The unifying hypothesis of this proposal is that the use of biomaterial scaffolds is critical to the development of successful therapies for spinal cord injury. In the absence of a biomaterial scaffold that can help bridge the injury site, the lack of regeneration promoting substrates in the injured spinal cord limits the efficacy of current drug delivery and cell transplantation approaches. We hypothesize that the biomaterial scaffolds can be used to direct the differentiation of embryonic stem cell-derived progenitor motor neurons (pMNs), present growth factor trophic cues and deliver drugs to overcome the inhibitory nature of the adult spinal cord. Through the use of a biomaterial scaffold we hypothesize that we will be able to present combination therapies necessary to achieve significant regeneration following spinal cord injury. This hypothesis will be tested systematically by addressing the following specific aims, all of which are necessary to achieve the goal of spinal cord regeneration.
The aims of this proposal are: (1) to test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable the survival and differentiation of embryonic stem cell-derived progenitor motor neurons (pMNs) into motoneurons in an in vitro setting at levels comparable to or better than that observed with traditional differentiation protocols. (2) To test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable enhanced survival and differentiation of embryonic stem cell-derived motoneuron progenitors (pMNs) into motoneurons compared with pMN transplantation alone (no scaffold) in the in vivo setting of sub-acute (14 day) spinal cord injury. (3) To test the hypothesis that the combination of a biomaterial scaffold (with growth factor delivery), cell transplantation, and delivery of drugs to overcome the inhibitory cues of the adult spinal cord, will provide a combination therapy that is able to achieve regeneration following sub-acute (14 day) spinal cord injury.

Public Health Relevance

Spinal cord injury is a major clinical problem. In the United States, about 12,000 people per year join the population of approximately 200,000 traumatic spinal cord injury patients. Spinal cord injuries typically occur in young patients (average age of 32, 55% of injuries occur at ages 16 to 30) and the impact of these injuries on the quality of life and productivity of these individuals is dramatic. In addition, the average cost of caring for a patient during the first year following spinal cord injury is $307,847(58). Therapeutic approaches to be developed and the mechanistic knowledge gained in this study may contribute to future clinical therapies for spinal cord injury patients. Approaches for the transplantation of motoneurons developed in this project may also be useful for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051454-08
Application #
8464811
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Ludwig, Kip A
Project Start
2005-04-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$314,445
Indirect Cost
$107,573
Name
Washington University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
McCreedy, Dylan A; Brown, Chelsea R; Butts, Jessica C et al. (2014) A new method for generating high purity motoneurons from mouse embryonic stem cells. Biotechnol Bioeng 111:2041-55
Sakiyama-Elbert, Shelly E (2014) Incorporation of heparin into biomaterials. Acta Biomater 10:1581-7
McCreedy, D A; Wilems, T S; Xu, H et al. (2014) Survival, Differentiation, and Migration of High-Purity Mouse Embryonic Stem Cell-derived Progenitor Motor Neurons in Fibrin Scaffolds after Sub-Acute Spinal Cord Injury. Biomater Sci 2:1672-1682
Brown, Chelsea R; Butts, Jessica C; McCreedy, Dylan A et al. (2014) Generation of v2a interneurons from mouse embryonic stem cells. Stem Cells Dev 23:1765-76
Marquardt, Laura M; Sakiyama-Elbert, Shelly E (2013) Engineering peripheral nerve repair. Curr Opin Biotechnol 24:887-92
Jesuraj, Nithya J; Nguyen, Peter K; Wood, Matthew D et al. (2012) Differential gene expression in motor and sensory Schwann cells in the rat femoral nerve. J Neurosci Res 90:96-104
McCreedy, Dylan A; Sakiyama-Elbert, Shelly E (2012) Combination therapies in the CNS: engineering the environment. Neurosci Lett 519:115-21
McCreedy, Dylan A; Rieger, Cara R; Gottlieb, David I et al. (2012) Transgenic enrichment of mouse embryonic stem cell-derived progenitor motor neurons. Stem Cell Res 8:368-78
Jesuraj, Nithya J; Santosa, Katherine B; Newton, Piyaraj et al. (2011) A systematic evaluation of Schwann cell injection into acellular cold-preserved nerve grafts. J Neurosci Methods 197:209-15
Johnson, Philip J; Tatara, Alexander; McCreedy, Dylan A et al. (2010) Tissue-engineered fibrin scaffolds containing neural progenitors enhance functional recovery in a subacute model of SCI. Soft Matter 6:5127-5137

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