October 2002 issue, BioElectRx Business Report
October 31, 2002 | In recent weeks, the National Institutes of Health has awarded millions of dollars in funding to research institutions and commercial firms pursuing novel bioelectronic medicine therapies and diagnostics.
The NIH’s SPARC program (Stimulating Peripheral Activity to Relieve Conditions) has been instrumental in funding the early development of the bioelectronic medicine industry. In Phase 1 of the program, SPARC supported the development of new tools and technologies, mapped the connections among a variety of different nerves and organ systems, and created a rich public resource that provides scientists with cutting-edge information and tools for advancing bioelectronic medicine.
Phase 2 of the program will consist of three projects, SPARC-V, devoted to vagus nerve mapping and physiology, SPARC-O, devoted to open source neuromodulation technologies, and SPARC-X devoted to targeted neuromodulation therapies. The NIH will continue to share data and digital resources through the SPARC Portal in Phase 2.
Earlier this month, the NIH announced the recipients of awards for the SPARC-V and SPARC-O projects. In the SPARC-V project, three teams were funded. The NIH awarded a $15.75 million contract to researchers led by Case Western Reserve and Duke universities to accelerate development of therapeutic devices that improve chronic medical conditions. The contract—specifically to Reconstruct Vagal Anatomy (REVA)—calls for researchers to map the vagus nerve using high-resolution imaging technology. The team’s goal will be to show precisely how vagus nerve tracts map to organs. Andrew Shoffstall from CWRU and Nikki Pelot from Duke will lead the team.
Another REVA recipient was the Feinstein Institutes for Medical Research, who received a $6.7 million award. The three-year research study is led by the Feinstein Institutes’ Stavros Zanos, and include collaborating scientists Theodoros Zanos and Larry Miller from the Feinstein Institutes, Zeinab Nassrallah from Zucker School of Medicine at Hofstra/Northwell, and Mary Barbe, from Temple University.
The third SPARC-V award was for a project called VESPA (VNS Endpoints from Standardized Parameters), which seeks to identify the physiological effects of altering vagus nerve activity to discover how best to stimulate nerve fibers for specific therapeutic effects. A team from the University of Minnesota received a $21 million award for its REVEAL project (Research Evaluating Vagal Excitation and Anatomical Links). REVEAL aims to study the anatomical connections and functional effects of vagus nerve stimulation. John Osborn, a professor of surgery at the University of Minnesota Medical School and director of the Minnesota Consortium for Autonomic Neuromodulation, will lead the team, along with colleagues that include Hubert Lim, who also serves as CSO of two bioelectronic medicine firms, SecondWave Systems and Neuromod Devices. Collaborating institutions include Mayo Clinic in Minnesota; Monash University in Australia; Stanford School of Medicine; Washington University in St. Louis; Medical University of South Carolina; Sheppard Pratt in Maryland; and Scuola Superiore Sant’Anna in Italy. Company partners include LivaNova, BRIGHT Research Partners, and BIOS Health.
In the SPARC-O project, the NIH selected two teams for awards. A team led by Kevin Kilgore from Case Western Reserve University and Cindy Chestek from the University of Michigan were selected for their COSMIIC project (Cleveland Open Source Modular Implant Innovators Community). That award was for $12.7 million over three years.
The second SPARC-O award went to a team from the USC Viterbi School of Engineering. The $11.7 million award will fund the new Center for Autonomic Nerve Recording and Stimulation Systems. CARSS is part of the Human Open Research Neural Engineering Technologies (HORNET) initiative [see BBR Sep22 p5]. The center will be co-led by Ellis Meng, Shelly and Ofer Nemirovsky Chair in Convergent Bioscience, Professor of Biomedical Engineering and Electrical and Computer Engineering, and Vice Dean for Technology Innovation and Entrepreneurship at USC, in collaboration with co-principal investigators Victor Pikov from Medipace and Raja Hitti from Med-Ally.
