Functional rewiring across spinal injuries via biomimetic nanofiber scaffolds

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Significance

Nanotechnology and neurobiology combined efforts might succeed in the design of hybrid microsystems that, once functionally integrated into the nervous tissue, might help in healing the injured spinal cord. A substantial challenge in this area is the development of structural scaffolds favoring spinal cord reconstruction. The future success of such smart devices resides also in the use of nanomaterials exploiting spinal microenvironment physical properties, such as mechanical and electrical ones, and their potential in promoting axonal regeneration. We synthesized an artificial scaffold based on nanomaterials with the necessary characteristics to guide axonal rewiring. The translational potential of introducing physics rules to neural tissue repair strategies was tested by implanting such a scaffold in spinal cord injury animal models.

Abstract

The regrowth of severed axons is fundamental to reestablish motor control after spinal-cord injury (SCI). Ongoing efforts to promote axonal regeneration after SCI have involved multiple strategies that have been only partially successful. Our study introduces an artificial carbon-nanotube based scaffold that, once implanted in SCI rats, improves motor function recovery. Confocal microscopy analysis plus fiber tracking by magnetic resonance imaging and neurotracer labeling of long-distance corticospinal axons suggest that recovery might be partly attributable to successful crossing of the lesion site by regenerating fibers. Since manipulating SCI microenvironment properties, such as mechanical and electrical ones, may promote biological responses, we propose this artificial scaffold as a prototype to exploit the physics governing spinal regenerative plasticity.

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Most cited references 50

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A sensitive and reliable locomotor rating scale for open field testing in rats.

D. Michele Basso, MICHAEL S. BEATTIE, JACQUELINE C. BRESNAHAN (1995)

Behavioral assessment after spinal cord contusion has long focused on open field locomotion using modifications of a rating scale developed by Tarlov and Klinger (1954). However, on-going modifications by several groups have made interlaboratory comparison of locomotor outcome measures difficult. The purpose of the present study was to develop an efficient, expanded, and unambiguous locomotor rating scale to standardize locomotor outcome measures across laboratories. Adult rats (n = 85) were contused at T7-9 cord level with an electromagnetic or weight drop device. Locomotor behavior was evaluated before injury, on the first or second postoperative day, and then for up to 10 weeks. Scoring categories and attributes were identified, operationally defined, and ranked based on the observed sequence of locomotor recovery patterns. These categories formed the Basso, Beattie, Bresnahan (BBB) Locomotor Rating Scale. The data indicate that the BBB scale is a valid and predictive measure of locomotor recovery able to distinguish behavioral outcomes due to different injuries and to predict anatomical alterations at the lesion center. Interrater reliability tests indicate that examiners with widely varying behavioral testing experience can apply the scale consistently and obtain similar scores. The BBB Locomotor Rating Scale offers investigators a more discriminating measure of behavioral outcome to evaluate treatments after spinal cord injury.

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Astrocyte scar formation aids central nervous system axon regeneration.

Mark A Anderson, Joshua Burda, Yilong Ren … (2016)

Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.

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Biomaterials. Electronic dura mater for long-term multimodal neural interfaces.

Ivan Minev, Pavel Musienko, Arthur Hirsch … (2015)

The mechanical mismatch between soft neural tissues and stiff neural implants hinders the long-term performance of implantable neuroprostheses. Here, we designed and fabricated soft neural implants with the shape and elasticity of dura mater, the protective membrane of the brain and spinal cord. The electronic dura mater, which we call e-dura, embeds interconnects, electrodes, and chemotrodes that sustain millions of mechanical stretch cycles, electrical stimulation pulses, and chemical injections. These integrated modalities enable multiple neuroprosthetic applications. The soft implants extracted cortical states in freely behaving animals for brain-machine interface and delivered electrochemical spinal neuromodulation that restored locomotion after paralyzing spinal cord injury.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 13 October 2020

Publication date (Electronic): 30 September 2020

Publication date PMC-release: 30 September 2020

Volume: 117

Issue: 41

Pages: 25212-25218

Affiliations

[1] ^aNeurobiology Department, International School for Advanced Studies (SISSA/ISAS) , Trieste 34136, Italy;

[2] ^bNano Innovation Laboratory , ELETTRA Synchrotron Light Source, Trieste 34149, Italy;

[3] ^cMolecular Imaging Unit, Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA) , San Sebastian 20014, Spain;

[7] ^dBionanotechnology Unit, CIC biomaGUNE, BRTA , San Sebastian 20014, Spain;

[4] ^eIkerbasque , Basque Foundation for Science, Bilbao 48009, Spain;

[5] ^fDepartment of Physics, University of Rome Tor Vergata , Rome 00133, Italy;

[6] ^gDepartment of Chemical and Pharmaceutical Sciences, University of Trieste , Trieste 34127, Italy

Author notes

¹To whom correspondence may be addressed. Email: ballerin@ 123456sissa.it or prato@ 123456units.it .

Edited by John A. Rogers, Northwestern University, Evanston, IL, and approved September 4, 2020 (received for review March 27, 2020)

Author contributions: M.P. and L.B. conceived the idea; L.B. designed research; S.U., A.F.B., M.M., D.S., R.C., E.R.A., D.P., A.E., and P.R.C. performed research; M.S. and M.D.C. contributed new reagents/analytic tools; S.U., A.F.B., M.M., D.S., R.C., E.R.A., D.P., A.E., and P.R.C. analyzed data; and L.B. wrote the paper.