Advances in ex vivo models and lab-on-a-chip devices for neural tissue engineering.

The technologies related to ex vivo models and lab-on-a-chip devices for studying the regeneration of brain, spinal cord, and peripheral nerve tissues are essential tools for neural tissue engineering and regenerative medicine research. The need for ex vivo systems, lab-on-a-chip technologies and disease models for neural tissue engineering applications are emerging to overcome the shortages and drawbacks of traditional in vitro systems and animal models. Ex vivo models have evolved from traditional 2D cell culture models to 3D tissue-engineered scaffold systems, bioreactors, and recently organoid test beds. In addition to ex vivo model systems, we discuss lab-on-a-chip devices and technologies specifically for neural tissue engineering applications. Finally, we review current commercial products that mimic diseased and normal neural tissues, and discuss the future directions in this field.

[1]  E. Bradbury,et al.  Review: Manipulating the extracellular matrix and its role in brain and spinal cord plasticity and repair , 2014, Neuropathology and applied neurobiology.

[2]  Estrela Neto,et al.  Axonal outgrowth, neuropeptides expression and receptors tyrosine kinase phosphorylation in 3D organotypic cultures of adult dorsal root ganglia , 2017, PloS one.

[3]  M. J. Moore,et al.  Facile micropatterning of dual hydrogel systems for 3D models of neurite outgrowth. , 2011, Journal of biomedical materials research. Part A.

[4]  K. Pešek Atherosclerotic Cardiovascular Disease , 2011 .

[5]  Nitish Thakor,et al.  Valve-based microfluidic compression platform: single axon injury and regrowth. , 2011, Lab on a chip.

[6]  Christine E Schmidt,et al.  Effects of collagen 1, fibronectin, laminin and hyaluronic acid concentration in multi-component gels on neurite extension , 2007, Journal of biomaterials science. Polymer edition.

[7]  H. Duffau,et al.  Adult human spinal cord harbors neural precursor cells that generate neurons and glial cells in vitro , 2008, Journal of neuroscience research.

[8]  Jürg Streit,et al.  Embryonic Cell Grafts in a Culture Model of Spinal Cord Lesion: Neuronal Relay Formation Is Essential for Functional Regeneration , 2016, Front. Cell. Neurosci..

[9]  D. K. Cullen,et al.  Collagen-Dependent Neurite Outgrowth and Response to Dynamic Deformation in Three-Dimensional Neuronal Cultures , 2007, Annals of Biomedical Engineering.

[10]  Guido Stoll,et al.  Degeneration and regeneration of the peripheral nervous system: From Augustus Waller's observations to neuroinflammation , 2002, Journal of the peripheral nervous system : JPNS.

[11]  Juergen A. Knoblich,et al.  Organogenesis in a dish: Modeling development and disease using organoid technologies , 2014, Science.

[12]  I. Black,et al.  Developmentally regulated expression of the nerve growth factor receptor gene in the periphery and brain. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[13]  David K. Menon,et al.  Traumatic Axonal Injury: Mechanisms and Translational Opportunities , 2016, Trends in Neurosciences.

[14]  Noo Li Jeon,et al.  Advances in microfluidics-based experimental methods for neuroscience research. , 2013, Lab on a chip.

[15]  Charles Rohde,et al.  An in vitro model of adult mammalian nerve repair , 2010, Experimental Neurology.

[16]  Jason B Shear,et al.  The effects of hyaluronic acid hydrogels with tunable mechanical properties on neural progenitor cell differentiation. , 2010, Biomaterials.

[17]  Jonathan V Sweedler,et al.  Laminar stream of detergents for subcellular neurite damage in a microfluidic device: a simple tool for the study of neuroregeneration , 2013, Journal of neural engineering.

[18]  Hyeon-Yeol Cho,et al.  Microdevice Platform for In Vitro Nervous System and Its Disease Model , 2017, Bioengineering.

[19]  S. Sakiyama-Elbert,et al.  Engineering peripheral nerve repair. , 2013, Current opinion in biotechnology.

[20]  Andreas Manz,et al.  Phaseguides: a paradigm shift in microfluidic priming and emptying. , 2011, Lab on a chip.

[21]  G. Taccola,et al.  Early spread of hyperexcitability to caudal dorsal horn networks after a chemically-induced lesion of the rat spinal cord in vitro , 2013, Neuroscience.

