Nerve repair surgery is frequently delayed after traumatic nerve injuries in patients including those injuries suffered from accidents, birth, trauma, and acts of violence (Borschel & Clarke, 2009; Sulaiman et al., 2011).
The delays frequently arise as a result of the sequelae of the multiple problems associated with these injuries. However, as problems of delayed nerve repair are being recognized, immediate repair is performed when possible.
Nonetheless, the injured neurons are subjected to chronic axotomy when injury occurs relatively far from denervated targets.
For brachial plexus injuries, for example, periods of more than a year pass before regenerating axons might be expected to reach denervated targets 1 m or more away.
During the long delays whilst axons regenerate over long distances, the axotomized neurons remain without target contact and, hence, suffer chronic axotomy. Similarly, the Schwann cells in the denervated nerve stumps suffer chronic denervation over these long periods, as do the target muscles and sense organs.
Experimental models in which the two branches of the sciatic nerve and a nerve autograft were used to independently control the duration of neuron axotomy, Schwann cell denervation, and/or muscle denervation prior to delayed nerve repair revealed the progressive deterioration of nerve regeneration and muscle reinnervation after delayed nerve repair (Fu & Gordon, 1995a, 1995b; Gordon et al., 2011).
The surgical procedures included (a) cross-suture of the proximal nerve stump of chronically axotomized neurons to a freshly denervated distal nerve stump or of a freshly cut proximal nerve stump to a chronically denervated distal nerve stump (Fu & Gordon, 1995a, 1995b) and (b) cross-suture of nerves via a contralateral autograph where the duration of axotomy, Schwann cell denervation and denervation of the target muscles can be controlled independently (Gordon et al., 2011).
The delays frequently arise as a result of the sequelae of the multiple problems associated with these injuries. However, as problems of delayed nerve repair are being recognized, immediate repair is performed when possible.
Nonetheless, the injured neurons are subjected to chronic axotomy when injury occurs relatively far from denervated targets.
For brachial plexus injuries, for example, periods of more than a year pass before regenerating axons might be expected to reach denervated targets 1 m or more away.
During the long delays whilst axons regenerate over long distances, the axotomized neurons remain without target contact and, hence, suffer chronic axotomy. Similarly, the Schwann cells in the denervated nerve stumps suffer chronic denervation over these long periods, as do the target muscles and sense organs.
Experimental models in which the two branches of the sciatic nerve and a nerve autograft were used to independently control the duration of neuron axotomy, Schwann cell denervation, and/or muscle denervation prior to delayed nerve repair revealed the progressive deterioration of nerve regeneration and muscle reinnervation after delayed nerve repair (Fu & Gordon, 1995a, 1995b; Gordon et al., 2011).
The surgical procedures included (a) cross-suture of the proximal nerve stump of chronically axotomized neurons to a freshly denervated distal nerve stump or of a freshly cut proximal nerve stump to a chronically denervated distal nerve stump (Fu & Gordon, 1995a, 1995b) and (b) cross-suture of nerves via a contralateral autograph where the duration of axotomy, Schwann cell denervation and denervation of the target muscles can be controlled independently (Gordon et al., 2011).
The transient nature of expression of regeneration-associated genes in both the axotomized neurons and the denervated Schwann cells has a negative impact on nerve regeneration (Figure 61.4b–e).
In contrast to the excellent regenerative capacity of axotomized neurons regenerating their axons through freshly denervated distal nerve stump after nerve transection and immediate nerve repair, the regenerative capacity of neurons declines progressively after chronic axotomy to a steady level of 33% of that after immediate nerve repair (Figures 61.4d and 61.8g).
Chronic denervation has an even greater negative impact on regenerative capacity of axotomized motoneurons, reducing the number of nerves that reinnervate denervated muscles to less than 5% of normal (Figure 61.8h) (Fu & Gordon, 1995a; You et al., 1997).
Motoneurons that do regenerate their axons after delayed nerve repair increase the number of muscle fibers that each neuron supplies—the innervation ratio—to a maximum of three- to fivefold (Figure 61.8i and j).
The innervation ratio was determined by depleting a single muscle unit (the muscle fibers innervated by a single motoneuron) of glycogen and counting the glycogen-depleted fibers whose fiber type was determined by histochemical markers on serial muscle cross-sections (Figure 61.8a–f).
