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A microchip that allows scientists to study the complexity of 3D cellular networks at unrivaled scale and precision has been added to 3Brain AG’s brain-on-chip portfolio. In collaboration with Swiss precision manufacturing experts, CSEM, 3Brain AG made the announcement today (August 22). The cell-electronic interface technology will also allow scientists to gain novel mechanistic insights into the inner workings of the most complex structure in the universe, the human brain. Developmental disorders 3Brain says understanding how organs form and how their cells behave is essential to finding the causes and treatment for developmental disorders, as well as understanding certain diseases. However, the company acknowledges studying most organs in live animals or humans is technically difficult, expensive, and invasive. It says new biotechnologies like human-derived stem cells offer to recapitulate the complexity and functionality of human tissues and allow for the generation of novel and exciting test systems including multicellular models, three-dimensional cultures and organ-on-a-chip. Model systems But the increasing complexity of these model systems brings new challenges for researchers and companies. The company says novel methods and devices are needed to meet accuracy, precision, sensitivity, specificity, and repeatability requirements for the evaluation of physiologically relevant endpoints in these systems. Electroactive tissues like the heart, brain or nervous system are built up from networks of cells that communicate with each other via rapid depolarization of their membrane potential mediated by the opening and closing of voltage-gated ion channels. Cell-electronic interfaces are devices that record or instigate dynamic changes in extracellular field potential close to the plasma membrane, corresponding to the flux of ions into or out of cells, and connect these bio-signals to computers in real-time. Label-free functional imaging 3Brain says its technology can connect to thousands of cells at the same time and process bio-signals at 20,000 frames per second in a spatially resolved pixel array, not unlike an ultra-high-speed HD camera, thereby effectively expanding the concept of label-free functional imaging beyond optical approaches. Currently, the company states, the cell-electronic interfaces like patch clamp and, more recently, high-density multi-electrode arrays are limited to 2D and suffer many limitations when it comes to measuring 3D model systems like brain organoids or tissue preparation because they cannot reach the necessary proximity to physiologically relevant cells. To tackle these challenges, 3Brain AG paired up with CSEM, a Swiss research and technology organization with expertise in precision manufacturing, to develop a 3D cell-electronic interface based on complementary metal-oxide semiconductor (CMOS) technology. Gold-electrodes The 3D CMOS microchip (named Accura-3D) is equipped with sensory gold-electrodes mounted on thousands of biopolymer-covered microneedles. Accura-3D enables the investigation of 3D cellular networks at unprecedented depths and resolution, which will open up unrivaled access to the complexities of biological systems. Mauro Gandolfo, CEO and co-founder of 3Brain AG, said: “What we really want is to empower researchers to ask new and daring biological questions that have so far been impossible to investigate. “Our cell-electronic interfaces expand the concept of optics-free functional imaging, all without the need for biological markers, fluorescent proteins or genetic manipulation of cellular networks. With Accura-3D, we created a first-in-class solution that can directly access the complex cytoarchitecture of 3D tissues and brain organoids. Biggest challenge “The biggest challenges are taking the vast amounts of data coming from cells and processing them without losing critical information in real-time. Accura-3D does a lot of the heavy lifting with on-chip processing, signal amplification and noise filtering, which basically makes the chip itself intelligent. “This integrated intelligence is a remarkable distinction from other instruments in the preclinical space and helps researchers to record or even actively stimulate bio signals at unprecedented depths. There is just no comparable solution out there.” 3Brain AG has been working on advanced microchip technology applied to life science for more than 15 years. Alessandro Maccione, CSO and co-founder of 3Brain AG, said: “We are very attentive to the opportunities offered by advanced cell models such as spheroids and organoids. We already have results showing that Accura-3D is vastly superior in measuring physiologically relevant cells and bio signals. Brain organoids “We started focusing on brain organoids because of their relevance to model devastating developmental and neurodegenerative diseases of the brain that pose a high burden for our society, for example Alzheimer's and epilepsy. Scientifically, Accura-3D is super exciting, because it will allow us to peek deeper into the inner workings of tissues and organoids and ask questions previously out of reach. Why, where and how does spontaneous activity emerge in brain organoids and how do coordinated brain waves start? “Does neuronal activity shape cytoarchitecture or is it the other way round? How does connectivity evolve over time? Are there differences in neuronal development in organoids derived from healthy versus at-risk patients? "The possibilities are almost endless, Accura-3D is opening the door into the galaxy of our own minds, and this is what I think many scientists will want to explore with us. For many, a three-dimensional cell-electronic interface that can collect cellular information directly from the inside of tissues and organoids might sound like science fiction. We made it a science fact.” For the development of Accura-3D, 3Brain has partnered with CSEM to push the boundaries of what is possible with 3D microfabrication. Microfabrication Michele Palmieri, VP Micro and Nanosystems at CSEM, said: “Together with 3Brain AG, our team has been developing cutting-edge microfabrication processes to create a dense, vertically developed microneedle array on top of preprocessed advanced CMOS wafer. “Such tall, vertically bound array goes above and beyond the state-of-the-art for microelectrode arrays, with an extreme electrode vertical/horizontal aspect ratio in excess of 8. To build it, it takes more than 80 process units, including photolithography and etch, multi-metal stack deposition, noble metal electroplating, structural polymeric material, planarization, etc. - to put it simply, it’s a microtechnology masterpiece – a technologist’s and neurobiologist’s ultimate dream.”

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