Periodic Reporting for period 2 - ByAxon (Towards an active bypass for neural reconnection)
Reporting period: 2019-01-01 to 2020-12-31
Spinal Cord Injuries (SCIs) caused by trauma are usually irreversible and have devastating consequences, including permanent full or partial paralysis, due to the interruption of neural connections through the spinal cord. According to the World Health Organization (WHO), between 250 000 and 500 000 people suffer a SCI every year with a two to five times higher probability of premature death.
In Europe, the incidence per million inhabitants/year has been of 10-20 since 2000. SCIs involve an extraordinary high cost, that in Europe are almost entirely covered by National governments. As an example, the estimated lifetime cost for complete quadriplegia occurring at 25 years old is 4.6 billion US dollar (NSCISC, 2013).
The ByAxon project aims to demonstrate that a new-generation of nanostructured sensors and electrodes can offer a novel way of bypassing locally a SCI by allowing interfacing of the spinal cord directly with a combination of high sensitivity and low tissue disturbance.
The objectives are specifically the fabrication of nanostructured high-resolution magnetic field sensors that can be used at room temperature, and nanowire-coated electrodes for neural interfacing. These will then be assessed on the performance, biocompatibility and biofunctionality of both interfaces. An initial evaluation of the synaptic-communication restoration in spinal cord cultures of a bypass prototype assembled with the new neural interfaces will be carried out in the latter part of the project.
In Europe, the incidence per million inhabitants/year has been of 10-20 since 2000. SCIs involve an extraordinary high cost, that in Europe are almost entirely covered by National governments. As an example, the estimated lifetime cost for complete quadriplegia occurring at 25 years old is 4.6 billion US dollar (NSCISC, 2013).
The ByAxon project aims to demonstrate that a new-generation of nanostructured sensors and electrodes can offer a novel way of bypassing locally a SCI by allowing interfacing of the spinal cord directly with a combination of high sensitivity and low tissue disturbance.
The objectives are specifically the fabrication of nanostructured high-resolution magnetic field sensors that can be used at room temperature, and nanowire-coated electrodes for neural interfacing. These will then be assessed on the performance, biocompatibility and biofunctionality of both interfaces. An initial evaluation of the synaptic-communication restoration in spinal cord cultures of a bypass prototype assembled with the new neural interfaces will be carried out in the latter part of the project.
During the first two years of the project, the main effort has been made on the development and characterization of the bypass parts materials. In addition, biocompatibility tests are already being carried out, as well as initial tests of the excitation ability of the nanostructured electrodes.
Regarding the magnetic sensors, first prototypes have been developed in GREYC/CNRS (France) by depositing thin films of La0.7Sr0.3MnO3 (LSMO) using the technique of Pulsed Laser Deposition. The on-bench performance of these sensors has been characterized both in GREYC/CNRS and IMDEA-Nanociencia (Spain), including their sensitivity, detectivity or bridge imbalance. Sub-nT/Hz-1/2 detectivity values have been obtained in the range 10-100 Hz, even before complete optimization of the system.
In parallel, nanostructured electrodes have been fabricated at IMDEA Nanociencia (Spain) using two approaches:
(1) Coating of vertical free-standing metallic nanowires grown by template assisted electrochemical deposition. We have successfully prepared coatings of nanowires of various metals, using two kinds of template.
(2) Coating of conductive polymeric nanopillars fabricated by nanoimprinting. Different compositions of polymer have been tested in order to optimize the conductivity of the pillars.
The teams of SISSA (Italy), SESCAM and CSIC (Spain) initiated the evaluation of the biocompatibility of the bypass parts and prototypes. Research efforts have focused on two main objectives:
(1) To evaluate the biocompatibility in vitro of the materials and nanostructured devices fabricated;
(2) To functionalize the bypass elements/prototype to enhance biocompatibility and reduce tissue disturbance.
An exhaustive screening of the interaction of the different materials and nanostructured devices fabricated with embryonic neural progenitor cells (CSIC+SESCAM), postnatal hippocampal cells (SISSA) and organotypic cultures (SISSA) were performed. Studies focused on neural cell adhesion, viability, morphology, differentiation, and simultaneous imaging of the intracellular calcium activity of living neurons. Material samples analyzed included:
(1) Electrodeposited nanowires in either a random or vertical position on the substrate;
(2) Vertical metallic nanowires up to 2 microns long of single metal samples and combinations of metals;
(3) Polymeric nanopillars of different electrical conductance;
(4) Reduced graphene oxide nanofibers.
