Biomedical Engineering Reference
In-Depth Information
2.1.
Pathophysiology
In both the CNS and PNS, tissue damage induces a cascade of regulated cellular,
physical and biochemical events that are time and severity dependent. In a
damaged axon, the proximal nerve segment first swells and retracts in a process
known as dieback (retrograde degeneration). Within hours, the distal nerve
undergoes Wallerian degeneration, events characterized by disruption of
microfilaments, axonal swelling, myelin breakdown and eventual disintegration
of the distal segment (Figure 3). If the initial trauma does not incur cell death, the
proximal axon sprouts multiple new projections.
In the PNS, new axonal branches are stimulated and guided by a host of
biochemical, cellular and physical factors [4]. Many of these cues are presented
by proliferating Schwann cells that have migrated into and distal to the injury
zone. However, even in the presence of Schwann cells, axons projecting into the
lesion are often “confused” due to insufficient guidance mechanisms. Moreover,
intrafascicular fibrosis is common as myofibroblasts invading the area can
synthesize scar tissue. The lack of directional stimulation and the accumulation
of scar can lead to aberrant regeneration, a condition signified by abnormal
axonal projection, misdirection and improper reinnervation [5]. Axons that
traverse the lesion eventually follow paths outlined by endoneurial tube
remnants. However, the rate of axonal regeneration is slow, on the order of
1mm/day. At these regeneration speeds, other problems arise, including motor
endplate degradation, intramuscular fibrosis and muscle atrophy [6].
In the adult CNS, the landscape is markedly different. The dogma that CNS
neurons cannot regenerate after injury has been recanted [7]. Indeed adult CNS
neurons have an intrinsic ability for regeneration and this observation was known
as early as 1911 [8]. However, the poor regenerative outcomes clinically
observed are predominately determined by a growth inhibiting
microenvironment. Endogenous molecules such as myelin-associated
glycoprotein, Nogo-A, oligodendrocyte-myelin glycoprotein and chondroitin
sulfate proteoglycans contribute to non-permissive milieu that causes abortive
regeneration [9]. Hypertrophic astrocytes also form a barrier to regeneration,
either through induction of a stop signal [10] or via formation of a physical scar.
Moreover, primary CNS damage often leads to secondary injury, which is a
progressive malady that incurs additional cell death. Secondary injury is initiated
by initial damage to cell membranes, which permits the influx of extracellular
ions, including Ca
+2
. Calcium dependent processes are then set into motion,
causing depolymerization of cytoskeleton, membrane damage and eventual cell
death. Dying neurons in turn, emit toxins, which spread to neighboring cells.
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