[22]  Qing Yang,et al.  Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor. , 2015, Biomicrofluidics.

[23]  C. Humpel,et al.  ORGANOTYPIC BRAIN SLICE CULTURES: A REVIEW , 2015, Neuroscience.

[24]  Jeremy L. Barth,et al.  Neural stem/progenitor cell properties of glial cells in the adult mouse auditory nerve , 2015, Scientific Reports.

[25]  Zhen Liu,et al.  Neuregulin-1β regulates outgrowth of neurites and migration of neurofilament 200 neurons from dorsal root ganglial explants in vitro , 2011, Peptides.

[26]  Michael J Cima,et al.  A three dimensional in vitro glial scar model to investigate the local strain effects from micromotion around neural implants. , 2017, Lab on a chip.

[27]  J. Elfar,et al.  Nerve physiology: mechanisms of injury and recovery. , 2013, Hand clinics.

[28]  Lonnie D. Shea,et al.  Gene delivery to overcome astrocyte inhibition of axonal growth: An in vitro Model of the glial scar , 2013, Biotechnology and bioengineering.

[29]  Eiji Kobayashi,et al.  Oligodendrocytes and Radial Glia Derived From Adult Rat Spinal Cord Progenitors: Morphological and Immunocytochemical Characterization , 2007, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[30]  Xi Chen,et al.  Development of a microfluidic platform with integrated power splitting waveguides for optogenetic neural cell stimulation , 2015, Biomedical microdevices.

[31]  Elena Naumovska,et al.  Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes , 2018 .

[32]  M. J. Moore,et al.  Photoreactive interpenetrating network of hyaluronic acid and Puramatrix as a selectively tunable scaffold for neurite growth. , 2015, Acta biomaterialia.

[33]  Jean-Louis Viovy,et al.  Wallerian-Like Degeneration of Central Neurons After Synchronized and Geometrically Registered Mass Axotomy in a Three-Compartmental Microfluidic Chip , 2010, Neurotoxicity Research.

[34]  P C Letourneau,et al.  Neurite extension by peripheral and central nervous system neurons in response to substratum-bound fibronectin and laminin. , 1983, Developmental biology.

[35]  Paul M Holloway,et al.  Modeling Ischemic Stroke In Vitro: Status Quo and Future Perspectives , 2016, Stroke.

[36]  D. Pankevich,et al.  International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary , 2013 .

[37]  Ronan M. T. Fleming,et al.  Differentiation of neuroepithelial stem cells into functional dopaminergic neurons in 3D microfluidic cell culture. , 2015, Lab on a chip.

[38]  Kavya Reddy,et al.  Soluble Neuregulin-1 Has Bifunctional, Concentration-Dependent Effects on Schwann Cell Myelination , 2010, The Journal of Neuroscience.

[39]  Roger D. Kamm,et al.  A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood-brain barrier. , 2017, Lab on a chip.

[40]  M. Tang-Schomer,et al.  3D axon growth by exogenous electrical stimulus and soluble factors , 2018, Brain Research.

[41]  M. Shoichet,et al.  Synthesis of cell-adhesive dextran hydrogels and macroporous scaffolds. , 2006, Biomaterials.

[42]  The Duy Nguyen,et al.  Generation of Schwann Cell-Derived Multipotent Neurospheres Isolated from Intact Sciatic Nerve , 2012, Stem Cell Reviews and Reports.

[43]  Hitoshi Kawano,et al.  An in vitro model of the inhibition of axon growth in the lesion scar formed after central nervous system injury , 2010, Molecular and Cellular Neuroscience.

[44]  Ying Yang,et al.  An in vitro spinal cord injury model to screen neuroregenerative materials. , 2014, Biomaterials.

[45]  Ying Li,et al.  Role of the lesion scar in the response to damage and repair of the central nervous system , 2012, Cell and Tissue Research.

[46]  David I Shreiber,et al.  Genipin-induced changes in collagen gels: correlation of mechanical properties to fluorescence. , 2008, Journal of biomedical materials research. Part A.

[47]  C. Gabel,et al.  Watching worms whither: modeling neurodegeneration in C. elegans. , 2011, Progress in molecular biology and translational science.

[48]  Magdalena Götz,et al.  Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain , 2008, Proceedings of the National Academy of Sciences.

[49]  S. Furber,et al.  To build a brain , 2012, IEEE Spectrum.