The maximum threefold increase in the innervation ratio was sufficient to compensate for the loss of motor units in the case of the 66% decline in regenerative capacity of chronically axotomized neurons (Figure 61.8k) but not in the case of the 95% decline in the number of freshly axotomized motoneurons that regenerated their axons through chronically denervated Schwann cells in the distal nerve stump (Figure 61.8l).
As a result, the reinnervated muscles fully recovered their normal contractile force after chronic axotomy of the motoneurons but not after chronic denervation of the Schwann cells in the distal nerve stump (cf Figure 61.8k and l) (Fu & Gordon, 1995a, 1995b; Gordon et al., 2011) (Figure 61.8l).
These experiments established that chronic axotomy reduced the regenerative capacity of motoneurons after transection and surgical repair and that the chronic denervation of nerve stumps reduced the ability of the Schwann cells to support the regeneration of nerves through the denervated nerve stumps.
In contrast to the excellent regenerative capacity of axotomized neurons regenerating their axons through freshly denervated distal nerve stump after nerve transection and immediate nerve repair, the regenerative capacity of neurons declines progressively after chronic axotomy to a steady level of 33% of that after immediate nerve repair (Figures 61.4d and 61.8g).
Chronic denervation has an even greater negative impact on regenerative capacity of axotomized motoneurons, reducing the number of nerves that reinnervate denervated muscles to less than 5% of normal (Figure 61.8h) (Fu & Gordon, 1995a; You et al., 1997).
Motoneurons that do regenerate their axons after delayed nerve repair increase the number of muscle fibers that each neuron supplies—the innervation ratio—to a maximum of three- to fivefold (Figure 61.8i and j).
The innervation ratio was determined by depleting a single muscle unit (the muscle fibers innervated by a single motoneuron) of glycogen and counting the glycogen-depleted fibers whose fiber type was determined by histochemical markers on serial muscle cross-sections (Figure 61.8a–f).
The maximum threefold increase in the innervation ratio was sufficient to compensate for the loss of motor units in the case of the 66% decline in regenerative capacity of chronically axotomized neurons (Figure 61.8k) but not in the case of the 95% decline in the number of freshly axotomized motoneurons that regenerated their axons through chronically denervated Schwann cells in the distal nerve stump (Figure 61.8l).
As a result, the reinnervated muscles fully recovered their normal contractile force after chronic axotomy of the motoneurons but not after chronic denervation of the Schwann cells in the distal nerve stump (cf Figure 61.8k and l) (Fu & Gordon, 1995a, 1995b; Gordon et al., 2011) (Figure 61.8l).
These experiments established that chronic axotomy reduced the regenerative capacity of motoneurons after transection and surgical repair and that the chronic denervation of nerve stumps reduced the ability of the Schwann cells to support the regeneration of nerves through the denervated nerve stumps.
That chronic denervation of nerve stumps drastically reduced the regenerative ability of axotomized motoneurons was confirmed in experiments in which nerves that regenerated through the distal nerve stump were back labeled with retrograde dyes (Sulaiman & Gordon, 2000, 2002).
The numbers of motoneurons having axons that regenerated into the denervated distal nerve stumps declined as an exponential function of the chronic denervation duration prior to delayed nerve repair and paralleled the same exponential decline in the numbers of reinnervated motor units (Figures 61.4e and 61.8l).
Chronically denervated muscles often undergo denervation atrophy to levels that have been mistaken as fatty replacement, but the remaining satellite cells can divide and fuse to reinstate functional and normally multinucleated muscle fibers after reinnervation (Schmalbruch & Lewis, 2000).
The number of the satellite cells may be limited, however. Thereby, this limit may fail to provide sufficient nuclei for the reinnervated muscle fibers to fully recover their normal size (Gordon et al., 2011; Rodrigues & Schmalbruch, 1995).
The numbers of motoneurons having axons that regenerated into the denervated distal nerve stumps declined as an exponential function of the chronic denervation duration prior to delayed nerve repair and paralleled the same exponential decline in the numbers of reinnervated motor units (Figures 61.4e and 61.8l).
Chronically denervated muscles often undergo denervation atrophy to levels that have been mistaken as fatty replacement, but the remaining satellite cells can divide and fuse to reinstate functional and normally multinucleated muscle fibers after reinnervation (Schmalbruch & Lewis, 2000).
The number of the satellite cells may be limited, however. Thereby, this limit may fail to provide sufficient nuclei for the reinnervated muscle fibers to fully recover their normal size (Gordon et al., 2011; Rodrigues & Schmalbruch, 1995).
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