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 to bridge the injury site, the lack of regeneration promoting substrates in the injured spinal cord limits the efficacy of growth factor delivery and cell transplantation approaches. We hypothesize that controlled release of growth factors over a prolonged period of time (weeks) from a fibrin-based biomaterial scaffold alone or in combination with embryonic stem cell-derived neural lineage cells (ESNLCs) is needed 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 a fibrin-based biomaterial scaffold enables sufficient controlled release of growth factor (neurotrophin-3) to enable enhanced short and long-term regeneration compared to uncontrolled growth factor release in a rat spinal cord injury model. (2) To test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable survival and differentiation of embryonic stem cell-derived neural lineage cells (ESNLCs) into neurons in an in vitro setting comparable to or better than that observed with traditional differentiation protocols. (3) To test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable enhance survival and differentiation of embryonic stem cell-derived neural lineage cells (ESNLCs) into neurons compared with ESNLCs alone (no scaffold) in vivo in the setting of spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051454-02
Application #
7013656
Study Section
Special Emphasis Panel (ZRG1-GDD (01))
Program Officer
Kleitman, Naomi
Project Start
2005-04-01
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
2
Fiscal Year
2006
Total Cost
$276,399
Indirect Cost
Name
Washington University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Iyer, Nisha R; Wilems, Thomas S; Sakiyama-Elbert, Shelly E (2017) Stem cells for spinal cord injury: Strategies to inform differentiation and transplantation. Biotechnol Bioeng 114:245-259
Iyer, Nisha R; Huettner, James E; Butts, Jessica C et al. (2016) Generation of highly enriched V2a interneurons from mouse embryonic stem cells. Exp Neurol 277:305-316
Xu, Hao; Sakiyama-Elbert, Shelly E (2015) Directed Differentiation of V3 Interneurons from Mouse Embryonic Stem Cells. Stem Cells Dev 24:2723-32
Wilems, Thomas S; Pardieck, Jennifer; Iyer, Nisha et al. (2015) Combination therapy of stem cell derived neural progenitors and drug delivery of anti-inhibitory molecules for spinal cord injury. Acta Biomater 28:23-32
Xu, Hao; Iyer, Nisha; Huettner, James E et al. (2015) A puromycin selectable cell line for the enrichment of mouse embryonic stem cell-derived V3 interneurons. Stem Cell Res Ther 6:220
Wilems, Thomas S; Sakiyama-Elbert, Shelly E (2015) Sustained dual drug delivery of anti-inhibitory molecules for treatment of spinal cord injury. J Control Release 213:103-11
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
Sakiyama-Elbert, Shelly E (2014) Incorporation of heparin into biomaterials. Acta Biomater 10:1581-7
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
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

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