Emerging field neuromodulation, or biostimulation, or electroceuticals, is emerging as an alternative to costly chemical and biologic drugs.

Rajesh Uppal March 22, 2021 BioScience, Soldier Comments Off on Emerging field neuromodulation, or biostimulation, or electroceuticals, is emerging as an alternative to costly chemical and biologic drugs. 186 Views

The human body is electric. Peripheral nerves connect all organs to the central nervous system, and those nerves are packaged in various bundles. The vagus nerve, for example, carries about 100,000 nerve fibers. It’s also the longest nerve in the body, linking the brain to organs from the esophagus to the intestines while controlling breathing and heart rate. Further evidence suggests it may be the direct link for that well-known gut-brain connection.

Hundreds of clinical trials are now underway to investigate how harnessing the body’s peripheral wiring might help broadly in the treatment of acute and chronic disease. The results so far appear promising. Kelly Owens, who spent her teens and 20s crippled by inflammatory arthritis and Crohn’s disease tried this treatment when a research team implanted a small device inside her chest to stimulate her vagus nerve. About four times a day, Owens swipes a magnet over her chest to activate the device implanted under her collar bone. For the next five minutes after each swipe, the device sends electrical currents to her vagus nerve. That’s enough to turn down her inflammation and keep her debilitating symptoms at bay “I hope many more people will benefit like Owens has,” says Tracey, president and CEO of the Feinstein Institutes for Medical Research in New York and a pioneer in the field of bioelectronic medicine.

The idea of electrically stimulating the body to alleviate illness is not new. Doctors have implanted patients with pacemakers, deep-brain stimulators, and other electrical devices for decades. Vagus nerve stimulation itself is currently US Food and Drug Administration (FDA)-approved for epilepsy and treatment-resistant depression. But these were “crude initial attempts” in communicating electrically with the body, says Datta-Chaudhuri.

The new field, which also goes by neuromodulation, biostimulation, or electroceuticals, is emerging as an alternative or add-on to costly chemical and biologic drugs. Dysfunctional neural circuits give rise to dysfunctional organs. The goal of bioelectronic medicine is to restore healthy patterns of electrical impulses—adjusting how neurons fire and, thereby, changing the concentrations of neurotransmitters traveling through those circuits.

Driving growth in bioelectronic medicine is a convergence of advances in neuroscience, electronics, materials science, molecular medicine, and biomedical engineering, alongside more than a billion dollars of investments from government and industry. Within the next decade, researchers say, modulating the body’s neural networks could become a mainstream therapy for many of today’s greatest health issues—from arthritis (1), asthma (2), and Alzheimer’s disease (3) to depression (4), diabetes (5), and digestive disorders (6, 7). Stimulating nerves also shows promise in treating cardiovascular disease (8) and septic shock (9), even in improving cognition (10).

The pharmaceutical industry is on board. Johnson & Johnson’s portfolio now includes a number of bioelectronic devices. And GlaxoSmithKline has made a big bet on bioelectronic medicine by investing—alongside Verily, formerly Google Life Sciences—$715 million in Galvani Bioelectronics, whose focus is on the design and development of neuromodulation systems. “They are investing in something that would clearly be a disruptive technology,” says Datta-Chaudhuri.

Market intelligence firms predict the bioelectronic device market will reach between $16 and $60 billion annually within the next 5 to 10 years . “We’ve already hit $10 billion a year,” says Kip Ludwig, who leads the Bioelectronic Medicines Laboratory at the University of Wisconsin–Madison. “It now looks like we’re at the slope in an exponential curve.”

US Military has also been pioneer in applying this technology. The National Institutes of Health (NIH) and the Defense Advanced Research Projects Agency (DARPA) have also invested significantly in the field through programs such as Stimulating Peripheral Activity to Relieve Conditions, or SPARC , and Electrical Prescriptions, or ElectRx.

DARPA’s BTO is developing capabilities to better prepare warfighters for their missions by improving readiness and resilience, and creating technologies to restore function to injured warfighters when necessary. DARPA launched Electrical Prescriptions (ElectRx) program in 2015, a blanket program for a diverse range of research being conducted in using electrical stimulation of the peripheral nerves to treat conditions such as chronic pain, inflammation, and post-traumatic stress disorder (PTSD). ElectRx seeks to deliver non-pharmacological treatments for pain, general inflammation, post-traumatic stress, severe anxiety, and trauma that employ precise, closed-loop, non-invasive modulation of the patient’s peripheral nervous system. “Much like a thermostat monitors, an ElectRx device would monitor and recognize when the system is moving away from homeostasis and into a diseased state. Eventually, a regulator would provide therapeutic stimulus, then a modulator would signal nerves,” Wu said .One recent study funded by DARPA’s ElectRx, for example, found that sacral nerve stimulation decreased inflammation in the colon.

