Neural Interfaces for Bioelectronic Medicine.

Neurological diseases can be treated in a whole new way with bioelectronic medicine, which uses neural connections to directly communicate with the nervous system. This field blends neuroscience, engineering, and clinical practice to make gadgets that can change nerve activity with a level of accuracy that has never been seen before. Recent progress in biomedical engineering has made it possible to create very complex neural connections that can record and trigger activity in neurones at the very small scale. For many neurological conditions, like Parkinson's disease, epilepsy, and chronic pain, these gadgets show promise as new ways to treat them. Traditionally, these conditions have been hard to control with medicine alone. Electrical activation of nerves to repair or change brain function is what bioelectronic medicine is all about. One example is vagus nerve stimulation (VNS), which has become a useful way to help people with refractory epilepsy and depression. This shows that neural interfaces can have big practical effects. Deep brain stimulation (DBS), which uses electrical signals to target specific parts of the brain, has also made a huge difference in the movement ability of people with Parkinson's disease. Adding bioelectronics to real-time data analytics and machine learning methods is also making it possible for treatments that can change based on the brain state of the patient? This personalized method not only makes treatments work better but also cuts down on side effects, which is a big change from the old way of doing things where one answer fits all. Biocompatibility of implanted devices, long-term security of neural interfaces, and ethical concerns about device placement and brain editing are some of the problems that this field is facing as it changes quickly. These problems are still being studied and tested in humans, with the goal of creating better, more successful, and less invasive solutions.

Next-generation medical devices in bioelectronic medicine integrate neurotechnology with precision therapy to modulate physiological functions in real time. Bioelectronic medicine is an emerging interdisciplinary field that combines biology, electronics, and medicine to provide novel therapeutic solutions for various chronic and acute diseases. With advancements in neurotechnology and biomedical engineering, bioelectronic devices are increasingly being considered alternatives or adjuncts to traditional pharmacological therapies. This paper explores the urgent need for bioelectronic medicine, emphasizing its potential to revolutionize modern health care by reducing drug dependency, minimizing side effects, and addressing economic challenges. Key research goals include the development of a visceral nerve atlas, early validation of therapeutic possibilities, and advancements in neural interfacing technologies. Technical milestones such as the discovery of the inflammatory reflex, innovations in electric implants, and modulation of the vagus nerve have further enhanced therapeutic applications. The clinical relevance of a wide range of bioelectronic devices—including artificial pacemakers, bioelectronic noses, biosensors, and visual prostheses—is discussed. The integration of bioelectronics in health care has shown promising results in treating conditions such as hypertension, diabetes mellitus, central nervous system disorders, rheumatoid arthritis, blindness, and spinal cord injuries. Technological advancements continue to refine signal decoding and device miniaturization, broadening the scope of bioelectronic interventions. However, challenges such as biocompatibility, long-term safety, accessibility, and ethical concerns must be addressed for successful widespread adoption. The article concludes with future directives focused on personalized bioelectronic therapies, regulatory frameworks, and collaborative research, highlighting the potential of bioelectronic medicine to become a cornerstone of precision medicine along with its ethical implications.

Recording neural signals from delicate autonomic nerves is a challenging task that requires the development of a low-invasive neural interface with highly selective, micrometer-sized electrodes. This paper reports on the development of a three-dimensional (3D) protruding thin-film microelectrode array (MEA), which is intended to be used for recording low-amplitude neural signals from pelvic nervous structures by penetrating the nerves transversely to reduce the distance to the axons. Cylindrical gold pillars (Ø 20 or 50 µm, ~60 µm height) were fabricated on a micromachined polyimide substrate in an electroplating process. Their sidewalls were insulated with parylene C, and their tips were optionally modified by wet etching and/or the application of a titanium nitride (TiN) coating. The microelectrodes modified by these combined techniques exhibited low impedances (~7 kΩ at 1 kHz for Ø 50 µm microelectrode with the exposed surface area of ~5000 µm²) and low intrinsic noise levels. Their functionalities were evaluated in an ex vivo pilot study with mouse retinae, in which spontaneous neuronal spikes were recorded with amplitudes of up to 66 µV. This novel process strategy for fabricating flexible, 3D neural interfaces with low-impedance microelectrodes has the potential to selectively record neural signals from not only delicate structures such as retinal cells but also autonomic nerves with improved signal quality to study neural circuits and develop stimulation strategies in bioelectronic medicine, e.g., for the control of vital digestive functions.

