communication between the neurons. Thereafter, two main methods for peripheral neuromodulation, which are electrical and optogenetic approaches, are introduced with the principles of the state-of-art devices. Finally, advanced applications of neuromodulation combined with the sensor, stimulator, and controller, called a closed-loop system are introduced with an example of bionic limbs.

Abstract Background Peripheral nerve reflexes enable organ systems to maintain long-term physiological homeostasis while responding to rapidly changing environmental conditions. Electrical nerve stimulation is commonly used to activate these reflexes and modulate organ function, giving rise to an emerging class of therapeutics called bioelectronic medicines. Dogma maintains that immune cell migration to and from organs is mediated by inflammatory signals (i.e. cytokines or pathogen associated signaling molecules). However, nerve reflexes that regulate immune function have only recently been elucidated, and stimulation of these reflexes for therapeutic effect has not been fully investigated. Methods We utilized both electrical and ultrasound-based nerve stimulation to activate nerve pathways projecting to specific lymph nodes. Tissue and cell analysis of the stimulated lymph node, distal lymph nodes and immune organs is then utilized to measure the stimulation-induced changes in neurotransmitter/neuropeptide concentrations and immune cellularity in each of these sites. Results and conclusions In this report, we demonstrate that activation of nerves and stimulated release of neurotransmitters within a local lymph node results in transient retention of immune cells (e.g. lymphocytes and neutrophils) at that location. Furthermore, such stimulation results in transient changes in neurotransmitter concentrations at distal organs of the immune system, spleen and liver, and mobilization of immune cells into the circulation. This report will enable future studies in which stimulation of these long-range nerve connections between lymphatic and immune organs can be applied for clinical purpose, including therapeutic modulation of cellularity during vaccination, active allergic response, or active auto-immune disease.

Abstract Modulation of the nervous system by delivering electrical or pharmaceutical agents has contributed to the development of novel treatments to serious health disorders. Recent advances in multidisciplinary research has enabled the emergence of a new powerful therapeutic approach called bioelectronic medicine. Bioelectronic medicine exploits the fact that every organ in our bodies is neurally innervated and thus electrical interfacing with peripheral nerves can be a potential pathway for diagnosing or treating diseases such as diabetes. In this context, a plethora of studies have confirmed the important role of the nervous system in maintaining a tight regulation of glucose homeostasis. This has initiated new research exploring the opportunities of bioelectronic medicine for improving glucose control in people with diabetes, including regulation of gastric emptying, insulin sensitivity, and secretion of pancreatic hormones. Moreover, the development of novel closed-loop strategies aims to provide effective, specific and safe interfacing with the nervous system, and thereby targeting the organ of interest. This is especially valuable in the context of chronic diseases such as diabetes, where closed-loop bioelectronic medicine promises to provide real-time, autonomous and patient-specific therapies. In this article, we present an overview of the state-of-the-art for closed-loop neuromodulation systems in relation to diabetes and discuss future related opportunities for management of this chronic disease.

Peripheral nerves carry sensory (afferent) and motor (efferent) signals between the central nervous system and other parts of the body. The peripheral nervous system (PNS) is therefore rich in targets for therapeutic neuromodulation, bioelectronic medicine, and neuroprosthetics. Peripheral nerve interfaces (PNIs) generally suffer from a tradeoff between selectivity and invasiveness. This work describes the fabrication, evaluation, and chronic implantation in zebra finches of a novel PNI that breaks this tradeoff by interfacing with small nerves. This PNI integrates a soft, stretchable microelectrode array with a 2‐photon 3D printed microclip (μcPNI). The advantages of this μcPNI compared to other designs are: a) increased spatial resolution due to bi‐layer wiring of the electrode leads, b) reduced mismatch in biomechanical properties with the nerve, c) reduced disturbance to the host tissue due to the small size, d) elimination of sutures or adhesives, e) high circumferential contact with small nerves, f) functionality under considerable strain, and g) graded neuromodulation in a low‐threshold stimulation regime. Results demonstrate that the μcPNIs are electromechanically robust, and are capable of reliably recording and stimulating neural activity in vivo in small nerves. The μcPNI may also inform the development of new optical, thermal, ultrasonic, or chemical PNIs as well. [ABSTRACT FROM AUTHOR]

Bioelectronic medicines (BEMs) constitute a branch of bioelectronic devices (BEDs), which are a class of therapeutics that combine neuroscience with molecular biology, immunology, and engineering technologies. Thus, BEMs are the culmination of thought processes of scientists of varied fields and herald a new era in the treatment of chronic diseases. BEMs work on the principle of neuromodulation of nerve stimulation. Examples of BEMs based on neuromodulation are those that modify neural circuits through deep brain stimulation, vagal nerve stimulation, spinal nerve stimulation, and retinal and auditory implants. BEDs may also serve as diagnostic tools by mimicking human sensory systems. Two examples of in vitro BEDs used as diagnostic agents in biomedical applications based on in vivo neurosensory circuits are the bioelectronic nose and bioelectronic tongue. The review discusses the ever-growing application of BEDs to a wide variety of health conditions and practices to improve the quality of life.

