Skip to main content
SpringerLink
Log in

Intraspinal Delivery of Schwann Cells for Spinal Cord Injury

  • Protocol
  • First Online:
Schwann Cells

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1739))

Abstract

Cell transplant-mediated tissue repair of the damaged spinal cord is being tested in several clinical trials. The current candidates are neural stem cells, stromal cells, and autologous Schwann cells (aSC). Due to their peripheral origin and limited penetration of astrocytic regions, aSC are transplanted intralesionally as compared to neural stem cells that are transplanted into intact spinal cord. Injections into either location can cause iatrogenic injury, and thus technical precision is important in the therapeutic risk-benefit equation. In this chapter, we discuss how we bridged from transplant studies in large animals to human application for two Phase 1 aSC transplant studies, one subacute and one chronic. Preclinical SC transplant studies conducted at the University of Miami in 2009–2012 in rodents, minipigs, and primates supported a successful Investigational New Drug (IND) submission for a Phase 1 trial in subacute complete spinal cord injury (SCI). Our studies optimized the safety and efficiency of intralesional cell delivery for subacute human SCI and led to the development of new simpler techniques for cell delivery into subjects with chronic SCI. Key parameters of delivery methodology include precision localization of the injury site, stereotaxic devices to control needle trajectory, method of entry into the spinal cord, spinal cord motion reduction, the volume and density of the cell suspension, rate of delivery, and control of shear stresses on cells.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Wirth ED 3rd et al (1992) In vivo magnetic resonance imaging of fetal cat neural tissue transplants in the adult cat spinal cord. J Neurosurg 76(2):261–274

    Article  PubMed  Google Scholar 

  2. Wirth ED 3rd et al (2001) Feasibility and safety of neural tissue transplantation in patients with syringomyelia. J Neurotrauma 18(9):911–929

    Article  PubMed  Google Scholar 

  3. Guest J, Santamaria AJ, Benavides FD (2013) Clinical translation of autologous Schwann cell transplantation for the treatment of spinal cord injury. Curr Opin Organ Transplant 18(6):682–689

    PubMed  PubMed Central  Google Scholar 

  4. Guest J et al (2011) Technical aspects of spinal cord injections for cell transplantation. Clinical and translational considerations. Brain Res Bull 84(4–5):267–279

    Article  PubMed  Google Scholar 

  5. Golden KL et al (2007) Transduced Schwann cells promote axon growth and myelination after spinal cord injury. Exp Neurol 207(2):203–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Anderson KD et al (2017) Safety of autologous human Schwann cell transplantation in subacute thoracic spinal cord injury. J Neurotrauma 34(21):2950–2963

    Article  PubMed  Google Scholar 

  7. Pearse DD et al (2004) cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Nat Med 10(6):610–616

    Article  CAS  PubMed  Google Scholar 

  8. Meijs MF et al (2004) Basic fibroblast growth factor promotes neuronal survival but not behavioral recovery in the transected and Schwann cell implanted rat thoracic spinal cord. J Neurotrauma 21(10):1415–1430

    Article  PubMed  Google Scholar 

  9. Barakat DJ et al (2005) Survival, integration, and axon growth support of glia transplanted into the chronically contused spinal cord. Cell Transplant 14(4):225–240

    Article  CAS  PubMed  Google Scholar 

  10. Fouad K et al (2005) Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord. J Neurosci 25(5):1169–1178

    Article  CAS  PubMed  Google Scholar 

  11. Flora G et al (2013) Combining neurotrophin-transduced schwann cells and rolipram to promote functional recovery from subacute spinal cord injury. Cell Transplant 22(12):2203–2217

    Article  PubMed  Google Scholar 

  12. Kanno H et al (2014) Combination of engineered Schwann cell grafts to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after spinal cord injury. J Neurosci 34(5):1838–1855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Williams RR et al (2015) Permissive Schwann cell graft/spinal cord interfaces for axon regeneration. Cell Transplant 24(1):115–131

    Article  PubMed  Google Scholar 

  14. Guest JD et al (1997) The ability of human Schwann cell grafts to promote regeneration in the transected nude rat spinal cord. Exp Neurol 148(2):502–522

    Article  CAS  PubMed  Google Scholar 

  15. Hill CE et al (2006) Labeled Schwann cell transplantation: cell loss, host Schwann cell replacement, and strategies to enhance survival. Glia 53(3):338–343

    Article  PubMed  Google Scholar 

  16. Fortun J, Hill CE, Bunge MB (2009) Combinatorial strategies with Schwann cell transplantation to improve repair of the injured spinal cord. Neurosci Lett 456(3):124–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hill CE et al (2010) A calpain inhibitor enhances the survival of Schwann cells in vitro and after transplantation into the injured spinal cord. J Neurotrauma 27(9):1685–1695

    Article  PubMed  PubMed Central  Google Scholar 

  18. Levi AD et al (1995) The influence of heregulins on human Schwann cell proliferation. J Neurosci 15(2):1329–1340

    CAS  PubMed  Google Scholar 

  19. Wood PM (1976) Separation of functional Schwann cells and neurons from normal peripheral nerve tissue. Brain Res 115(3):361–375

