The use of electrical stimuli in the therapeutic practice is not new, as it widely used since many years for example in pace-makers to correct irregular heart beat. The innovation in the field is represented by the wide range of diseases – from diabetes to osteoporosis, from auto-immune pathologies to obesity, just to make few examples – that might be treated in future by the so-called “bioelectronic medicine”. Electroceutics will be the key, as they may generate precisely dosed electrical impulses to be used to modulate nerves belonging to the autonomous nervous system. The main representative of such nerves is the vagus nerve.
«The neural network of the autonomous system pervades the entire human body, where it connects one another internal organs as well as internal organs with the central nervous system. We know that many pathologies are characterised by an abnormal activity of these nerves. The idea at the base of electroceutics and bioelectronic medicine is to implant electrodes close to autonomous nerves in order to restore the correct activity and thus ameliorate the pathological condition», explains Silvestro Micera, professor of Neuroengineering at the Scuola Superiore Sant’Anna in Pisa, Italy, and of Translational Neuroengineering at the École Polytechnique Fédérale in Lausanne, Switzerland.
An enormous potential
The study of electroceutical devices is still at an early, mainly pre-clinical stage, but the potential coming from its application in clinics is estimated to be enormous. The most advanced project carried on in Micera’s lab at the Scuola Sant’Anna sees the realisation of an “almost human” robotic hand, which is able to replicate movements very close to the ones of a real human hand. «We are also working on diabetes, within a collaboration we had with Glaxo SmithKline – tells Silvestro Micera -. We are also addressing some gynaecologic and obstetric problematics, we are still at an very early stage in these areas and we hope to obtain some result in few years».
SetPoint Medical is one of the most advanced companies active in the field at the international level; it has been founded by President and Ceo of the Feinstein Institute for Medical Research, Kevin Tracey, together with Shaw Warren of the Harvard Medical School. The company announced in March 2018 the stating of the first pilot clinical study in men to treat rheumatoid arthritis by stimulation of the vagus nerve. The target of the intervention is the reactivation of the patient’s natural inflammatory reflex, leading to inhibition of the production of pro-inflammatory molecules such as Tnf-α or IL-6 (figure 1). Galvani Bioelectronics is another company founded in 2016 as a joint-venture between Gsk and Verily (the healthcare branch of Google) with the mission to develop and commercialise new bioelectronic medicines. The Gsk Venture Fund is also among investors in SetPoint Medical, together with Medtronic, Boston Scientific and other capital partners.
Public research in bioelectronic medicines is also very active, as demonstrated by the launch in 2016 of the multi-disciplinar Sparc (Stimulating peripheral activity to relieve conditions) program by the US National Institutes of Health, for a total investment of $ 238 million by 2021. The aim of the program is to better understand the functioning of peripheral nerves and how their electric signals control the functions of the organs.
An action at the synaptic level
Many technological barriers still need to be overcome before achieving large scale development of bioelectronic devices, the main one being the need to efficiently connect the device with a large number of axons and neutrons. «Technologies used to build the electrodes are still “primitive” from this point of view – explains Silvestro Micera – The electrodes for the motor cortex used by disabled persons, for example, replicate in the best case few hundreds of neurons, while they should be able to record at least some hundreds of thousands. There is a sort of band difference. The other issue is the lack of continuity, with information degrading with time. Technology has greatly evolved in the past twenty years, but it is still not able to generate a very rich, selective and efficient connection».
The preferred way make by now use of devices implanted directly on the nerve or very close to it, a procedure quite invasive for the patient. Some example of not invasive systems are beginning to appear, even if according to Micera they present higher selectivity problems with respect to implantable devices. «It is as I would like to speak with a person closed inside a room, while I’m out of it. I can potentially do this even with the door closed, but selectivity for an implantable device is probably higher, at least on the medium period».
Electroceutics act at the level of a single nerve and the corresponding organ system, thus applications should address single pathologies; it is difficult to think a system “tunable” according to the specific need. Even at the level of the vagus nerve, which is very large, there is need to interact with a specific part of the nerve and it is thus difficult to develop a “general purpose” solution. The starting point is always represented by the understanding of the specific neural system involved in the pathology. «We need to be selective for this nerve, to then appropriately select the simulation parameters in order to restore the nerve’s activity. A possibility is to study the pathological mechanism in order to understand what is needed and how to provide it. Another possibility is to use the information closing the control mechanism: there is a change of parameters in real time on the base of the registered information», explains Silvestro Micera.
