Bioelectronics ‘jump-start’ the next wave of device therapeutics

| Artigo

Medical science has advanced tremendously over recent years, reaching a point where for many patients and conditions, the current standard of care is quite good. Two decades ago, many would have said the same thing from a medical device perspective; the world already had laparoscopic surgery, stereotactic radiosurgery (precision radiation treatment) and heart stents that could replace many traditional heart bypass surgeries. And yet over the past two decades, technology has advanced so much further in an attempt to address remaining unmet patient needs: these same areas mentioned above have seen the development of robotic surgery, proton beam radiation therapy and percutaneous heart valves.

A number of themes currently dominate medical research headlines—for example gene therapy, gene silencing via siRNA, CRISPR and gene editing, immuno-oncology and the gut microbiome-brain axis, but there is an under-recognized modality in development in healthcare that takes advantage of the body’s innate electrical systems that could play a substantial role over the next two decades of progress: bioelectronics.

The extent to which the electrical systems of the body contribute to healthy functioning and disease remains underappreciated, even within the medical field. Pacemakers for abnormal heart rhythms and electroshock therapy for depression have long been mainstays of medical treatment. More recently, electrical stimulators have been used to control seizures for epileptics. While these approaches deliver enormous therapeutic benefits, they do so by resetting or altering existing electrical pathways.

One of the newer applications for electrical therapy is its potential use in conditions controlled by “biological circuits.” One of the first areas where this jump is occurring is in the field of inflammation. Over the past decade, researchers have defined a key role played by the nervous system in immune function. In the so-called inflammatory reflex, the vagus nerve—the longest cranial nerve in the body, a “superhighway” running from the brain to the abdomen—helps control the level of tumor necrosis factor (TNFα), which in turn regulates immune pathways and cells and is a common target for drug-based interventions, such as Humira for rheumatoid arthritis and Crohn’s disease.

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Today, implantable bioelectronic devices that electrically affect this inflammatory reflex are in fact being tested as treatments for rheumatoid arthritis and Crohn’s disease. Other chronic diseases affecting the immune system, such as multiple sclerosis, could soon follow. The advantages that bioelectronic devices offer (e.g., precise, localized and focused regulation of TNF release versus unfocused, diffuse exogenous control by drug-based interventions and their potential adverse effects) could, for some patients, possibly eliminate the need for such drugs. Just as the development of pacemakers depended on a detailed knowledge of the electrical circuits and pathways that lead to healthy function or disease in the heart, a better understanding of the electrical circuits and pathways for other diseases should render them increasingly amenable to bioelectronic treatments. As this therapeutic approach is applied more widely, the lines demarcating when a medical device versus pharmaceutical therapy should be used will continue to blur.

Compelling advantages with bioelectronics

In principle, the medical use of bioelectronics and electroceuticals has several advantages (Exhibit 1). First, and most important to patients, it holds out the promise of treating conditions that today’s drugs and medical procedures are either unable to address, such as severe spinal-cord injuries and blindness or only partially address, such as Crohn’s disease. Second, miniaturized electric stimulators have the potential to deliver true precision medicine. Consider patients with paralysis caused by CNS damage in a stroke or by traumatic brain injury; a bioelectronics therapeutics application to restore motor transmission by precisely bridging the damaged site is conceptually simple to imagine, whereas a pharmaceutical approach is too diffuse, lacking the precision targeting needed. Almost all drugs have the potential for undesired systemic effects. Some of these effects can even impact compliance, such as a hypertensive patient reducing medication use because of dizziness. On the other hand, at least in theory, precise targeting enabled by an electroceutical application could limit the number and extent of side effects.

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Additionally, equipping electroceutical treatments with sophisticated algorithms that will allow adjustments to treatment analogous to dosing by a pharmaceutical agent could help overcome drug adherence concerns and potentially be adapted to patient-specific circumstances. This may be particularly important in potential electroceuticals applications such as treating Parkinson’s disease due to the need to finely titrate the amount of dopamine available in the basal ganglia, a key motion-controlling part of the brain. An electrical current can be increased or reduced far more easily than the concentration of a drug in the blood, and unlike surgical procedures, the effects of stimulation are reversible: the current can be switched off. One can imagine a smartphone or tablet used by a physician (or patient) as a control interface, and indeed such applications are being developed along with the actual devices. Exhibit 2 highlights some example applications and industry participants.

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Overcoming hurdles

A wave of such technologies has established proof of concept and begun to demonstrate quality-of-life improvements in select subsets of patients. However, significant advances will be needed before bioelectronics can deliver widespread clinical impact. Exhibit 3 illustrates some recent and ongoing efforts. Exciting as they are, these early examples inform us as to the kinds of challenges that the field will need to overcome to address more patients and diseases.

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These hurdles span three main categories: basic biology hurdles such as decoding neural language, device engineering hurdles such as miniaturization and resistance to biodegradation, and commercial adoption hurdles such as regulatory approval and pricing models as well as patient and physician acceptance. Each hurdle must be addressed individually, but also as interrelated pieces requiring coordination to ensure effective and consistent solutions.