With respect to the functionalization of the substrates aimed to improve their biocompatibility, various treatments are under study. Initial stimulation tests on dissociated hippocampal cultures using some of the nanostructured electrodes have been performed in SISSA (Italy), using live calcium imaging to monitor the activity response.
Regarding the magnetic sensors, first prototypes have been developed in GREYC/CNRS (France) by depositing thin films of La0.7Sr0.3MnO3 (LSMO) using the technique of Pulsed Laser Deposition. The on-bench performance of these sensors has been characterized both in GREYC/CNRS and IMDEA-Nanociencia (Spain), including their sensitivity, detectivity or bridge imbalance. Sub-nT/Hz-1/2 detectivity values have been obtained in the range 10-100 Hz, even before complete optimization of the system.
In parallel, nanostructured electrodes have been fabricated at IMDEA Nanociencia (Spain) using two approaches:
(1) Coating of vertical free-standing metallic nanowires grown by template assisted electrochemical deposition. We have successfully prepared coatings of nanowires of various metals, using two kinds of template.
(2) Coating of conductive polymeric nanopillars fabricated by nanoimprinting. Different compositions of polymer have been tested in order to optimize the conductivity of the pillars.
The teams of SISSA (Italy), SESCAM and CSIC (Spain) initiated the evaluation of the biocompatibility of the bypass parts and prototypes. Research efforts have focused on two main objectives:
(1) To evaluate the biocompatibility in vitro of the materials and nanostructured devices fabricated;
(2) To functionalize the bypass elements/prototype to enhance biocompatibility and reduce tissue disturbance.
An exhaustive screening of the interaction of the different materials and nanostructured devices fabricated with embryonic neural progenitor cells (CSIC+SESCAM), postnatal hippocampal cells (SISSA) and organotypic cultures (SISSA) were performed. Studies focused on neural cell adhesion, viability, morphology, differentiation, and simultaneous imaging of the intracellular calcium activity of living neurons. Material samples analyzed included:
(1) Electrodeposited nanowires in either a random or vertical position on the substrate;
(2) Vertical metallic nanowires up to 2 microns long of single metal samples and combinations of metals;
(3) Polymeric nanopillars of different electrical conductance;
(4) Reduced graphene oxide nanofibers.
With respect to the functionalization of the substrates aimed to improve their biocompatibility, various treatments are under study. Initial stimulation tests on dissociated hippocampal cultures using some of the nanostructured electrodes have been performed in SISSA (Italy), using live calcium imaging to monitor the activity response.
The project’s findings will lead to new opportunities for the healthcare industry, and could as well give place to future spin-offs. By implanting the probes we propose in specific targets, they will be selectively sensitive for e.g. activity in motor or sensory pathways.
In particular, magnetic field sensing is present in many technologies from research to consumer electronics. In the context of biomedicine, a magnetic field sensor able to reach picotesla resolution for low frequencies and at RT will mean a significant impact in several applications. This technique would not require high magnetic fields produced by superconducting magnets, but instead a performing sensor able to detect low signals at low frequencies.
A number of technological areas will potentially benefit from our proposed new generation of high resolution low-field sensors operating at room temperature as such as metal defects and geophysical anomalies detectors, water cleaning treatments, magnetic ink and nanoparticles recognition, amongst others.
The ByAxon consortium assembles key actors for the emergence of a genuine innovation ecosystem and will promote the education and professional formation of a new community of young researchers engaged in these unique research approaches.
In particular, magnetic field sensing is present in many technologies from research to consumer electronics. In the context of biomedicine, a magnetic field sensor able to reach picotesla resolution for low frequencies and at RT will mean a significant impact in several applications. This technique would not require high magnetic fields produced by superconducting magnets, but instead a performing sensor able to detect low signals at low frequencies.
A number of technological areas will potentially benefit from our proposed new generation of high resolution low-field sensors operating at room temperature as such as metal defects and geophysical anomalies detectors, water cleaning treatments, magnetic ink and nanoparticles recognition, amongst others.
The ByAxon consortium assembles key actors for the emergence of a genuine innovation ecosystem and will promote the education and professional formation of a new community of young researchers engaged in these unique research approaches.