[50]  Scott R. Whittemore,et al.  The expression, localization and functional significance of β-nerve growth factor in the central nervous system , 1987, Brain Research Reviews.

[51]  Subhash Chandra Parija,et al.  Ethics of involving animals in research , 2013, Tropical parasitology.

[52]  R V Bellamkonda,et al.  Dorsal root ganglia neurite extension is inhibited by mechanical and chondroitin sulfate‐rich interfaces , 2001, Journal of neuroscience research.

[53]  Sylvie Girard,et al.  Microglia and Macrophages Differentially Modulate Cell Death After Brain Injury Caused by Oxygen-Glucose Deprivation in Organotypic Brain Slices , 2013, Glia.

[54]  N. Lehman,et al.  Axonal Outgrowth and Dendritic Plasticity in the Cortical Peri-Infarct Area After Experimental Stroke , 2012, Stroke.

[55]  Lin Yang,et al.  Enhanced differentiation of neural stem cells to neurons and promotion of neurite outgrowth by oxygen–glucose deprivation , 2015, International Journal of Developmental Neuroscience.

[56]  Mathis O. Riehle,et al.  Microtopographical cues promote peripheral nerve regeneration via transient mTORC2 activation , 2017, Acta biomaterialia.

[57]  Renaud Renault,et al.  Asymmetric axonal edge guidance: a new paradigm for building oriented neuronal networks. , 2016, Lab on a chip.

[58]  Teruo Fujii,et al.  Generation of a Motor Nerve Organoid with Human Stem Cell-Derived Neurons , 2017, Stem cell reports.

[59]  Prakhar Mishra,et al.  The overwhelming use of rat models in nerve regeneration research may compromise designs of nerve guidance conduits for humans , 2015, Journal of Materials Science: Materials in Medicine.

[60]  Jean-Louis Viovy,et al.  In-mold patterning and actionable axo-somatic compartmentalization for on-chip neuron culture. , 2016, Lab on a chip.

[61]  S. Cullheim,et al.  Integrin-laminin interactions controlling neurite outgrowth from adult DRG neurons in vitro , 2008, Molecular and Cellular Neuroscience.

[62]  Mark K. Borsody,et al.  I. Nerve Physiology , 2007 .

[63]  Estrela Neto,et al.  Sensory neurons and osteoblasts: close partners in a microfluidic platform. , 2014, Integrative biology : quantitative biosciences from nano to macro.

[64]  Manoel Baldoino Leal-Filho Spinal cord injury: From inflammation to glial scar , 2011, Surgical neurology international.

[65]  Michael J Yaszemski,et al.  The Value of Systematic Reviews in Estimating the Cost and Barriers to Translation in Tissue Engineering. , 2016, Tissue engineering. Part B, Reviews.

[66]  A. Höke,et al.  Dorsal root ganglia sensory neuronal cultures: a tool for drug discovery for peripheral neuropathies , 2009, Expert opinion on drug discovery.

[67]  Antonio Belli,et al.  S100B and Glial Fibrillary Acidic Protein as Indexes to Monitor Damage Severity in an In Vitro Model of Traumatic Brain Injury , 2015, Neurochemical Research.

[68]  Nikolaj Gadegaard,et al.  Development of a Novel 3D Culture System for Screening Features of a Complex Implantable Device for CNS Repair , 2013, Molecular pharmaceutics.

[69]  Luca Cucullo,et al.  In vitro blood-brain barrier models: current and perspective technologies. , 2012, Journal of pharmaceutical sciences.

[70]  Regina C. Armstrong,et al.  White matter involvement after TBI: Clues to axon and myelin repair capacity , 2016, Experimental Neurology.

[71]  Mark M. Stecker,et al.  In-vitro stability of peripheral nerve preparations: Relation to ischemic responses , 2010, Brain Research.

[72]  H. Dai,et al.  Degradation of chondroitin sulfate proteoglycans potentiates transplant‐mediated axonal remodeling and functional recovery after spinal cord injury in adult rats , 2006, The Journal of comparative neurology.

[73]  Noo Li Jeon,et al.  Microfluidic Multicompartment Device for Neuroscience Research. , 2003, Langmuir : the ACS journal of surfaces and colloids.

[74]  M. Shuler,et al.  Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening , 2017, Biotechnology and bioengineering.

[75]  M. J. Moore,et al.  Microengineered peripheral nerve-on-a-chip for preclinical physiological testing. , 2015, Lab on a chip.

