Periodic Reporting for period 2 - BRAINSTORM (Wireless deep BRAIN STimulation thrOugh engineeRed Multifunctinal nanomaterials)
Periodo di rendicontazione: 2024-04-01 al 2025-09-30
Neurodegenerative diseases remain among the leading causes of disability and death worldwide, highlighting the urgent need for neuromodulation technologies that can safely and selectively target deep brain circuits. While existing approaches such as deep brain electrical stimulation or transcranial magnetic stimulation provide clinical benefits, they remain invasive, lack focality at depth, and cannot discriminate between neuronal cell types. At the same time, opto- or chemogenetic methods are not yet clinically translatable. Consequently, many neurological and psychiatric disorders continue to be managed only palliatively.
At this point of the project, BRAINSTORM has successfully achieved all key research objectives and established the technological foundations for a nanoinvasive, wireless neuromodulation platform capable of high spatiotemporal precision. We have developed and validated a novel class of multifunctional, biocompatible magnetic nanomaterials that can be selectively actuated at arbitrary brain depths to generate controlled magneto-mechanical forces and are working on the finalization of implementing localized thermal effects. These bimodal mechanisms will enable targeted activation or inhibition of mechanosensitive or thermosensitive neurons, and are further enhanced through advanced polymer functionalization, piezoelectric coatings, and antibody-based targeting strategies. In parallel, we have prototyped next-generation driving electronics with miniaturized, power-efficient coils and established a focused-ultrasound-based delivery method that enables safe blood–brain barrier passage without intracranial injection. Initial biological testing using calcium imaging and network electrophysiology has confirmed the feasibility of precise on-demand neuromodulation.
In the next phase, these components will be integrated into a unified therapeutic platform and evaluated in complex in vitro models and in vivo in a mouse model of fragile X syndrome. By enabling implant-free, cell-type-selective neuromodulation, BRAINSTORM is on track to overcome major barriers in the treatment of neurological and psychiatric diseases and to lay the groundwork for future clinical applications with significant societal and economic impact.
At this point of the project, BRAINSTORM has successfully achieved all key research objectives and established the technological foundations for a nanoinvasive, wireless neuromodulation platform capable of high spatiotemporal precision. We have developed and validated a novel class of multifunctional, biocompatible magnetic nanomaterials that can be selectively actuated at arbitrary brain depths to generate controlled magneto-mechanical forces and are working on the finalization of implementing localized thermal effects. These bimodal mechanisms will enable targeted activation or inhibition of mechanosensitive or thermosensitive neurons, and are further enhanced through advanced polymer functionalization, piezoelectric coatings, and antibody-based targeting strategies. In parallel, we have prototyped next-generation driving electronics with miniaturized, power-efficient coils and established a focused-ultrasound-based delivery method that enables safe blood–brain barrier passage without intracranial injection. Initial biological testing using calcium imaging and network electrophysiology has confirmed the feasibility of precise on-demand neuromodulation.
In the next phase, these components will be integrated into a unified therapeutic platform and evaluated in complex in vitro models and in vivo in a mouse model of fragile X syndrome. By enabling implant-free, cell-type-selective neuromodulation, BRAINSTORM is on track to overcome major barriers in the treatment of neurological and psychiatric diseases and to lay the groundwork for future clinical applications with significant societal and economic impact.
BRAINSTORM is developed by an interdisciplinary, international team of researchers, that gather their expertise to bring this innovative technology to life. The fundamental building block for the BRAINSTORM technology are functional nanomaterials, that respond to distinct magnetic filed frequencies leading to generation of mechanical forces through magnetization shifts or heat dissipation through hysteretic losses. These materials are designed and synthesized by one part of the team, while other members are developing the functional coating for these nanomaterials, that allow electrical stimulation as well as thermal release of selected compounds to enable targeted activation or inhibition of sensory neurons. In parallel, genetic editing of ion channel constructs is handled by another team and permits selective expression of excitatory or inhibitory targets for conjugation and neuromodulation.