    Article  CAS  PubMed  Google Scholar 

  20. Beattie MS et al (1997) Endogenous repair after spinal cord contusion injuries in the rat. Exp Neurol 148(2):453–463

    Article  CAS  PubMed  Google Scholar 

  21. Zhang SX et al (2011) Histological repair of damaged spinal cord tissue from chronic contusion injury of rat: a LM observation. Histol Histopathol 26(1):45–58

    PubMed  Google Scholar 

  22. Blakemore WF, Patterson RC (1978) Suppression of remyelination in the CNS by X-irradiation. Acta Neuropathol 42(2):105–113

    Article  CAS  PubMed  Google Scholar 

  23. Gilmore SA, Duncan D (1968) On the presence of peripheral-like nervous and connective tissue within irradiated spinal cord. Anat Rec 160(4):675–690

    Article  CAS  PubMed  Google Scholar 

  24. Hill CE et al (2007) Early necrosis and apoptosis of Schwann cells transplanted into the injured rat spinal cord. Eur J Neurosci 26(6):1433–1445

    Article  PubMed  Google Scholar 

  25. Priest CA et al (2015) Preclinical safety of human embryonic stem cell-derived oligodendrocyte progenitors supporting clinical trials in spinal cord injury. Regen Med 10(8):939–958

    Article  CAS  PubMed  Google Scholar 

  26. Raore B et al (2011) Cervical multilevel intraspinal stem cell therapy: assessment of surgical risks in Gottingen minipigs. Spine (Phila Pa 1976) 36(3):E164–E171

    Article  Google Scholar 

  27. Mackay-Sim A et al (2008) Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial. Brain 131(Pt 9):2376–2386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lammertse DP et al (2012) Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial. Spinal Cord 50(9):661–671

    Article  CAS  PubMed  Google Scholar 

  29. Federici T et al (2012) Surgical technique for spinal cord delivery of therapies: demonstration of procedure in gottingen minipigs. J Vis Exp 70:e4371

    Google Scholar 

  30. Riley JP et al (2011) Platform and cannula design improvements for spinal cord therapeutics delivery. Neurosurgery 69(2 Suppl Operative):ons147–ons154. discussion ons155

    PubMed  Google Scholar 

  31. Blesch A, Tuszynski MH (2009) Spinal cord injury: plasticity, regeneration and the challenge of translational drug development. Trends Neurosci 32(1):41–47

    Article  CAS  PubMed  Google Scholar 

  32. Blight AR (1994) Effects of silica on the outcome from experimental spinal cord injury: implication of macrophages in secondary tissue damage. Neuroscience 60(1):263–273

    Article  CAS  PubMed  Google Scholar 

  33. Dumont RJ et al (2001) Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 24(5):254–264

    Article  CAS  PubMed  Google Scholar 

  34. Blight AR (1992) Macrophages and inflammatory damage in spinal cord injury. J Neurotrauma 9(Suppl 1):S83–S91

    PubMed  Google Scholar 

  35. Blight AR (1985) Delayed demyelination and macrophage invasion: a candidate for secondary cell damage in spinal cord injury. Cent Nerv Syst Trauma 2(4):299–315

    Article  CAS  PubMed  Google Scholar 

  36. Reier PJ, Houle JD (1988) The glial scar: its bearing on axonal elongation and transplantation approaches to CNS repair. Adv Neurol 47:87–138

    CAS  PubMed  Google Scholar 

  37. Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5(2):146–156

    Article  CAS  PubMed  Google Scholar 

  38. Kakulas BA (1999) The applied neuropathology of human spinal cord injury. Spinal Cord 37(2):79–88

    Article  CAS  PubMed  Google Scholar 

  39. Kakulas BA (1999) A review of the neuropathology of human spinal cord injury with emphasis on special features. J Spinal Cord Med 22(2):119–124

    Article  CAS  PubMed  Google Scholar 

  40. Guest JD, Hiester ED, Bunge RP (2005) Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury. Exp Neurol 192(2):384–393

    Article  CAS  PubMed  Google Scholar 

  41. Ihnatsenka B, Boezaart AP (2010) Ultrasound: basic understanding and learning the language. Int J Shoulder Surg 4(3):55–62

    Article  PubMed  PubMed Central  Google Scholar 

  42. Gabriel EM, Nashold BS Jr (1996) History of spinal cord stereotaxy. J Neurosurg 85(4):725–731

    Article  CAS  PubMed  Google Scholar 

  43. Chen KS, Sakowski SA, Feldman EL (2016) Intraspinal stem cell transplantation for amyotrophic lateral sclerosis. Ann Neurol 79(3):342–353

    Article  PubMed  PubMed Central  Google Scholar 

  44. Boulis NM et al (2011) Translational stem cell therapy for amyotrophic lateral sclerosis. Nat Rev Neurol 8(3):172–176