Background: Placement of the clinical vagus nerve stimulating cuff is a standard surgical procedure based on anatomical landmarks, with limited patient specificity in terms of fascicular organization or vagal anatomy. As such, the therapeutic effects are generally limited by unwanted side effects of neck muscle contractions, demonstrated by previous studies to result from stimulation of (1) motor fibers near the cuff in the superior laryngeal and (2) motor fibers within the cuff projecting to the recurrent laryngeal. Objective: Conventional non-invasive ultrasound, where the transducer is placed on the surface of the skin, has been previously used to visualize the vagus with respect to other landmarks such as the carotid and internal jugular vein. However, it lacks sufficient resolution to provide details about the vagus fascicular organization, or detail about smaller neural structures such as the recurrent and superior laryngeal branch responsible for therapy limiting side effects. Here, we characterize the use of ultrasound with the transducer placed in the surgical pocket to improve resolution without adding significant additional risk to the surgical procedure in the pig model. Methods: Ultrasound images were obtained from a point of known functional organization at the nodose ganglia to the point of placement of stimulating electrodes within the surgical window. Naïve volunteers with minimal training were then asked to use these ultrasound videos to trace afferent groupings of fascicles from the nodose to their location within the surgical window where a stimulating cuff would normally be placed. Volunteers were asked to select a location for epineural electrode placement away from the fascicles containing efferent motor nerves responsible for therapy limiting side effects. 2-D and 3-D reconstructions of the ultrasound were directly compared to post-mortem histology in the same animals. Results: High-resolution ultrasound from the surgical pocket enabled 2-D and 3-D reconstruction of the cervical vagus and surrounding structures that accurately depicted the functional vagotopy of the pig vagus nerve as confirmed via histology. Although resolution was not sufficient to match specific fascicles between ultrasound and histology 1 to 1, it was sufficient to trace fascicle groupings from a point of known functional organization at the nodose ganglia to their locations within the surgical window at stimulating electrode placement. Naïve volunteers were able place an electrode proximal to the sensory afferent grouping of fascicles and away from the motor nerve efferent grouping of fascicles in each subject (n = 3). Conclusion: The surgical pocket itself provides a unique opportunity to obtain higher resolution ultrasound images of neural targets responsible for intended therapeutic effect and limiting off-target effects. We demonstrate the increase in resolution is sufficient to aid patient-specific electrode placement to optimize outcomes. This simple technique could be easily adopted for multiple neuromodulation targets to better understand how patient specific anatomy impacts functional outcomes. [ABSTRACT FROM AUTHOR]

Bioelectronic medicines (BEMs) constitute a branch of bioelectronic devices (BEDs), which are a class of therapeutics that combine neuroscience with molecular biology, immunology, and engineering technologies. Thus, BEMs are the culmination of thought processes of scientists of varied fields and herald a new era in the treatment of chronic diseases. BEMs work on the principle of neuromodulation of nerve stimulation. Examples of BEMs based on neuromodulation are those that modify neural circuits through deep brain stimulation, vagal nerve stimulation, spinal nerve stimulation, and retinal and auditory implants. BEDs may also serve as diagnostic tools by mimicking human sensory systems. Two examples of in vitro BEDs used as diagnostic agents in biomedical applications based on in vivo neurosensory circuits are the bioelectronic nose and bioelectronic tongue. The review discusses the ever-growing application of BEDs to a wide variety of health conditions and practices to improve the quality of life. [ABSTRACT FROM AUTHOR]

Abstract Neuromodulation of central and peripheral neural circuitry brings together neurobiologists and neural engineers to develop advanced neural interfaces to decode and recapitulate the information encoded in the nervous system. Dysfunctional neuronal networks contribute not only to the pathophysiology of neurological diseases, but also to numerous metabolic disorders. Many regions of the central nervous system (CNS), especially within the hypothalamus, regulate metabolism. Recent evidence has linked obesity and diabetes to hyperactive or dysregulated autonomic nervous system (ANS) activity. Neural regulation of metabolic functions provides access to control pathology through neuromodulation. Metabolism is defined as cellular events that involve catabolic and/or anabolic processes, including control of systemic metabolic functions, as well as cellular signaling pathways, such as cytokine release by immune cells. Therefore, neuromodulation to control metabolic functions can be used to target metabolic diseases, such as diabetes and chronic inflammatory diseases. Better understanding of neurometabolic circuitry will allow for targeted stimulation to modulate metabolic functions. Within the broad category of metabolic functions, cellular signaling, including the production and release of cytokines and other immunological processes, is regulated by both the CNS and ANS. Neural innervations of metabolic (e.g. pancreas) and immunologic (e.g. spleen) organs have been understood for over a century, however, it is only now becoming possible to decode the neuronal information to enable exogenous controls of these systems. Future interventions taking advantage of this progress will enable scientists, engineering and medical doctors to more effectively treat metabolic diseases.

