BIOELECTRONICS: A DIFFERENT WAY OF TREATMENT
Getting on your nerves can be healing
Bioelectronics (or electroceuticals) are implanted devices that stimulate the nervous system using electrical impulses to prevent or treat severe chronic diseases.
They consist of tiny electrodes attached directly to a nerve, connected through a wire to a pulse generator, which stimulates the nerve’s activity. This is called neuromodulation. The pulse generator, along with a data processing and data storage unit, is contained within a case that is about the size of a watch. This case sits under the skin in the breast area, where it controls the nerve impulses and monitors nerve activity.
Simple non-feedback, ‘open-loop’ devices are already in use to treat Parkinson’s disease, depression, epilepsy, and other conditions. These use consistent, pre-programmed nerve stimulations to targeted regions of the brain or peripheral nerves. However, newer state-of-the-art ‘closed loop’ bioelectronics are being developed that adjust treatment based on the detection of pathological nerve activity. These may provide more precise and personalized treatment than ‘open loop’ systems.
Recently, a woman was successfully treated for depression with an experimental closed-loop implant . But the potential for these bioelectronic devices extends far beyond psychiatric and neurological disorders. By developing bioelectronics that can target specific regions of the peripheral nerves (as well as the brain) the approach can be expanded to a wide range of complex and common diseases.
“Bioelectronic devices with a simple two-channel electrode are already on the market,” explains Robert Spoelgen, our Head of Bioelectronics, “but these only deliver a predetermined electrical impulse and don’t monitor nerve activity or respond to feedback. We aim to develop more sophisticated bioelectronic devices that have multiple channels allowing us to target precise sub-regions of the nerve. The goal is to first record nerve activity to find the relevant physiological area of the nerve linked to certain disorders and then subsequently precisely stimulate only this sub-segment.”
Did you know?
of chronic inflammatory disease patients do not respond adequately to treatment 
is the number of electrodes on our new bioelectronic devices
is the diameter of the implanted pulse generator of a bioelectronic device
Correcting the imbalance of the nervous system
Bioelectronics have the potential to stimulate various nerves, but we are focusing on the vagus nerve. Running from the back of the brain via the neck and chest down to the abdomen, this major nerve carries an extensive range of signals from the internal organs to the brain and vice versa.
The vagus nerve is involved in a biological feedback loop called the ‘inflammatory reflex’ [3-5]. In this feedback process, the vagus nerve senses the presence of inflammatory molecules and then signals to the brain to regulate their production through immune cells produced by the spleen. In other words, it is thought to play a key role in regulating inflammation in the body. This is important as research has shown that chronic inflammation is linked with diseases such as heart disease, diabetes, and multiple sclerosis.
“The vagus nerve has been implicated in many diseases and disorders, but our initial goal is to focus on its role in chronic inflammatory disorders, to see if we can develop bioelectronics that can precisely downregulate the chronic inflammation that causes symptoms like pain.”
Early clinical studies in rheumatoid arthritis have shown that stimulating the vagus nerve with simple bioelectronic devices could offer an exciting new approach for treating patients with this disease. Results suggest the use of these devices not only reduce the levels of pro-inflammatory molecules, but also improve patient-reported pain and mobility .
Overcoming neuromodulation challenges
Approved devices that target the vagus nerve and are used for depression or epilepsy most likely only help a subset of patients where the electrical impulse hits the right fibers in the nerve by chance, and the small impulse is enough to have an effect.
“The problem is that you cannot use a lot of electrical currents because otherwise, you would hit various functions of the vagus nerve. You could dysregulate the function of the heart and lungs, resulting in life-threatening conditions. Common side effects are shortness of breath, hoarseness, voice alteration, nausea, diarrhea, and burning or prickling sensations in the skin,” says Spoelgen.
But it is hoped that our new multi-channel electroceuticals will identify the exact spot where the chronic inflammation is regulated. “If you're systematically working through all of the nerve’s functions, you have an excellent opportunity to help patients in a much more efficient and targeted way, but also a means of helping many different patients with a single type of treatment,” says Spoelgen.
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Amazingly, Bioelectronics and our central nervous system both speak the same language. These tiny medical devices will allow a personalised and more holistic approach to treat patients. Experts explain how.
