Biodegradable Polymer Implants for Spinal Cord Repair

Summary

Principal Investigator: ANTHONY JOHN WINDEBANK
Affiliation: Mayo Clinic
Country: USA
Abstract: Spinal cord axons have the capacity to regenerate following injury. However, functional improvement following spinal cord injury (SCI) in patients and in experimental animal models has been elusive. We have brought together a new research group combining expertise in polymer-based tissue engineering, cellular and molecular neurobiology, spine surgery, neurosurgery, and spinal cord injury. We have developed a series of novel biodegradable polymer implants for use in the treatment of SCI. Pilot studies of the implant in the rat transected spinal cord model demonstrated the potential for promoting axon regeneration. Implants were well-tolerated in the spinal cord and were loaded with Schwann cells that survive. During three months after implantation, there was axon growth throughout the length of the graft. We hypothesize that the implant can serve as a scaffold to support axon growth across a gap, as a source of supporting cells, and as a vehicle for controlled local delivery of agents that promote regeneration. We now propose to systematically manipulate the structural, cellular and molecular environment of the regenerating cord. In the first aim, we will study the degradation characteristics and biocompatibility of two polymers; poly (lactic-coglycolic)acid (PLGA) and poly(caprolactone fumarate) (PCLF). We will use computer-aided design to generate the three-dimensional structure of the scaffold and then determine whether vacuum molding or free-form fabrication (micro-printing) produces the best architecture. In the second aim we will examine the effect of scaffold geometry on regeneration by testing PLGA and PCLF scaffolds with varying diameter channels. The number and direction of axons regenerating through the scaffolds will be measured. In the third aim we will compare the ability of two cell types (primary Schwann cells and a Schwann cell line;SpL201) to support regeneration and to act as a source of biomolecules that promote regeneration. In the fourth aim we will examine the role of the biodegradable polymer as a delivery vehicle for therapeutic agents. Chondritinase-ABC will be used as a model protein. It is an enzyme that enhances axonal regeneration in the cord. Delivery of active enzyme after encapsulation in microspheres or in the graft will be compared and the effect of enzyme delivery in the regenerating cord will be assessed. Imaging with Micro-CT and MR microscopy will be combined with histological and functional assessments to measure success in promoting regeneration.
Funding Period: 2003-09-30 - 2007-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Optimizing conditions and avoiding pitfalls for prolonged axonal tracing with carbocyanine dyes in fixed rat spinal cords
    Bingkun K Chen
    Neuroscience Research Program and Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    J Neurosci Methods 154:256-63. 2006
  2. ncbi Multiple-channel scaffolds to promote spinal cord axon regeneration
    Michael J Moore
    Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Biomaterials 27:419-29. 2006
  3. pmc Stimulation of neurite outgrowth using positively charged hydrogels
    Mahrokh Dadsetan
    Department of Orthopedic Surgery, Mayo Clinic College of Medicine, 200 First Street SW, MS 3 69, Rochester, MN 55905, USA
    Biomaterials 30:3874-81. 2009
  4. pmc Axon regeneration through scaffold into distal spinal cord after transection
    Bing Kun Chen
    Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA
    J Neurotrauma 26:1759-71. 2009
  5. pmc Relationship between scaffold channel diameter and number of regenerating axons in the transected rat spinal cord
    Aaron J Krych
    Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Acta Biomater 5:2551-9. 2009
  6. pmc Neural stem cell- and Schwann cell-loaded biodegradable polymer scaffolds support axonal regeneration in the transected spinal cord
    Heather E Olson
    Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Tissue Eng Part A 15:1797-805. 2009
  7. pmc Rigid fixation of the spinal column improves scaffold alignment and prevents scoliosis in the transected rat spinal cord
    Gemma E Rooney
    Departments of Neurology and Molecular Neuroscience, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Spine (Phila Pa 1976) 33:E914-9. 2008
  8. pmc Accuracy of motor axon regeneration across autograft, single-lumen, and multichannel poly(lactic-co-glycolic acid) nerve tubes
    Godard C de Ruiter
    Cellular Neurobiology Laboratory and Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota 55905, USA
    Neurosurgery 63:144-53; discussion 153-5. 2008
  9. doi Electrophysiologic findings and grip strength after nerve injuries in the rat forelimb
    Huan Wang
    Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA
    Muscle Nerve 38:1254-65. 2008
  10. pmc Misdirection of regenerating motor axons after nerve injury and repair in the rat sciatic nerve model
    Godard C W de Ruiter
    Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA
    Exp Neurol 211:339-50. 2008

