期刊
JOURNAL OF NEURAL ENGINEERING
卷 13, 期 1, 页码 -出版社
IOP PUBLISHING LTD
DOI: 10.1088/1741-2560/13/1/016019
关键词
neurotransplantation; transplantation; bioengineering; cell replacement; axonal tracts; tissue engineering; biomaterials
资金
- Penn Medicine Neuroscience Center
- National Science Foundation [DGE-1321851]
- National Institutes of Health [T32-NS043126, T32-GM007517]
- Department of Veterans Affairs (RRD Merit Review) [B1097-I]
- US Army Medical Research and Materiel Command through the Joint Warfighter Medical Research Program [W81XWH-13-207 004]
Objective. Connectome disruption is a hallmark of many neurological diseases and trauma with no current strategies to restore lost long-distance axonal pathways in the brain. We are creating transplantable micro-tissue engineered neural networks (micro-TENNs), which are preformed constructs consisting of embedded neurons and long axonal tracts to integrate with the nervous system to physically reconstitute lost axonal pathways. Approach. We advanced micro-tissue engineering techniques to generate micro-TENNs consisting of discrete populations of mature primary cerebral cortical neurons spanned by long axonal fascicles encased in miniature hydrogel micro-columns. Further, we improved the biomaterial encasement scheme by adding a thin layer of low viscosity carboxymethylcellulose (CMC) to enable needle-less insertion and rapid softening for mechanical similarity with brain tissue. Main results. The engineered architecture of cortical micro-TENNs facilitated robust neuronal viability and axonal cytoarchitecture to at least 22 days in vitro. Micro-TENNs displayed discrete neuronal populations spanned by long axonal fasciculation throughout the core, thus mimicking the general systems-level anatomy of gray matter-white matter in the brain. Additionally, micro-columns with thin CMC-coating upon mild dehydration were able to withstand a force of 893 +/- 457 mN before buckling, whereas a solid agarose cylinder of similar dimensions was predicted to withstand less than 150 mu N of force. This thin CMC coating increased the stiffness by three orders of magnitude, enabling needle-less insertion into brain while significantly reducing the footprint of previous needle-based delivery methods to minimize insertion trauma. Significance. Our novel micro-TENNs are the first strategy designed for minimally invasive implantation to facilitate nervous system repair by simultaneously providing neuronal replacement and physical reconstruction of long-distance axon pathways in the brain. The micro-TENN approach may offer the ability to treat several disorders that disrupt the connectome, including Parkinson's disease, traumatic brain injury, stroke, and brain tumor excision.
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