Periodic Reporting for period 4 - eAXON (Electronic AXONs: wireless microstimulators based on electronic rectification of epidermically applied currents)
Berichtszeitraum: 2021-11-01 bis 2023-04-30
Building interfaces between the electronic domain and the human nervous system is one of the most demanding challenges of nowadays engineering. Fascinating developments have already been performed such as visual cortical implants for the blind and cochlear implants for the deaf. Yet implantation of most electrical stimulation systems requires complex surgeries which hamper their use in some clinical scenarios. In particular, previously developed systems based on central stimulation units are not adequate for applications in which a large number of sites must be individually stimulated over large and mobile body parts, thus hindering neuroprosthetic solutions for patients suffering paralysis due to spinal cord injury or other neurological disorders. A technological solution to address this challenge can consist in deploying a network of addressable single-channel wireless microstimulators implantable with simple procedures such as injection. Such a solution was proposed and tried in the past. However, previous attempts did not achieve satisfactory success because the developed implants were stiff and too large. That is, those devices were too invasive for dense implantation. Further miniaturization was prevented because of the use of inductive coupling and batteries as energy sources. In the eAXON project we explored an innovative method for performing electrical stimulation in which the implanted microstimulators operate as rectifiers of bursts of innocuous high frequency current supplied through skin electrodes shaped as garments. This approach has the potential to reduce the diameter of the implants to a fraction of the diameter of current microstimulators and, more significantly, to allow that most of the implants’ volume consists of materials whose density and flexibility match those of neighboring living tissues for minimizing invasiveness.
The main global objective of the eAXON project was to develop and in vivo demonstrate, in acute and chronic assays, electrical stimulation systems consisting of addressable wireless microelectronic implants (eAXONs) whose actuation principle is based on electronic rectification of epidermically applied currents. These systems exhibit an unprecedented level of minimal invasiveness which, in turn, will yield novel modes of application of electrical stimulation for therapeutics. A subjacent global objective of the proposal was to develop and demonstrate these systems specifically aiming at neuromuscular stimulation for developing neuroprosthetic systems of the type grouped under the term Functional Electrical Stimulation (FES).
The main global objective of the eAXON project was to develop and in vivo demonstrate, in acute and chronic assays, electrical stimulation systems consisting of addressable wireless microelectronic implants (eAXONs) whose actuation principle is based on electronic rectification of epidermically applied currents. These systems exhibit an unprecedented level of minimal invasiveness which, in turn, will yield novel modes of application of electrical stimulation for therapeutics. A subjacent global objective of the proposal was to develop and demonstrate these systems specifically aiming at neuromuscular stimulation for developing neuroprosthetic systems of the type grouped under the term Functional Electrical Stimulation (FES).
Threadlike addressable neuromuscular microstimulators (eAXONs) have been developed and in vivo demonstrated. These injectable implants have a submillimetric diameter (0.97 mm diameter, 35 mm length) and consist of a microcircuit, which contains a single custom-developed integrated circuit, housed within a titanium capsule (0.7 mm diameter, 6.5 mm length), and two platinum–iridium coils that form two electrodes (3 mm length) located at opposite ends of a silicone body (Journal of Neural Engineering, 2022, 19(5): 056015 (doi: 10.1088/1741-2552/ac8dc4)). These devices are deployed percutaneously by injection and can form a network of microstimulators that can be controlled independently for producing complex movement patterns.
Several in vivo assays have been performed with the eAXON technology to demonstrate its potential for neuroprosthetics. For instance, in acute assays with anesthetized rabbits, it was demonstrated that antagonist movements of the foot can be produced by activating either eAXONs implanted in the tibialis anterior or in the gastrocnemius medialis muscles. And in acute assays with anesthetized sheep, in which eAXONs were implanted in the finger extensor muscle, in the finger flexor muscle, in the foot flexor muscle, and, in the foot extensor muscle, complex movement patterns were generated (e.g. the anesthetized sheep draw elliptical shapes on a whiteboard). Furthermore, a chronic study in rabbits has been carried out to demonstrate the long-term robustness of the eAXONs. (These results are pending publication.)
Because of its minimal invasiveness, a remarkable advantage offered by the eAXON technology is the capability to independently stimulate portions of a muscle. In addition to allowing finer muscle control, this allows activating the muscle fibers in a more physiological way for preventing muscle fatigue. This scheme is known as interleaved stimulation and its feasibility was demonstrated early in the project with conventional intramuscular electrodes (Journal of Neural Engineering, 2020, 17(4):046037 (doi: 10.1088/1741-2552/aba99e)) and later in the project with eAXONs implanted in sheep (pending publication).
In essence, the eAXON project not only has achieved the technological and scientific objectives originally planned but it has gone further by laying the foundations of a novel sensing technology (IEEE Transactions on Biomedical Circuits and Systems, 2020, 14(4):867-878 (doi: 10.1109/TBCAS.2020.3002326)) and of a brain stimulation and recording technology (patent application pending publication). In addition, co-developments within the EXTEND collaborative project (H2020-ICT-2017-1, grant agreement 779982) have demonstrated the eAXON technology in humans, a test scenario not considered in the eAXON project.