Detail Information

Publications13

  1. ncbi Optimizing conditions and avoiding pitfalls for prolonged axonal tracing with carbocyanine dyes in fixed rat spinal cords
    Bingkun K Chen
    Neuroscience Research Program and Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    J Neurosci Methods 154:256-63. 2006
    ..Our data suggested that higher temperature facilitated dye diffusion along the axons, and demonstrated that with caution DiI and DiO could be used as specific tracers in the same spinal cords...
  2. ncbi Multiple-channel scaffolds to promote spinal cord axon regeneration
    Michael J Moore
    Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Biomaterials 27:419-29. 2006
    ..Axon regeneration was demonstrated by three-dimensional reconstruction of serial histological sections...
  3. pmc Stimulation of neurite outgrowth using positively charged hydrogels
    Mahrokh Dadsetan
    Department of Orthopedic Surgery, Mayo Clinic College of Medicine, 200 First Street SW, MS 3 69, Rochester, MN 55905, USA
    Biomaterials 30:3874-81. 2009
    ..These findings suggest that charged OPF hydrogels are capable of sustaining both primary nerve cells and the neural support cells that are critical for regeneration...
  4. pmc Axon regeneration through scaffold into distal spinal cord after transection
    Bing Kun Chen
    Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA
    J Neurotrauma 26:1759-71. 2009
    ..The pattern of myelination, with extracellular collagen and basal lamina, was characteristic of SC myelination. Our results show that FB labeling is an effective way to measure the origin of regenerating axons...
  5. pmc Relationship between scaffold channel diameter and number of regenerating axons in the transected rat spinal cord
    Aaron J Krych
    Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Acta Biomater 5:2551-9. 2009
    ..Optimization of this scaffold environment establishes a platform for future studies of the effects of cell types, trophic factors or pharmacological agents on the regenerative capacity of the injured spinal cord...
  6. pmc Neural stem cell- and Schwann cell-loaded biodegradable polymer scaffolds support axonal regeneration in the transected spinal cord
    Heather E Olson
    Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Tissue Eng Part A 15:1797-805. 2009
    ..Further, these multichannel biodegradable polymer scaffolds effectively serve as platforms for quantitative analysis of axonal regeneration...
  7. pmc Rigid fixation of the spinal column improves scaffold alignment and prevents scoliosis in the transected rat spinal cord
    Gemma E Rooney
    Departments of Neurology and Molecular Neuroscience, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Spine (Phila Pa 1976) 33:E914-9. 2008
    ..A controlled study to evaluate a new technique for spinal rod fixation after spinal cord injury in rats. Alignment of implanted tissue-engineered scaffolds was assessed radiographically and by magnetic resonance imaging...
  8. pmc Accuracy of motor axon regeneration across autograft, single-lumen, and multichannel poly(lactic-co-glycolic acid) nerve tubes
    Godard C de Ruiter
    Cellular Neurobiology Laboratory and Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota 55905, USA
    Neurosurgery 63:144-53; discussion 153-5. 2008
    ..We also present the concept of the multichannel nerve tube that may limit dispersion by separately guiding groups of regenerating axons...
  9. doi Electrophysiologic findings and grip strength after nerve injuries in the rat forelimb
    Huan Wang
    Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA
    Muscle Nerve 38:1254-65. 2008
    ..We conclude that it is possible to conduct minimally invasive electrophysiologic testing in rat forelimbs. The CMAP is a valid parameter that shows the typical time course of nerve regeneration and reinnervation...
  10. pmc Misdirection of regenerating motor axons after nerve injury and repair in the rat sciatic nerve model
    Godard C W de Ruiter
    Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA
    Exp Neurol 211:339-50. 2008
    ..The results of this study can be used as basis for developing new nerve repair techniques that may improve the accuracy of regeneration...
  11. ncbi Two-dimensional digital video ankle motion analysis for assessment of function in the rat sciatic nerve model
    Godard C de Ruiter
    Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
    J Peripher Nerv Syst 12:216-22. 2007
    ..2D digital video ankle motion analysis is a practical and sensitive method to assess function in the rat sciatic nerve model...
  12. ncbi Methods for in vitro characterization of multichannel nerve tubes
    Godard C de Ruiter
    Cellular Neurobiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA
    J Biomed Mater Res A 84:643-51. 2008
    ..The methods presented in this study can be used as a basis for optimizing these properties for future, possibly clinical, application...
  13. pmc Importance of the vasculature in cyst formation after spinal cord injury
    Gemma E Rooney
    Department of Neurology and Molecular Neuroscience, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    J Neurosurg Spine 11:432-7. 2009
    ..The objective of this study was to examine the surgical methods that may be used to assess the factors that influence the level of scar and cystic formation in SCI...