This provides the most conclusive
evidence to date that severed nerve fibers in the
spinal cord can, in fact, regenerate for long distances
and establish proper functional connections.
The body's spinal cord is like a super highway
of nerves. When an injury occurs, the body's policing
defenses put up a roadblock in the form of a scar
to prevent further injury, but it stops all neural
traffic from moving forward.
Researchers from Case Western Reserve University,
Drexel University and the University of Arkansas
bypassed this roadblock in the spinal cord. First,
the researchers regenerated the severed nerve fibers,
also called axons, around the initial large lesion
with a segment of peripheral nerve taken from the
leg of the same animal that suffered the spinal
injury. Next, they jump started neural traffic
by allowing many nerve fibers to exit from the
end of the bridge. This was accomplished, for the
first time, by using an enzyme that stopped growth
inhibitory molecules from forming in the small
scar that forms at the exit ramp of the bridge,
where it is inserted into the spinal cord on the
other side of the lesion. This allowed the growing
axons to reconnect with the spinal cord.
Jerry Silver, a professor of neurosciences at the
Case School of Medicine, was senior author among
the researchers reporting in the Journal of Neuroscience
article, "Combining an Autologous Peripheral Nervous
System 'Bridge' and Matrix Modification by Chondroitinase
Allows Robust Functional Regeneration beyond a
Hemisection Lesion of the Adult Rat Spinal Cord." The
other researchers were John Houle, the lead author,
and Veronica Tom (a Case alum) from Drexel University
College of Medicine; and Gail Wagoner and Napoleon
Phillips from the University of Arkansas.
The researchers employed a combination of two strategies--one
old and one new--in efforts to regenerate nerves
in the spinal cord and restore movement, said Silver.
For more than 100 years, researchers have used
grafts of peripheral nerves from the rib area or
parts of the leg. While peripheral nerves can be
used successfully as grafts in the limbs, spinal
cord injuries put up defenses called inhibitory
chondroitin sulfate proteoglycans that create molecular
guardrails within scars at the lesion site. These
scars act as a barrier to regenerating axons and
result in loss of the ability to breathe or move
arms or legs, depending upon the injury site.
Silver said the medical community also assumed
that the cut axon tips died when they hit the scar
wall. In prior research in his lab by his graduate
student, Tom, it was discovered that axons are
alive and continue to attempt to grow for years.
Silver describes them as "trucks stuck in mud going
no where." It also explains why some people gain
some movement back or come out of comas after many
years as the nerve fibers sprout through weakened
or remodeled areas of the scar.
About 16 years ago, Silver also made another find
that proteoglycans, a sugary protein, is present
at the site of spinal cord lesions. He also knew
that a particular enzyme from the bacteria Proteus
vulgaris, called chondroitinase, might dismantle
the proteoglycans by clipping their sugar branches,
thereby preventing the scar wall from building.
In a National Institutes of Health-supported animal
study, 12 rats had spinal injuries at the cervical
level 3 (C3) that resulted in impaired motor functions
to their right side limbs. The animals had trouble
moving, climbing or grooming.
Combining the old with the new, the researchers
grafted a 1.5 centimeter piece of the tibial branch
of he sciatic nerve to the C3 area of the spinal
cord and allowed the nerve fibers to grow and regenerate
over three weeks. .
At approximately two and a half weeks into the
new nerve growth, Houle implanted a small pump
that delivered a steady dose of chondroitinase
to a new incision site near C5 where the researchers
hoped to reconnect the other end of the bridge
to the spinal cord, but also prevent further scarring.
They also primed the newly re-grown axons for rapid
regeneration by clipping their ends.
Silver said this method resulted in approximately
20 percent of the nerve fibers leaving the bridge
and reconnecting with the spinal cord. It brought
about markedly improved mobility for the seven
rats given the chondroitinase treatment.
A control group of five rats underwent the same
procedure. Instead of the chondroitinase, they
were given a saline solution. None showed any nerve
growth out of the bridge or improvement in their
limbs.
To test whether something other than regeneration
was at work in restoring movement, the neural bridges
were severed and the rats lost all movement gained
from the combination of treatments. This provides
the most conclusive evidence to date that severed
nerve fibers in the spinal cord can, in fact, regenerate
for long distances and establish proper functional
connections.
Silver said if the method is perfected and successful
with primates, it could go to human trials within
a relatively short time.
His next step is a neural bridge that would help
quadriplegics, who are unable to breathe without
assistance, move their diaphragms on their own.
In future animal studies he plans to undertake
nerve grafts from the leg to bridge the area of
the spinal cord that controls breathing.
"While this was one small step for a rat, it was
one giant leap for man," said Silver.
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