    Article  PubMed  Google Scholar 

  45. Blanquer M et al (2010) A surgical technique of spinal cord cell transplantation in amyotrophic lateral sclerosis. J Neurosci Methods 191(2):255–257

    Article  PubMed  Google Scholar 

  46. Blanquer M et al (2012) Neurotrophic bone marrow cellular nests prevent spinal motoneuron degeneration in amyotrophic lateral sclerosis patients: a pilot safety study. Stem Cells 30(6):1277–1285

    Article  CAS  PubMed  Google Scholar 

  47. Feron F et al (2005) Autologous olfactory ensheathing cell transplantation in human spinal cord injury. Brain 128(Pt 12):2951–2960

    Article  CAS  PubMed  Google Scholar 

  48. Appadu B, Lin T (2017) Respiratory physiology. In: Lin T, Smith T, Pinnock C (eds) Fundamentals of anesthesia. Cambridge University Press, Cambridge, pp 399–400

    Google Scholar 

  49. Qazi H, Shi ZD, Tarbell JM (2011) Fluid shear stress regulates the invasive potential of glioma cells via modulation of migratory activity and matrix metalloproteinase expression. PLoS One 6(5):e20348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dimmeler S et al (1996) Shear stress inhibits apoptosis of human endothelial cells. FEBS Lett 399(1–2):71–74

    Article  CAS  PubMed  Google Scholar 

  51. Iordan A, Duperray A, Verdier C (2008) Fractal approach to the rheology of concentrated cell suspensions. Phys Rev E Stat Nonlin Soft Matter Phys 77(1 Pt 1):011911

    Article  CAS  PubMed  Google Scholar 

  52. Guest JD, Vanni S, Silbert L (2004) Mild hypothermia, blood loss and complications in elective spinal surgery. Spine J 4(2):130–137

    Article  PubMed  Google Scholar 

  53. Habiba S et al (2017) Risk factors for surgical site infections among 1,772 patients operated on for lumbar disc herniation: a multicentre observational registry-based study. Acta Neurochir 159(6):1113–1118

    Article  PubMed  Google Scholar 

  54. Croft LD et al (2015) Risk factors for surgical site infections after pediatric spine operations. Spine (Phila Pa 1976) 40(2):E112–E119

    Article  Google Scholar 

  55. Riley J et al (2014) Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I trial, cervical microinjection, and final surgical safety outcomes. Neurosurgery 74(1):77–87

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The experiments were supported by the Miami Project to Cure Paralysis clinical trials initiative and the Buoniconti Fund to Cure Paralysis. Dr. Ed Wirth, M.D., Ph.D., provided access to the SPD, participated in the initial testing in naive animals, and provided helpful advice. Dr. Nicholas Boulis, M.D., Ph.D., demonstrated the floating cannula injection system used in Neuralstem ALS trials. Human aSC transplant procedures were performed together with Dr. Allan Levi, M.D., Ph.D. The clinical trial sponsor is Dr. Dalton Dietrich, Ph.D., and the coordinator is Kim Anderson, Ph.D. The cells were prepared by the aSC team initially supervised by Dr. Pat Wood, Ph.D., and Dr. Gagani Athauda, M.D., and subsequently carried by Aisha Khan, M.B.A., Adriana Brooks-Perez, Maxwell Donaldson, and Risett Silvera-Rodriguez. Yohjans Nunez-Gomez, D.V.M., and Luis Guada Delgado, M.D., assisted with minipig transplant surgeries. The impetus to consider Schwann cell transplantation for human spinal cord injury was an idea of Richard and Mary Bunge in the early 1970s. The achievement of derivation of aSC from a small biopsy and substantial culture expansion required years of scientific exploration and animal testing carried by many members of the Bunge scientific family including Drs: Patrick Wood, James Guest, Allan Levi, Xiao Ming Xu, Giles Plant, Martin Oudega, Damien Pearse, Cristina Fernandez-Valle and Caitlin Hill. Finally, despite her husband’s untimely death in 1996, Mary Bartlett Bunge persisted in helping advance this work to clinical trials until her retirement in 2017.

Author information

Authors and Affiliations

  1. The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, FL, USA

    Andrea J. Santamaría, Francisco D. Benavides & James D. Guest

  2. Pediatric Critical Care, University of Miami, Miller School of Medicine, Miami, FL, USA

    Juan P. Solano

  3. Neurological Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA

    James D. Guest

Authors
  1. Andrea J. Santamaría
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juan P. Solano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francisco D. Benavides
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James D. Guest
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James D. Guest .

Editor information

Editors and Affiliations

  1. Department of Neurological Surgery, University of Miami, Miami, Florida, USA

    Paula V. Monje

  2. Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA

    Haesun A. Kim

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Science+Business Media, LLC

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Santamaría, A.J., Solano, J.P., Benavides, F.D., Guest, J.D. (2018). Intraspinal Delivery of Schwann Cells for Spinal Cord Injury. In: Monje, P., Kim, H. (eds) Schwann Cells. Methods in Molecular Biology, vol 1739. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7649-2_31

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-7649-2_31

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7648-5

  • Online ISBN: 978-1-4939-7649-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation