Resumen de Interfícies neuronals flexibles basades en grafè per a electrofisiologia intracortical al cervell
Recent years have witnessed novel technology developments of neural implants for medical applications which are expected to pave the way to unveil functionalities of the central nervous system. Understanding the human brain is commonly considered one of the biggest scientific challenges of our time; as a consequence, we are witnessing an intensified research in the development of brain-machine-interfaces (BMIs), which would allow us to both read and stimulate brain activity. Nevertheless, currently available neural implants offer a modest clinical efficacy, partly due to the limitations posed by the invasiveness of the implants materials and technology and by the metals used at the electrical interface with the tissue. Such materials compromise the interfacing resolution, the performance and the long term stability of neural implants. Development of flexible electronics using biocompatible materials is key for the realisation of minimally invasive neural implants, which can be chronically implanted without causing rejection from the immune system.
A relatively young yet very promising research field, that is increasingly drawing attention is the use of two dimensional materials, such as graphene, for bioelectronic applications. Graphene solution-gated field effect transistor (gSGFET) is one of several emerging new neural technologies. These devices can overcome the above-mentioned limitations thanks to the outstanding properties of graphene, such as mechanical flexibility, electrochemical inertness, biocompatibility and high sensitivity.
In this PhD thesis, arrays of gSGFETs have been fabricated and iteratively optimized in terms of sensitivity and signal-to-noise ratio, adopting wafer-scale micro-fabrication methods. The 1/f noise in gSGFETs has been characterised and the optimisation of both, contact and channel noises was achieved by UVO-treatment at the metal/graphene interface, as well as by decoupling the graphene channel from the substrate, using different nanomaterials such as graphene encapsulation with hexagonal boron nitride (hBN), self assembled monolayers and double transferred graphene.
Moreover, flexible and ultra-thin epicortical and intracortical neural probes, containing arrays of gSGFETs, have been successfully fabricated and used during in vivo microelectrocorticography recordings in anaesthesized and awake rodents. Flexible intracortical devices were inserted into the brain using a back-coating stiffening protocol with bioresobable silk fibroin protein, developed during this PhD thesis. The results presented in this PhD demonstrate the superior spatio-temporal resolution of gSGFETs compared to standard microelectordes technology; particularly the ability to map with high fidelity, infraslow activity (ISA, < 0.1 Hz) together with signals in the typical local field potential bandwidth.
Today it is known that infraslow brain activity, including spreading depolarisations, contribute to the pathophysiology of several neurological disorders such as stroke, traumatic brain injury, migraine and epilepsy. However, this activity is seldom recorded due to intrinsic technical limitations of conventional AC-coupled electrodes.
To demonstrate the usefulness of the developed flexible gSGFET arrays technology, recordings have been obtained with multichannel flexible graphene depth neural probes (gDNP) in relevant awake animal models of seizures and established epilepsy. ISA was detected and mapped through different cortical layers and subcortical regions, whilst simultaneously recording epileptiform activity in more conventional frequency bands (1-600Hz). Furthermore, the assessment of the long term recording stability and functionality, as well as biocompatibility of the gDNP has also been demonstrated as part of this thesis.
The graphene based bioelectronic technology here described has the potential to become a gold standard tool for full bandwidth electrophysiology. This technology is envisioned to have a great impact on a broad and multidisciplinary community including neurotechnology researchers, biomedical engineers, neuroscientists studying wide-band cortical dynamics associated with spontaneous behaviour and/or brain states, as well as clinical researchers interested in the role of infraslow activity in epilepsy, stroke and migraine.
