Engineering Novel Spinal Circuits to Promote Recovery after Spinal Injury

Abstract

We have developed an innovative way to establish a functional bridge around a spinal lesion. We disconnected the T13 nerve from its muscle targets, leaving the proximal end intact. The cut end was inserted either into an intact spinal cord, to assess regeneration of T13 axons into the cord and synapse formation with spinal neurons, or caudal to a hemisection at L2/3, to assess restoration of function below the injury. Four to 28 weeks later, anterograde tracers indicated that axons from the inserted T13 nerve regenerated into the ventral horn, the intermediate zone, and dorsal horn base, both in intact and hemisected animals. Antibodies to cholinergic markers showed that many regenerating axons were from T13 motoneurons. Electrical stimulation of the T13 nerve proximal to the insertion site 4 weeks or more after insertion into the intact cord evoked local field potentials in the intermediate zone and ventral horn, which is where T13 axons terminated. Stimulation of T13 in 71% of the animals (8 hemisected, 7 intact) evoked contraction of the back or leg muscles, depending on the level of insertion. Animals in which T13 was inserted caudal to hemisection had significantly less spasticity and muscle wasting and greater mobility at the hip, knee, ankle, and digits in the ipsilateral hindlimb than did animals with a hemisection only. Thus, T13 motor axons form novel synapses with lumbosacral motor circuits. Because the T13 motor neurons retain their connections to the brain, these novel circuits might restore voluntary control to muscles paralyzed below a spinal lesion.

Spinal cord bypass surgery using peripheral nerve transfers: review of translational studies and a case report on its use following complete spinal cord injury in a human

“…Furthermore, this strategy partially ameliorated the spasticity that results following cord hemisection. 2 In the current report, we describe a patient with a complete spinal cord injury who underwent bilateral transfer of the T-11 nerves into the spinal canal below the level of injury. We chose to insert the transferred intercostal nerves into the spinal canal but not into the spinal cord itself, to avoid causing further cord injury.…”

“…2 An intercostal nerve was transferred into the spinal cord caudal to an ipsilateral hemisection. Peripheral nerve fibers grew into the ventral horn of the spinal cord and made functional synapses on alpha motor neurons.…”

“…Peripheral nerve fibers grew into the ventral horn of the spinal cord and made functional synapses on alpha motor neurons. 2,3 Stimulation of the transferred nerve generated visible contractions in the paralyzed lower extremity. Furthermore, this strategy partially ameliorated the spasticity that results following cord hemisection.…”

“…Thus, this technique differs quite a bit from that in the rodent model described above. 2 A strategy involving the direct insertion of nerves into the spinal cord would be appropriate only in the setting of chronic spinal cord injury in which the level of recovery is absent and stable below the level of injury. It is our opinion that the incisions needed to insert the nerves into the cord may cause unacceptable damage to a partially injured spinal cord in the acute setting, and thus compromising its ability to recover.…”

Peripheral Nerve Grafts Support Regeneration after Spinal Cord Injury

“…Here, we will discuss some basic technical aspects of using a PNG to promote regeneration, the application of PNGs to a variety of injury conditions (including a delayed grafting [chronic injury] approach), the use of PNGs in a combinatorial treatment strategy, and the translation of peripheral nerve (PN) grafting to large animal models of spinal cord injury (SCI). This review focuses on results obtained from grafting peripheral nerve segments into the injured spinal cord, but it would be remiss not to mention that alternative approaches using components of peripheral nerves (e.g., purified Schwann cells in implantable guidance channels [11][12][13][14][15][16][17][18][19][20][21], or the re-routing of a peripheral nerve from its target muscle to enter the spinal cord distal to an injury [22][23][24]) have demonstrated considerable success in establishing connectivity across a lesion site. Notably, the number of Electronic supplementary material The online version of this article (doi:10.1007/s13311-011-0024-6) contains supplementary material, which is available to authorized users.…”