Bioelectronic technologies for modulating the signaling capabilities of the nervous system could pose challenges for producers of medicinal materials and chemicals – but also for regulators.

The commercialization of bioelectronics has been hailed as the next stage in the growing domination of biologics in medicines. The market launch of the first major bioelectronic products may be as long as 10 years away but already leading pharmaceutical companies have started work on their development using as a platform R&D breakthroughs by top universities and research institutes.

Technology of Bioelectronics

Around 30 years after biopharmaceuticals started making inroads into a global drugs market monopolized by small molecules, bioelectronics could be poised to provide strong competition to both chemicals and existing biological medicines. Bioelectronic medicines are fundamentally different because they are combinations of devices and drugs and in some cases may not be considered to be pharmaceuticals at all.

They are applied through micro-sized devices to neural pathways to diagnose, monitor and treat diseases. They can stimulate, block or otherwise modulate nerve activity by being implanted on a nerve or located on the skin. By being able to change specific nerve behavior, they can alter functions in organs and modify or cure diseases without the complicated side effects of pharmaceuticals.

Bioelectronic devices have already been tested successfully to treat inflammatory diseases such as rheumatoid arthritis and Crohn’s disease. They have the potential to treat a wide range of other conditions, including diseases such as cancers and chronic conditions like diabetes and asthma. Some will be able to combine diagnosis and treatment by detecting irregular nerve signals and then correcting them.

Bioelectronics will open up new opportunities for producers of medical materials and chemicals. The biggest demand could be for conductive polymers, especially organic ones, with a high degree of biocompatibility. Also there will be a big need for chemicals and biologicals which can provide functional surface interfaces with nerve cells.

Meeting the Requirements of Individual Patients

In addition to advancing the reach of biologics, bioelectronics will introduce a new type of personalized medicine with its products being customized to meet the requirements of individual patients. Like other personalized therapies—such as gene therapy and cell tissue engineering—bioelectronics production may be decentralized with manufacturing taking place at sites close to hospitals specializing in the technology.

On the other hand, the amount of personalization could be constrained by pressure to bring down costs through the high-volume manufacture of devices and their components. One solution could be the standardization of polymers and other basic materials while customization would be achieved through modifications to the surface cell-interacting substances. Another is the predominant use of organic polymers and surface additives with both being tuned to the characteristics of the nerve cells.

Bioelectronics have moved close to the forefront of medicine as a result of the lengthy accumulation of knowledge of bioelectricity in animals and humans since the Italian physicist and biologist Luigi Galvani discovered in 1780 that the legs of a dead frog could be made to twitch by applying a small voltage. It gradually became clear that all the human body’s organs are influenced by its nervous system via patterns of electrical impulses which run along the nerve fibers. Abnormalities in the impulse patterns—or the complete absence of them—cause disease and incapacities.

With the emergence of microelectronics, key advances in the development of bioelectronics for diagnosing and treating disease were made in the 1990s. A big impetus behind the current surge in interest in bioelectronics has been research work linking inflammatory diseases like rheumatoid arthritis with signaling patterns from the brain.

Nerve-Modulating Opportunities

The leading figure in the research has been Dr. Kevin Tracey of the Feinstein Institute in New York who discovered around 15 years ago the inflammatory reflex, a neural circuit between the brain and the vagus nerve regulating the immune system.

The cell signaling protein tumor necrosis factor (TNF) involved in systemic inflammation is, for example, controlled through impulses from the brain along the vagus nerve to the body’s central organs. Tracey also found that electrical signals from the brain can also trigger vagus nerve endings to produce acetylcholine, a signaling chemical, which can instruct white blood cells to stop making TNF.

These discoveries have presented opportunities for using nerve-modulating devices to replace drugs, some with severe side effects, for treating autoimmune diseases like rheumatoid arthritis.

UK-based GlaxoSmithKline (GSK) was the first of the Big Pharma companies to start exploring in 2012 the potential for managing nerve-signaling processes through bioelectronic medicines. It invested $50 million in US venture capital companies specializing in bioelectronics and was soon financing over 30 academic research projects across the world. Last year it set up a $715 million joint venture, called appropriately Galvani Bioelectronics, with Verily Life Sciences, part of Google, to develop bioelectronic treatments for diseases like arthritis, asthma and diabetes.

Other leading pharmaceutical companies which have moved into research in bioelectronic diagnostics and treatments include Johnson & Johnson, Novartis, Sanofi and Abbott Laboratories. At the same time relatively large R&D funds have been channeled into bioelectronic research projects in universities and institutes in North America and Europe.

Developing More Effective Materials

In the US the Obama administration launched four years ago BRAIN initiative for Brain Research through Advancing Innovative Neurotechnologies. A lot of the current research in North America and Europe is focused on achieving greater understanding of the mechanisms and pathways behind signaling in neural circuits. Another priority is the development of more effective materials and chemicals for controlling nerve impulses.

Many of the micro devices and their components used currently in bioelectronics are based on equipment applied in other sectors, like environmental care, energy, agriculture, food and even consumer products. Their materials and surface substances are being found to be unsuitable for applications inside the human body.

Indium-tin oxide (ITO), for example, a conductor used in solar cells, sensors and electronic displays, has been considered by researchers to be inappropriate for bioelectronic devices because of its brittleness, need for high-temperature processing and limited transparency. As a result it is being replaced by materials like graphene, which is regarded as more adaptable to neural interfacing requirements.

The need for materials with effective neural interfacing properties is a big influence on the development of bioelectronic conductive polymers as alternatives to conventional, established materials like silicon and organic polymers such as polydimethylsiloxane (PDMS), poly 3,4-ethylenedioxythiopene (PEDOT) and combinations like PEDOT and polystyrene sulphonic acid (PEDOT:PSS).

Some scientists favor silicon because of its great conductivity and durability. But there is a growing group of researchers who reckon that the future of bioelectronics lies with organic polymers because their inherent biocompatibility can be extended to create a wide range of neural interfacing structures and functions.

“This combination of structural and functional flexibility makes (organic polymers) especially well suited to applications in the medical field since it allows precise modelling of various attributes of cells and human tissues,” says Professor Agneta Richter-Dahlfors of the neuroscience department of Sweden’s Karolinska Institute.

Just how quickly the first bioelectronic products come to market will depend a lot on the regulators, whose first task is to decide whether they should be legally classified as primarily devices or drugs. In the European Union, for example, the classification will dictate what quality, safety and efficacy standards have to be demonstrated by developers, with the requirements being stricter for drugs than devices.

Under EU law, a product is considered to be a drug if it is administered “with a view to modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis." Many bioelectronic products would be regarded as having those characteristics. Once bioelectronic treatments are categorized as drugs they could face lengthy clinical trials because they will have to be assessed on the basis of end-points, which are rarely applied in the current clinical trials system.