Systematic review of the therapeutic use of Schwann cells in the repair of peripheral nerve injuries: Advancements from animal studies to clinical trials.

Objective: To systematically evaluate the literature on the therapeutic use of Schwann cells (SC) in the repair of peripheral nerve injuries. Methods: The Cochrane Library and PubMed databases were searched using terms [("peripheral nerve injury" AND "Schwann cell" AND "regeneration") OR ("peripheral nerve injuries")]. Studies published from 2008 to 2022 were eligible for inclusion in the present study. Only studies presenting data from in-vivo investigations utilizing SCs in the repair of peripheral nerve injuries qualified for review. Studies attempting repair of a gap of ≥10 mm were included. Lastly, studies needed to have some measure of quantifiable regenerative outcome data such as histomorphometry, immunohistochemical, electrophysiology, or other functional outcomes. Results: A search of the PubMed and Cochrane databases revealed 328 studies. After screening using the abstracts and methods, 17 studies were found to meet our inclusion criteria. Good SC adherence and survival in conduit tubes across various studies was observed. Improvement in morphological and functional outcomes with the use of SCs in long gap peripheral nerve injuries was observed in nearly all studies. Conclusion: Based on contemporary literature, SCs have demonstrated clear potential in the repair of peripheral nerve injury in animal studies. It has yet to be determined which nerve conduit or graft will prove superior for delivery and retention of SCs for nerve regeneration. Recent developments in isolation and culturing techniques will enable further translational utilization of SCs in future clinical trials.

Optimal Technique for Introducing Schwann Cells Into Peripheral Nerve Repair Sites.

Peripheral nerve injury (PNI) is found in a relatively large portion of trauma patients. If the injury is severe, such as with the presence of a long segmental gap, PNI can present a challenge for treatment. The current clinical standard of nerve harvest for the repair of long segmental gap PNI can lead to many potential complications. While other methods have been utilized, recent evidence indicates the relevance of cell therapies, particularly through the use of Schwann cells, for the treatment of PNI. Schwann cells (SCs) are integral in the regeneration and restoration of function following PNI. SCs are able to dedifferentiate and proliferate, remove myelin and axonal debris, and are supportive in axonal regeneration. Our laboratory has demonstrated that SCs are effective in the treatment of severe PNI when axon guidance channels are utilized. However, in order for this treatment to be effective, optimal techniques for cellular placement must be used. Thus, here we provide relevant background information, preclinical, and clinical evidence for our method in the treatment of severe PNI through the use of SCs and axon guidance channels.

Phase 1 Safety Trial of Autologous Human Schwann Cell Transplantation in Chronic Spinal Cord Injury.

A phase 1 open-label, non-randomized clinical trial was conducted to determine feasibility and safety of autologous human Schwann cell (ahSC) transplantation accompanied by rehabilitation in participants with chronic spinal cord injury (SCI). Magnetic resonance imaging (MRI) was used to screen eligible participants to estimate an individualized volume of cell suspension to be implanted. The trial incorporated standardized multi-modal rehabilitation before and after cell delivery. Participants underwent sural nerve harvest, and ahSCs were isolated and propagated in culture. The dose of culture-expanded ahSCs injected into the chronic spinal cord lesion of each individual followed a cavity-filling volume approach. Primary outcome measures for safety and trend-toward efficacy were assessed. Two participants with American Spinal Injury Association Impairment Scale (AIS) A and two participants with incomplete chronic SCI (AIS B, C) were each enrolled in cervical and thoracic SCI cohorts (n = 8 total). All participants completed the study per protocol, and no serious adverse events related to sural nerve harvest or ahSC transplantation were reported. Urinary tract infections and skin abrasions were the most common adverse events reported. One participant experienced a 4-point improvement in motor function, a 6-point improvement in sensory function, and a 1-level improvement in neurological level of injury. Follow-up MRI in the cervical (6 months) and thoracic (24 months) cohorts revealed a reduction in cyst volume after transplantation with reduced effect over time. This phase 1 trial demonstrated the feasibility and safety of ahSC transplantation combined with a multi-modal rehabilitation protocol for participants with chronic SCI.

Scalable culture techniques to generate large numbers of purified human Schwann cells for clinical trials in human spinal cord and peripheral nerve injuries.

OBJECTIVE: Schwann cells (SCs) have been shown to play an essential role in axon regeneration in both peripheral nerve injuries (PNIs) and spinal cord injuries (SCIs). The transplantation of SCs as an adjunctive therapy is currently under investigation in human clinical trials due to their regenerative capacity. Therefore, a reliable method for procuring large quantities of SCs from peripheral nerves is necessary. This paper presents a well-developed, validated, and optimized manufacturing protocol for clinical-grade SCs that are compliant with Current Good Manufacturing Practices (CGMPs). METHODS: The authors evaluated the SC culture manufacturing data from 18 clinical trial participants who were recruited for autologous SC transplantation due to subacute SCI (n = 7), chronic SCI (n = 8), or PNIs (n = 3). To initiate autologous SC cultures, a mean nerve length of 11.8 ± 3.7 cm was harvested either from the sural nerve alone (n = 17) or with the sciatic nerve (n = 1). The nerves were digested with enzymes and SCs were isolated and further expanded in multiple passages to meet the dose requirements for transplantation. RESULTS: An average yield of 87.2 ± 89.2 million cells at P2 and 150.9 ± 129.9 million cells at P3 with high viability and purity was produced. Cell counts and rates of expansion increased with each subsequent passage from P0 to P3, with the largest rate of expansion between P2 and P3. Larger harvest nerve lengths correlated significantly with greater yields at P0 and P1 (p < 0.05). In addition, a viability and purity above 90% was sustained throughout all passages in nearly all cell products. CONCLUSIONS: This study presents reliable CGMP-compliant manufacturing methods for autologous SC products that are suitable for regenerative treatment of patients with SCI, PNI, or other conditions.

Culture and Expansion of Rodent and Porcine Schwann Cells for Preclinical Animal Studies.

Cell-based therapies have become a major focus in preclinical research that leads to clinical application of a therapeutic product. Since 1990, scientists at the Miami Project to Cure Paralysis have generated extensive data demonstrating that Schwann cell (SC) transplantation supports spinal cord repair in animals with spinal cord injury. After preclinical efforts in SC transplantation strategies, efficient methods for procuring large, essentially pure populations of SCs from the adult peripheral nerve were developed for rodent and pig studies. This chapter describes a series of simple procedures to obtain and cryopreserve large cultures of highly purified adult nerve-derived SCs without the need for additional purification steps. This protocol permits the derivation of ≥90% pure rodent and porcine SCs within 2-4 weeks of culture.