Periodic Reporting for period 1 - MINIGRAPH (Minimally Invasive Neuromodulation Implant and implantation procedure based on ground-breaking GRAPHene technology for treating brain disorders)
Reporting period: 2022-10-01 to 2023-09-30
Neurostimulation therapies hold the promise to treat brain diseases refractory to pharmacological treatment. However, these therapies are not fully adopted due to important technological and clinical challenges, such as highly invasive implantation, multiple side effects due to off-target stimulation, low signal resolution and lack of personalized therapies. The MINIGRAPH project aims to develop a ground-breaking neuromodulation therapy that addresses current needs of the field. The ultimate objective of MINIGRAPH is to develop and validate a new generation of brain implants with closed-loop neuromodulation capabilities, enabled by skull implanted flexible electronics unit and miniature and high-density arrays of graphene microelectrodes. Our implant will feature high miniaturization, large spatial resolution and optimal biocompatibility with brain tissue. The closed-loop capabilities will enable to develop personalized and adaptive therapies depending on patients’ needs. In addition, we will also develop and validate a minimally invasive implantation procedure with high precision implantation and low invasiveness through a single small skull incision.
The MINIGRAPH project will contribute to revolutionize the way we treat neurological and neuropsychiatric diseases in the near future. To achieve our ambitious objectives, we have put together an interdisciplinary consortium formed by high-renowned research centers and two high-promising SMEs pioneering novel technologies in advanced neuromodulation and robotic surgery, with all the expertise and resources needed to complete the project within time and budget. Our project addresses the objectives of the “Tools to measure and stimulate activity in brain tissue” pathfinder challenge, as it provides 1) miniature and minimally invasive brain implants, 2) closed-loop neuromodulation therapy for personalized medicine, 3) biocompatible ultra-thin and flexible neuroelectrodes, and 4) minimized power consumption solution.
The MINIGRAPH project will contribute to revolutionize the way we treat neurological and neuropsychiatric diseases in the near future. To achieve our ambitious objectives, we have put together an interdisciplinary consortium formed by high-renowned research centers and two high-promising SMEs pioneering novel technologies in advanced neuromodulation and robotic surgery, with all the expertise and resources needed to complete the project within time and budget. Our project addresses the objectives of the “Tools to measure and stimulate activity in brain tissue” pathfinder challenge, as it provides 1) miniature and minimally invasive brain implants, 2) closed-loop neuromodulation therapy for personalized medicine, 3) biocompatible ultra-thin and flexible neuroelectrodes, and 4) minimized power consumption solution.
Considering the overall goal of this project, which is to demonstrate the functionality of a new generation of brain implants with closed-loop neuromodulation capabilities based on graphene microelectrode technologies and a minimally invasive robotic implantation procedure for the treatment of brain disorders, the main achievements of MINIGRAPH during the first year of the project have been the following:
1) With respect to technology of epicortical and subcortical neural probes, we have designed, fabricated and characterized a first generation (polymer-only encapsulation) of graphene-based neural probes. The design (dimensions and layout of microelectrodes) considered input from end-users (clinicians and neuroscientists partners) and from electronic design partners. Furthermore, a fabrication strategy to improve hermeticity of neural leads has started based on a stack of inorganic/organic thin layers.
2) Regarding the development of the integrated electronic system to interface with the neural probes, a first version of the ASIC with recording and stimulation channels (16 independent stimulation channels and 240 recording channels) has been designed and simulated. In addition, the architecture of a non-implantable data-acquisition system to enable first in vivo experiments has been defined.
3) In the case of the implantable functional prototype that integrates the neural probes and the ASIC, we have evaluated and assessed different microfabrication strategies (at 8’ wafer scale) combining polymer and inorganic thin-film technology.
4) In the area of minimally invasive robotic surgical procedure, the requirements for the magnetic carrier and delivery system, as well as for the human-machine interface, have been identified, and an initial concept for the robotic system set-up has been defined and validated.