[76]  C. Hughes,et al.  Of Mice and Not Men: Differences between Mouse and Human Immunology , 2004, The Journal of Immunology.

[77]  Estrela Neto,et al.  Compartmentalized Microfluidic Platforms: The Unrivaled Breakthrough of In Vitro Tools for Neurobiological Research , 2016, The Journal of Neuroscience.

[78]  Huijing Zhao,et al.  Preparation of uniaxial multichannel silk fibroin scaffolds for guiding primary neurons. , 2012, Acta biomaterialia.

[79]  Tamara Roitbak,et al.  Neural Stem/Progenitor Cells Promote Endothelial Cell Morphogenesis and Protect Endothelial Cells against Ischemia via HIF-1α-Regulated VEGF Signaling , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[80]  M. J. Moore,et al.  Light-reactive dextran gels with immobilized guidance cues for directed neurite growth in 3D models. , 2014, Biomaterials science.

[81]  Malin Parmar,et al.  Strengths and limitations of the neurosphere culture system , 2006, Molecular Neurobiology.

[82]  Clemens Kiecker,et al.  Endogenous GFAP-positive neural stem/progenitor cells in the postnatal mouse cortex are activated following traumatic brain injury. , 2012, Journal of neurotrauma.

[83]  John W Haycock,et al.  An aligned 3D neuronal-glial co-culture model for peripheral nerve studies. , 2012, Biomaterials.

[84]  Veronica Estrada,et al.  Pharmacological Suppression of CNS Scarring by Deferoxamine Reduces Lesion Volume and Increases Regeneration in an In Vitro Model for Astroglial-Fibrotic Scarring and in Rat Spinal Cord Injury In Vivo , 2015, PloS one.

[85]  Jerry Silver,et al.  Studies on the Development and Behavior of the Dystrophic Growth Cone, the Hallmark of Regeneration Failure, in an In Vitro Model of the Glial Scar and after Spinal Cord Injury , 2004, The Journal of Neuroscience.

[86]  Madeline A. Lancaster,et al.  Stem Cell Models of Human Brain Development. , 2016, Cell stem cell.

[87]  Michael Chopp,et al.  Animal models of traumatic brain injury , 2013, Nature Reviews Neuroscience.

[88]  Virginia M Ayres,et al.  Nanofibrillar scaffolds induce preferential activation of Rho GTPases in cerebral cortical astrocytes , 2012, International journal of nanomedicine.

[89]  Eun-Mi Hur,et al.  Coculture of Primary Motor Neurons and Schwann Cells as a Model for In Vitro Myelination , 2015, Scientific Reports.

[90]  R. Lindsay,et al.  Nerve growth factors (NGF, BDNF) enhance axonal regeneration but are not required for survival of adult sensory neurons , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[91]  D. Wendt,et al.  The role of bioreactors in tissue engineering. , 2004, Trends in biotechnology.

[92]  R V Bellamkonda,et al.  Polylysine-functionalised thermoresponsive chitosan hydrogel for neural tissue engineering. , 2007, Biomaterials.

[93]  Hossein Baharvand,et al.  Scalable Expansion of Human Pluripotent Stem Cell-Derived Neural Progenitors in Stirred Suspension Bioreactor Under Xeno-free Condition. , 2016, Methods in molecular biology.

[94]  A. Faden,et al.  New in vitro model of traumatic neuronal injury: evaluation of secondary injury and glutamate receptor-mediated neurotoxicity. , 1997, Journal of neurotrauma.

[95]  Miguel Torres,et al.  A new in vitro model of the glial scar inhibits axon growth , 2008, Glia.

[96]  Clark T Hung,et al.  Optimization of Schwann cell adhesion in response to shear stress in an in vitro model for peripheral nerve tissue engineering. , 2003, Tissue engineering.

[97]  B. Barres,et al.  Contrasting the glial response to axon injury in the central and peripheral nervous systems. , 2014, Developmental cell.

[98]  Rania Kronfli,et al.  Enteric Neurospheres Are Not Specific to Neural Crest Cultures: Implications for Neural Stem Cell Therapies , 2015, PloS one.

[99]  David D Fuller,et al.  Injectable hydrogels of optimized acellular nerve for injection in the injured spinal cord , 2018, Biomedical materials.