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Take advantage of data
A further advantage of bioelectronics is the ability to use these devices to learn about a condition, in a way that pharmacological interventions cannot. “What we are about to develop, is a device and system that includes one or more sensors. And when we combine that in one dimension with the signals from the nerve itself, we can get a very high-resolution understanding of a disease in that person,” explained Spoelgen.
Capturing this real-world data from these patients over years allows physicians to better understand individual disease conditions and adjust the treatment regimen of the device accordingly for each individual patient. Not only does this inform physicians about a patient’s condition long-term, but there is also a real-time opportunity to gather deeper insights into the disease progression and enable improved disease treatments in the future.
“If you consider people who have regular flare-ups of their disease, with these devices you could probably see the signs of this a couple of days before the worsening of symptoms happens. Then you can ask patients to come to the doctor's office.” Similarly, if someone is doing well and all the data suggest that the disease is well under control, their doctor could know that the patient doesn't need to come into the clinic that month, saving patients’ time as well as healthcare resources.
Who could benefit from these bioelectronics?
For around two-thirds of patients with chronic inflammatory diseases, there is currently no adequate treatment available that can keep their symptoms under control.
“We are talking about a group of patients with such severe disease that they need to stay at home. They don't participate in work or a social life anymore,” explained Spoelgen.
“Many of these patients are young women who often cannot take the available medications because they still want to get pregnant. We want to use innovations in bioelectronics to address this very important need for patients with these severe forms of the disease,” he added.
In what way do bioelectronics appeal to you most?
Good impulses from partners
To drive these innovative devices forwards, we are building on our existing capabilities in pioneering new treatments through internal collaborations between our innovation teams and our Healthcare division. In addition, we are working closely with expert external partners to move the bioelectronics field forward.
The first bioelectronic products we are developing in partnership will be designed for people with severe chronic inflammatory diseases who do not respond to the gold standard of anti-inflammatory drug treatments.
In 2021, we announced two new alliances. The first, with the start-up company Neuroloop (a subsidiary of B. Braun, Germany), will see us collaborate to further develop their multichannel electrode platform into a selective neurostimulator bioelectronic device to stimulate the vagus nerve . A second partnership with Innervia Bioelectronics (as a subsidiary of Inbrain Neuroelectronics in Barcelona, Spain) complements this by exploring the use of graphene-based electrodes across a range of therapeutic areas . Graphene is a two-dimensional material that allows precise signal recording to specific regions of the nerve, while also decreasing the power consumption of the device – an important consideration as these devices become further miniaturized.
“From what we know so far, we believe there is potential to achieve efficacies comparable to gold standard drug treatments of these severe disorders,” says Spoelgen. “If so, we may also achieve the goal of avoiding side effects associated with available medications, but beyond that we can enable remote patient monitoring or the treatment of other coinciding conditions.”
Our bioelectronics developments illustrate how innovation is truly powered by data and digital and how we advancing in this groundbreaking field to improve patients’ lives.
“It’s exciting to bring all these different disciplines together – engineers, physicians, data scientists, pharmacologists, and regulatory experts – to work on these devices,” says Spoelgen. “I think it is important to understand that these devices will definitely come to the market. They will be offered along with traditional pharmaceuticals and they will make us understand how remote patient monitoring, personalized medicine, and mobile healthcare devices will change the healthcare landscape in the future. Ultimately, we want to be successful for patients, but we will also learn a lot along the way.”
 Bystrom J, Clanchy FI, Taher TE, et al. Response to Treatment with TNFα Inhibitors in Rheumatoid Arthritis Is Associated with High Levels of GM-CSF and GM-CSF+ T Lymphocytes. Clin Rev Allergy Immunol. 2017;53(2):265-276. doi:10.1007/s12016-017-8610-y
 Scangos, K.W., Khambhati, A.N., Daly, P.M. et al. Closed-loop neuromodulation in an individual with treatment-resistant depression. Nat Med (2021). https://doi.org/10.1038/s41591-021-01480-w
 Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000);
 Zanos, T. P. et al. Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity. Proceedings of the National Academy of Sciences 115, E4843–E4852 (2018)
 Kressel, A. M. et al. Identification of a brainstem locus that inhibits tumor necrosis factor. Proceedings of the National Academy of Sciences 117, 29803–29810 (2020).
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