Biodegradable Polymer Implants for Spinal Cord Repair
Principal Investigator: ANTHONY JOHN WINDEBANK
Affiliation: Mayo Clinic
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
- Optimizing conditions and avoiding pitfalls for prolonged axonal tracing with carbocyanine dyes in fixed rat spinal cordsBingkun 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...
- Multiple-channel scaffolds to promote spinal cord axon regenerationMichael 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...
- Stimulation of neurite outgrowth using positively charged hydrogelsMahrokh 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...
- Axon regeneration through scaffold into distal spinal cord after transectionBing 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...
- Relationship between scaffold channel diameter and number of regenerating axons in the transected rat spinal cordAaron 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...
- Neural stem cell- and Schwann cell-loaded biodegradable polymer scaffolds support axonal regeneration in the transected spinal cordHeather 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...
- Rigid fixation of the spinal column improves scaffold alignment and prevents scoliosis in the transected rat spinal cordGemma 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...
- Accuracy of motor axon regeneration across autograft, single-lumen, and multichannel poly(lactic-co-glycolic acid) nerve tubesGodard 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...
- Electrophysiologic findings and grip strength after nerve injuries in the rat forelimbHuan 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...
- Misdirection of regenerating motor axons after nerve injury and repair in the rat sciatic nerve modelGodard 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...
- Two-dimensional digital video ankle motion analysis for assessment of function in the rat sciatic nerve modelGodard 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...
- Methods for in vitro characterization of multichannel nerve tubesGodard 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...
- Importance of the vasculature in cyst formation after spinal cord injuryGemma 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...