5) with respect to the closed-loop software for brain neuromodulation and the functional validation of the prototype in a translational model, we have first developed a porcine acute model for testing the developed devices, validating synchronized recording of animal behaviour by measuring pathological metrics, brain signals, closed-loop stimulation and therapy effects on the behavioural metrics reflecting therapy. In addition, we demonstrated a closed-loop dataflow in the porcine animal model incorporating machine learning models to close the loop with stimulation in real-time.
6) Regarding the regulatory strategy for approval of implant and implantation procedure, we have a preliminary draft of a detailed strategy & plan for biological safety verification of the manufactured, packaged, and sterilised investigational devices demonstrating compliance with applicable ISO standards.
7) Through an EU Hope on facility call, we have incorporated a partner (in July 2023) to evaluate the fundamental toxicity of neural probes on cellular and molecular level. We have already drafted a detailed plan for the in vitro cytotoxicity tests, and we have initiated the definition of prototype models for in-silico evaluation of interactions of graphene-based materials with lipid membranes.
1) With respect to technology of epicortical and subcortical neural probes, we have designed, fabricated and characterized a first generation (polymer-only encapsulation) of graphene-based neural probes. The design (dimensions and layout of microelectrodes) considered input from end-users (clinicians and neuroscientists partners) and from electronic design partners. Furthermore, a fabrication strategy to improve hermeticity of neural leads has started based on a stack of inorganic/organic thin layers.
2) Regarding the development of the integrated electronic system to interface with the neural probes, a first version of the ASIC with recording and stimulation channels (16 independent stimulation channels and 240 recording channels) has been designed and simulated. In addition, the architecture of a non-implantable data-acquisition system to enable first in vivo experiments has been defined.
3) In the case of the implantable functional prototype that integrates the neural probes and the ASIC, we have evaluated and assessed different microfabrication strategies (at 8’ wafer scale) combining polymer and inorganic thin-film technology.
4) In the area of minimally invasive robotic surgical procedure, the requirements for the magnetic carrier and delivery system, as well as for the human-machine interface, have been identified, and an initial concept for the robotic system set-up has been defined and validated.
5) with respect to the closed-loop software for brain neuromodulation and the functional validation of the prototype in a translational model, we have first developed a porcine acute model for testing the developed devices, validating synchronized recording of animal behaviour by measuring pathological metrics, brain signals, closed-loop stimulation and therapy effects on the behavioural metrics reflecting therapy. In addition, we demonstrated a closed-loop dataflow in the porcine animal model incorporating machine learning models to close the loop with stimulation in real-time.
6) Regarding the regulatory strategy for approval of implant and implantation procedure, we have a preliminary draft of a detailed strategy & plan for biological safety verification of the manufactured, packaged, and sterilised investigational devices demonstrating compliance with applicable ISO standards.
7) Through an EU Hope on facility call, we have incorporated a partner (in July 2023) to evaluate the fundamental toxicity of neural probes on cellular and molecular level. We have already drafted a detailed plan for the in vitro cytotoxicity tests, and we have initiated the definition of prototype models for in-silico evaluation of interactions of graphene-based materials with lipid membranes.
The MINIGRAPH project aims at building a novel closed-loop neuromodulation concept based on the superior properties of graphene, together with a minimally invasive robotic surgical procedure for implantation of the medical device. This technology is expected to be a game-changer for the generation of neuromodulation therapies that, in the long-term, will 1) provide a better and safer treatment options for Parkinson’s disease, 2) allow to treat other neurological and neuropsychiatric disorders that are refractory to pharmacological treatment, 3) develop personalized therapies based on closed-loop stimulation strategies. The clinical translation and posterior commercialization of the project outcomes are currently being led by two pioneering EU start-ups participating in this project (INBRAIN Neuroelectronics and NanoFlex Robotics). While the outcomes of this projects are expected to have a wide impact on scientific, technological, clinical, societal and economic fields, these impacts have not yet materialized given the relatively early stage of the project.