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The suitability of flexible graphene depth neuralprobes for in vivo electrophysiology research

  • A study published in “Nature Nanotechnology” shows that flexible brain probes made of graphene micro-transistors can be used to record pathological brain signals associated with epilepsy with excellent fidelity and high spatial resolution.
  • This research was led by the Catalan Institute of Nanoscience and Nanotechnology (ICN2), the Institute of Microelectronics of Barcelona (IMB-CNM-CSIC) and the University College London Queen Square Institute of Neurology (UK).

Barcelona, Wednesday 22 December 2021. The ability to record and map the full range of brain signals using electrophysiological probes will greatly advance our understanding of brain diseases and aid the clinical management of patients with diverse neurological disorders. However, current technologies are limited in their ability to accurately obtain with high spatial fidelity ultraslow brain signals. In a paper published today in Nature Nanotechnology, an international team of researchers report a flexible neural probe made of graphene-based field-effect transistors capable of recording the full spectrum of brain signals, including infraslow; and demonstrate the ability of these devices to detect with high fidelity electrographic signatures of the epileptic brain.

Epilepsy is the most common serious brain disorder worldwide, with up to 30% of people unable to control their seizures using traditional anti-epileptic drugs. For drug-refractory patients, epilepsy surgery may be a viable option. Surgical removal of the area of the brain where the seizures first start can result in seizure freedom; however, the success of surgery relies on accurately identifying the seizure onset zone (SOZ).  Epileptic signals span over a wide range of frequencies –much larger than the band monitored in conventional EEG.  Electrographic biomarkers of a SOZ include very fast oscillations as well as infraslow activity and direct-current (DC) shifts. The latter, in particular, can provide very relevant information associated with seizure onset but are seldom used due to the poor performance of current probes to record these types of slow brain signals. Application of this technology will allow researchers to investigate the role infraslow oscillations play in promoting susceptibility windows for the transition to seizure, as well as improving detection of clinically relevant electrophysiological biomarkers associated with epilepsy.

The graphene depth neural probe (gDNP) developed by the authors of this research consists of a millimetre-long linear array of micro-transistors imbedded in a micrometre-thin polymeric flexible substrate. The flexible gDNP devices were chronically implanted in small animal models of seizures and epilepsy. The implanted devices provided outstanding spatial resolution and very rich wide bandwidth recording of epileptic brain signals over weeks. In addition, extensive chronic biocompatibility tests confirmed no significant tissue damage and neuro-inflammation, attributed to the biocompatibility of the used materials, including graphene, and the flexible nature of the gDNP device.

Future clinical translation of this technology offers the possibility to identify and confine much more precisely the zones of the brain responsible for seizure onset before surgery, leading to less extensive resections and better outcomes. Ultimately, this technology can also be applied to improve our understanding of other neurological diseases associated with ultraslow brain signals, such as traumatic brain injury, stroke and migraine.

This study was led by ICREA Prof. Jose A Garrido, head of the ICN2 Advanced Electronic Materials and Devices Group, Dr Anton Guimerà-Brunet, from the Institute of Microelectronics of Barcelona (IMB-CNM-CSIC) & CIBER-BBN, and Dr Rob Wykes, from the University College London Queen Square Institute of Neurology (UK) & the Nanomedicine Lab of the University of Manchester (UK). First author of the paper is Dr Andrea Bonaccini Calia, a former member of Prof. Garrido’s group. This study was conducted in the frame of the EU project Graphene Flagship. It benefited from multidisciplinary collaborations and received valuable contributions from researchers at the Nanomedicine Lab of the University of Manchester (UK), the Universitat Autònoma de Barcelona (Spain), the CIBER-BBN with the participation of its ICTS NANBIOSIS and g.tec medical engineering GmbH (Austria).

NANBIOSIS U8. Micro – Nano Technology Unit has been used for the deposit of thin layers (Polyimide) for the manufacture of flexible devices (U8-S05) and for the growth and transfer of graphene (U8-S02) in flexible device disks.