[100]  H G Dyar THE CLASSIFICATION OF MOSQUITOES. , 1906, Science.

[101]  Rui Liu,et al.  Spatiotemporally controlled and multifactor involved assay of neuronal compartment regeneration after chemical injury in an integrated microfluidics. , 2012, Analytical chemistry.

[102]  Peter T C So,et al.  Simultaneous or Sequential Orthogonal Gradient Formation in a 3D Cell Culture Microfluidic Platform. , 2015, Small.

[103]  M C LaPlaca,et al.  An in vitro model of traumatic neuronal injury: loading rate-dependent changes in acute cytosolic calcium and lactate dehydrogenase release. , 1997, Journal of neurotrauma.

[104]  Estrela Neto,et al.  Microfluidics co-culture systems for studying tooth innervation , 2014, Front. Physiol..

[105]  K Isahara,et al.  The interaction of vascular endothelial cells and dorsal root ganglion neurites is mediated by vitronectin and heparan sulfate proteoglycans. , 1995, Brain research. Developmental brain research.

[106]  S A Riboldi,et al.  Bioreactors in tissue engineering: scientific challenges and clinical perspectives. , 2009, Advances in biochemical engineering/biotechnology.

[107]  V. Rahimi-Movaghar,et al.  Animal models of spinal cord injury: a systematic review , 2017, Spinal Cord.

[108]  G. Whitesides The origins and the future of microfluidics , 2006, Nature.

[109]  Pamela Habibovic,et al.  Regeneration-on-a-chip? The perspectives on use of microfluidics in regenerative medicine. , 2013, Lab on a chip.

[110]  David L. Kaplan,et al.  Silk Hydrogels as Soft Substrates for Neural Tissue Engineering , 2013 .

[111]  Colin Blakemore,et al.  Implementing the 3Rs in Neuroscience Research: A Reasoned Approach , 2012, Neuron.

[112]  Violetta Zujovic,et al.  Adult DRG Stem/Progenitor Cells Generate Pericytes in the Presence of Central Nervous System (CNS) Developmental Cues, and Schwann Cells in Response to CNS Demyelination , 2015, Stem cells.

[113]  Christine E. Schmidt,et al.  Sacrificial Crystal Templated Hyaluronic Acid Hydrogels As Biomimetic 3D Tissue Scaffolds for Nerve Tissue Regeneration. , 2017, ACS biomaterials science & engineering.

[114]  Molly M Stevens,et al.  Fabrication of Hemin-Doped Serum Albumin-Based Fibrous Scaffolds for Neural Tissue Engineering Applications , 2018, ACS applied materials & interfaces.

[115]  V van Duinen,et al.  96 perfusable blood vessels to study vascular permeability in vitro , 2017, Scientific Reports.

[116]  Tessa Gordon,et al.  Electrical Stimulation Promotes Motoneuron Regeneration without Increasing Its Speed or Conditioning the Neuron , 2002, The Journal of Neuroscience.

[117]  Jean-Louis Viovy,et al.  β-amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed neuronal network , 2014, Acta neuropathologica communications.

[118]  Tsuyoshi Murata,et al.  {m , 1934, ACML.

[119]  J. Streit,et al.  Functional regeneration of intraspinal connections in a new in vitro model , 2014, Neuroscience.

[120]  Joseph Mainzer,et al.  FOR THE EXPRESSION , 2013 .

[121]  G. Goodhill,et al.  A dual compartment diffusion chamber for studying axonal chemotaxis in 3D collagen , 2013, Journal of Neuroscience Methods.

[122]  K. Lampe,et al.  Design of three-dimensional engineered protein hydrogels for tailored control of neurite growth. , 2013, Acta biomaterialia.

[123]  Shuichi Takayama,et al.  Organization of Endothelial Cells, Pericytes, and Astrocytes into a 3D Microfluidic in Vitro Model of the Blood-Brain Barrier. , 2016, Molecular pharmaceutics.

[124]  J. Povlishock,et al.  A new model for rapid stretch-induced injury of cells in culture: characterization of the model using astrocytes. , 1995, Journal of neurotrauma.

[125]  Ken Arai,et al.  Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology , 2015, Scientific Reports.

[126]  Vijay Viswam,et al.  High-resolution CMOS MEA platform to study neurons at subcellular, cellular, and network levels. , 2015, Lab on a chip.

