Therapies For Injured Peripheral Nerve

Crush injuries of peripheral nerves regenerate relatively well because the proximal and distal segments of the nerve remain aligned so that proximal axon stumps can regenerate into distal endoneurial tubes. Transections, or injuries that necessitate removing segments of nerve, are more difficult to repair. The cut ends of the nerves retract, and it is difficult to suture them back together. Fibroblasts invade the wound space, resulting in the formation of scar tissue that leads sprouting proximal axons to form neuromas. Continuous longitudinal sutures have been used successfully to bridge small gaps in the rat sciatic nerve (Scherman et al., 2004), but this does not suffice for larger gaps.

The strategy to regenerate nerves across large gaps is to bridge the gap with tissue autografts or biomimetic materials that promote the survival, elongation, and guidance of regenerating axons. Autografts of nerve trunks from elsewhere in the body are currently the treatment of choice to bridge gaps in nerves because they contain endoneurial tubes to guide regenerating axons and blood vessels that can quickly connect to the local circulation. The current gold standard is a sensory nerve autograft, such as the sural nerve or saphenous branch of the femoral nerve. However, endoneurial tubes appear to have some degree of specificity in the type of nerve axon they will support. Sensory nerve autografts have been found to support the regeneration of mixed nerves poorly compared to motor and mixed nerve autografts (Nichols et al., 2004). Most peripheral nerves are mixed nerves, suggesting that motor or mixed nerve allografts might be a better choice for inducing regeneration across gaps. The main limitation to this idea is that there are few expendable motor or mixed nerves. Thus, surgeons have turned to autografts of other tissues such as freeze-dried muscle, blood vessels, and tendons, but these have not worked as well as nerve autografts (Hall, 1997; Hems and Glasby, 1993), even when cultured Schwann cells are added to them (Nishiura et al., 2004). Furthermore, any auto-graft taken from one nerve to repair another nerve requires two surgeries and compromises the site innervated by the donor nerve, a general limitation of autografts.

The limitations of autografted tissues have prompted a search for biomimetic materials to serve as bridges for gap regeneration of peripheral nerves (figure 6.1). Nonbiodegradable silicon tubes are the reference standard for comparison with bridges made from other biomaterials (Lundborg et al., 1982). The metric for comparison is the critical axon elongation length (Lc), defined as the injury gap length at which the frequency of reinnervation drops below 50% (Yannas, 2001; Yannas and Hill, 2004). The rat sciatic nerve is a commonly used model of peripheral nerve regeneration. The Lc for the regeneration of the rat sciatic nerve in a silicon tube is 9.7 ± 1.8 mm (Yannas, 2001). This is equivalent to the performance of a nerve autograft, but to be more clinically useful than nerve autografts,

Tubular bridge

Axons

Neuron cell bodies

Regeneration template material

FIGURE 6.1 Bridging gaps in transected peripheral nerves. The cut ends of the nerve are inserted into the ends of a biomaterial tube that can be left empty or filled with regeneration template material that enhances axon elongation.

bridge materials need to support regeneration across gaps of 25-80 mm.

The course of regeneration after insertion of the distal and proximal ends of a transected rat sciatic nerve into a silicon tube is as follows (Yannas, 2001). The tube first fills with endoneurial-derived hypertonic wound fluid containing PDGF, FGF-1, and NGF. By 7 days, the fluid coagulates into a cable of longitudinally oriented fibrin fibers containing fibronectin and trapped red blood cells. Over the course of the next month, Schwann cells, fibroblasts, and blood vessels grow from the proximal and distal cut ends of the nerve to meet in the middle of the tube, and nonmyelinated and myelinated axons grow through the tube from the proximal nerve stump, using the dedifferentiated Schwann cells as adhesive substrates. A connective tissue sheath of myofibroblasts is formed around the regenerating nerve. Axons that fail to re-enter endoneurial tubes do not synthesize an endoneurium, although they are bundled together in minifascicles by a perineurium. The regenerated nerve never reaches the diameter of the normal nerve and does not synthesize an epineu-rium, resulting in a lower conduction velocity.

A wide variety of biomaterial tubes, including silicon, ethylene-vinyl acetate (EVAc), poly (lactic-co-glycolic acid) (PLGA), polyhydroxybutyrate (PHB), and type I collagen, with or without supplementation with adhesion, growth and neurotrophic factors, have been tested for their effectiveness as regeneration templates (Bellamkonda and Aebischer, 1995; Yannis, 2001; Constans, 2004). The degree of successful regeneration depends on four parameters: chemical composition of the tube and its supplements; orientation of the structural materials of the tube wall surface; porosity of the tube; and the degradation rate of the biomaterial (Yannas, 2001). Tubes composed of longitudinally oriented collagen and related ECM materials that are permeable to cells and degrade relatively rapidly are superior to synthetic polymers (Yannas, 2001). Longitudinally oriented molecules or microgrooves in the tube walls promote the straight growth of neurites better than molecules oriented perpendicularly. The porosity of the walls has to be large enough to allow gas and nutrient exchange between the inside of the guide and the external environment. Biodegradability of nerve guide tubes is a desirable feature; otherwise the tubes must be removed from the regenerated nerve by a second surgical operation. Biodegradable guides need to survive for -4-12 weeks, and their degradation products should not have an adverse effect on regeneration.

