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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB002390-04
Application #
7090637
Study Section
Special Emphasis Panel (ZRG1-SSS-M (57))
Program Officer
Kelley, Christine A
Project Start
2003-09-30
Project End
2007-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
4
Fiscal Year
2006
Total Cost
$331,053
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Grahn, Peter J; Vaishya, Sandeep; Knight, Andrew M et al. (2014) Implantation of cauda equina nerve roots through a biodegradable scaffold at the conus medullaris in rat. Spine J 14:2172-7
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Rooney, Gemma E; Knight, Andrew M; Madigan, Nicolas N et al. (2011) Sustained delivery of dibutyryl cyclic adenosine monophosphate to the transected spinal cord via oligo [(polyethylene glycol) fumarate] hydrogels. Tissue Eng Part A 17:1287-302
de Boer, Ralph; Knight, Andrew M; Spinner, Robert J et al. (2010) In vitro and in vivo release of nerve growth factor from biodegradable poly-lactic-co-glycolic-acid microspheres. J Biomed Mater Res A 95:1067-73
Dadsetan, Mahrokh; Knight, Andrew M; Lu, Lichun et al. (2009) Stimulation of neurite outgrowth using positively charged hydrogels. Biomaterials 30:3874-81
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Chen, Bing Kun; Knight, Andrew M; de Ruiter, Godard C W et al. (2009) Axon regeneration through scaffold into distal spinal cord after transection. J Neurotrauma 26:1759-71
Krych, Aaron J; Rooney, Gemma E; Chen, Bingkun et al. (2009) Relationship between scaffold channel diameter and number of regenerating axons in the transected rat spinal cord. Acta Biomater 5:2551-9
Rooney, Gemma E; Endo, Toshiki; Ameenuddin, Syed et al. (2009) Importance of the vasculature in cyst formation after spinal cord injury. J Neurosurg Spine 11:432-7

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