Meng said the implantable device system would enable the therapeutic stimulation of autonomic nerves—so doctors can manipulate the communication between a patient’s nerves, organs, and brain to treat a vast range of chronic conditions. The project would also enable sensing so that researchers and doctors can understand more about what is happening within the body during disease progression and in response to the applied neuromodulation therapy. The unique open-source nature of the project would allow the entire research community to access the technology and adapt the implantable system for many therapeutic and clinical research applications.
“The goal of the project is to enable different researchers to access the technology, so they can do whatever study they want clinically and advance different therapies for patients,” Meng said. “We’re putting this technology out there, and researchers will have the ability to program it the way they want — to customize the body interfaces they need. I’m excited by it. But it will also be uncharted territory for this whole field because this is not a concept that really exists.”
One of the sub-projects within the new USC center will focus on developing technology for electrochemical, mechanical, and temperature sensing within the peripheral nervous system, with the research to be led by assistant professor of biomedical engineering Maral Mousavi and assistant professor of aerospace and mechanical engineering Hangbo Zhao. Mousavi and Zhao will develop tools to look at two different sensing aspects.
“One aspect will be sensing of physical parameters such as the temperature and motion of organs.” Zhao said. “The temperature of internal organs is maintained with a narrow range and small temperature variations could perturb organ functions. We will also monitor the motion of certain organs, for example, the expansion and contraction of the bladder. We will be creating implantable sensors that can accurately measure these physical parameters to inform us organs’ functional states.”
Mousavi said the second area the project would examine would be electrochemical sensing, looking specifically at biomarkers and neurotransmitters, for example, measuring dopamine and serotonin levels within the environment of the peripheral nervous system. The project will also measure acetylcholine—a neurotransmitter that has implications for memory and learning and is particularly important in Alzheimer’s research. The team would also create sensors to measure pH.
“The pH of an environment is a good general indicator of what’s going on. If there’s anything off balance, it will often influence the local pH and cause pH changes,” Mousavi said. Mousavi said she was excited to be part of the center, which would bring together expertise from industry and research to create unique modular technologies.
Referring to the CWRU REVA award, Shoffstall said, “Over the next three years, we are hoping to make a big impact in the field of autonomic neuromodulation, which has tremendous potential to treat a number of chronic diseases. If we can better understand how the vagus nerve is organized, we can more rationally design devices and procedures to isolate and regulate its many pathways.”
“The multiple types of imaging data will provide unrivaled accuracy to our computational models to predict neuromodulation stimulation efficacy and side effects, so that we can use high performance computing approaches to develop new treatments and improve our understanding of existing therapies,” Pelot said.
Electrical stimulation of the vagus nerve has been used to treat epilepsy, rheumatoid arthritis, and heart failure, among many other conditions. But there is insufficient anatomical data available to map the roughly 100,000 fibers of the human vagus nerve to their target organs to develop therapies which are more effective and with fewer side effects.
The research team will conduct multimodal, multiscale imaging of 100 human vagus nerves from cadaveric donors of the CWRU Anatomical Gift Program, using multiple 3D-imaging technologies, such as MRI and microCT.
The team will also use a novel imaging tool developed at CWRU and UC Davis, known as 3D-MUSE, which uses what is known as ultraviolet surface excitation to rapidly collect microscopic images of the nerve while slicing through it at about one-30th the width of a hair. The technique will provide an unprecedented opportunity to directly track nerve fibers at high resolution across the long length of the vagus nerve, which spans from the brain to the intestines.
“By performing the most comprehensive imaging analysis of the human vagus nerve and its branches ever completed—and establishing a neuroanatomical repository for the vagus nerve—this work will seed and accelerate the development of novel neuromodulation therapies for autonomic regulation,” Shoffstall said.
Shoffstall is a 2013 CWRU Ph.D. alumnus who returned to the university as an assistant professor in July 2019. He is also co-founder of Neuronoff Inc., a clinical-stage start-up company commercializing minimally invasive neuromodulation devices that interface with peripheral nerves to treat chronic conditions.
