Biohybrid Synapses for Interactive Neuronal Networks

Project Information

BRAIN-ACT

Grant agreement ID: 949478

DOI

10.3030/949478

EC signature date 26 November 2020

Start date 1 January 2022

End date 31 December 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 859 062,00

EU contribution

€ 1 859 062,00

Coordinated by

FORSCHUNGSZENTRUM JULICH GMBH
Germany

Periodic Reporting for period 2 - BRAIN-ACT (Biohybrid Synapses for Interactive Neuronal Networks)

Reporting period: 2023-07-01 to 2024-12-31

Summary of the context and overall objectives of the project

Neurodegenerative disorders such as Parkinson’s and Alzheimer’s affect over 10 million people globally, leading to progressive and irreversible loss of functional capabilities in daily life. These impairments stem primarily from disrupted communication within the brain, caused by the degeneration of neurons and the subsequent breakdown of synaptic connectivity within neural circuits.
Traditionally, in vitro bioelectronic platforms have been used to passively monitor and stimulate neuronal activity, aiming to characterize the electrical signatures and connectivity of neuronal networks. However, these systems offer limited control over neuronal behavior and cannot interact dynamically and bidirectionally with biological tissues.
Understanding and ultimately repairing the damaged communication pathways in the brain is crucial for developing effective therapeutic strategies for neurodegenerative diseases. The ability to interface seamlessly with neural networks holds transformative potential for next-generation brain-machine interfaces, neuroprosthetics, and biohybrid systems designed to restore or augment cognitive and motor functions.
BRAIN-ACT aims to develop a novel class of biohybrid devices by coupling biological neuronal networks with organic artificial neurons. The project proposes, for the first time, the electrical and mechanical interaction between living neurons and an artificial counterpart, marking a significant step beyond existing passive bioelectronic systems.
The overarching objectives of the project include:
• Understanding neuronal vesicle dynamics. Neurons communicate through the release and uptake of synaptic vesicles, which carry neurotransmitters essential for signal transmission. A critical aspect of the project is achieving the extraction, reassembly, and functionalization of vesicles on engineered surfaces - an ambitious step toward controlling synaptic transmission mechanisms.
• Development of adaptive biomaterials. The project addresses the challenge of engineering organic materials that can seamlessly integrate into organic neuromorphic devices. This involves designing and fabricating materials that mimic the biophysical and electrochemical properties of neurons, enabling long-term and stable integration with biological tissues.
• Integration of new materials in neuromorphic devices. The challenge is to create chip-based systems with nano- and microfabrication techniques to enable real-time, synapse-like interactions between artificial and biological elements.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

1. Development of Neurotransmitter-Mediated Organic Synapses
A major achievement involves the creation of organic electrochemical transistors (OECTs) capable of mimicking synaptic plasticity through neurotransmitter-mediated modulation. Specifically, dopamine and hydrogen peroxide were used to dynamically adjust the doping level of PEDOT:PSS, enabling reversible conductance changes akin to learning and memory. A closed-loop control system based on PID algorithms was implemented to precisely modulate the conductance states in real time, emulating Pavlovian associative conditioning. (10.1039/d3mh02202a)
2. Engineering a Glutamate-Based Artificial Synapse
The device successfully demonstrated glutamate sensitivity with conductance modulation corresponding to neurotransmitter concentration. These devices showed promising neuromorphic behavior, with evidence of both short- and long-term retention states (https://doi.org/10.1002/adma.202409614).
3. Azobenzene-based optoelectronic transistors for neurohybrid building blocks
To expand on this light-responsiveness, a novel class of organic photoelectrochemical transistors (OPECTs) was developed by crosslinking different azobenzene-based molecules to a PEDOT:PSS backbone. (https://doi.org/10.1038/s41467-023-41083-2).
5. 3D Patterning of PEDOT:PSS. Three-dimensional topography influenced neurite outgrowth directionality, while the elastic nature of the micropillars facilitated anchoring and wrapping of elongating neurites, thereby increasing the number of cell–electrode contact points—an essential feature for effective neural interfacing (https://doi.org/10.1002/admi.202200709)
8. Light-Responsive Polymers for Multimodal Cellular Stimulation
At the core of the platform is the light-sensitive polymer poly(disperse red 1 methacrylate) (pDR1m), which exhibits controllable deformation at micro- and nano-scales when exposed to light. (https://doi.org/10.1002/adhm.202303812).
9. Lipid Bilayers and Ion Channel Functionality
The convergence of biological membranes with organic electronics was further demonstrated through the formation of supported lipid bilayers (SLBs) composed of both artificial and native neuronal blebs on PEDOT:PSS electrodes and OECTs. (https://doi.org/10.1002/advs.202305860).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The BRAIN-ACT project has introduced several key breakthroughs in the development of biohybrid neural interfaces, advancing the frontier of interaction between biological neurons and neuromorphic computing devices.
One of the most notable achievements is the development of reshapable 3D neuromorphic devices that emulate dendritic synapses in both form and function. These devices are constructed using dynamic azopolymer materials, which enable them to undergo controlled morphological changes in response to optical stimulation. This dynamic reshaping ability mirrors aspects of synaptic plasticity observed in biological systems, marking a significant advancement in neuromorphic engineering. The successful integration of a conductive PEDOT:PSS layer enhances both the electrical responsiveness and biocompatibility of the devices, ensuring stable and functional coupling with biological neurons.
Another major innovation is the creation of azobenzene-based organic electrochemical neuromorphic devices. These devices exhibit synapse-like behavior through conductance modulation, allowing them to perform memory-like functions. The use of soft, organic materials, unlike traditional rigid, silicon-based systems, offers enhanced biocompatibility, flexibility, and adaptability. This breakthrough establishes a new paradigm for organic neuromorphic systems that can integrate more naturally with living tissues.
Together, these advances position BRAIN-ACT at the forefront of efforts to create a new generation of brain-inspired bioelectronic systems. The project has demonstrated the feasibility of bidirectional communication between living neurons and artificial neuromorphic components, establishing foundational technologies for future neuroprosthetic applications.
Expected results by the end of the project include:
• Demonstration of stable, long-term interaction between reshaping neuromorphic devices and in vitro neuronal networks.
• Further optimization of the mechanical and electrical properties of the organic interfaces to enhance their synapse-mimicking capabilities.
• Deeper insights into vesicle dynamics and their functional reconstitution on engineered surfaces.
• Consolidation of an interdisciplinary framework combining neurobiology, polymer science, and organic electronics to guide future developments in adaptive, neuron-like devices.

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