For the professor of the École Polytechnique it is still not possibile to tell if electroceutics might completely replace in future more traditional pharmacological treatments, or if they shall act complementary. Artificial intelligence will also play a fundamental role for the success of electroceutics, for example in making the system more efficient or in modifying its parameters in real time. «The so collected information allow to better understand how the information itself should be correctly used. This has a deep impact, because it allows to better characterise what we are doing and to personalise it for each patient», adds Micera.
Risk evaluation is still to be fully accomplished
The main risk in the use of electroceutical devices are by now connected to the choice of biocompatible materials for their production, while informatics security is still to be fully addressed as the technology is at an early stage of development. «Theoretically, everything representing an electronic medical device might be hackered, but these systems are quite safe by now. We are currently focusing in understanding the true feasibility of this technology; the security issue will arise once we have many people implanted with it – tells Silvestro Micera -. There is currently no issue with augmentation, because we are not so performing. We shall consider it from the ethical point of view sooner or later, but it is still something far». How far might depend from the specific application: the ones intended to support disabled persons shall be probably the first one to become available. «This does not mean that there will be a massive use, but that the first clinical trials will start in few years. To reach massive application we need to wait at least ten years», is the final forecast made by Silvestro Micera.
The autonomous nervous system and the vagus nerve
The autonomous nervous system (also called vegetative or visceral) reaches all organs and glands and it controls all essential, not voluntary functions of the body. The nerves irradiates from the brain and the spinal cord to reach all organ systems.
The vagus nerve is the tenth cranial nerve (on a total of 12) and its right and left branches represents the longer and widely branched cranial nerves in the body. They start from the brainstem, pass through the jugular foramen and the thorax to finally reach the abdominal region. The vagus nerve is part of the parasympaphetic portion of the autonomous nervous system and reaches all organs apart the adrenal glands. It is the responsible of many fundamental processes, i.e. the regulation of heart beat and gastrointestinal peristalsis, bronchoconstriction, bile production and sweating.
The first trials in men
SetPoint Medical announced at the end of March 2018 the starting of the first pilot clinical study in men, to be carried out in the US. It will focus on the use of bioelectronic devices to treat rheumatoid arthritis refractory to standard therapies, including biological agents. According to the company, the device will be implanted on the vagus nerve and it will release pre-dosed quantities of electricity. The study was approved by the Fda under the Investigational device exemption (Ide), and it will allow to assess the safety and tolerability of the method. According to SetPoint Medical, it should include approx. 15 patients aged 22-75, reclute across seven different clinical centres.
Results of a previous proof-of-concept study conducted in Europe was published in 2016 in Pnas (https://doi.org/10.1073/pnas.1605635113). Eleven of the 17 patients showed an improvement of the Disease activity score, as well as five over the seven patients not respondent to conventional treatments.
The inflammatory reflex
The inflammatory reflex was discover in 2000 by Kevin Tracey, founder of SetPoint Medical. It consists of a neurophysiological effect according to which signals generated by inflammatory processes, senses or tissue damages are sent to the central nervous system. After elaboration of the signals, the CNS sends its feedback to muscles and organs through the vagus nerve. Norepinephrine is a neurotransmitter central to this process, as it activates T cells in the spleen. These cells then release acetilcholine, another neurotransmitter acting on monocytes and macrophages produced by the spleen and involved in the reduction of the levels of molecules involved in inflammation, such as tumor necrosis factor-α and IL-6.
The vagus nerve contains approx. 100 thousands nerve fibres, reaching different organs. According to Nature (doi:10.1038/545020a), the quantity of electricity needed to reactivate neural response can vary up to 50 times among different nervous fibres. The quantities of electricity needed to deactivate inflammatory processes would be some eight times less intense that those used to treat epilepsy. A further advantage is represented by the fact that a single electric discharge might inhibit pro-inflammatory cytokine production up to 24 hours.