The Use of Autologous Schwann Cells to Supplement Sciatic Nerve Repair with a Large Gap: First in Human Experience

Insufficient donor nerve graft material in peripheral nerve surgery remains an obstacle for successful long-distance regeneration. Schwann cells (SCs) can be isolated from adult mammalian peripheral nerve biopsies and can be grown in culture and retain their capacity to enhance peripheral nerve regeneration within tubular repair strategies in multiple animal models. Human Schwann cells (hSCs) can be isolated, expanded in number, and retain their ability to promote regeneration and myelinate axons, but have never been tested in a clinical case of peripheral nerve injury. A sural nerve biopsy and peripheral nerve tissue from the traumatized sciatic nerve stumps was obtained after Food and Drug Administration (FDA) and Institutional Review Board (IRB) approval as well as patient consent. The SCs were isolated after enzymatic digestion of the nerve and expanded with the use of heregulin β1 (0.1 μg/ml) and forskolin (15 mM). After two passages the Schwann cell isolates were combined with sural nerve grafts to repair a large sciatic nerve defect (7.5 cm) after a traumatic nerve injury. The sural nerve and the traumatized sciatic nerve ends both served as an excellent source of purified (90% and 97%, respectively) hSCs. Using ultrasound and magnetic resonance imaging (MRI) we were able to determine continuity of the nerve graft repair and the absence of tumor formation. The patient had evidence of proximal sensory recovery and definitive motor recovery distal to the repair in the distribution of the tibial and common peroneal nerve. The patient did experience an improvement in her pain scores over time. The goals of this approach were to determine the safety and clinical feasibility of implementing a new cellular repair strategy. In summary, this approach represents a novel strategy in the treatment of peripheral nerve injury and represents the first reported use of autologous cultured SCs after human peripheral nerve injury.

[1]  S. Moran,et al.  Early Clinical Outcomes with the Use of Decellularized Nerve Allograft for Repair of Sensory Defects Within the Hand , 2009, Hand.

[2]  E. Lazartigues Louisiana State University Health Sciences Center , 1999 .

[3]  J. Gousheh,et al.  Therapeutic Results of Sciatic Nerve Repair in Iran-Iraq War Casualties , 2008, Plastic and reconstructive surgery.

[4]  Christina K. Magill,et al.  Limitations of Conduits in Peripheral Nerve Repairs , 2009, Hand.

[5]  Daniel H. Kim,et al.  Management and results of sciatic nerve injuries: a 24-year experience. , 1998, Journal of neurosurgery.

[6]  A. Levi,et al.  Challenges in sciatic nerve repair: anatomical considerations. , 2014, Journal of neurosurgery.

[7]  D. Wise,et al.  Influence of glial growth factor and Schwann cells in a bioresorbable guidance channel on peripheral nerve regeneration. , 2000, Tissue engineering.

[8]  M. Wiberg,et al.  A composite poly‐hydroxybutyrate–glial growth factor conduit for long nerve gap repairs , 2003, Journal of anatomy.

[9]  Zheng-rong Chen,et al.  Fabricating autologous tissue to engineer artificial nerve , 2002, Microsurgery.

[10]  M. Berens,et al.  The Role of Cultured Schwann Cell Grafts in the Repair of Gaps within the Peripheral Nervous System of Primates , 1997, Experimental Neurology.

[11]  Ranjan Gupta,et al.  Transplantation of Schwann cells in a collagen tube for the repair of large, segmental peripheral nerve defects in rats. , 2013, Journal of neurosurgery.

[12]  A. Aydın,et al.  The results of surgical repair of sciatic nerve injuries. , 2010, Acta orthopaedica et traumatologica turcica.

[13]  R. Bunge,et al.  Studies of Myelin Formation after Transplantation of Human Schwann Cells into the Severe Combined Immunodeficient Mouse , 1994, Experimental Neurology.

[14]  O. Riedl,et al.  Anatomy of the Sural Nerve: Cadaver Study and Literature Review , 2013, Plastic and reconstructive surgery.

[15]  M. Sliwkowski,et al.  The influence of heregulins on human Schwann cell proliferation , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[16]  M. Meek,et al.  Functional assessment of sciatic nerve recovery: biodegradable poly (DLLA‐ϵ‐CL) nerve guide filled with fresh skeletal muscle , 2003, Microsurgery.

[17]  J. Murovic LOWER‐EXTREMITY PERIPHERAL NERVE INJURIES: A LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER LITERATURE REVIEW WITH COMPARISON OF THE OPERATIVE OUTCOMES OF 806 LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER SCIATIC, COMMON PERONEAL, AND TIBIAL NERVE LESIONS , 2009, Neurosurgery.

[18]  S. Petković,et al.  Missile-induced complete lesions of the tibial nerve and tibial division of the sciatic nerve: results of 119 repairs. , 2005, Journal of neurosurgery.

[19]  R. Bunge,et al.  Improved method for harvesting human Schwann cells from mature peripheral nerve and expansion in vitro , 1996, Glia.

[20]  M. Dauge,et al.  Nerve repair using a composite graft of vein and denatured skeletal muscle: morphologic analysis. , 2002, Journal of reconstructive microsurgery.

[21]  J. Murovic UPPER‐EXTREMITY PERIPHERAL NERVE INJURIES: A LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER LITERATURE REVIEW WITH COMPARISON OF THE OPERATIVE OUTCOMES OF 1837 LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER MEDIAN, RADIAL, AND ULNAR NERVE LESIONS , 2009, Neurosurgery.

