Perspectives: Hybrid Cell Silicon Neural Implants

Hybrid Cell Silicon Neural Implants: A New Avenue for Epilepsy Therapies

by Jenna L. Rickus, PhD

Approximately thirty percent of the 2.7 million patients with epilepsy in the United States have seizures that are resistant to pharmacological treatment. Many other patients suffer with intolerable drug side effects. Resective surgery is an alternative and effective treatment, but not all patients are potential candidates. A large number of patients have uncontrolled seizures and may suffer physical injury, enter status epilepticus, develop depression, suffer cognitive decline, or fall victim to "sudden unexplained death in epilepsy" (SUDEP). New alternatives to drug therapies are needed.

While the specific mechanisms of drug-resistance remain unclear, poor targeting of orally ingested drugs to specific brain regions, reduced drug concentration at target sites by multi-drug transporters, and adaptation to continuous drug exposure are likely culprits (Schmidt et al. 2005). Poor or improper spatio-temporal targeting is also a significant cause of unwanted side effects. Spatial and temporal targeting of drug action to specific brain regions immediately prior to and during seizure onset would represent a significant advancement in our ability to stop seizures without side effects.

Engineering Closed Loop Therapies

The 2000 National Institutes of Health Curing Epilepsy Conference resulted in a specific research benchmark to "successfully use a biosensor device (comprised of a biodetector, mini-pump, microstimulator, or other detector systems) that reliably anticipates or identifies seizures, and applies targeted treatment to abort seizures in at least one form of epilepsy."

The current engineering response to this challenge is the application of traditional devices with electrical, mechanical and chemical components.

Closed-loop electrical devices that stimulate endogenous brain tissue to inhibit or stop a seizure show promise and are currently in clinical trials. Questions of efficacy and mechanism remain unanswered and alternatives need to be pursued simultaneously.

• Implanted drug pumps: These provide temporal and spatial delivery, but the problem of a chronic drug reservoir poses many challenges. Implanted devices must function for many years or decades. Ultimately an open path between the brain and the outside world is required for periodic refilling of the drug due to limitations in storage capacity.
• The biological approach: The transplantation of biomolecule-releasing cells provides spatial delivery of drug, but cannot yet provide closed-loop seizure-triggered control of release. In addition, transplanted cells in animal models have generally showed an ability to reduce seizure intensity, threshold or duration, but not inhibit them completely.

Hybrid Cell Silicon Devices as an Alternative

A few years ago my colleague, Pedro Irazoqui, and I proposed the idea of creating a hybrid cell silicon device to utilize the advantages of microfabricated electrical devices for closed-loop seizure prediction and stimulation with exogenous cells that provide a large and replenishing source of drug or neurotransmitter. Citizens United for Research for Epilepsy (CURE) funded the proof-of-concept work conducted in our labs at Purdue University.

• The first prototype: During that first year we built and tested the first prototype, which is wireless (transmitting up to 64 electrodes simultaneously), low power (< 10 mW), and fully reprogrammable by the physician at any time. The power management system and inductive powering circuitry would enable approximately 27 years of function without battery changes given the patient recharges each night during sleep.
• In vitro testing: This demonstrated that the release of the inhibitory neurotransmitter GABA could be controlled and calibrated by the device stimulation parameters. We are currently moving into in vivo testing in animal models of epilepsy.

Broader Impact of Findings: A test bed

A beneficial outcome of the hybrid cell silicon device research has been results that inform mechanisms relevant to other therapies. For example, we developed an in vitro system to test the integration of neuronal cells with the microfabricated device and to calibrate controlled neurotransmitter release using the hybrid device. The resulting calibration curves show differences in calibration characteristics including optimal stimulation frequencies for inhibitory and excitatory cells. Such findings and experimental paradigms, therefore, may provide a test bed for optimizing stimulation parameters for electrical inhibition of seizure by methods such as responsive neural stimulation (RNS).

The Cell Device Interface

Hybrid cell silicon devices require a seamless integration of living neural cells with microfabricated devices. Work on the device has also resulted in fundamental understanding of how to increase survival and influence the phenotype of neurons when in contact with inorganic engineered devices. This basic problem has broad significance not only for hybrid devices but also for better engineering the brain machine interface in general. Neuronal death and gliosis near implanted electrodes remain challenges for chronic recordings in neural implants.

It is our belief that understanding new ways to create seamless and natural integration of inorganic materials with living neural cells and tissues will be essential to any of the device based therapies for epilepsy.

Jenna L. Rickus, PhD, is an Assistant Professor of Biological Engineering in the department of Agricultural and Biological Engineering and the Weldon School of Biomedical Engineering, and is co-leader of the Physiological Sensing Facility in the Bindley Bioscience Center. A graduate from Purdue University, she completed doctoral training in neuroscience at UCLA and was the first graduate of the NeuroEngineering program. At UCLA she co-trained in cellular and molecular neurobiology and in materials science research. During her graduate studies Dr. Rickus developed novel optical materials for measuring neurotransmitters and for interfacing with neurons.

Now at Purdue, Dr. Rickus continues to develop novel biologically functional materials that mimic and modulate cell physiology. These materials have broad application in neural implants, biosensors, and artificial extracellular niches. Dr. Rickus brings this work and a highly interdisciplinary background to bear on the problem of epilepsy. With her colleague, Dr. Pedro Irazoqui, she is pioneering hybrid cell silicon devices as a novel type of neural prosthesis. These devices integrate living cells as an engineered component, enabling closed loop control of neurotransmitter delivery to the brain.

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