Ultrastructural Appearance of Intentionally Frustrated Axonal Regeneration in Rat Sciatic Nerve

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Abstract
The ultrastructural appearance of axons regenerating after crush injury was examined in rat sciatic nerves in which proximodistal growth was interrupted (frustrated regeneration) by placement of a tight ligature 1 cm distal to the original crush injury, and in nerves lacking a distal tie (unimpeded regeneration). Examination of unimpeded regenerating axons four and seven days after injury showed minute axonal sprouts as well as scattered dilated (2–10 μm) axonal profiles containing large numbers of anastomosing tubulovesicular elements and vacuoles. These dilated profiles were consistent with the appearance of growth cones, the motile tips of regenerating axons, as described in various in vivo and in vitro systems. The ultrastructural appearance of regenerating axons accumulating proximal to a frustrating tie was a function of time after arrival at the ligature. At the earliest time examined (one week) large numbers of axonal profiles accumulated at the ligature which were qualitatively similar to growth cones seen in unimpeded regeneration, although slightly larger in diameter. With time, the uniform population of growth cones proximal to the frustrating ligature was replaced by dilated axons containing large numbers of neurofilaments, dense collections of heterogeneous membranous organelles, or delicate to coarse tubulovesicular elements admixed with a variety of subcellular organelles. Rare examples of axonal dystrophy were demonstrated after chronic frustration of regeneration; however, they represented only a small percentage (less than 1%) of frustrated axons. Frustrated regeneration was accompanied by scattered examples of demyelination/remyelination of large axons proximal to the ligature as well as transperineurial growth of axons as microfascicles to escape the site of ligation.