[127]  Jia Yu,et al.  Therapy response testing of breast cancer in a 3D high-throughput perfused microfluidic platform , 2017, BMC Cancer.

[128]  Antonio Belli,et al.  Transcriptomics of traumatic brain injury: gene expression and molecular pathways of different grades of insult in a rat organotypic hippocampal culture model. , 2010, Journal of neurotrauma.

[129]  Muhammad H Zaman,et al.  Schwann cell response on polypyrrole substrates upon electrical stimulation. , 2014, Acta biomaterialia.

[130]  Noo Li Jeon,et al.  Microfluidic-based strip assay for testing the effects of various surface-bound inhibitors in spinal cord injury , 2008, Journal of Neuroscience Methods.

[131]  Jin Kim,et al.  Recapitulation of in vivo-like paracrine signals of human mesenchymal stem cells for functional neuronal differentiation of human neural stem cells in a 3D microfluidic system. , 2015, Biomaterials.

[132]  Yves De Koninck,et al.  Rapid Mechanically Controlled Rewiring of Neuronal Circuits , 2016, The Journal of Neuroscience.

[133]  Peter Grütter,et al.  Atomic force microscopy reveals important differences in axonal resistance to injury. , 2012, Biophysical journal.

[134]  C. Schmidt,et al.  Biodegradable hydrogels composed of oxime crosslinked poly(ethylene glycol), hyaluronic acid and collagen: a tunable platform for soft tissue engineering , 2015, Journal of biomaterials science. Polymer edition.

[135]  J. Pesic,et al.  Brain injury activates microglia that induce neural stem cell proliferation ex vivo and promote differentiation of neurosphere-derived cells into neurons and oligodendrocytes , 2010, Neuroscience.

[136]  Wei-guo Zhang,et al.  An integrated microfluidic device for screening the effective concentration of locally applied tacrolimus for peripheral nerve regeneration , 2014, Experimental and therapeutic medicine.

[137]  N. Jeon,et al.  Microfluidic culture platform for neuroscience research , 2006, Nature Protocols.

[138]  Michael R Hamblin,et al.  Microfluidic systems for stem cell-based neural tissue engineering. , 2016, Lab on a chip.

[139]  Hannah Monyer,et al.  Mouse Subependymal Zone Explants Cultured on Primary Astrocytes , 2016 .

[140]  Anders Edström,et al.  Early regeneration in vitro of adult mouse sciatic axons is dependent on local protein synthesis but may not involve neurotrophins , 1994, Neuroscience Letters.

[141]  Changkyun Im,et al.  A Low Permeability Microfluidic Blood-Brain Barrier Platform with Direct Contact between Perfusable Vascular Network and Astrocytes , 2017, Scientific Reports.

[142]  A. Salgado,et al.  From basics to clinical: A comprehensive review on spinal cord injury , 2014, Progress in Neurobiology.

[143]  Anja Schneider,et al.  The release and trans-synaptic transmission of Tau via exosomes , 2017, Molecular Neurodegeneration.

[144]  Vicky Robinson,et al.  Finding alternatives: an overview of the 3Rs and the use of animals in research , 2005 .

[145]  Noo Li Jeon,et al.  One-photon and two-photon stimulation of neurons in a microfluidic culture system. , 2016, Lab on a chip.

[146]  Viviana Versace,et al.  Functional reorganization after hemispherectomy in humans and animal models: What can we learn about the brain’s resilience to extensive unilateral lesions? , 2017, Brain Research Bulletin.

[147]  Justin R. Siebert,et al.  Chondroitin Sulfate Proteoglycans in the Nervous System: Inhibitors to Repair , 2014, BioMed research international.

[148]  Marja Nissinen,et al.  Myelination in mouse dorsal root ganglion/Schwann cell cocultures , 2008, Molecular and Cellular Neuroscience.

[149]  Frauke Ohl,et al.  Ethical issues associated with the use of animal experimentation in behavioral neuroscience research. , 2015, Current topics in behavioral neurosciences.

[150]  David F Williams,et al.  Neural tissue engineering options for peripheral nerve regeneration. , 2014, Biomaterials.

[151]  A. Khademhosseini,et al.  Fabrication of microchannels in methacrylated hyaluronic acid hydrogels , 2009, 2009 IEEE 35th Annual Northeast Bioengineering Conference.

[152]  Sarahlouise Jones,et al.  Neural progenitors from isolated postnatal rat myenteric ganglia: Expansion as neurospheres and differentiation in vitro , 2008, Brain Research.

