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Growth cones of regenerating nerves, following crush injury to the rat peripheral nerve system, were studied by electron microscopy and synaptophysin. Localization in the growth cones was revealed by immunohistochemistry at the ultrastructural level. Many regenerating growth cones grew along the Schwann-cell basal laminae tubes at the crushed site. These cones revealed an abundance of organelles, such as heterogenous vesicles and many mitochondria, and a scarcity of cytoskeletons, including microtubules and neurofilaments in the cytoplasm. The periphery of the growth cones (corresponding to the lamellipodia or filopodia of cultured neurons) contained rich electron-dense filamentous materials. Cellular protrusions, such as filopodia, were rarely seen. These growth cones exhibited intense immunoreactivity for synaptophysin by light microscopy. Immunoelectron microscopy demonstrated that immunoreactivity was distributed diffusely in the cytoplasm.

The ultrastructure of the early regenerative response in an end-to-side neurorrhaphy rat model was studied using transmission electron microscopy. The ipsilateral saphenous nerve was grafted to the sciatic nerve under the following conditions: Group 1, the epineurium and perineurium of the sciatic nerve remained intact; Group 2, an epineurial and perineurial window was created at the site of the lateral neurorrhaphy; Group 3, the same as in Group 2 and, in addition, the sciatic nerve sustained a partial neurectomy. Rats were perfused through the heart with fixative containing 2 percent paraformaldehyde and 2.5 percent glutaraldehyde in 0.1 M cacodylate buffer (pH 7.4) at 4, 8, 12, 24 and 48 hr after surgery. In Group 1, no regenerating axons were observed and the myelin sheath in the donor nerve did not demonstrate any degenerative changes through 48 hr. In Group 2, an increased diameter of the unmyelinated axons and growth cones was observed in the donor nerve proximal to the coaptation site after 12 hr. Degenerative changes in the myelin sheath were observed after 12 hr within the several layers under the coaptation site. In Group 3, many growth cone-like structures were observed in the area proximal to the coaptation site after 12 hr. After 24 hr, proximal regenerating axons elongated to the coaptation site and, at 48 hr, many regenerating nerves grew inside the Schwann cell basement membrane of the graft nerve. These results indicate that the perineurial window and nerve graft are the critical conditions for inciting nerve regeneration in the donor nerve.

Hippocrates provided the first written description of the peripheral nervous system (PNS), as early as the 4th century B.C., and later Herophilus identified nerves as such, distinguished them from tendons; he also traced nerves to the spinal cord. The traditional Hippocratic teaching of the time, however, doubted that nerve healing occurred. Through the subsequent centuries, several papers were written about the PNS but, without sufficient understanding of anatomy, physiology, and the regenerative capacity of the PNS, it is not difficult to comprehend the frustration that might have been encountered by surgeons in dealing with nerve injuries and their subsequent repair. This was probably the reason why nerve repair was rarely actually undertaken prior to the 19th century. A plethora of studies on the PNS and its regeneration has been reported over the last 150 years and has provided us with current knowledge. It is important, before describing the most recent developments in the area of peripheral nerve regeneration, to briefly outline the major advances over the last century. Currently, the therapeutic approaches taken toward the patient with peripheral nerve injury change continuously. Sophisticated advances in technology, cellular and molecular neurobiology, and electron microscopy will doubtless optimize reconstructive strategies in treating nerve injury. A greater awareness and understanding of the nerve ultrastructure, as well as the underlying mechanisms of the regenerative process and those factors detrimental to nerve regeneration, will assist in the successful repair of nerve injury. This paper reviews the cellular, biochemical, and ultrastructural elements of nerve injury and repair, and the rationale for current reconstructive strategies and techniques.