Many different kinds of tubes and tube fills have been tested for their efficacy in promoting peripheral nerve regeneration across variable-sized gaps (see TABLE 6.1, Yannas, 2001). Silicon tubes filled with a collagen/chondroitin 6-sulphate matrix or an agarose matrix containing the laminin recognition peptide CDPGYIGSR or FGF promote sciatic nerve regeneration beyond the Lc, but the increase in length does not approach the desirable 25 mm (Yannas, 2001; Aebischer et al., 1989; Bellamkonda and Aebischer, 1995). Regeneration is enhanced to a Lc of over 21 in the presence of a Schwann cell suspension (Ansselin et al., 1997). Porous collagen, poly-L-lactic acid, and polygly-colic acid promote substantial regeneration of the sciatic nerve as well (Henry et al., 1985; Molander et al., 1983; Yannas, 2001). The best regeneration was obtained with a collagen tube filled with a copolymer of type I collagen and chondroitin 6-sulfate with longitudinally oriented pores. This construct produced an Lc of 25, more than three times that of a silicon tube (Spilker, 2000; cited in Yannas, 2001). This template also promoted an increase in average axon diameter from 30-60 weeks when used to bridge a 10-mm gap in rat sciatic nerve and significantly increased the conduction velocity and amplitude of the regenerated nerve over a control phosphobuffered saline-filled collagen tube (Chamberlain et al., 1998).

Functional assessment of template-guided sciatic nerve regeneration showed that it does not restore normal walking patterns in rats (Ijkema-Paassen et al., 2004). There are long-term abnormalities in walking and electromyographic patterns, as well as abnormalities in neuromuscular contacts and shifts in the histo-chemical properties of target muscles. These deficits are likely due to the lack of specificity of the biomaterial templates for guiding regenerating axons into their previous endoneurial tubes distally, resulting in random

TABLE 6.1 Damage and Regeneration-Inhibitory Factors Involved in SCI, Their Effects, and the Strategies and Therapies That Have Been Devised to Mitigate Them

Factor Effect Strategy/Therapy

TABLE 6.1 Damage and Regeneration-Inhibitory Factors Involved in SCI, Their Effects, and the Strategies and Therapies That Have Been Devised to Mitigate Them

Factor Effect Strategy/Therapy

Compression

Kills neurons by trauma

Relieve compression

Glutamate toxicity, free radical toxicity

Secondary damage leading to apoptosis of healthy neurons

Neuroprotective molecules and cell transplants

Myelin inhibitory proteins

Growth cone collapse

Neutralize proteins or the pathways they activate Regeneration templates, with or without glial cells

Glial scar components

Collapse growth cones, mechanical barrier

Inhibit inflammatory cells, enzymatic digestion

All

Loss of neural circuitry

NSC transplants Bioartificial spinal cord Rehabilitation programs

innervation of target muscles, and failure to synthesize endoneurium and epineurium. Higher-quality outcomes of peripheral nerve regeneration might be achieved by making bridges of many parallel nanotubes that replicate the features of sensory and motor endo-neurial tubes and give specific guidance cues to sensory and motor targets.

Near-infrared laser or LED light has been reported to accelerate the rate of peripheral nerve regeneration. Daily transcutaneous irradiation of the facial nerve of rats after crush injury, as assessed by retrograde transport of HRP, resulted in a statistically significant increase in the number of labeled neurons in the facial motor nucleus as compared to nonirradiated controls (Anders et al., 1993). Crush injury to the sciatic nerve drastically lowers the electrophysiological activity of the nerve, but irradiation of either the crush injury or the neuron cell bodies in the spinal cord at the sciatic nerve level maintains the activity at near-normal levels (Rochkind et al., 1987, 2001). Again, cytochrome c oxidase is implicated in absorption of the light energy and increasing ATP levels. Irradiation of cultured primary neurons with a 670-nm LED upregulates the activity of this enzyme in cultured primary neurons. Potassium cyanide (KCN) irreversibly inhibits cytochrome c oxidase. LED irradiation at 10-100-^M KCN partially restores the inhibited enzyme activity and significantly reduces neuron death, but at 1-100-mM KCN, the neuroprotective effect of the LED is abolished (Wong-Riley et al., 2005).

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