[153]  P. Claude,et al.  Expression of NGF receptor in the developing and adult primate central nervous system , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[154]  Diane Hoffman-Kim,et al.  Three-Dimensional Neural Spheroid Culture: An In Vitro Model for Cortical Studies. , 2015, Tissue engineering. Part C, Methods.

[155]  David R. Colman,et al.  Substrate Micropatterning as a New in Vitro Cell Culture System to Study Myelination , 2011, ACS chemical neuroscience.

[156]  Adrian Ranga,et al.  3D Reconstitution of the Patterned Neural Tube from Embryonic Stem Cells , 2014, Stem cell reports.

[157]  M. Dickey,et al.  Integration of pre-aligned liquid metal electrodes for neural stimulation within a user-friendly microfluidic platform. , 2013, Lab on a chip.

[158]  Danny Baranes,et al.  Superior survival and durability of neurons and astrocytes on 3-dimensional aragonite biomatrices. , 2007, Tissue engineering.

[159]  H. Würbel More than 3Rs: the importance of scientific validity for harm-benefit analysis of animal research , 2017, Lab Animal.

[160]  Nitish Thakor,et al.  A two-compartment organotypic model of mammalian peripheral nerve repair , 2014, Journal of Neuroscience Methods.

[161]  Hiroyuki Fujita,et al.  Constraining the connectivity of neuronal networks cultured on microelectrode arrays with microfluidic techniques: a step towards neuron-based functional chips. , 2006, Biosensors & bioelectronics.

[162]  Marco Rasponi,et al.  Controlled electromechanical cell stimulation on-a-chip , 2015, Scientific Reports.

[163]  Li-Ru Zhao,et al.  Journal of Neurology and Neurobiology Open Access a Review of Traumatic Brain Injury Animal Models: Are We Lacking Adequate Models Replicating Chronic Traumatic Encephalopathy? , 2022 .

[164]  W B Greene,et al.  In vitro spinal cord trauma. , 1988, Laboratory investigation; a journal of technical methods and pathology.

[165]  Joseph R Madsen,et al.  The postnatal human filum terminale is a source of autologous multipotent neurospheres capable of generating motor neurons. , 2013, Neurosurgery.

[166]  M. Gillette,et al.  New perspectives on neuronal development via microfluidic environments , 2012, Trends in Neurosciences.

[167]  Per A. R. Ekström,et al.  Neurones and glial cells of the mouse sciatic nerve undergo apoptosis after injury in vivo and in vitro , 1995, Neuroreport.

[168]  Juan Felipe Diaz Quiroz,et al.  Development of a 3D matrix for modeling mammalian spinal cord injury in vitro , 2016, Neural regeneration research.

[169]  Michelle C LaPlaca,et al.  Trauma-induced plasmalemma disruptions in three-dimensional neural cultures are dependent on strain modality and rate. , 2011, Journal of neurotrauma.

[170]  Kapil Pant,et al.  SyM-BBB: a microfluidic Blood Brain Barrier model. , 2013, Lab on a chip.

[171]  Ning Zhang,et al.  Evaluation of spinal cord injury animal models , 2014, Neural regeneration research.

[172]  Alan C. Bovik,et al.  A Fully Automated Microfluidic Femtosecond Laser Axotomy Platform for Nerve Regeneration Studies in C. elegans , 2014, PloS one.

[174]  A. Nistri,et al.  Kainate and metabolic perturbation mimicking spinal injury differentially contribute to early damage of locomotor networks in the in vitro neonatal rat spinal cord , 2008, Neuroscience.

[175]  D. Beebe,et al.  Fundamentals of microfluidic cell culture in controlled microenvironments. , 2010, Chemical Society reviews.

[176]  Christian Franck,et al.  Strain and rate-dependent neuronal injury in a 3D in vitro compression model of traumatic brain injury , 2016, Scientific Reports.

[177]  David L Kaplan,et al.  Bioengineered functional brain-like cortical tissue , 2014, Proceedings of the National Academy of Sciences.

[178]  Jos Joore,et al.  High-throughput compound evaluation on 3D networks of neurons and glia in a microfluidic platform , 2016, Scientific Reports.

[179]  Rosanne M Guijt,et al.  Microfluidic culture platform for studying neuronal response to mild to very mild axonal stretch injury. , 2014, Biomicrofluidics.

