title: Advanced biomaterial strategies to transplant preformed micro-tissue engineered neural networks into the brain.
abstract: 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.
  
  
  METHODS
  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.
  
  
  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 μN 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Brain Injury and Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Harris
authors.forename: L A
authors.initials: LA
authors.lastname: Struzyna
authors.forename: P L
authors.initials: PL
authors.lastname: Murphy
authors.forename: D O
authors.initials: DO
authors.lastname: Adewole
authors.forename: E
authors.initials: E
authors.lastname: Kuo
authors.forename: D K
authors.initials: DK
authors.lastname: Cullen
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D001921:Brain / Q000166:cytology* / Q000601:surgery; D002478:Cells, Cultured; D004867:Equipment Design; D019544:Equipment Failure Analysis; D048091:Guided Tissue Regeneration / Q000295:instrumentation*; D008422:Materials Testing; D008904:Miniaturization; D009415:Nerve Net / Q000166:cytology*; D009474:Neurons / Q000166:cytology / Q000637:transplantation*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023822:Tissue Engineering / Q000295:instrumentation*; D054457:Tissue Scaffolds
chemical_list: D001672:Biocompatible Materials