The driving electronics are concurrently realized by another subgroup within the BRAINSTORM team. This challenging task of fabricating devices that enable magnetic field shifts between frequencies at a sub-second rate and can be handled in a convenient format is underway.
The neuronal stimulation by BRAINSTORM multifunctional nanomaterials is tested in cellular, ex-vivo and in-vivo models. Delivery of the nanomaterials to the brain is achieved by a team of researchers elaborating groundbreaking techniques for non-invasive delivery of systems to the brain via opening the blood-brain barrier. Another part of the team is establishing imaging techniques, capturing neuronal responses in the model systems, to tune and evaluate the functionality of the BRAINSTORM suite.
Only the combined efforts of all the experts working on the BRAINSTORM project will enable a successful integration of the different building blocks required to bring the BRAINSTORM technology to life.
The driving electronics are concurrently realized by another subgroup within the BRAINSTORM team. This challenging task of fabricating devices that enable magnetic field shifts between frequencies at a sub-second rate and can be handled in a convenient format is underway.
The neuronal stimulation by BRAINSTORM multifunctional nanomaterials is tested in cellular, ex-vivo and in-vivo models. Delivery of the nanomaterials to the brain is achieved by a team of researchers elaborating groundbreaking techniques for non-invasive delivery of systems to the brain via opening the blood-brain barrier. Another part of the team is establishing imaging techniques, capturing neuronal responses in the model systems, to tune and evaluate the functionality of the BRAINSTORM suite.
Only the combined efforts of all the experts working on the BRAINSTORM project will enable a successful integration of the different building blocks required to bring the BRAINSTORM technology to life.
Overall, BRAINSTORM has made significant progress during the first year, in line with the initial objectives. Synthesis of newly designed smart anisotropic magnetic nanomaterials (SMNs), including the confirmation of their colloidal stability under physiological conditions has been successfully completed.
Performance of the SMNs for mechanical stimulation was assessed in HEK293 cells selectively expressing mechanosensory ion channels, and in parallel demonstrates high biocompatibility of the nanomaterials. Functional polymers for thermo-responsive coatings have been designed and are currently being implemented in coating of SMNs.
The design of viral vectors for genetic neuronal targeting and conjugation of SMNs to specific sensory channels was concluded for lentiviral vectors, while preparation of adenovirus-based systems for larger ion channels are currently underway.
Electronic components of the technology are successfully being fabricated, including the development of tunable Helmholtz Coils, which are currently integrated in a customized in-house setup for actuation of SMNs.
Furthermore, significant progress ahead of the timeline was made with respect to application of focused ultrasound as a means of opening the blood-brain barrier as well as imaging techniques for visualization of the technology in cellular models, in- and ex-vivo.
Generally, BRAINSTORM is advancing towards fulfilling its anticipated goals, showing encouraging indications of scientific, technological, health-related, societal, and economic impacts.
Performance of the SMNs for mechanical stimulation was assessed in HEK293 cells selectively expressing mechanosensory ion channels, and in parallel demonstrates high biocompatibility of the nanomaterials. Functional polymers for thermo-responsive coatings have been designed and are currently being implemented in coating of SMNs.
The design of viral vectors for genetic neuronal targeting and conjugation of SMNs to specific sensory channels was concluded for lentiviral vectors, while preparation of adenovirus-based systems for larger ion channels are currently underway.
Electronic components of the technology are successfully being fabricated, including the development of tunable Helmholtz Coils, which are currently integrated in a customized in-house setup for actuation of SMNs.
Furthermore, significant progress ahead of the timeline was made with respect to application of focused ultrasound as a means of opening the blood-brain barrier as well as imaging techniques for visualization of the technology in cellular models, in- and ex-vivo.
Generally, BRAINSTORM is advancing towards fulfilling its anticipated goals, showing encouraging indications of scientific, technological, health-related, societal, and economic impacts.