An additional global objective of the eAXON project was to illustrate that galvanic coupling through living tissues at high frequencies can be effectively and safely used for powering electronic implants in general; as an alternative to current energy transfer and harvest methods which require embedding bulky components within the implants. This objective was also achieved through a number of studies presented in journals and conferences that demonstrated that thread-like implants can safely draw powers in the order of a few milliwatts by galvanic coupling. Of particular relevance are the journal publications IEEE Access 2020, 8:37808-37820 (doi: 10.1109/ACCESS.2021.3096729) and IEEE Access, 2021, 9:100594-100605 (doi: 10.1109/ACCESS.2020.2975597). And, although these results were performed within the framework of the EXTEND project, it is also worth noting a study performed in humans published in IEEE Transactions on Biomedical Engineering, 2023, 70(2):659-670 (doi: 10.1109/TBME.2022.3200409).
Several in vivo assays have been performed with the eAXON technology to demonstrate its potential for neuroprosthetics. For instance, in acute assays with anesthetized rabbits, it was demonstrated that antagonist movements of the foot can be produced by activating either eAXONs implanted in the tibialis anterior or in the gastrocnemius medialis muscles. And in acute assays with anesthetized sheep, in which eAXONs were implanted in the finger extensor muscle, in the finger flexor muscle, in the foot flexor muscle, and, in the foot extensor muscle, complex movement patterns were generated (e.g. the anesthetized sheep draw elliptical shapes on a whiteboard). Furthermore, a chronic study in rabbits has been carried out to demonstrate the long-term robustness of the eAXONs. (These results are pending publication.)
Because of its minimal invasiveness, a remarkable advantage offered by the eAXON technology is the capability to independently stimulate portions of a muscle. In addition to allowing finer muscle control, this allows activating the muscle fibers in a more physiological way for preventing muscle fatigue. This scheme is known as interleaved stimulation and its feasibility was demonstrated early in the project with conventional intramuscular electrodes (Journal of Neural Engineering, 2020, 17(4):046037 (doi: 10.1088/1741-2552/aba99e)) and later in the project with eAXONs implanted in sheep (pending publication).
In essence, the eAXON project not only has achieved the technological and scientific objectives originally planned but it has gone further by laying the foundations of a novel sensing technology (IEEE Transactions on Biomedical Circuits and Systems, 2020, 14(4):867-878 (doi: 10.1109/TBCAS.2020.3002326)) and of a brain stimulation and recording technology (patent application pending publication). In addition, co-developments within the EXTEND collaborative project (H2020-ICT-2017-1, grant agreement 779982) have demonstrated the eAXON technology in humans, a test scenario not considered in the eAXON project.
An additional global objective of the eAXON project was to illustrate that galvanic coupling through living tissues at high frequencies can be effectively and safely used for powering electronic implants in general; as an alternative to current energy transfer and harvest methods which require embedding bulky components within the implants. This objective was also achieved through a number of studies presented in journals and conferences that demonstrated that thread-like implants can safely draw powers in the order of a few milliwatts by galvanic coupling. Of particular relevance are the journal publications IEEE Access 2020, 8:37808-37820 (doi: 10.1109/ACCESS.2021.3096729) and IEEE Access, 2021, 9:100594-100605 (doi: 10.1109/ACCESS.2020.2975597). And, although these results were performed within the framework of the EXTEND project, it is also worth noting a study performed in humans published in IEEE Transactions on Biomedical Engineering, 2023, 70(2):659-670 (doi: 10.1109/TBME.2022.3200409).
The eAXON project has laid out the foundations for a novel technology, with unprecedented minimal invasiveness, for neuroprosthetic solutions for patients suffering paralysis due to spinal cord injury, stroke, or other neurological disorders.
The developed implant prototypes, the eAXONs, have been built using materials, encapsulation methods, and fabrication procedures common in the medical devices industry for robustness and for regulatory compliance. Since the conception of the technology, both the implants and the generators have been designed taking into account safety and regulatory aspects. All this grants a relatively rapid transition to actual clinical applications.
Furthermore, the eAXON project has exposed, and set the modeling framework for, the use of galvanic coupling, or, more precisely, coupling by volume conduction, for powering threadlike electronic implants in general; as an alternative to current energy transfer and harvest methods which require embedding bulky components within the implants.
The developed implant prototypes, the eAXONs, have been built using materials, encapsulation methods, and fabrication procedures common in the medical devices industry for robustness and for regulatory compliance. Since the conception of the technology, both the implants and the generators have been designed taking into account safety and regulatory aspects. All this grants a relatively rapid transition to actual clinical applications.
Furthermore, the eAXON project has exposed, and set the modeling framework for, the use of galvanic coupling, or, more precisely, coupling by volume conduction, for powering threadlike electronic implants in general; as an alternative to current energy transfer and harvest methods which require embedding bulky components within the implants.