[22]  P. Bhardwaj,et al.  Motor grading of elbow flexion – is Medical Research Council grading good enough? , 2009, Journal of Brachial Plexus and Peripheral Nerve Injury.

[23]  M. Meek,et al.  Morphology of nerve fiber regeneration along a biodegradable poly (DLLA‐ϵ‐CL) nerve guide filled with fresh skeletal muscle , 2003, Microsurgery.

[24]  M. Sliwkowski,et al.  Axon-induced mitogenesis of human Schwann cells involves heregulin and p185erbB2. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  A. Papalois,et al.  Beneficial effect of nerve growth factor‐7S on peripheral nerve regeneration through inside‐out vein grafts: An experimental study , 2004, Microsurgery.

[26]  B. Rosén,et al.  Tubular versus conventional repair of median and ulnar nerves in the human forearm: early results from a prospective, randomized, clinical study. , 1997, The Journal of hand surgery.

[27]  Xavier Navarro,et al.  Nerve Guides Seeded with Autologous Schwann Cells Improve Nerve Regeneration , 2000, Experimental Neurology.

[28]  Paul L. Evans,et al.  Cold storage of peripheral nerves: An in vitro assay of cell viability and function , 1994, Glia.

[29]  O. Riedl,et al.  Sural Nerve Harvesting beyond the Popliteal Region Allows a Significant Gain of Donor Nerve Graft Length , 2008, Plastic and reconstructive surgery.

[30]  P. Aebischer,et al.  The functional characteristics of Schwann cells cultured from human peripheral nerve after transplantation into a gap within the rat sciatic nerve , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[31]  D. Boyd,et al.  FDA approved guidance conduits and wraps for peripheral nerve injury: a review of materials and efficacy. , 2012, Injury.

[32]  Nancy Parks,et al.  Effects of collagen nerve guide on neuroma formation and neuropathic pain in a rat model. , 2007, American journal of surgery.

[33]  D. Terris,et al.  Brain-derived neurotrophic factor-enriched collagen tubule as a substitute for autologous nerve grafts. , 2001, Archives of otolaryngology--head & neck surgery.

[34]  Y. Tabata,et al.  Poly lactic acid-caprolactone copolymer tube with a denatured skeletal muscle segment inside as a guide for peripheral nerve regeneration: A morphological and electrophysiological evaluation of the regenerated nerves , 2003, Anatomical science international.

[35]  B. Rosén,et al.  Tubular Repair of the Median or Ulnar Nerve in the Human Forearm: A 5-Year Follow-Up , 2004, Journal of hand surgery.

[36]  H. Seddon,et al.  The use of autogenous grafts for the repair of large gaps in peripheral nerves , 1947, The British journal of surgery.

[37]  M. Meek,et al.  Effects of nerve growth factor on nerve regeneration through a vein graft across a gap. , 1999, Plastic and reconstructive surgery.

[38]  Jian Zhang,et al.  Autogenous venous graft with one-stage prepared Schwann cells as a conduit for repair of long segmental nerve defects. , 2002, Journal of reconstructive microsurgery.

[39]  D. E. Weinstein,et al.  Autologous Schwann cells drive regeneration through a 6-cm autogenous venous nerve conduit. , 2001, Journal of reconstructive microsurgery.

[40]  G. Keilhoff,et al.  Tissue engineering of peripheral nerves: Epineurial grafts with application of cultured Schwann cells , 2003, Microsurgery.

[41]  A L Dellon,et al.  An Alternative to the Classical Nerve Graft for the Management of the Short Nerve Gap , 1988, Plastic and reconstructive surgery.

[42]  Daniel H. Kim,et al.  Management and outcomes in 353 surgically treated sciatic nerve lesions. , 2004, Journal of neurosurgery.

[43]  L. Olson,et al.  Assessment of the malignant potential of mitogen stimulated human Schwann cells. , 1999, Journal of the peripheral nervous system : JPNS.

[44]  B. Rosén,et al.  Collagen conduit versus microsurgical neurorrhaphy: 2-year follow-up of a prospective, blinded clinical and electrophysiological multicenter randomized, controlled trial. , 2013, The Journal of hand surgery.

[45]  A. Levi Characterization of the technique involved in isolating Schwann cells from adult human peripheral nerve , 1996, Journal of Neuroscience Methods.

[46]  P H Robinson,et al.  Electronmicroscopical evaluation of short-term nerve regeneration through a thin-walled biodegradable poly(DLLA-epsilon-CL) nerve guide filled with modified denatured muscle tissue. , 2001, Biomaterials.

[47]  Susan E. Mackinnon,et al.  Clinical Nerve Reconstruction with a Bioabsorbable Polyglycolic Acid Tube , 1990, Plastic and reconstructive surgery.

[48]  R. Bunge,et al.  Isolation and functional characterization of Schwann cells derived from adult peripheral nerve , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[49]  Paul L. Evans,et al.  Cold preserved nerve allografts: Changes in basement membrane, viability, immunogenicity, and regeneration , 1998, Muscle & nerve.

[50]  D. F. Davey,et al.  Peripheral nerve regeneration through nerve guides seeded with adult Schwann cells , 1997, Neuropathology and applied neurobiology.