EGNITE: Grafeno diseñado para interfaz neuronal

Damià Viana Casals

José Antonio Garrido

Neural implants offer therapeutic options for patients suffering from certain neurological disorders and other neural deficiencies such as deafness, blindness, Parkinson's disease, or amputations. Currently, this technology consists of implantable devices that electrically record or stimulate the nervous system using millimeter-scale metal electrodes. At this scale, however, the electrodes cannot record neuronal activity or stimulate neural tissue with sufficient definition and complexity to transduce signals as if they were occurring naturally, which limits the effectiveness of the therapies. To achieve wider acceptance of neural implants as a therapy, a radical change is needed in improving their efficacy and safety so that the therapeutic benefit far outweighs the risks of surgical implantation. To achieve this, it is necessary to obtain a bidirectional and stable neural interface at the micrometer scale. However, the functionality of current metal electrode technology cannot be extended below the millimeter scale due to the limited performance of its electrical interface with the tissue. Graphene is a very suitable material for use in neural interfaces due to its combination of properties such as flexibility, carbon-based nature and high conductivity, which confers it high stability, biocompatibility and great potential to transduce electrical signals between neurological tissues and electronic devices. However, to achieve optimal performance and effectively establish bidirectional communication with nervous tissue at the millimeter scale, it is necessary to develop a highly porous graphene-based material. In this thesis I present a microelectrode technology based on EGNITE, a porous graphene material that provides a stable and high-performance bidirectional neural interface. This material has been specially designed for this application, and it is in the first chapter that I describe the development process, as well as its characterization and production. In the second chapter, I present the integration of this material into flexible neural implants and its electrochemical characterization. These devices have been produced at the wafer level, which is the standard way to manufacture electronic devices industrially. Compared to standard microelectrode devices, EGNITE micrometer electrodes can safely inject 200 times more charge for more than 100 million pulses. In the third chapter, I show preliminary results of the material's biocompatibility and present in vivo proof-of-concept experiments with devices containing EGNITE microelectrode arrays. With these, I record epicortical electrical activity with high fidelity, stimulate sciatic nerve muscle activity with high selectivity, and test a new generation of retinal implants that have the potential to restore vision in blind patients with high resolution. In summary, the neural implant technology developed during this doctoral thesis surpasses the stability and spatial resolution of currently available technology. This technology can be used for basic and applied neuroscience research and, potentially, improve the efficacy and safety of neuromodulation therapies.

In recent years, there has been a growing interest in bioelectronic medicine. Bioelectronic medicine is an exciting new field at the intersection of molecular medicine, neuroscience, and bioengineering. It has the potential to revolutionize the way we treat disease by developing devices that interact with the central and peripheral nervous systems to modulate organ and metabolic functions. This is a crucial new field in medicine that builds on the success of devices such as pacemakers. The bioelectronics market is segmented and can be divided into implantable devices, biofuel cells, prostheses, molecular motors, and artificial organs. It is estimated to be a $20 trillion market today and will grow to $38 trillion by 20251. Within the bioelectronics market, there is the field of neuromodulation. Neuromodulation is “the alteration of nerve activity by the targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body.” It is performed to normalize, or modulate, the function of nervous tissue. Neuromodulation can be magnetic, electrical, or chemical and can be delivered using invasive or noninvasive techniques. The neuromodulation market is estimated to be worth $6.5 trillion globally today with a forecast of $15 trillion by 2025. 2 Within the invasive field of neuromodulation, neuroelectronics, also known as neural interfaces, enable the transfer of information between the nervous system and an external device. 3 These devices typically take the form of electrodes to record or modulate neural activity by transducing cellular activity into actionable information (recording/sensing) or delivering current to the tissue (stimulation). 4 Neural interfaces are currently being applied in both research and clinical contexts, from answering basic neuroscience questions about behavior, information encoding, and injury mechanisms, such as cochlear implants to restore hearing loss, deep brain stimulation to treat Parkinson's disease, direct control of prostheses, limbs, or other peripheral devices, treatment of spinal cord injuries or neuropathic pain, etc.5. Continued progress in this field of medicine will require: (1) improvements in our understanding of the mechanisms of neural control over organ function and (2) advances in technologies to precisely modulate these functions in a programmable manner. The ultimate clinical goal in neuro and bioelectronics is to drive personalized, closed-loop therapies that automatically adapt to each patient's condition by modulating the therapeutic response to the patient's disease state in real time.

Implantes neuronales; Opciones terapéuticas; Trastornos neurológicos; Deficiencias neuronales; Sordera; Ceguera; Enfermedad de Parkinson; Amputaciones; Dispositivos implantables; Registro eléctrico; Estimulación eléctrica; Sistema nervioso; Electrodos metálicos; Actividad neuronal; Tejido neuronal; Definición; Complejidad; Transducción de señales; Mejora de la eficacia; Mejora de la seguridad; Beneficio terapéutico; Riesgos de la implantación quirúrgica; Interfaz neuronal bidireccional; Escala micrométrica; Grafeno; Flexibilidad; Naturaleza basada en carbono; Alta conductividad; Alta estabilidad; Biocompatibilidad; Transducción de señales eléctricas; Tejidos neurológicos; Dispositivos electrónicos; Material altamente poroso basado en grafeno; Tecnología de microelectrodos; EGNITE; Interfaz neuronal estable; Interfaz neuronal de alto rendimiento; Interfaz neuronal bidireccional; Desarrollo de materiales; Caracterización; Producción; Implantes neuronales flexibles; Caracterización electroquímica; Producción a nivel de oblea; Fabricación industrial; Dispositivos de microelectrodos estándar; Inyección de carga; Conteo de pulsos; Biocompatibilidad; Experimentos de prueba de concepto in vivo; Matrices de microelectrodos EGNITE; Actividad eléctrica epicortical; Registro de alta fidelidad; Actividad muscular del nervio ciático; Estimulación de alta selectividad; Implantes de retina; Restauración de la visión; Pacientes ciegos; Alta resolución; Resolución espacial; Investigación en neurociencia; Terapias de neuromodulación.