Epidermal reinnervation after intracutaneous axotomy in man

Abstract

Two distinct patterns of reinnervation occur after injury to the cutaneous nerves: regenerative growth of the injured nerve and "collateral sprouting" of neighboring intact nerves. We describe two complementary models of regrowth of transected small sensory fibers in human skin. The "incision" model uses a circular incision that transects the subepidermal plexus, resulting in Wallerian degeneration of the nerve fibers that enter the incised cylinder, leaving a defined zone of denervated dermis and epidermis. The "excision" model utilizes an identical incision, followed by removal of the incised cylinder of skin, leaving a denervated area in which Schwann cells are absent. In the incision model, the earliest reinervation of denervated epidermis occurred by collateral sprouting from the terminals of epidermal axons from just outside the incision line. These axon terminals extended horizontally across the incision line and through the superficial layers of the epidermis, beneath the stratum corneum. By 13 days, numerous regenerating axons appeared in the deeper dermis derived from transected axons. These regenerating axons grew toward and ultimately into the epidermis, so that epidermal axonal density had normalized by 30-75 days. The invasion of these axons was associated with regression of the horizontally growing collateral sprouts. In the excision model, new fibers arose by terminal elongation of the epidermal axons outside the incision line, as in the incision model, and especially by collateral branching of epidermal fibers at the incision margins. These collaterals reached the epidermal surface of the basal lamina at the dermal-epidermal junction and then grew slowly toward the center of the denervated circle. In contrast to the incision model, however, complete reinnervation was not achieved even after 23 months. These models can be used to study reinnervation of denervated skin in man in different injury models and have relevance for exploring the stimuli for axonal growth and remodeling.

Improved Outcome after Peripheral Nerve Injury in Mice with Increased Levels of Endogenous Omega-3 Polyunsaturated Fatty Acids

“…Additionally, it could be hypothesized that -3 PUFAs led to an increase in collateral sprouting from spared axons in the sciatic nerve, and this could further contribute to the increased rate of recovery seen in mice expressing the fat-1 gene. The distances over which regeneration must sometimes occur in humans are much greater than in the mouse, and collateral sprouting in humans is limited compared with that seen in rodents (Healy et al, 1996;Rajan et al, 2003); therefore, a therapy that could protect nerves and enhance collateral sprouting may be beneficial.…”

Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain

“…Specifically, density counts do not take into account the extent of nerve fiber arborization. Since elongation and branching of existing nerve fibers is the major mechanism underlying regrowth, 32 IENFD is an insensitive measure of change. In contrast, quantification of new nerve fiber length using GAP-43 as a marker directly captures alterations in the cutaneous nerve fiber net.…”

Impaired reinnervation in HIV infection following experimental denervation

“…Collateral regeneration occurs through sprouting of undamaged fibers from outside the excised area peripheral to the incision line. 9,11 The purpose of this study was to determine whether peripheral nerve regeneration is altered in HIV-positive subjects, and if such alterations precede the signs of peripheral sensory neuropathy. Finally, we sought to identify factors including ApoE ε4 that influence the rate of nerve fiber regeneration in this population.…”

“…9,10 In the capsaicin model, topical capsaicin, the noxious ingredient in hot chili pepper, is applied in an occlusive dressing and produces a uniform denervation of the epidermis and subepidermal dermis. The loss of epidermal fibers is accompanied by reduced sensitivity to nociceptive stimuli and heat.…”

“…The only remaining mechanism that this region can become reinnervated is for nerve fibers from the periphery of the 3-mm biopsy site to grow centripetally into the reepithelialized epidermis through a process of collateral spouting. 9,11 The collateral sprouting distance (CSD) is defined as the farthest centripetal distance from the 3-mm biopsy incision 11 and was measured in five healthy subjects and 5 HIV-infected people. For each subject, at least four sections were analyzed and the collateral sprout distance from at least two sections was taken.…”