Periodic Reporting for period 3 - IN-FET (Ionic Neuromodulation For Epilepsy Treatment)
Reporting period: 2023-01-01 to 2024-03-31
Current therapies, regulating nerve cell activity in brain dysfunctions, suffer from severe limitations. Most pharmaceuticals's effectiveness and containment of undesired side-effects are poor. For Epilepsy, drugs are ineffective in ~35% of the cases, so that neurosurgery remains the only treatment despite its obvious risks.
IN-FET focused on epilepsy as a major brain disorders, affecting ~1.2% of the population (i.e. more than 50M of people worldwide). It has a broad spectrum of underlying causes, and it is associated to repeated occurrence of seizures with a major negative impact on their overall quality of life. These are "electric storms" in the brain, altering the physiological activity of nerve cells. While intervening on root causes of epilepsy involves an array of interventions (e.g. gene therapy, phenotyping, personalised medicine, etc.), regulating the sudden occurrence of seizures might be within reach.
In the last years, societies and investors witnessed a strong interest for neurotechnologies for brain disorders. Electrical/optical/magnetic/piezo stimulation of nerve cells require no systemic drug administration and can be computer-controlled. This appears uniquely positioned for effectively tackling seizure suppression. And yet, all require invasive interventions, with necessary gene manipulation or “augmentation” whose long-term effects are unknown.
IN-FET proposed a breakthrough microtechnological and microelectronic alternative to neuro-modulation. Alternative to traditional electrical brain pacemakers and genetic engineering, the innovative technology IN-FET has dreamt of aims at controlling the pathological “excess” of electrical activity in nerve cells by altering the local concentration of ions, key to neuronal activity, such as potassium and calcium. IN-FET called it "ionic actuation" and performed substantial research and innovation activities to pave the road for this concept to be validated and possibly adopted in the near future.
IN-FET overall aimed at exploring ionic actuation for altering neuronal excitability. Setting the ground for such an ambitious long-term challenge, IN-FET focused towards three short-term objectives:
1) the in-depth electrochemical characterisation of the most appropriate polymers for electro-actuating ion release;
2) the biophysical, device-level, and device-electrolyte-membrane interface modelling for understanding strength and weaknesses of ionic actuation;
3) the experimental assessment of biocompatibility and effectiveness of ionic control of neuronal activity, across a series of in vitro experimental model of physiological and pathological activity.
While these were only partly achieved, IN-FET's results led to advancing our neurobiological, microtechnological, electrochemical, and modeling understanding. These advances lay the foundations for a subsequent exploitation of the technology in implantable devices for preclinical applications, where a clear road-map has been provided.
IN-FET focused on epilepsy as a major brain disorders, affecting ~1.2% of the population (i.e. more than 50M of people worldwide). It has a broad spectrum of underlying causes, and it is associated to repeated occurrence of seizures with a major negative impact on their overall quality of life. These are "electric storms" in the brain, altering the physiological activity of nerve cells. While intervening on root causes of epilepsy involves an array of interventions (e.g. gene therapy, phenotyping, personalised medicine, etc.), regulating the sudden occurrence of seizures might be within reach.
In the last years, societies and investors witnessed a strong interest for neurotechnologies for brain disorders. Electrical/optical/magnetic/piezo stimulation of nerve cells require no systemic drug administration and can be computer-controlled. This appears uniquely positioned for effectively tackling seizure suppression. And yet, all require invasive interventions, with necessary gene manipulation or “augmentation” whose long-term effects are unknown.
IN-FET proposed a breakthrough microtechnological and microelectronic alternative to neuro-modulation. Alternative to traditional electrical brain pacemakers and genetic engineering, the innovative technology IN-FET has dreamt of aims at controlling the pathological “excess” of electrical activity in nerve cells by altering the local concentration of ions, key to neuronal activity, such as potassium and calcium. IN-FET called it "ionic actuation" and performed substantial research and innovation activities to pave the road for this concept to be validated and possibly adopted in the near future.
IN-FET overall aimed at exploring ionic actuation for altering neuronal excitability. Setting the ground for such an ambitious long-term challenge, IN-FET focused towards three short-term objectives:
1) the in-depth electrochemical characterisation of the most appropriate polymers for electro-actuating ion release;
2) the biophysical, device-level, and device-electrolyte-membrane interface modelling for understanding strength and weaknesses of ionic actuation;
3) the experimental assessment of biocompatibility and effectiveness of ionic control of neuronal activity, across a series of in vitro experimental model of physiological and pathological activity.
While these were only partly achieved, IN-FET's results led to advancing our neurobiological, microtechnological, electrochemical, and modeling understanding. These advances lay the foundations for a subsequent exploitation of the technology in implantable devices for preclinical applications, where a clear road-map has been provided.
Despite our recruitment, lab access, and semiconductor availability was affected by COVID-19, IN-FET succeeded to bring its goals within reach: recording and modulating neuronal activity by novel micro and nanotechnologies. An innovative micro fabrication post-processing was achieved, augmenting CMOS devices. This means that "brain chips", manufactured by commercial Si-wafers foundries, can be easily modified in their performances, e.g. going from 2d to 3d nano-scale. Importantly, this process was fully validated in terms of biocompatibility.
The close collaboration between (non)academic partners delivered an in vitro prototype system platform for multisite neuronal recordings, with no extra development for hardware and software, immediately beneficial for IN-FET adoption in a lab context, as originally planned.
The continuous interaction between electrochemists and bioengineers made it possible to very quickly arrive at a theory-and simulation-based design principles formulation for planar and protruding electrodes. Modeling of conductive polymers supported by continuous interaction with fabrication partners was helpful in defining the specifications of the polymer for ionic actuation. At the same time models available in the literature demonstrated not to be adequate for K+ selective polymers that were instead successfully fabricated by the technological partners.