On the basic biology side, further progress is needed to understand the neural circuitry at a systems level to be able to decode neural language to more precisely target electrical therapies. Recent advances in imaging technology and computing power have moved us closer to understanding electrical activity for a few hundred or even thousands of neurons at once, but we are still a long way from being able to fully understand how extremely complex pathways like those found in the brain (with more than 100 billion neurons) or the gastrointestinal tract (with more than 100 million neurons) behave as a system. The field of quantitative systems biology attempts to model complex, interrelated biological systems using computational and mathematical techniques. Its concept is based on the belief that biological systems are better understood if approached holistically, rather than the more conventional reductive approach that has dominated biological and medical research for decades. Improved understanding of complex systems will help point the way to new targets and pathways for therapies.

There are already examples of potentially successful quantitative systems biology approaches in the medical field (albeit applied to pharmaceutical applications), but it is a small jump to adapt these techniques for bioelectronics applications.

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Advances in device engineering have also opened new frontiers for research and therapy. For example, ultraminiaturized nerve cuffs allow the targeting of very small (dozens of nerve axons) peripheral nerves and carry lower risk of shredding or tearing fragile tissue than traditional methods. And advances in materials science have enabled the production of soft, flexible electrodes that are easier and safer to use on small peripheral nerves—like the end-organ nerves that control vascular tone and blood pressure—because they transmit less mechanical force and are therefore less likely to cause nerve or tissue damage. Improved devices should ultimately enable precision targeting for very small groups of nerves as well as improve the duration of patient responses by avoiding side-effects, such as patient scarring, that can reduce signal transmission.

Further technological advances will be needed to make ultraminiaturized stimulators practical to use. Apart from the challenge of which nerve fibers to target, it is difficult to power and wirelessly control small devices that are used in deep tissues, as normal body tissues cause signal attenuation. Novel approaches, such as using piezoelectric crystals as stimulators, may be able to address this in time. However, at this early stage, most bioelectronic applications are likely to be limited to bigger nerves that are relatively easy to target surgically, such as the vagus nerve (Exhibit 4).

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Beyond the technical aspects, the bioelectronics community will also need to address issues affecting commercial adoption. As a surgically based intervention, bioelectronics has a different risk and cost profile than other modalities, such as pharmaceuticals. Bioelectronics will likely have a higher upfront risk and cost than pharmaceuticals, but with a correspondingly lower long-term risk and cost. Until longer term safety and efficacy data are available, bioelectronics players may need to focus on patient subsegments with high unmet need but few, if any approved treatments. One example would be patients that are either inadequately controlled by conventional therapies, despite having tried all prior line options, or happen to be specifically suited to a bioelectronic device approach.

If these hurdles are overcome, bioelectronics has the potential to move from a relatively niche field today to becoming a mainstay of medical treatment—not just a treatment of “last resort” for otherwise intractable conditions (Exhibit 5). As a rough analog, consider the development of continuous glucose monitoring in type 1 and type 2 diabetes. Not only were technology advances required, but also establishing reimbursement and overcoming patient and physician attitudes were needed to establish the treatment itself as an emerging standard of care.

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Assessing value

Not surprisingly, the breadth of diseases addressed will also play a significant role in determining the growth in bioelectronics therapy market, as pricing and reimbursement will be shaped in part by the cost of these alternative treatments. As more and more diseases become amenable to a bioelectronics treatment approach, the economics of disease therapy will become a more pressing issue. For instance, how will the total costs of care compare with pharmaceutical therapies, particularly generics? And as much of the cost will be incurred upfront (that is, at implantation), what will payers require for reimbursement, given frequent insurance coverage changes for many patients?

Another potential hurdle could arise if essentially the same bioelectronic device can be used to treat multiple conditions. As an example, if a new device can treat both routine hypertension (with multiple inexpensive drug alternatives) and severe inflammatory bowel disease, how will payers and other stakeholders react if there are pricing differences across the two conditions? Will different software and algorithms that help determine disease specific treatment parameters be enough to validate pricing differences under such a scenario? The healthcare market is not unfamiliar with this problem as it routinely deals with new and more sophisticated therapies for a disease that incrementally improve patient outcomes when compared with an older, cheaper, less sophisticated drug and occasionally must deal with the repurposing of the same drug for a different therapeutic application. On the face of it, pricing a bioelectronic therapy differently depending on the disease it is treating—versus a drug that is priced the same regardless of the disease it treats—may be justified because part of its value is in its software and the intellectual property that goes into reprograming it to benefit each disease. Nevertheless, these are but a handful of the non-technical questions that the field will need to address over the coming years.


Exciting times seem to be ahead for the new era of bioelectronics and electroceuticals—and for the patients that can benefit from them. Although considerable hurdles must be overcome, early successes have established the promising potential of cybermedicine. While today’s applications have likely only begun to scratch the surface of what is possible, bioelectronics has the potential to become a pillar of medical treatment and play a key role in the next horizon of medical technology innovation.

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