Painful terminal neuromas in the upper limb due to nerve injury are common. Neuroma symptoms include a sharp and burning sensation, cold intolerance, dysesthesia, pain, numbness, and paresthesia. These symptoms could have a negative impact on the functional ability of the patient and quality of life. In addition, Prostheses use might be abandoned by amputees due to neuroma-induced pain. Many clinicians face challenges while managing neuromas. Contemporary “active” methods like regenerative peripheral nerve interface (RPNI), targeted muscle reinnervation (TMR), and processed nerve allograft repair (PNA) are replacing the conventional “passive” approaches such as excision, transposition, and implantation techniques. RPNI involves inducing axonal sprouting by transplanting the free end of a peripheral nerve into a free muscle graft. TMR includes reassigning the role of the peripheral nerve by the transfer of the distal end of a pure sensory or a mixed peripheral nerve to a motor nerve of a nearby muscle segment. To give the peripheral nerve a pathway to re-innervate its target tissue, PNA entails implanting a sterile extracellular matrix prepared from decellularized and regenerated human nerve tissue with preserved epineurium and fascicles. Of these, RPNI and TMR appear to hold a promising treatment for nerve-ending neuromas and prevent their relapse. In contrast, PNA may reduce neuroma pain and allow meaningful nerve repair. The aim of this article is to provide an overview of the newer approaches of TMR, RPNI, and PNA and discuss their implications, surgical techniques, and reported consequences.

BackgroundOlfactory ecto-mesenchymal stem cells (OE-MSC) are mesenchymal stem cells derived from the lamina propria of the nasal mucosa. They display neurogenic and immunomodulatory properties and were shown to induce recovery in animal models of spinal cord trauma, hearing loss, Parkinsons’s disease, amnesia, and peripheral nerve injury. As a step toward clinical practice, we sought to (i) devise a culture protocol that meets the requirements set by human health agencies and (ii) assess the efficacy of stem cells on neuron differentiation.MethodsNasal olfactory mucosa biopsies from three donors were used to design and validate the good manufacturing process for purifying stem cells. All processes and procedures were performed by expert staff from the cell therapy laboratory of the public hospital of Marseille (AP-HM), according to aseptic handling manipulations. Premises, materials and air were kept clean at all times to avoid cross-contamination, accidents, or even fatalities. Purified stem cells were cultivated for 24 or 48 h and conditioned media were collected before being added to the culture medium of the neuroblastoma cell line Neuro2a.ResultsCompared to the explant culture-based protocol, enzymatic digestion provides higher cell numbers more rapidly and is less prone to contamination. The use of platelet lysate in place of fetal calf serum is effective in promoting higher cell proliferation (the percentage of CFU-F progenitors is 15.5%), with the optimal percentage of platelet lysate being 10%. Cultured OE-MSCs do not show chromosomal rearrangement and, as expected, express the usual phenotypic markers of mesenchymal stem cells. When incorporated in standard culture medium, the conditioned medium of purified OE-MSCs promotes cell differentiation of Neuro2a neuroblastoma cells.ConclusionWe developed a safer and more efficient manufacturing process for clinical grade olfactory stem cells. With this protocol, human OE-MSCs will soon be used in a Phase I clinical based on their autologous transplantation in digital nerves with a neglected injury. However, further studies are required to unveil the underlying mechanisms of action.

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