Neuromodulation, biostimulation, or electroceuticals

Because of its size and breadth, as well as recent progress in understanding exactly how it influences various parts of the body, the vagus nerve has become a major target for the burgeoning field . “The vagus nerve goes everywhere, so it’s an easy way to get access to a bunch of different targets,” says Timir Datta-Chaudhuri, an investigator at the Feinstein Institutes for Medical Research. “It’s like going to the main fuse box.”

Datta-Chaudhuri is among researchers who believe the greatest promise for bioelectronic medicine is in manipulating the vagus nerve to control inflammation and the immune response—both of which drive most chronic disease. In a groundbreaking study published in Nature in 2000, Tracey and his colleagues showed that stimulating the vagus nerve could significantly reduce inflammation in rats (13). Acetylcholine, the principal neurotransmitter that stems from the vagus nerve, inhibited the production of cytokines such as tumor necrosis factor (TNF), an inflammatory molecule involved in rheumatoid arthritis. His team followed up with studies in humans and found the same.

“We have known that the vagus nerve is a fundamental component of reflexes that control the physiology of organs—the heart, the intestines, the liver,” says Tracey. “But we never thought it would control the immune system.”

One of the holy grails in bioelectronic medicine, says Tracey, is closed-loop therapy. Such a device could not only talk to the nerves but also listen in on their conversations with the rest of the body to decipher how best to respond in real-time—whether by stimulating or blocking nerve signals. In the case of diabetes, that might entail telling the pancreas to make more insulin when it’s needed. In the gastrointestinal system, an electrode might sense the motility rate of the gut and then determine the optimal frequency of pulses to speed it up or slow it down. The goal is to restore a healthy pattern of electrical pulses. “In a healthy body, all the parts are there and talking to each other like they should be,” says Datta-Chaudhuri. “In a diseased body, either the parts there are not functioning as they should or they are not communicating to each other as they should. So a good approach is to listen in on the messages sent between different parts of the body and insert information.”

Of course, a bioelectronic device is not likely to be a panacea. The Inspire system requires an invasive surgery and carries a high price—between $40,000 and $100,000 including the requisite surgery. Ludwig notes that this one-time investment is often offset by the cost savings of not having to pop expensive pills. But there may be additional drawbacks. For example, some Inspire models need to be removed before an MRI scan. And then there are the unknown risks associated with any new technology. Implanted devices will likely become less invasive with increased miniaturization and more sophisticated electronics. “This field is governed by Moore’s Law,” says Ludwig. “The devices will get smaller and smaller to the point where they will be as invasive as a tattoo.”

While a short, maybe 30-minute surgical procedure would be expected for such an implant today, Ludwig suggests that technological advances will soon allow wireless devices to be injected under lidocaine, eliminating the need for invasive surgery. “That’s when this starts taking over for drugs,” he says. “It changes the regulatory pathway so that it is much less expensive and quicker to market.” Sidestepping surgery and avoiding wires would likely allow a company to submit a 510(k) premarket notification instead of a premarket approval to the FDA. “That’s the difference between costing your company 7 years and $150 million versus and a 6-month study and $5 million,” he says.

Noninvasive bioelectronic devices can also take the form of handheld devices, which are generally used for short-term illnesses. In January, the FDA approved a noninvasive bioelectronic treatment for sinus pain. Tivic Health’s ClearUP Sinus opens up the sinuses via transcutaneous nerve stimulation on the cheeks, nose, and brow bones (18). Researchers are also investigating the potential health benefits of stimulating the vagus nerve through the outer ear (19). One study published in July found the self-administered stimulation boosted the quality of life, mood, and sleep compared with a sham treatment in older adults (20).

National Institute of Health’s SPARC Initiative

Peripheral nerves, the nerves outside of the brain and spinal cord, make connections with and influence the function of every organ in the body. Modulation of peripheral nerve signals to control the functions of the organs they supply has been recognized as a potentially powerful way to treat many diseases and conditions, such as hypertension, heart failure, gastrointestinal disorders, type II diabetes, inflammatory disorders, and more, says NIH.

However, the underlying physiology and mechanisms of action for neuromodulation therapies are poorly understood. The design of more effective and minimally invasive neuromodulation therapies requires knowing exactly what nerves one must stimulate and how they must be stimulated to achieve the desired effect on organ function. It also requires knowing exactly what nerves one must avoid to prevent unwanted side-effects.

The Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) is uniquely positioned to serve as a community resource that provides the broader public and private research communities with the scientific foundation necessary to advance neuromodulation therapies towards precise neural control of end-organ system function to treat diseases and conditions.