Modulation of the peripheral nervous system (PNS) has a great potential for therapeutic intervention as well as restore bodily functions. Recent interest has focused on autonomic nerves, as they regulate extensive functions implicated in organ physiology, chronic disease state and appear tractable to targeted modulation of discrete nerve units. Therapeutic interventions based on specific bioelectronic neuromodulation depend on reliable neural interface to stimulate and record autonomic nerves. Furthermore, the function of stimulation and recording requires energy which should be delivered to the interface. Due to the physiological and anatomical challenges of autonomic nerves, various forms of this active neural interface need to be developed to achieve next generation of neural interface for bioelectronic medicine. In this article, we present an overview of the state-of-the-art for peripheral neural interface technology in relation to autonomic nerves. Also, we reveal the current status of wireless neural interface for peripheral nerve applications. Recent studies of a novel concept of self-sustainable neural interface without battery and electronic components are presented. Finally, the recent results of non-invasive stimulation such as ultrasound and magnetic stimulation are covered and the perspective of the future research direction is provided.

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.

Numerous clinical and research applications necessitate the ability to interface with peripheral nerve fibers to read and control relevant neural pathways. Visceral organ modulation and rehabilitative prosthesis are two areas which could benefit greatly from improved neural interfacing approaches. Therapeutic neural interfacing, or ‘bioelectronic medicine’, has potential to affect a broad range of disorders given that all the major organs of the viscera are neurally innervated. However, a better understanding of the neural pathways that underlie function and a means to precisely interface with these fibers are required. Existing peripheral nerve interfaces, consisting primarily of electrode-based designs, are unsuited for highly specific (individual axon) communication and/or are invasive to the tissue. Our laboratory has explored an optogenetic approach by which optically sensitive reporters and actuators are targeted to specific cell (axon) types. The nature of such an approach is laid out in this short perspective, along with associated technologies and challenges.

Biomaterials-based bioengineering strategies for bioelectronic medicine

Battery-free neuromodulator for peripheral nerve direct stimulation

The peripheral nervous system interacts with all the organs and tissues of the body, making it an ideal interface for treating many diseases. Neurons act like transducers, converting electrical signals from some neuromodulating device into relevant control signals for the body. For example, in the case of spinal cord injury, a neuroprosthetic implant could be used to stimulate motoneurons whose connection to the spinal cord has been interrupted. The therapeutic neural interface is the principle upon which bioelectronic medicine (BEM) is built. BEM is a platform that requires many different functional elements, from sensors to stimulators, a power source, biocompatible packaging, etc., and all new BEM systems go through rigourous testing before becoming mainstream in the clinic. This roadmap discusses each of these functional components in terms of the current state-of-the-art and development challenges, and where the technology must go in order to support the advancement of bioelectronics. Successful strategies for moving BEM devices from the bench into the clinic will require cross-disciplinary efforts and widespread use of investigational devices that collect data to inform robust models and simulations of BEM systems. Using these tools to increase our understanding of the biological underpinnings in certain disease states will be key to developing more effective and accessible bioelectronics.KeywordsNeural interfacesNeural modulationImplantable devicesPackagingModelingClinical translationTechnology timeline

Bioelectronic medicine (BM) is an emerging new approach for developing novel neuromodulation therapies for pathologies that have been previously treated with pharmacological approaches. In this review, we will focus on the neuromodulation of autonomic nervous system (ANS) activity with implantable devices, a field of BM that has already demonstrated the ability to treat a variety of conditions, from inflammation to metabolic and cognitive disorders. Recent discoveries about immune responses to ANS stimulation are the laying foundation for a new field holding great potential for medical advancement and therapies and involving an increasing number of research groups around the world, with funding from international public agencies and private investors. Here, we summarize the current achievements and future perspectives for clinical applications of neural decoding and stimulation of the ANS. First, we present the main clinical results achieved so far by different BM approaches and discuss the challenges encountered in fully exploiting the potential of neuromodulatory strategies. Then, we present current preclinical studies aimed at overcoming the present limitations by looking for optimal anatomical targets, developing novel neural interface technology, and conceiving more efficient signal processing strategies. Finally, we explore the prospects for translating these advancements into clinical practice.