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Reference article:

Andrea Bonaccini Calia, Eduard Masvidal-Codina, Trevor M. Smith, Nathan Schäfer, Daman Rathore, Elisa Rodríguez-Lucas, Xavi Illa, Jose M. De la Cruz, Elena Del Corro, Elisabet Prats-Alfonso, Damià Viana, Jessica Bousquet, Clement Hébert, Javier Martínez-Aguilar, Justin R. Sperling, Matthew Drummond, Arnab Halder, Abbie Dodd, Katharine Barr, Sinead Savage, Jordina Fornell, Jordi Sort, Christoph Guger, Rosa Villa, Kostas Kostarelos, Rob Wykes, Anton Guimerà-Brunet, and Jose A. Garrido, Full bandwidth electrophysiology of seizures and epileptiform activity enabled by flexible graphene micro-transistor depth neural probes. Nature Nanotechnology, 2021. DOI: https://dx.doi.org/10.1038/s41565-021-01041-9

For more information:

Institut Català de Nanociència i Nanotecnologia (ICN2)
Marketing and Communication Department
Àlex Argemí, Head of Marketing and Communication
alex.argemi@icn2.cat; +34 635 861 543


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Graphene active sensor arrays for long-term and wireless mapping of wide frequency band epicortical brain activity

Researchers of Nanbiosis U8 Micro– Nano Technology Unit, from CIBER-BBN and IMB-CNM-CSCIC have published an article in Nature Communications on Graphene arrays for long-term and wireless mapping of epicortical brain activity. A collaborative work in the framework of the Brain Com and Graphene EU projects. The article mentions the participation of NANBIOSIS-ICTS.

Graphene active sensors have demonstrated promising capabilities for the detection of electrophysiological signals in the brain. Their functional properties, together with their flexibility as well as their expected stability and biocompatibility have raised them as a promising building block for large-scale sensing neural interfaces. However, in order to provide reliable tools for neuroscience and biomedical engineering applications, the maturity of this technology must be thoroughly studied. Here, we evaluate the performance of 64-channel graphene sensor arrays in terms of homogeneity, sensitivity and stability using a wireless, quasi-commercial headstage and demonstrate the biocompatibility of epicortical graphene chronic implants. Furthermore, to illustrate the potential of the technology to detect cortical signals from infra-slow to high-gamma frequency bands, we perform proof-of-concept long-term wireless recording in a freely behaving rodent. Our work demonstrates the maturity of the graphene-based technology, which represents a promising candidate for chronic, wide frequency band neural sensing interfaces.

Article:

Garcia-Cortadella, R., Schwesig, G., Jeschke, C. et al. Graphene active sensor arrays for long-term and wireless mapping of wide frequency band epicortical brain activity. Nat Commun 12, 211 (2021). https://www.nature.com/articles/s41467-020-20546-w

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Unlocking the brain with novel graphene technology

Researchers of NANBIOSIS U8 Micro– Nano Technology Unit of CIBER-BBN at the Barcelona Institute of Microelectronics have participated in the recent developments of a new graphene-based detection platform that could be the gateway to unlock superior understanding of the brain by providing a measure of high brain activity resolution and in real time. This research has been developed within the framework of the EU BrainCom project.

The European Union’s Horizon 2020 research project, BrainCom, is coordinated by the ICN2 Advanced Electronic Materials and Devices Group led by Professor José A. Garrido and the CIBER BBN GBIO Group and the Nanbiosis U8 platform participate. (Anton Guimera, Xavier Illa, Ana Moya, Elisabet Prats and Rosa Villa)

Arguably, a better understanding of the working principles of the human brain remains one of the major scientific challenges of our time. Despite significant advances made in the field of neurotechnology in recent years, neural sensing interfaces still fall short of equally meeting requirements on biocompatibility, sensitivity, and high spatio-temporal resolution. The European Union Horizon 2020 research project BrainCom, coordinated by the ICN2 Advanced Electronic Materials and Devices Group led by ICREA Prof. José A. Garrido, is tackling these problems. BrainCom brings together experts from the fields of neurotechnology, neuroscience, and ethics to develop novel technologies capable of overcoming these limitations and shed light onto the mechanisms of information encoding and processing in the brain.

In four research articles published between March and April 2020 — featured in Elsevier’s Carbon, IOP’s 2D Materials, Wiley’s Small, and American Chemical Society’s Nano Letters — researchers from the BrainCom consortium present the technological advances achieved in the project, discuss in-depth methodology, and demonstrate novel capabilities for high resolution sensing of the brain’s electrical activity. The recent developments exploit the unique properties of graphene, an atom-thick layer of carbon, which conforms with the soft and convoluted surface of the brain providing an excellent neural sensing interface. Graphene sensors have an additional advantage that represents a turning point in neural engineering: the sensing mechanism of these graphene active sensors (so-called transistors) is compatible with  electronic multiplexing, a technology that enables transmitting the signals detected by multiple sensors through a single micrometric wire. This implies that the number of sensors on the neural implants can be increased while minimizing the footprint of the connectors required to link the implants to external electronic equipment.

