Bioelectronic Medicine: From Preclinical Studies on the Inflammatory Reflex to New Approaches in Disease Diagnosis and Treatment

Abstract

Bioelectronic medicine is an evolving field in which new insights into the regulatory role of the nervous system and new developments in bioelectronic technology result in novel approaches in disease diagnosis and treatment. Studies on the immunoregulatory function of the vagus nerve and the inflammatory reflex have a specific place in bioelectronic medicine. These studies recently led to clinical trials with bioelectronic vagus nerve stimulation in inflammatory diseases and other conditions. Here, we outline key findings from this preclinical and clinical research. We also point to other aspects and pillars of interdisciplinary research and technological developments in bioelectronic medicine.

Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.

Figures

Figure 1.

From Scribonius to the inflammatory reflex and bioelectronic medicine. The long evolution of using electricity for therapeutic benefit allegedly starting with Scribonius recently culminated in designing revolutionary approaches of electrical neuromodulation in the field of bioelectronic medicine. The recent realization that the vagus nerve plays a role in controlling inflammation within the inflammatory reflex was key in using and developing implanted device-generated vagus nerve stimulation (VNS) in the first clinical trials in patients with inflammatory diseases. Left panel is the compilation of an engraving of a torpedo fish embedded in the foreground of a page from Scribonius Largus 1655 (wellcomecollection.org/works/dwu4cdy6). (Torpedo fish image reprinted from John Hunter's paper to the Royal Society Royal College of Surgeons of England and reprinted courtesy of the public domain; page from Scribonius Largus 1655, provided by the Österreichische Nationalbibliothek and available for reprint because it is in the public domain. Middle panel is reprinted from Tracey 2002, with permission, from the author. Right panel reprinted from noosphereventures.com/bioelectronics-the-next-level-of-leveraging-the-body-s-potential-and-treating-diseases, with permission, from Noosphere Venture Partners LP 2018.)

Figure 2.

The inflammatory reflex. In the inflammatory reflex, the activity of afferent vagus nerve fibers residing in the nodose ganglion is stimulated by cytokines and pathogen-associated molecular patterns (PAMPs). The signal is transmitted to the nucleus tractus solitarius (NTS). Reciprocal connections between the NTS and dorsal motor nucleus (DMN) of the vagus mediate communication with and activation of efferent vagus nerve fibers from the DMN. The signal is propagated to the celiac ganglia and the superior mesenteric ganglion in the celiac plexus, where the splenic nerve originates. Norepinephrine (NE) released from the splenic nerve interacts with β2-adrenergic receptors (β2-ARs) and causes the release of acetylcholine (ACh) from T cells containing functional choline acetyltransferase (T-ChAT) cells. ACh interacts with α7 subunit-containing nicotinic acetylcholine receptors (α7nAChRs) on macrophages and suppresses proinflammatory cytokine release and inflammation. The inflammatory reflex can be activated through brain muscarinic acetylcholine receptor (mAChR)-mediated mechanisms by centrally acting M1 mAChR agonists and acetylcholinesterase (AChE) inhibitors. Somatosensory activation by electroacupuncture at the Hegu point also causes activation of brain mAChR signaling, which then results in activation of efferent vagus and splenic anti-inflammatory signaling. Electroacupuncture at a different acupuncture point activates sciatic nerve signals, which by unknown mechanisms convert to efferent vagus nerve signaling to the adrenal medulla, resulting in dopamine release. Dopamine suppresses inflammation and improves survival in a model of sepsis. Vagus nerve and splenic nerve signaling mediated through α7nAChR on splenocytes controls inflammation in acute kidney injury and alleviates the condition. (Figure created by Debbie Maizels, Springer Nature, for Pavlov and Tracey 2017; reprinted, with permission, from the authors in conjunction with Springer Nature.)

Figure 3.

Current aspects and constituents of bioelectronic medicine. Bioelectronic medicine is a growing and evolving field. It brings together colleagues with diverse specializations in basic research and clinical disciplines. Ongoing research efforts by these multidisciplinary teams provide new mechanistic insight into the regulatory functions of the nervous system and their deviations in disease settings, identify new molecular targets, and evaluate new diagnostic and therapeutic approaches with relevance to neuromodulation. In parallel, advances in biomaterials, electrodes, sensors, interfaces, bioelectronic devices, and artificial intelligence elements substantially facilitate the implementation of bioelectronic approaches in disease settings. Although many of these approaches are based on targeting neural circuits, others, such as the “artificial pancreas” are not strictly related to neuromodulation. All of these efforts culminate in new clinical trials in many diseases under the umbrella of bioelectronic medicine. (Background figure from MotionCow 2018; reprinted, with permission, from TurboSquid.com.)