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype. [ABSTRACT FROM AUTHOR]

Abstract Diabetes is a disease caused by a breakdown in the glucose metabolic process resulting in abnormal blood glucose fluctuations. Traditionally, control has involved external insulin injection in response to elevated blood glucose to substitute the role of the beta cells in the pancreas which would otherwise perform this function in a healthy individual. The central nervous system (CNS), however, also plays a vital role in glucose homoeostasis through the control of pancreatic secretion and insulin sensitivity which could potentially be used as a pathway for enhancing glucose control. In this review, we present an overview of the brain regions, peripheral nerves and molecular mechanisms by which the CNS regulates glucose metabolism and the potential benefits of modulating them for diabetes management. Development of technologies to interface to the nervous system will soon become a reality through bioelectronic medicine and we present the emerging opportunities for the treatment of type 1 and type 2 diabetes.

Recently, methods for the treatment of chronic diseases and disorders through the modulation of peripheral and autonomic nerves have been proposed. To investigate various treatment methods and results, experiments are being conducted on animals such as rabbits and rat. However the diameter of the targeted nerves is small (several hundred μm) and it is difficult to modulate small nerves. Therefore, a neural interface that is stable, easy to implant into small nerves, and is biocompatible is required. Here, to develop an advanced neural interface, a thiol-ene/acrylate-based shape memory polymer (SMP) was fabricated with a double clip design. This micro-patterned design is able to be implanted on a small branch of the sciatic nerve, as well as the parasympathetic pelvic nerve, using the shape memory effect (SME) near body temperature. Additionally, the IrO2 coated neural interface was implanted on the common peroneal nerve in order to perform electrical stimulation and electroneurography (ENG) recording. The results demonstrate that the proposed neural interface can be used for the modulation of the peripheral nerve, including the autonomic nerve, towards bioelectronic medicine.

Background: Acupuncture has been widely accepted for treatments of many diseases. This study was performed to determine effects and mechanisms of electroacupuncture (EA) by chronically implanted electrodes at acupoint ST36 on colonic inflammation induced by TNBS in rats. Methods: After intrarectal administration of TNBS, the rats were treated with sham‐EA, EA1/EA2 (two sets of parameters) for 3 weeks. Disease activity index (DAI), macroscopic and microscopic lesions, plasma levels of TNF‐α, IL‐1β and IL‐6 were observed as evaluation of inflammatory responses. The autonomic function was assessed by analysis of the heart rate variability. Results: (a) Vagal activity was significantly increased with both acute and chronic EA1/EA2; (b) DAI was significantly decreased with both chronic EA1 and EA2, and EA2 was more potent than EA1 (P < 0.05); (c) The macroscopic score was 6.4 ± 0.6 with sham‐EA and reduced to 4.9 ± 0.1 with EA1 (P < 0.05) and 4.0 ± 0.2 with EA2 (all P < 0.05). The histological score was 4.05 ± 0.58 with sham‐EA and remained unchanged (3.71 ± 0.28) with EA1 (P > 0.05) but reduced to 3.0 ± 0.3 with EA2 (P < 0.01); (d) The plasma levels of TNF‐α, IL‐1β and IL‐6 were significantly decreased with EA2. Conclusions: Electrical stimulation at ST36 improves colonic inflammation in TNBS‐treated rats by inhibiting pro‐inflammatory cytokines via the autonomic mechanism. [ABSTRACT FROM AUTHOR]

The Barostim neo™ electrode was developed by CVRx, Inc.to deliver baroreflex activation therapy (BAT)™ to treat hypertension and heart failure. The neo electrode concept was designed to deliver electrical stimulation to the baroreceptors within the carotid sinus bulb, while minimizing invasiveness of the implant procedure. This device is currently CE marked in Europe, and in a Pivotal (akin to Phase III) Trial in the United States. Here we present the in vitro and in vivo safety testing that was completed in order to obtain necessary regulatory approval prior to conducting human studies in Europe, as well as an FDA Investigational Device Exemption (IDE) to conduct a Pivotal Trial in the United States. Stimulated electrodes (10 mA, 500 μs, 100 Hz) were compared to unstimulated electrodes using optical microscopy and several electrochemical techniques over the course of 27 weeks. Electrode dissolution was evaluated by analyzing trace metal content of solutions in which electrodes were stimulated. Lastly, safety testing under Good Laboratory Practice guidelines was conducted in an ovine animal model over a 12 and 24 week time period, with results processed and evaluated by an independent histopathologist. Long-term stimulation testing indicated that the neo electrode with a sputtered iridium oxide coating can be stimulated at maximal levels for the lifetime of the implant without clinically significant dissolution of platinum or iridium, and without increasing the potential at the electrode interface to cause hydrolysis or significant tissue damage. Histological examination of tissue that was adjacent to the neo electrodes indicated no clinically significant signs of increased inflammation and no arterial stenosis as a result of 6 months of continuous stimulation. The work presented here involved rigorous characterization and evaluation testing of the neo electrode, which was used to support its safety for chronic implantation. The testing strategies discussed provide a starting point and proven framework for testing new neuromodulation electrode concepts to support regulatory approval for clinical studies.