This technology, developed in close collaboration with Dr Anton Guimerà at the CSIC Institute of Microelectronics of Barcelona (IMB-CNM, CSIC), has been evaluated in pre-clinical studies at the laboratory of neuroscientist Prof. Anton Sirota at Ludwig-Maximilians Universität (LMU, Munich). A collaborative and multidisciplinary approach is crucial for the success of the project, which aims at addressing a very hard scientific and technological challenge. The human brain has an astonishing complexity, consisting out of as many as 100 billion neurons. To fully understand the underlying principles of such a convoluted system requires the simultaneous detection of the electrical activity of large neural populations with a high spatial and temporal resolution. Unfortunately, current neural sensing technologies present a trade-off between spatial resolution and large-area coverage of the brain surface. The work carried out by the BrainCom project’s researchers shows how graphene-based sensors represent an outstanding building block for such large scale and highly sensitive neural interfaces. As explained in the recently published papers, graphene sensors can be reduced in size to the dimension of about one single neuron, while maintaining a high signal quality. In addition, their sensitivity expands over a wide range of frequencies; from infra-slow oscillations to very fast signals elicited by individual cells.

These findings clear the path for a scale-up of graphene sensor technology towards arrays with an ultra-high-count of sensors. Such biocompatible and high bandwidth neural interfaces can have a great impact on the development of neuroprosthesis, which enable a direct communication between the brain and a computer. These results represent the fruition of long-term EU research initiatives, which pursue the ambitious goal of restoring speech to impaired patients by reading the signals in their brains, which are related to their intentional speech. The research consortium will now focus on upscaling the production of these neural interfaces and testing their performance in safe human clinical trials. This and other applications of graphene sensors are also supported by the EU Graphene Flagship within the Biomedical Technologies work package.

Reference Articles:

Garcia-Cortadella R, Schaefer N, Cisneros-Fernández J, Re L, Illa X, Moya-Lara A ,Santiago S, Guirado G, Villa R, Sirota A, Serra-Graells F, Garrido JA, Guimerà-Brunet A Switchless Multiplexing of Graphene Active Sensor Arrays for Brain Mapping Nano Letters (2020) DOI: 10.1021/acs.nanolett.0c00467

Garcia-Cortadella R, Masvidal-Codina E, de la Cruz J, Schaefer N, Schwesig G, Jeschke C, Martínez-Aguilar J, Sánchez-Vives MV, Villa R, Illa X, Sirota A, Guimerà-Brunet A, Garrido JA Distortion‐Free Sensing of Neural Activity Using Graphene Transistors Small (2020) 1906640, March 2020. DOI: 10.1002/smll.201906640

Schaefer N, Garcia-Cortadella R, Martínez-Aguilar J, Schwesig G, Illa X, Moya Lara A, Santiago S, Hébert C, Guirado G, Villa R, Sirota A, Guimerà-Brunet A, Garrido JA Multiplexed Neural Sensor Array of Graphene Solution-Gated Field-Effect Transistors 2D Materials 7(2), 2020. DOI: 10.1088/2053-1583/ab7976

Schaefer N, Garcia-Cortadella R, Bonaccini Calia A, Mavredakis N, Illa X, Masvidal-Codina E, de la Cruz J, del Corro E, Rodríguez L, Prats-Alfonso E, Bousquet J, Martínez-Aguilar J, Pérez-Marín AP, Hébert C, Villa R, Jiménez D, Guimerà-Brunet A, Garrido JA Improved metal-graphene contacts for low-noise, high-density microtransistor arrays for neural sensing Carbon 161, 647-655, 2020. DOI: 10.1016/j.carbon.2020.01.066

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Elisabet Prats is a young scientist, researcher at Biomonitoring group of CIBER-BBN and  CNM, which coordinates Unit 8 of NANBIOSIS, and a science disseminator with comedian monologues at “Big Van”.

[Elisabet Prats in Informativos.net]

As a science disseminator, Elisabet has recently appeared in media and forums explaining the progress made by her research group in the European project Graphene Flagship. For example, a graphene sensor to detect brain electrical activity, successfully presented at Mobile World Congress. Elisabet clearly explains “We are able to measure the electrical signals of the brain with graphene, graphene due to its versatility, allows the reduction in size of the sensors, giving much more information to the doctor” and describes a future in which “we shall control mechanical arms with brains implants”.

Nanbiosis_U8 - Biomedical applications of graphene, Elisabet Prats in Informativos.net
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