High on/off ratio (10^5), low operating voltage (0.1V) low-cost MEA arrays on ITO-coated glass with PEDOT:PSS actuators with high selectivity were demonstrated. The actuators are capable of 10x higher K+ storage than that required for local neuromodulation, as demonstrated via Inductively Coupled Plasma Optical Emission Spectroscopy. The sensors integrated on the MEA were tested experimentally with neuronal cultures. The experimental design of the actuators led to new knowledge on charge storage capacity of polymers, volumetric capacitance, and methods to analyse redox-doped polymers compared to capacitively doped counterparts, whose model is currently still under development.
Both microtechnological and electrochemical breakthroughs were step-by-step validated in terms of biocompatibility and accompanied by neurobiological efforts. A series of “disease models in a dish” were obtained and validated, for ultimately allowing the inquiry on altered excitability, together with novel paradigm for probing neuronal excitability - based on Optogenetics - and for anatomically structuring neuronal connectivity - based on 2-photon printing for microfluidics.
A start-up company was launched and committed to acquire license of IN-FET's IP. Dissemination and outreach matured substantially, through publications, press-releases, and online/in person conferences or events, aimed at the scientific community and the public. This also included establishing synergies with other EIC-funded projects, framing the contributions of IN-FET in a much broader European perspective.
The close collaboration between (non)academic partners delivered an in vitro prototype system platform for multisite neuronal recordings, with no extra development for hardware and software, immediately beneficial for IN-FET adoption in a lab context, as originally planned.
The continuous interaction between electrochemists and bioengineers made it possible to very quickly arrive at a theory-and simulation-based design principles formulation for planar and protruding electrodes. Modeling of conductive polymers supported by continuous interaction with fabrication partners was helpful in defining the specifications of the polymer for ionic actuation. At the same time models available in the literature demonstrated not to be adequate for K+ selective polymers that were instead successfully fabricated by the technological partners.
High on/off ratio (10^5), low operating voltage (0.1V) low-cost MEA arrays on ITO-coated glass with PEDOT:PSS actuators with high selectivity were demonstrated. The actuators are capable of 10x higher K+ storage than that required for local neuromodulation, as demonstrated via Inductively Coupled Plasma Optical Emission Spectroscopy. The sensors integrated on the MEA were tested experimentally with neuronal cultures. The experimental design of the actuators led to new knowledge on charge storage capacity of polymers, volumetric capacitance, and methods to analyse redox-doped polymers compared to capacitively doped counterparts, whose model is currently still under development.
Both microtechnological and electrochemical breakthroughs were step-by-step validated in terms of biocompatibility and accompanied by neurobiological efforts. A series of “disease models in a dish” were obtained and validated, for ultimately allowing the inquiry on altered excitability, together with novel paradigm for probing neuronal excitability - based on Optogenetics - and for anatomically structuring neuronal connectivity - based on 2-photon printing for microfluidics.
A start-up company was launched and committed to acquire license of IN-FET's IP. Dissemination and outreach matured substantially, through publications, press-releases, and online/in person conferences or events, aimed at the scientific community and the public. This also included establishing synergies with other EIC-funded projects, framing the contributions of IN-FET in a much broader European perspective.
IN-FET's results went beyond the state-of-the-art in neurotech, modelling, and electrochemistry.
The scietal and economic benefit will be large, as our proofs-of-concept offers
• immediately a novel platform for in vitro drug screening and studying neuronal activity in (dys)functional brain circuits;
• an electroceutical alternative to pharmacological epilepsy treatment;
• immediately complement existing designs of neuropixel-like integrated arrays of microelectrodes, mainly used today as recording devices only;
• compare more favourable for biocompatibility than genetic manipulations;
• a generation of neuroprostheses, capable of neuron-selective signal transduction in clinical therapies;
• a boost for our understanding of neuronal information processing at single-cell levels.
Thanks to its industrial players, IN-FET’s impact on miniaturized biomedical technologies, drug-screening microsystems that already employ automated array systems and microfluidics will be large. It will strengthen the global competitiveness of the EU industry in testing neuroactive compounds and drug-discovery, which today employ quite expensive automated patching platforms, one-cell at a time.
Ultimately, intense collaboration at the level of junior scientists, co-supervised by different senior investigators contributed to the next generation of innovators at the boundary between biology and ICT, keeping EU at the forefront of future emerging technologies.
The scietal and economic benefit will be large, as our proofs-of-concept offers
• immediately a novel platform for in vitro drug screening and studying neuronal activity in (dys)functional brain circuits;
• an electroceutical alternative to pharmacological epilepsy treatment;
• immediately complement existing designs of neuropixel-like integrated arrays of microelectrodes, mainly used today as recording devices only;
• compare more favourable for biocompatibility than genetic manipulations;
• a generation of neuroprostheses, capable of neuron-selective signal transduction in clinical therapies;
• a boost for our understanding of neuronal information processing at single-cell levels.
Thanks to its industrial players, IN-FET’s impact on miniaturized biomedical technologies, drug-screening microsystems that already employ automated array systems and microfluidics will be large. It will strengthen the global competitiveness of the EU industry in testing neuroactive compounds and drug-discovery, which today employ quite expensive automated patching platforms, one-cell at a time.
Ultimately, intense collaboration at the level of junior scientists, co-supervised by different senior investigators contributed to the next generation of innovators at the boundary between biology and ICT, keeping EU at the forefront of future emerging technologies.