The advancement of technology is continuing to change the world. Bioelectronic medicine, the convergence of molecular medicine, neuroscience, engineering and computing to develop devices to diagnose and treat diseases, is at the forefront of a potential revolution in disease management. The discipline bioelectronic medicine arose from groundbreaking discoveries of mechanisms for neural control of biological processes that underlie disease, and the development of devices to modulate these specific neural circuits as therapy using electrons instead of drugs. Bioelectronic medicine has emerged at a convergent epicentre in health care, technology and science.
Development of new therapies relies on detailed understanding of the molecular mechanisms of disease. Pharmaceutical drugs are optimized to target defined molecular mechanisms, but often lack anatomical and cellular specificity, which inevitably causes toxicity from off-target effects. Drugs are not inherently designed to adapt to individual treatment, so both under- and overdosing are common, resulting in therapy failure or unwanted side effects. Advances in bioelectronic medicine hold promise to address some of these challenges and provide personalized treatment of disease.
Neural reflexes establish homoeostasis in organ systems. Recent advances in neuroscience and immunology have revealed reflex mechanisms that regulate innate and adaptive immunity. For example, ‘the inflammatory reflex’, in which the vagus nerve plays a key role, maintains immunological homoeostasis by regulating cytokine production and inflammation. Recent clinical trials indicate that it may be feasible to target the inflammatory reflex in humans to inhibit cytokine release as treatment of inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease [1]. Both afferent and efferent signals in peripheral nerves have been directly implicated in the reflex control of immunity. Importantly, sensory neurons are activated by inflammation, and the resulting neural signals modulate cytokine release and the “inflammatory potential” of infiltrating monocytes and macrophages [2]. Hence, it may be possible to develop therapeutic devices that both record and modulate neural signals in inflammation regulating reflex circuits.
The mapping of these homoeostatic reflex neural circuits is critically important for rapid progress in bioelectronic medicine. Advances in optical tools to enable molecular resolution, genetic approaches to anatomical mapping and recording of high-speed physiological dynamics give promise for a new era in systematic mapping of the central and peripheral nervous systems [3]. New developments in neuron barcoding may significantly improve highthroughput interrogation of brain circuit anatomy by transforming complex and painstaking microscopy into a problem of sequencing [4]. This will be crucial for the field, which requires a new level of precision beyond indistinct designations of the autonomic peripheral nervous system as ‘sympathetic’ or ‘parasympathetic’. The previously unimaginable specificity of these approaches will reveal selective neural circuits that can be targeted for bioelectronic intervention.
New technology in implantable, biocompatible devices has the potential to improve the interface between the brain and electronics. Examples include synthetic magnetic nanoparticles and multifunctional flexible probes produced by fibredrawing techniques [5]. In experimental animals, ferritin-tagged molecules can now be used to control ion channels (e.g. TRPV1) with radio waves or magnetic fields. Aptamer-based technology for real-time, implantable biosensors is capable of continuously tracking the levels of a wide range of biomolecules without a supply of exogenous reagents and can deliver subminute resolution drug concentration readings in rats [6]. Combining the technologies of nerve stimulation and biosensing will enable deployment of ‘closed-loop devices’. Such devices would be capable of monitoring and analysing the internal milieu, for example hormone levels, and respond by adjusting the output of nerve stimulators to re-establish homoeostasis by modulating neural activity targeting a specific therapeutic molecular mechanism [7]. Corresponding future devices hold promise to become an alternative or a supplement to some pharmaceuticals and potentially establish a pathway to personalized medicine.
Bioelectronic medicine is increasingly becoming applied in clinical trials. Patients suffering from rheumatoid arthritis that were implanted with a vagus nerve stimulator to activate the inflammatory reflex showed significant improvement of clinical signs and symptoms – also in patients with previously therapy-resistant disease [8]. In another clinical study of Crohńs inflammatory bowel disease, electrical vagus nerve stimulation improved clinical and endoscopic signs of disease [9]. This indicates that implanted devices for electrical stimulation of the inflammatory reflex may be feasible and beneficial in treatment of select diseases.
Bioelectronic devices are also used in the central nervous system. Intracortically recorded signals by an implanted device can now be decoded to reveal information about cognitive intentions and allow paralysed individuals to control computers and robotic arms simply by thinking about the intended movement [10]. In a first-in-human clinical study, intracortically recorded signals were deconvoluted to restore forearm movement in a paralysed patient [11]. Novel methods in machine learning, symbolic reasoning and signal processing are under development to improve deconvolution of the electrical activity in both the central and peripheral nervous system.
Progress in the new field of bioelectronic medicine and underlying neurophysiological and molecular mechanisms make it possible to target specific circuits to treat disease and improve organ function. Implantable devices capable of electrical activation of signals in anatomically discrete neural reflex circuits will facilitate precision treatment of defined tissues of interest. Coupled with future developments of implantable biosensors and bioanalytical tools, it is conceivable that closed-loop devices will monitor internal physiological parameters and respond continuously to adjust treatment delivery to the individual needs. That prospect certainly promises a significant leap forward in both treatment efficacy and safety, based upon utilizing electrons to replace drugs.
Footnotes
Conflict of interest statement
The authors declare no conflicts of interest.
References
- 1.Koopman FA, van Maanen MA, Vervoordeldonk MJ, Tak PP. Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis. J Intern Med 2017; 282: 64–75. [DOI] [PubMed] [Google Scholar]
- 2.Lai NY, Mills K, Chiu IM. Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence. J InternMed 2017; 282: 5–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Tillberg PW, Chen F, Piatkevich KD et al. Protein-retention expansion microscopy of cells and tissues labeled using standard fluorescent proteins and antibodies. Nat Biotechnol 2016; 34: 987–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kebschull JM, Garciada SilvaP,Reid AP,Peikon ID,Albeanu DF, Zador AM. High-throughput mapping of single-neuron projections by sequencing of barcoded RNA. Neuron 2016; 91:975–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Park S, Guo Y, Jia X et al. One-step optogenetics with multifunctional flexible polymer fibers. Nat Neurosci 2017; 20: 612–619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Ferguson BS, Hoggarth DA, Maliniak D et al. Real-time, aptamer-based tracking of circulating therapeutic agents in living animals. Sci Transl Med 2013; 5: 213ra165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Loffler S, Melican K, Nilsson KP, Richter-Dahlfors A. Organic bioelectronics in medicine. J Intern Med 2017; 282: 24–36. [DOI] [PubMed] [Google Scholar]
- 8.Koopman FA, Chavan SS, Miljko S et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci USA 2016; 113: 8284–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Bonaz B, Sinniger V, Pellissier S. Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. J Intern Med 2017; 282: 46–63. [DOI] [PubMed] [Google Scholar]
- 10.Bouton CE. Cracking the neural code, treating paralysis and the future of bioelectronic medicine. J Intern Med 2017; 282: 37–45. [DOI] [PubMed] [Google Scholar]
- 11.Bouton CE, Shaikhouni A, Annetta NV et al. Restoring cortical control of functional movement in a human with quadriplegia. Nature 2016; 533: 247–50. [DOI] [PubMed] [Google Scholar]