The Feinstein REVA program will create and ultimately share with the scientific community a map of the anatomical connectivity of vagus nerve fibers from the brainstem, where the vagus nerve starts, all the way down to organs in the neck, chest and abdomen. It will also provide Feinstein researchers with visuals that capture detail and scope that have never been done before.
“The vagus nerve, with its thousands of sensory and motor fibers, continuously conveys large amounts of information between the brain and peripheral organs and, by doing so, it helps control and coordinate many basic physiological functions,” said Stavros Zanos, associate professor in the Institute of Bioelectronic Medicine at the Feinstein Institutes. “How sensory and motor fibers are arranged inside the vagus nerve and pathways to different organs are essentially unknown. With the support of the NIH we hope to characterize the nerve’s microscopic structure so that we better understand its function in health and disease, which will ultimately lead to new ways to treat disease with bioelectronic devices through vagus nerve stimulation.”
This multi-step research will dissect, image, and map the locations and trajectories of the bundles and nerve fibers throughout the length of the vagus nerve and its branches in 60 nerves collected from 30 human cadavers.
Next, detailed tomographic imaging will produce detailed, high-definition 3D images. Going microscopic, the team will create a microanatomy atlas of the nerve, staining individual fiber elements and imaging them through a powerful microscope.
All of that data will then be correlated and analyzed through artificial intelligence and computer vision algorithms to produce a multi-modal map of the vagus nerve and its fibers in unprecedented detail. This map will then be shared with researchers worldwide.
“The large amounts of data generated by those techniques, along with the need for highly detailed anatomical maps, down to the level of single nerve fibers, makes manual creation of such maps impossible,” said Theodoros Zanos, associate professor at Feinstein Institutes and the investigator leading the Data Analysis and Visualization core of the program. “To properly and efficiently analyze data, we will develop automated methods based on cutting-edge machine learning and computer vision algorithms tailored to this specific application.”
When functioning properly, the vagus nerve contributes to the maintenance of our body’s homeostasis. However, diseases like Crohn’s disease and rheumatoid arthritis, chronic heart diseases, diabetes and even some cancers are associated with inflammation and abnormal vagus nerve function.
Through the use of electrical stimulation of the vagus nerve, researchers try to “reset” vagus nerve activity and fight inflammation. The desired and undesired effects of VNS on body functions are determined by how bioelectronic devices stimulate nerve fibers. Knowledge of the detailed arrangement of vagal fibers will contribute to developing more effective and safe VNS devices to fight inflammation, restore homeostatic functions and help treat diseases.
The University of Minnesota’s REVEAL program incorporates a large-scale clinical study with up to 144 VNS patients along with three ancillary studies. Together, these studies will assess autonomic, cardiovascular, metabolic, immune, and gastrointestinal function in response to a broad range of VNS parameters. Researchers hope to generate one of the largest publicly available datasets on VNS function in humans.
“The vagus nerve conveys information from the brain to most organs in the body and vice versa,” said Osborn, a professor of surgery at the University of Minnesota Medical School and director of the Minnesota Consortium for Autonomic Neuromodulation. “Dysregulation of the vagus nerve underlies many pathological conditions, and we are just now discovering ways to modulate it to treat them.”
“VNS has a proven record treating refractory epilepsy and depression,” said Ziad Nahas, a professor at the University of Minnesota Medical School and a psychiatrist at M Physicians. “The exciting aspect of REVEAL is that it will set the stage for novel therapeutic applications of VNS to autonomic, immune, cardiovascular, and metabolic diseases.”
During the REVEAL studies, participants with implanted VNS devices will receive a wide range of tests to measure physiological, molecular, imaging, genetic, and neural responses to VNS, along with many other experimental and computational outcomes.
“A project involving so many types of measures and physiological systems requires a huge interdisciplinary team. We are fortunate to bring unique experts together involving more than 40 researchers from around the world, including 30 from the University of Minnesota,” said Lim, a biomedical engineering professor in the University of Minnesota College of Science and Engineering with a joint appointment in the Medical School.
