title: Biomaterial bridges enable regeneration and re-entry of corticospinal tract axons into the caudal spinal cord after SCI: Association with recovery of forelimb function.
abstract: Severed axon tracts fail to exhibit robust or spontaneous regeneration after spinal cord injury (SCI). Regeneration failure reflects a combination of factors, including the growth state of neuronal cell bodies and the regeneration-inhibitory environment of the central nervous system. However, while spared circuitry can be retrained, target reinnervation depends on longitudinally directed regeneration of transected axons. This study describes a biodegradable implant using poly(lactide-co-glycolide) (PLG) bridges as a carrier scaffold to support regeneration after injury. In order to detect regeneration of descending neuronal tracts into the bridge, and beyond into intact caudal parenchyma, we developed a mouse cervical implantation model and employed Crym:GFP transgenic mice. Characterization of Crym:GFP mice revealed that descending tracts, including the corticospinal tract, were labeled by green fluorescent protein (GFP), while ascending sensory neurons and fibers were not. Robust co-localization between GFP and neurofilament-200 (NF-200) as well as GFP and GAP-43 was observed at both the rostral and caudal bridge/tissue interface. No evidence of similar regeneration was observed in mice that received gelfoam at the lesion site as controls. Minimal co-localization between GFP reporter labeling and macrophage markers was observed. Taken together, these data suggest that axons originating from descending fiber tracts regenerated, entered into the PLG bridge at the rostral margin, continued through the bridge site, and exited to re-enter host tissue at the caudal edge of the intact bridge. Finally, regeneration through implanted bridges was associated with a reduction in ipsilateral forelimb errors on a horizontal ladder task.
authors.affiliation: Institute for Memory Impairments and Neurological Disorders (iMIND), University of California, Irvine, CA, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Pawar
authors.affiliation: Institute for Memory Impairments and Neurological Disorders (iMIND), University of California, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, USA; Department of Physical Medicine and Rehabilitation, University of California, Irvine, CA, USA; Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Cummings
authors.affiliation: Department of Chemical and Biological Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA.
authors.forename: Aline
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Department of Chemical and Biological Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA.
authors.forename: Lonnie D
authors.initials: LD
authors.lastname: Shea
authors.affiliation: Salk Institute, San Diego, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Levine
authors.affiliation: Salk Institute, San Diego, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Pfaff
authors.affiliation: Institute for Memory Impairments and Neurological Disorders (iMIND), University of California, Irvine, CA, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, USA; Department of Physical Medicine and Rehabilitation, University of California, Irvine, CA, USA; Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA. Electronic address: aja@uci.edu.
authors.forename: Aileen J
authors.initials: AJ
authors.lastname: Anderson
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D001672:Biocompatible Materials / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D005552:Forelimb / Q000502:physiology / Q000503:physiopathology; D019922:GAP-43 Protein / Q000378:metabolism; D048091:Guided Tissue Regeneration; D008124:Locomotion; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration; D010587:Phagocytosis; D011098:Polyglactin 910 / Q000737:chemistry / Q000627:therapeutic use*; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000628:therapy*; D054457:Tissue Scaffolds / Q000737:chemistry; D000090803:mu-Crystallins
chemical_list: D001672:Biocompatible Materials; C000716470:Crym protein, mouse; D019922:GAP-43 Protein; D011098:Polyglactin 910; D000090803:mu-Crystallins
keywords: Bridge; Cylinder reaching; Growth associated protein 43 (GAP-43); Ladder beam; Macrophage; Nerve guide; Poly(lactide-co-glycolide) (PLG); Regeneration; Spinal cord injury