Commentary: Therapeutic Seizure Monitoring: A Closed-Loop Device for Direct Delivery of Antiseizure Therapeutics

Abstract

Multifunctional hydrogel electronics for closed-loop antiepileptic treatment

Qu J., Xie K., Chen S., He X., Wang Y., Chamberlin M., Zhao X., Zhu G., Xu C., Shi P. Sci Adv. 2024;10,(47):eadq9207.

Closed-loop strategies offer advanced therapeutic potential through intelligent disease management. Here, we develop a hydrogel-based, single-component, organic electronic device for closed-loop neurotherapy. Fabricated out of conductive hydrogels, the device consists of a flexible array of microneedle electrodes, each of which can be individually addressed to perform electrical recording and control chemical release with sophisticated spatiotemporal control, thus pioneering a smart antiseizure therapeutic system by combining electrical and pharmacological interventions. The recorded neural signal acts as the trigger for a voltage-driven drug release in detected pathological conditions predicted by real-time electrophysiology analysis. When implanted into epileptic animals, the device enables autonomous antiseizure management, where the dosing of antiepileptic drug is controlled in a time-sensitive, region-selective, and dose-adaptive manner, allowing the inhibition of seizure outbursts through the delivery of just-necessary drug dosages. The side effects are minimized with dosages three orders of magnitude lower than the usage in approaches simulating existing clinical treatments.

Commentary

“Closed-loop” (or responsive) drug delivery devices autonomously regulate drug release upon detection of abnormal biological signals. Beyond the reduction of pill or injection load, the analysis of medical data guides personalized treatment and can be harnessed for predicting potential future events. ¹ The coronavirus disease 2019 (COVID-19) pandemic has demonstrated another benefit of responsive drug delivery: it is easier to start the system remotely by telemedicine. ²

“Closed-loop” devices are best known for their use in patients with diabetes, a disease characterized by a clear and specific biomarker (glucose). They are also applied for the management of other conditions, eg, maintenance of general anesthesia.^1,3 Epilepsy is more challenging because it has multiple phenotypes with no clearly defined cut-off standards for severity. The currently approved “closed-loop” epilepsy therapies monitor EEG at the suspected epileptogenic zones or heart rate and respond to abnormal activity by triggering neurostimulation. Responsive delivery systems for antiseizure medications (ASMs), eg, with programmable infusion pumps, ⁴ have been tested in animals but have not yet made it to the market.

The featured article presents a novel responsive drug delivery device developed by Qu et al ⁵ to improve biocompatibility and cerebral drug distribution. The core chip was designed based on the Utah arrays of multiple high-density metal electrodes approved by the FDA as investigational devices. ⁶ The Utah arrays have a planar configuration (visually reminiscent of miniaturized cat hair brushes). In contrast, the device developed by Qu et al ⁷ is a flexible thin film printed with integral pyramidal electrodes. It is made of conductive hydrogels, that is—polymer-based materials similar to biological tissues. Consequently, the device is built as a single component, unlike modular devices that integrate different parts built of different materials such as microelectrodes and microfluidic pumps. The film flexibility allows its placement on curved brain structures and each microneedle electrode can record neuronal signals and respond with drug release. The dimensions of the film are in the millimetric range, with a thickness of 1 mm. The murine version of the entire device is slightly larger than 1 cm³. Real-time seizure prediction by electrophysiological analysis allows on-demand intervention. Down the road, the system design and activity are planned to be AI-guided.

The device was first assessed ex vivo using agarose gel phantoms and demonstrated voltage-driven release of GABA, valproate, and fluorescein. Despite a slight leakage, the cumulative escape of GABA was estimated to be insufficient to interfere with spontaneous neural activity. The system was then tested in mice with 4-aminopyridine (4-ap)–induced seizures. A threshold was defined for seizure-like activity, and the device demonstrated GABA-mediated seizure suppression, with ∼80% reduction in the number of events and reduced duration of high-power β oscillations. These effects were not observed in control animals carrying “blank” electrodes without GABA. The device suppressed seizures more effectively than preemptive or responsive intraperitoneal valproate or direct CNS valproate infusion. In addition, the dose was orders of magnitude lower (50 ng total as opposed to 100 to 2500 μg via the other routes of administration). In humans, this could translate to several micrograms versus oral daily valproate doses of hundreds of milligrams or grams.

Valproate is a good choice for this technology because the advantages of targeted nanodosing for reducing toxicity are straightforward. Potential beneficiaries who first come to mind are children (2 years old or younger) and women of childbearing age, given that both valproate hepatotoxicity and teratogenicity, respectively, are exposure-dependent.^8,9 This concept also applies to systemic adverse reactions of other ASMs and possibly to some untoward ASM effects, such as ataxia, that may originate in remote brain regions. Moreover, the therapeutic assortment can be expanded to polar molecules that poorly distribute across the BBB. Such compounds might even be advantageous because they would be removed more slowly from the brain via the cerebral vasculature.

The system is unique because each microelectrode serves as a distinct drug delivery system, generating multiple foci of high drug levels and concentration gradients. This might be a double-edged sword, though. In mice, the amount of released drug from single electrodes near the seizure focus was sufficient for suppressing abnormal neuronal activity, however, sustained exposure to some ASMs, eg, benzodiazepines, can lead to receptor desensitization. In addition, larger brains would require multiple electrodes and finely tuned drug dosing to bridge the between-electrode distances. The authors also discussed the development of larger devices for surveilling neural signals, and for on-time drug delivery during seizure occurrences. This concept could be extended to target predicted brain areas of seizure spread. As to depth, the electrodes developed for this study were ∼0.67 mm long, implying that they penetrate half the depth of a typical murine cortex. In humans, the array may consist of longer electrodes or combine electrodes of distinct lengths to reach deeper cortical structures and promptly deliver therapeutic compounds. Accordingly, the spatial organization may be patient- and region-specific. These complexities were not captured by the murine 4-ap model.

The device contains a microfluidic system for external drug refill for prolonged use. In line with this goal, the results of water adsorption, decay, and biodegradation tests were encouraging. Over the four-week study period, water uptake into the electrodes and hydrogel degradation were minimal and the device did not induce gliosis or other inflammatory responses. However, the biocompatibility and working life of the device or its advanced versions should be assessed over longer periods.

By definition, responsive drug-releasing devices offer symptomatic treatment, but there is more than meets the AI: For example, improvement in the outcomes of responsive neurostimulation can steadily develop over years, suggesting mechanisms of action more complex than “simple” seizure suppression. ¹⁰ Will this phenomenon be shared with responsive drug delivery? Another question is whether drug-resistant seizures will respond to local drug delivery. This might be achievable if the high local ASM concentrations overcome resistance due to poor ASM distribution across the blood-brain barrier. The next steps in the development of “closed-loop” antiseizure drug delivery systems can yield fascinating new data that will shed new light on both epilepsy and epileptogenesis.