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Journal article
Tissue engineered nigrostriatal pathway for treatment of Parkinson's disease
Journal of tissue engineering and regenerative medicine, v 12(7), pp 1702-1716
01 Jul 2018
PMID: 29766664
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The classic motor deficits of Parkinson's disease are caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in the loss of their long-distance axonal projections that modulate the striatum. Current treatments only minimize the symptoms of this disconnection as there is no approach capable of replacing the nigrostriatal pathway. We are applying microtissue engineering techniques to create living, implantable constructs that mimic the architecture and function of the nigrostriatal pathway. These constructs consist of dopaminergic neurons with long axonal tracts encased within hydrogel microcolumns. Microcolumns were seeded with dopaminergic neuronal aggregates, while lumen extracellular matrix, growth factors, and end targets were varied to optimize cytoarchitecture. We found a 10-fold increase in axonal outgrowth from aggregates versus dissociated neurons, resulting in remarkable axonal lengths of over 6mm by 14days and 9mm by 28days in vitro. Axonal extension was also dependent upon lumen extracellular matrix, but did not depend on growth factor enrichment or neuronal end target presence. Evoked dopamine release was measured via fast scan cyclic voltammetry and synapse formation with striatal neurons was observed in vitro. Constructs were microinjected to span the nigrostriatal pathway in rats, revealing survival of implanted neurons while maintaining their axonal projections within the microcolumn. Lastly, these constructs were generated with dopaminergic neurons differentiated from human embryonic stem cells. This strategy may improve Parkinson's disease treatment by simultaneously replacing lost dopaminergic neurons in the substantia nigra and reconstructing their long-projecting axonal tracts to the striatum.
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Details
- Title
- Tissue engineered nigrostriatal pathway for treatment of Parkinson's disease
- Creators
- Laura A. Struzyna - Center for Neurotrauma, Neurodegeneration & Restoration Corporal Michael J. Crescenz Veterans Affairs Medical Center Philadelphia PA USAKevin D. Browne - University of PennsylvaniaZachary D. Brodnik - Drexel UniversityJustin C. Burrell - Center for Neurotrauma, Neurodegeneration & Restoration Corporal Michael J. Crescenz Veterans Affairs Medical Center Philadelphia PA USAJames P. Harris - University of PennsylvaniaH. Isaac Chen - University of PennsylvaniaJohn A. Wolf - University of PennsylvaniaKate V. Panzer - University of PennsylvaniaJames Lim - University of PennsylvaniaJohn E. Duda - Center for Neurotrauma, Neurodegeneration & Restoration, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.Rodrigo A. Espana - Drexel UniversityD. Kacy Cullen - Center for Neurotrauma, Neurodegeneration & Restoration Corporal Michael J. Crescenz Veterans Affairs Medical Center Philadelphia PA USA
- Publication Details
- Journal of tissue engineering and regenerative medicine, v 12(7), pp 1702-1716
- Publisher
- Wiley
- Number of pages
- 15
- Grant note
- T32NS091006 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) DGE-1321851 / National Science Foundation; National Science Foundation (NSF) Penn Medicine Neuroscience Pilot Award / University of Pennsylvania I01BX003748 / Veterans Affairs; US Department of Veterans Affairs T32-NS091006; T32-NS043126; R01-DA031900; F31-DA042505; U01-NS094340 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA I01-BX003748 / Department of Veterans Affairs; US Department of Veterans Affairs 9998 / Michael J. Fox Foundation R01DA031900 / NATIONAL INSTITUTE ON DRUG ABUSE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA); European Commission
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000437837600014
- Scopus ID
- 2-s2.0-85049677826
- Other Identifier
- 991019167759604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biotechnology & Applied Microbiology
- Cell & Tissue Engineering
- Cell Biology
- Engineering, Biomedical