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Integrated Implant Technology for Multi-modal Brain Interfaces

Periodic Reporting for period 2 - IntegraBrain (Integrated Implant Technology for Multi-modal Brain Interfaces)

Reporting period: 2019-10-01 to 2021-03-31

Neuroprosthetic technologies aim to restore functions of the nervous system affected by injury or disease. They are often implantable electronic devices that establish communication between brain and machine. Future implants are likely to be multi-modal, i.e. additionally enabled in the biochemical, optical, thermal and mechanical domains and seamlessly integrated in the soft tissues of the nervous system. Technologically this is challenging to achieve. For example, neural electrode arrays available today are rarely customisable in a way that allows the clinician to adapt them to the specific anatomy of a patient, the mechanical environment or the multiple modalities of information flow in neural tissue. This may result in sub-optimal biointegration and limit the effectiveness and possibilities for personalised therapies.

Bioelectronic implants can be applied in soft tissue organs, especially in the nervous system, where injury or degeneration can result in chronic disability. They can become an alternative strategy for treating epilepsy, Parkinson’s disease, stroke, acute and chronic neurotrauma, where presently only systemic pharmacological or surgical approaches exist.
A key objective of the action is the development of additive manufacture (3D printing) methods for rapid prototyping of implants that are mechanically soft, multi-modal and customised. We will validate the capacities of the technology in vivo. In the central nervous system, we will demonstrate multi-modal neuromodulation in a pre-clinical model of epilepsy. In the periphery, we will demonstrate soft implants tailored to specific niches of the neuromuscular system. Overall, with the IntegraBrain project, we hope to catalyse pre-clinical development of implantable human-machine interfaces.
Experimental work is progressing according to the Gantt chart for the action.
The objective of WP1 was to assemble a palette of printable materials, each supporting the function of a sensor or actuator. We identified a number of silicones with appropriate rheological, optical and dielectric properties. The printing parameters were optimised to achieve features on the sub-millimetre scale. We also developed composite based inks for direct writing of conductive traces and electrodes. Beyond the objectives of the action, we developed a hydrogel based conductive ink. This material is even softer than the silicone based composites and can be functionalised with bioactive molecules to promote active adhesion of cells. This approach is interesting because it may allow us to go beyond soft inorganics and blur the boundaries between tissue and implant [Small 15, 1901406 (2019)]. As part of work for WP1 we also evaluated the biocompatibility of the various inks [npj Flexible Electronics 4, 16 (2020)].

The objective of WP2 was to fabricate sensors and actuators by direct ink writing. We printed stretchable electrodes, optical waveguides and microfluidics and integrated them in arrays. We then demonstrated multimodal bio-interfacing of stem-cell derived cardiomyocytes. This was done to validate the functionality of the integrated arrays before proceeding with implantable devices. As model biological system, we used optogentically sensitised induced pluripotent stem cells (iPSs). Using entirely printed devices we paced the contraction of the cardiomyocytes using light and/or via drug delivery (isoproterenol) while simultaneously measuring field potentials [npj Flexible Electronics 4, 16 (2020)]. Beyond the scope of WP2 we tested the functionality of printed soft implants in vivo (collaboration with Prof Pavel Musienko, St Petersburg State University and Pavlov Institute of Physiology). Implants were restricted to the electrical modality however we demonstrated that implant design can be easily tailored for a number of nodes of the nervous system (muscle, peripheral nerve, spinal cord, brain surface) also in several animal models (fish, rat, cat). Using printed implants we were able to either record neural activity or stimulate the above mentioned system nodes, also in long-term implanted animals [Nature Biomedical Engineering 4, 1010-1022 (2020)]. The study serves as an important validation before commencing work with an epilepsy model (WP4).

The objective of WP3 is to design a compact Auxiliary Driver Unit (ADU). The ADU will use microcontrollers to deploy the various neuromodulation types (thermal, optical, drug delivery) of the implant. Work on this WP is ongoing although restrictions during the pandemic in 2020 have caused some delay. We performed a modelling study, which established that focal brain cooling can be delivered through a miniature thermoelectric cooler element (2x2 mm2) embedded on the implant. This will simplify the design and control of the system, which initially was planned to incorporate a microfluidic loop. We have designed and are currently implementing a closed loop controller that will ensure predictable and rapid cooling via the thermoelectric element (as well as the remaining sensing and actuating features). We initiated an important collaboration with Dr Jason Berwick within the host institution who has an established rat epilepsy model for studying the effects of focal brain cooling. We obtained a wealth of seizure recordings, which will help us train our ADU microcontroller for seizure recognition. Additionally, this collaboration will save time for the preparation of the animal licensing documentation, as our activity will be added to an existing license.

Overall and despite some COVID related delays, progress in the action is in on track. Our expectation is to begin work on WP4 within the next 12-18 months.
A key outcome from WP1 and WP2 was a pioneering demonstration of rapid prototyping of bioelectronic probes using soft functional materials. The hybrid printing technology (NeuroPrint) enables the production of neuromuscular implants for monitoring and enabling functional states of the nervous system. Due to adapted geometries and mechanical softness, the NeuroPrint interfaces can be applied to various nodes of the nervous system, model species and tasks. Using a variety of electrode configurations, we stimulated and recorded biopotentials from the brain, spinal cord and peripheral nerve, as well as striated and smooth muscles. Typically, hardware for these diverse tasks takes months and years to develop and requires considerable investment and cleanroom facilities. The NeuroPrint technology has allowed us to explore multi-modal biointerfacing in vitro that goes beyond the electrical modality to incorporate light and drug delivery as complementary methods. Although devices with similar functionality can be assembled using other approaches, for example by manually gluing optical fibres and cannulas to commercially available electrode arrays, such approach would be low throughput and may result in high batch variability.

For the second part of the action (WP3 and WP4), we will focus on delivering an integrated and autonomous (closed-loop) system capable of multi-modal neuromodulation in vivo. This will be tested in a pre-clinical rodent model of epilepsy. We will explore any synergistic effects arising from the combination of focal thermal cooling, drug delivery and rapid seizure detection. These findings may be useful beyond the planned demonstration in the epilepsy model and influence pre-clinical research in other disorders of the nervous system.
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