Closing The Loop For Bioelectronic Medicine

By Gaurav Sharma, Battelle, and Doug Weber, Battelle and University of Pittsburgh

Bioelectronic medicine has shown tremendous promise for the treatment of a broad range of conditions, from heart arrhythmia to depression. To fully realize this potential, medical device developers will need to find ways to move beyond "set and forget" biostimulation devices to closed-loop systems that can provide more responsive and personalized treatments. 

Drug therapies remain the standard of care for a broad range of medical conditions, including high blood pressure, chronic pain, autoimmune diseases, and psychiatric disorders. However, in recent years, bioelectronic medicine has risen as a viable alternative for the treatment of many disorders.

Bioelectronic medicine uses devices that connect to the brain or nervous system to monitor, stimulate, or modulate the electronic signals that enable communication between the brain and all body systems. By tapping directly into the body's own electrical communication system, bioelectronic devices can evoke specific responses, such as modulating blood pressure or heart rhythm, reducing inflammation in body systems, or stimulating muscles for sensory-motor rehabilitation.

Biostimulation is especially promising for management of neurological disorders and other chronic conditions that can be regulated through stimulation of the central or peripheral nervous system. Biostimulation devices implanted in the brain (known as deep brain stimulation, or DBS) already are in use for treatment of a number of neurological conditions, including essential tremor, epilepsy, Parkinson's disease, and dystonia. DBS has also shown promise in treating psychiatric disorders including depression, obsessive-compulsive disorder, and Tourette's syndrome, as well as some types of chronic pain.

The peripheral nervous system also can be targeted to treat many diseases. Promising applications include blood pressure management, treatment of inflammatory diseases such as rheumatoid arthritis or Crohn's disease, and management of chronic pain, especially low back pain or peripheral neuropathy. As more is learned about how the nervous system regulates body systems, the potential applications for bioelectronic treatments will continue to grow.

Biostimulation could provide significant advantages for treatment of many chronic conditions. Most drug therapies make their way throughout the body, which can lead to unwanted side effects. In addition, some drugs used to treat chronic conditions, especially those used to treat pain, can be addictive. Bioelectronic therapies, in contrast, can be targeted to specific parts of the nervous system, resulting in fewer side effects and less addictive potential.

Preconfigured vs. Closed-Loop Biostimulation Systems

Most bioelectronic devices used today — for example, pacemaker devices that control heart rhythm — are configured in the doctor's office with settings that are not changed between visits. These devices can respond to real-time changes only within the range allowed by these settings. This is similar to the way drug therapies are prescribed: the patient follows the prescribed regimen for a period of time and then goes back to the doctor, who will evaluate their response to the treatment and make adjustments to the prescription, if necessary.

A closed-loop system, in contrast, is able to continuously monitor specific body signals and make adjustments in real time as the body responds to external conditions, internal states, or to the device itself. A number of artificial pancreases currently under development for Type 1 diabetes provide examples of what this looks like in the pharmaceutical world. These devices are intended to monitor blood sugar levels and deliver the exact dose of insulin the patient needs. This allows such systems to adjust the delivery of insulin in real time to the patient's activity levels and eating patterns.

Closed-loop systems allow for tighter control of body systems that can be modulated by drug or bioelectronic therapies. Ultimately, this translates into better control of symptoms, with fewer side effects.

The development of closed-loop bioelectronic technologies would open up many more opportunities for novel treatments, and would make existing applications much more effective. For example:

• A closed loop system for depression could deliver targeted stimulation to areas of the brain known to alleviate depression, monitor specific neurotransmitter levels to determine how well the patient is responding to treatment, and adjust its stimulation levels in response to changes over time.
• A device that stimulates the vagus nerve to control inflammatory response could modulate stimulation in response to changing levels of cytokines that indicate inflammation.
• A biostimulation device for control of blood pressure could modulate its stimulation levels as blood pressure changes in response to stress, activity, or other stimuli.  

Elements Of A Closed-Loop Biostimulation System

A closed-loop biostimulation system requires several elements:

• Identification of a treatment pathway (i.e., the specific body system we want to stimulate) that can be used to evoke the desired response
• Identification of a specific biomarker, or set of biomarkers, that can be used to monitor the condition the device is meant to treat, as well as the patient's response to treatment. These can be chemical (e.g., neurotransmitters or blood chemistry), electrical (neuron or nerve impulses), or basic vital signs (e.g. blood pressure, heart rate or temperature).
• Sensors or diagnostic instruments that can detect and measure the biomarker(s)
• An algorithm that can use the biomarker information to make decisions about the level and type of stimulation the device should deliver
• A stimulation device that can be connected to the body to provide stimulation

Ultimately, these devices will need to be delivered in an integrated, ready-to-use package that is easy for both prescribers and patients to use and understand, and requires minimal adjustment on the part of the doctor or the patient.

Breaking The Barriers To Closed-Loop Bioelectronic Medicine

Currently, only a few clinical neuromodulation devices operate under closed-loop control, including a spinal cord stimulator for chronic pain relief and a neuromodulation device for epilepsy treatment. These devices provide two different examples of how sensors can be used to “close the loop”:

• Saluda Medical’s Evoke spinal cord stimulator system measures neural activity evoked by spinal cord stimulation, enabling the device to make automatic and real-time adjustments of stimulation parameters to maintain consistent responses.
• The Neuropace RNS system uses bioelectric sensors in the brain to detect epileptic seizures, delivering neurostimulation therapy using stimulation parameters that are set by a physician.

To get more closed-loop devices into the market, more research is needed along several fronts. Some of the most exciting opportunities for advancement include:

• Identification of measurable biomarkers that provide clear and precise diagnostic information for a broader range of conditions, along with the sensors or assays needed to monitor them in a home environment
• Development of non- or minimally-invasive devices that can detect and stimulate nervous system activity and target individual nerves
• Development of new biocompatible materials for implantable devices that minimize immune responses, which can reduce device performance over time
• Better algorithms, based on machine learning techniques, to process large volumes of neurological or biochemical data, extract relevant features, decode, and make predictions to refine device functioning over time in response to data.

Putting It All Together: A More Personalized Approach To Medicine

Currently, bioelectronic devices are often recommended only after patients have failed to respond to pharmacotherapies, which remain the standard of care for many medical conditions. As the industry evolves and the usability and efficacy of closed-loop bioelectronic devices improves, it is possible that some of these devices may become front-line treatment options for many conditions.

To get there, the devices will need to be smarter, less invasive, and easier to use. Ideally, they will work seamlessly and invisibly with body systems, so patients don't have to think about the device at all on a day-to-day basis. Developers also need to address cybersecurity risks for connected devices.

While much research remains to be done, the potential benefits for patients living with neurological disorders and other chronic conditions are tremendous. These devices will enable treatments that are more targeted, responsive, and personalized. "Closing the loop" will allow the industry to fully realize the potential of bioelectronic medicine.

About The Authors

Dr. Gaurav Sharma is the Lead Investigator and Senior Research Scientist on the Battelle Medical Devices and Neuromodulation team. His work — which applies advanced engineering to overcome problems in the human body and brain — has helped a paralyzed patient regain control of his hand and enabled delivery of drugs across the blood-brain barrier.

Dr. Doug Weber is Director of Neurotechnology Research and Development at Battelle. He has more than 20 years of experience on the front lines of neurotechnology innovation, with a career that has resulted in eight patents (and counting) and a biotechnology startup. At Battelle, Doug is focusing on further development of Battelle NeuroLife, a neural bridging technology that allowed a paralyzed man to regain conscious, dexterous control of his hand and fingers.