This high-risk, goal-driven program is structured as a consortium of four distinct research areas that will function in an integrated and iterative way, fostering discovery and broad dissemination of the fundamental physiology and biological mechanisms underlying peripheral autonomic and sensory control of internal organ function and changes attributable to disease states and conditions.

In turn, these discoveries will enable development of next generation closed-loop neuromodulation therapies, investigation of approved devices for new indications and adoption of improved computational tools and modeling methods. The SPARC program tentatively plans to support interdisciplinary teams of investigators to deliver neural circuit maps of several organ systems, novel electrode designs, minimally invasive surgical procedures, and stimulation protocols, driven by an end goal to develop new neuromodulation therapies.

Current plans include initiatives to:

Capitalize on recent technology advances and anticipated new technology developments facilitated by the program to deliver detailed, predictive, functional and anatomical neural circuit maps of the autonomic and sensory innervation of multiple internal organs or organ systems.
Leverage recent biological discoveries to develop technologies including novel electrode designs and sensors, stimulation protocols, and minimally invasive surgical procedures with an end goal to improve existing and pilot new, next generation closed-loop neuromodulation therapies.
Establish effective public-private partnerships to use existing approved neuromodulation technologies and therapies to explore new indications.
Assemble data from other SPARC initiatives into a publicly available and centralized resource for the wider research community to access as well as provide new computer modeling methods and user-friendly computational tools.

SPARC-funded investigators (link is external) are working collectively as a consortium to address the program’s aims and goals via:

Biological projects to develop detailed anatomical and functional maps that illustrate how peripheral nerves control organ function;
Technology development projects to create or improve tools to measure and manipulate nerve-organ interactions and isolate their functions;
Collaborations between private-sector scientists and academic researchers, to expedite the development of new therapeutic strategies;
Expertise leveraged from many different sources, including academic laboratories, independent inventors, start-ups, small and large businesses, and international organizations; and
SPARC program-developed data and tools shared through a central online resource

NCATS-Administered SPARC Projects

Five preclinical projects, funded through the U18 mechanism, were initiated across two RFA calls. Three projects began in September 2016 in response to RFA-RM-16-009(link is external), and NCATS added two more projects in August 2017 in response to RFA-RM-16-027(link is external). Through these projects, SPARC investigators have initiated collaborations with device companies to explore the usefulness of existing industry devices in new therapeutic applications. View the NCATS-administered SPARC projects:

Project Titles	Principal Investigators	Institutions
Closed-Loop Neuroelectric Control of Emesis and Gastric Motility(link is external)	Charles Horn, Ph.D.	University of Pittsburgh
Neuromodulation for Asthma(link is external)	Brendan J. Canning, Ph.D. Marian Kollarik, M.D., Ph.D. Wayne Mitzner, Ph.D.	Johns Hopkins University
Smart Spinal Cord Stimulation for Gastroparesis(link is external)	Jiande Chen, Ph.D.	Johns Hopkins University
Subcutaneous Nerve Stimulation for Arrhythmia Control(link is external)	Peng-Sheng Chen, M.D.	Indiana University
Vagal Nerve Stimulation for Diabetes(link is external)	Jieyun Yin, M.D.	Transtimulation Research, Inc.

Bioelectric Barriers

Despite all the promise, it won’t be easy to bring bioelectronic medicine into the mainstream. Gene Civillico, the Program Manager for NIH’s SPARC, notes some resistance to the devices. “When a lot of people think about therapies, they first think, ‘Is there a drug?’ And if that drug didn’t work, ‘Is there another drug?’” says Civillico.

Another key obstacle is the lack of interoperability of data and tools. “This limits our ability, and perhaps more importantly, software’s ability, to tell stories across labs and data sets,” says Civillico. A better understanding of nerve signals and their exact effects, alongside improved technology to target specific nerve fibers, is also critical to broader adoption of bioelectronic medicine. Toward that end, many more basic science and translational efforts are in the works, thanks in part to SPARC.

“I really think this is going to be an enlightened moment when more of the community recognizes the importance of the interactions between the immune system and the nervous system,” says Marthe Howard, a SPARC investigator and neuroscientist at the University of Toledo in Ohio. Howard is collecting data to help bioengineers develop an electrode array that, when placed on the gut, could optimally hit neurons or the synapses between them based on the treatment goal.

A high priority for the seven-year, $240 million SPARC program, says Ludwig, is a detailed map of the nervous system and how it influences and regulates organs throughout the body. Without a map, future devices might simply not work or, worse, they could end up interfering with the wrong signals, resulting in pain or other problems. “Right now we’re just banging our forearm on a really complex keyboard and hoping that it helps,” says Ludwig. “As it becomes more precise, we hope to play Beethoven’s 5th.”