BackgroundThe loss of motor functions resulting from spinal cord injury can have devastating implications on the quality of one’s life. Functional electrical stimulation has been used to help restore mobility, however, current functional electrical stimulation (FES) systems require residual movements to control stimulation patterns, which may be unintuitive and not useful for individuals with higher level cervical injuries. Brain machine interfaces (BMI) offer a promising approach for controlling such systems; however, they currently still require transcutaneous leads connecting indwelling electrodes to external recording devices. While several wireless BMI systems have been designed, high signal bandwidth requirements limit clinical translation. Case Western Reserve University has developed an implantable, modular FES system, the Networked Neuroprosthesis (NNP), to perform combinations of myoelectric recording and neural stimulation for controlling motor functions. However, currently the existing module capabilities are not sufficient for intracortical recordings.MethodsHere we designed and tested a 1 × 4 cm, 96-channel neural recording module prototype to fit within the specifications to mate with the NNP. The neural recording module extracts power between 0.3–1 kHz, instead of transmitting the raw, high bandwidth neural data to decrease power requirements.ResultsThe module consumed 33.6 mW while sampling 96 channels at approximately 2 kSps. We also investigated the relationship between average spiking band power and neural spike rate, which produced a maximum correlation of R = 0.8656 (Monkey N) and R = 0.8023 (Monkey W).ConclusionOur experimental results show that we can record and transmit 96 channels at 2ksps within the power restrictions of the NNP system and successfully communicate over the NNP network. We believe this device can be used as an extension to the NNP to produce a clinically viable, fully implantable, intracortically-controlled FES system and advance the field of bioelectronic medicine.

In the absence of approved treatments to repair damage to the central nervous system, the role of neurosurgeons after spinal cord injury (SCI) often remains confined to spinal cord decompression and vertebral fracture stabilization. However, recent advances in bioelectronic medicine are changing this landscape. Multiple neuromodulation therapies that target circuits located in the brain, midbrain, or spinal cord have been able to improve motor and autonomic functions. The spectrum of implantable brain-computer interface technologies is also expanding at a fast pace, and all these neurotechnologies are being progressively embedded within rehabilitation programs in order to augment plasticity of spared circuits and residual projections with training. Here, we summarize the impending arrival of bioelectronic medicine in the field of SCI. We also discuss the new role of functional neurosurgeons in neurorestorative interventional medicine, a new discipline at the intersection of neurosurgery, neuro-engineering, and neurorehabilitation.

Modulation of peripheral nerve is an emerging field for neuroprosthesis and bioelectronic medicine. With the developing neural interfacing technology that directly communicates with peripheral nerves, several powering schemes have been investigated for long-term use of implantable devices such as wireless and conversion of human body energy. But due to the limitations such as energy conversion efficiency and complexity, none of these methods can fully replace the current battery-based neuroprosthetic systems. This study proposes a new scheme based on programmable triboelectric nanogenerators for self-powered neural stimulations. The device can generate current pulses of more than 100 V by slightly shaking the device. The capability of neural stimulation is validated by sciatic nerve stimulation. Furthermore, the shaking frequency can control the measured kicking force of the rat leg. This prototype can be further minimized and optimized for a fully implantable self-powered/wireless neuroprosthetic system.

Bioelectronic medicine is a rapidly growing field that explores targeted neuromodulation in new treatment options addressing both disease and injury. New bioelectronic methods are being developed to monitor and modulate neural activity directly. The therapeutic benefit of these approaches has been validated in recent clinical studies in various conditions, including paralysis. By using decoding and modulation strategies together, it is possible to restore lost function to those living with paralysis and other debilitating conditions by interpreting and rerouting signals around the affected portion of the nervous system. This, in effect, creates a bioelectronic "neural bypass" to serve the function of the damaged/degenerated network. By learning the language of neurons and using neural interface technology to tap into critical networks, new approaches to repairing or restoring function in areas impacted by disease or injury may become a reality.

Bioelectronic medicine is an emerging field that relies on electrical signals to modulate complex neuronal circuits, particularly in the peripheral nervous system, as an alternative to drug-enabled therapeutics. Small autonomic nerves are one of the targets in this field, however, interfacing peripheral nerves smaller than 300 μm remains a challenge. Here we report the development of a Microchannel Electrode Array (DCEA) capable of interfacing nerve fascicles as small as 50-300μm. The current μCEA records and stimulates from 28 channels and is designed for easy implantation and removal, bearing promise to enable neural interfacing in BM.