Target Receptors of Regenerating Nerves: Neuroma Formation and Current Treatment Options

Abstract

Neuromas form as a result of disorganized sensory axonal regeneration following nerve injury. Painful neuromas lead to poor quality of life for patients and place a burden on healthcare systems. Modern surgical interventions for neuromas entail guided regeneration of sensory nerve fibers into muscle tissue leading to muscle innervation and neuroma treatment or prevention. However, it is unclear how innervating denervated muscle targets prevents painful neuroma formation, as little is known about the fate of sensory fibers, and more specifically pain fiber, as they regenerate into muscle. Golgi tendon organs and muscle spindles have been proposed as possible receptor targets for the regenerating sensory fibers; however, these receptors are not typically innervated by pain fibers, as these free nerve endings do not synapse on receptors. The mechanisms by which pain fibers are signaled to cease regeneration therefore remain unknown. In this article, we review the physiology underlying nerve regeneration, the guiding molecular signals, and the target receptor specificity of regenerating sensory axons as it pertains to the development and prevention of painful neuroma formation while highlighting gaps in literature. We discuss management options for painful neuromas and the current supporting evidence for the various interventions.

Keywords: RPNI; TMR; VDMT; neuroma; peripheral nerve regeneration; target receptors; targeted reinnervation.

FIGURE 1

Summary of mechanisms of nerve regeneration, neuroma formation, and target receptors for regenerating fibers. (A) Nerve injury leads to Wallerian degeneration of nerve fiber back to first node of Ranvier. (B) Nerve fiber regeneration by axolemma sprouting, and growth cone and lamellipodia/filopodia formation under influence of NTFs. (C) Formed neuroma treated by: (D) BIM: excision and nerve tuck under muscle, neuroma reforms but is protected from physical and chemical stimuli or (E) TMR: sensory nerves regenerate into coapted motor nerve stump and into muscle to reinnervate muscle spindles and Golgi tendon organs to prevent neuroma formation, or (F) RPNI or (G) VDMT: sensory nerves directly reinnervate muscle spindles in small free muscle grafts (RPNI) or vascularized, denervated portions of muscle (VDMT) to prevent neuroma formation.