title: Long-term usability and bio-integration of polyimide-based intra-neural stimulating electrodes.
abstract: Stimulation of peripheral nerves has transiently restored lost sensation and has the potential to alleviate motor deficits. However, incomplete characterization of the long-term usability and bio-integration of intra-neural implants has restricted their use for clinical applications. Here, we conducted a longitudinal assessment of the selectivity, stability, functionality, and biocompatibility of polyimide-based intra-neural implants that were inserted in the sciatic nerve of twenty-three healthy adult rats for up to six months. We found that the stimulation threshold and impedance of the electrodes increased moderately during the first four weeks after implantation, and then remained stable over the following five months. The time course of these adaptations correlated with the progressive development of a fibrotic capsule around the implants. The selectivity of the electrodes enabled the preferential recruitment of extensor and flexor muscles of the ankle. Despite the foreign body reaction, this selectivity remained stable over time. These functional properties supported the development of control algorithms that modulated the forces produced by ankle extensor and flexor muscles with high precision. The comprehensive characterization of the implant encapsulation revealed hyper-cellularity, increased microvascular density, Wallerian degeneration, and infiltration of macrophages within the endoneurial space early after implantation. Over time, the amount of macrophages markedly decreased, and a layer of multinucleated giant cells surrounded by a capsule of fibrotic tissue developed around the implant, causing an enlargement of the diameter of the nerve. However, the density of nerve fibers above and below the inserted implant remained unaffected. Upon removal of the implant, we did not detect alteration of skilled leg movements and only observed mild tissue reaction. Our study characterized the interplay between the development of foreign body responses and changes in the electrical properties of actively used intra-neural electrodes, highlighting functional stability of polyimide-based implants over more than six months. These results are essential for refining and validating these implants and open a realistic pathway for long-term clinical applications in humans.
authors.affiliation: Bertarelli Foundation Chair in Translational Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; International Paraplegic Foundation Chair in Spinal Cord Repair, Center for Neuroprosthetics and Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Wurth
authors.affiliation: Bertarelli Foundation Chair in Translational Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; The Biorobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Capogrosso
authors.affiliation: Bertarelli Foundation Chair in Translational Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; The Biorobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Raspopovic
authors.affiliation: International Paraplegic Foundation Chair in Spinal Cord Repair, Center for Neuroprosthetics and Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Gandar
authors.affiliation: Bertarelli Foundation Chair in Translational Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Federici
authors.affiliation: Bertarelli Foundation Chair in Translational Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Kinany
authors.affiliation: The Biorobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cutrone
authors.affiliation: Laboratory Animals Pathology Unit, Institute of Animal Pathology, University of Bern, Bern, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Piersigilli
authors.affiliation: International Paraplegic Foundation Chair in Spinal Cord Repair, Center for Neuroprosthetics and Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Pavlov Institute of Physiology, St Petersbourg, Russia.
authors.forename: N
authors.initials: N
authors.lastname: Pavlova
authors.affiliation: Bioimaging and Optics Platform, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Guiet
authors.affiliation: The Biorobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Taverni
authors.affiliation: Bertarelli Foundation Chair in Translational Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; SAMBA Lab, International School for Advanced Studies, Trieste, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Rigosa
authors.affiliation: International Paraplegic Foundation Chair in Spinal Cord Repair, Center for Neuroprosthetics and Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Pavlov Institute of Physiology, St Petersbourg, Russia.
authors.forename: P
authors.initials: P
authors.lastname: Shkorbatova
authors.affiliation: Institute of Neurosciences, Department of Cell Biology, Physiology, and Immunology, Universitat Autònoma de Barcelona, and CIBERNED, Bellaterra, Spain.
authors.forename: X
authors.initials: X
authors.lastname: Navarro
authors.affiliation: International Paraplegic Foundation Chair in Spinal Cord Repair, Center for Neuroprosthetics and Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Q
authors.initials: Q
authors.lastname: Barraud
authors.affiliation: International Paraplegic Foundation Chair in Spinal Cord Repair, Center for Neuroprosthetics and Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Courtine
authors.affiliation: Bertarelli Foundation Chair in Translational Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; The Biorobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy. Electronic address: silvestro.micera@epfl.ch.
authors.forename: S
authors.initials: S
authors.lastname: Micera
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D004558:Electric Stimulation / Q000295:instrumentation*; D004867:Equipment Design; D019544:Equipment Failure Analysis; D005260:Female; D058542:Implantable Neurostimulators; D008137:Longitudinal Studies; D008839:Microelectrodes; D051381:Rats; D011917:Rats, Inbred Lew; D012117:Resins, Synthetic / Q000737:chemistry*; D012584:Sciatic Nerve / Q000166:cytology / Q000502:physiology*; D016896:Treatment Outcome
chemical_list: D001672:Biocompatible Materials; D012117:Resins, Synthetic; C029945:polyimide resin
keywords: Biocompatibility; Control; Intra-neural electrode; Selectivity; Stability