Periodic Reporting for period 1 - BRAINSTORM (Wireless deep BRAIN STimulation thrOugh engineeRed Multifunctinal nanomaterials)
Période du rapport: 2023-04-01 au 2024-03-31
Neurodegenerative diseases are among the leading causes of disability and death worldwide. Among the therapeutic tools that allow interfacing with the brain, neuromodulation is the most promising approach. However, existing therapeutic paradigms, such as deep brain electrical stimulation (ES) or transcranial magnetic stimulation, suffer from major drawbacks, such as mechanical invasiveness, inability to focally stimulate deep brain regions and discriminate between neuronal cell types. Opto- and chemo- genetic approaches do not currently appear translatable to humans without major medical and ethical concerns. Hence, the therapeutic management of numerous degenerative brain diseases is still palliative. BRAINSTROM takes on this challenge by developing ‘nanoinvasive’, wireless neuromodulation paradigms with high spatiotemporal precision and the ability to activate or inhibit selected neuronal circuits on demand. BRAINSTORM´s innovative technological approach uses a novel class of biocompatible and functional magnetic nanomaterials, that are selectively activated by external magnetic fields at arbitrary brain depths. These multifunctional nanomaterials generate mechanical forces through magnetisation shifts and dissipate heat through hysteretic losses at selected activation frequencies. This intrinsic bimodal functionality will permit precise activation or inhibition of thermosensitive or mechanosenitive neurons, and it will be boosted by advanced polymer functionalization to transform torque into electrical signals trough piezoelectric coatings, as well as delivery to endogenous sensory channels though antibody targeting. The BRAINSTORM technology includes development of novel driving electronics, including miniaturized coils for power efficient and rapid control of ‘mechanical’ or ‘thermal’ modalities, and a focused ultrasound-based delivery framework, allowing extravasation of functional nanomaterials, hence avoiding cranial injection. After in vitro validation, the therapeutic potential of the BRAINSTORM platform will be validated in vitro through calcium imaging and network electrophysiology and piloted in vivo in a mouse model of fragile X syndrome. The ability to precisely identify targeted neuronal tissue and activate/inhibit neurons on demand will radically advance current neuromodulation technologies, paving the way for therapeutic applications to not only currently incurable neurological and psychiatric diseases (Alzheimer’s and Parkinson’s diseases, panic disorder, depression) but also to neurooncology. We will establish an implant-free, clinically scalable medical device that will overcome major barriers in the treatment of brain diseases. The more effective and less invasive treatment modalities for brain disease will deliver a huge socioeconomic impact, potentially improving the quality of life of a large share of society in Europe and the world.
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.