[180]  Christine E Schmidt,et al.  Cell-laden hydrogel constructs of hyaluronic acid, collagen, and laminin for neural tissue engineering. , 2010, Tissue engineering. Part A.

[181]  M. Messerli,et al.  Extracellular Electrical Fields Direct Wound Healing and Regeneration , 2011, The Biological Bulletin.

[182]  J. Lilien,et al.  Promotion of retinal neurite outgrowth by substratum-bound fibronectin. , 1981, Developmental biology.

[183]  Serpil Erdogan,et al.  ADAMTS1, ADAMTS5, ADAMTS9 and aggrecanase-generated proteoglycan fragments are induced following spinal cord injury in mouse , 2013, Neuroscience Letters.

[184]  Yang Liu,et al.  An in vitro model of neurotrauma in organotypic spinal cord cultures from adult mice. , 2002, Brain research. Brain research protocols.

[185]  Madeline A. Lancaster,et al.  Cerebral organoids model human brain development and microcephaly , 2013, Nature.

[186]  Milos Pekny,et al.  A novel method for three-dimensional culture of central nervous system neurons. , 2014, Tissue engineering. Part C, Methods.

[187]  Nitish Thakor,et al.  Investigation of nerve injury through microfluidic devices , 2014, Journal of The Royal Society Interface.

[188]  J Heikenfeld,et al.  The microfluidics of the eccrine sweat gland, including biomarker partitioning, transport, and biosensing implications. , 2015, Biomicrofluidics.

[189]  Mauro Alini,et al.  Relevance of bioreactors and whole tissue cultures for the translation of new therapies to humans , 2017, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[190]  Nic D. Leipzig,et al.  Differentiation of neural stem cells in three-dimensional growth factor-immobilized chitosan hydrogel scaffolds. , 2011, Biomaterials.

[191]  W Shain,et al.  Fabrication and optimization of alginate hydrogel constructs for use in 3D neural cell culture , 2011, Biomedical materials.

[192]  Shuzhen Guo,et al.  Dysfunctional Cell-Cell Signaling in the Neurovascular Unit as a Paradigm for Central Nervous System Disease , 2009, Stroke.

[193]  R. Eskandari,et al.  A novel technology to model pressure-induced cellular injuries in the brain , 2018, Journal of Neuroscience Methods.

[194]  Olga Minaeva,et al.  Considerations for Experimental Animal Models of Concussion, Traumatic Brain Injury, and Chronic Traumatic Encephalopathy—These Matters Matter , 2017, Front. Neurol..

[195]  M. Houslay,et al.  Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model , 2014, British journal of pharmacology.

[196]  Kristi S Anseth,et al.  Three-dimensional growth and function of neural tissue in degradable polyethylene glycol hydrogels. , 2006, Biomaterials.

[197]  Karl H. Plate,et al.  Angiogenesis after cerebral ischemia , 2009, Acta Neuropathologica.

[198]  Milos Nikolic,et al.  Recent Zika Virus Isolates Induce Premature Differentiation of Neural Progenitors in Human Brain Organoids. , 2017, Cell stem cell.

[199]  Nadine Collaert,et al.  Open-cell recording of action potentials using active electrode arrays. , 2012, Lab on a chip.

[200]  D. K. Cullen,et al.  Strain rate-dependent induction of reactive astrogliosis and cell death in three-dimensional neuronal–astrocytic co-cultures , 2007, Brain Research.

[201]  Tessa Gordon,et al.  Electrical stimulation promotes sensory neuron regeneration and growth-associated gene expression , 2007, Experimental Neurology.

[202]  Rosanne M. Guijt,et al.  Mild and repetitive very mild axonal stretch injury triggers cystoskeletal mislocalization and growth cone collapse , 2017, PloS one.

[203]  Fang Chen,et al.  Development of a miniaturized bioreactor for neural culture and axon stretch growth , 2014, 2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[204]  V. Yong,et al.  Pathophysiology of the brain extracellular matrix: a new target for remyelination , 2013, Nature Reviews Neuroscience.

[205]  J. Hubbell,et al.  Development of fibrin derivatives for controlled release of heparin-binding growth factors. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[206]  Maria Antfolk,et al.  In Vitro Blood-Brain Barrier Models-An Overview of Established Models and New Microfluidic Approaches. , 2015, Journal of pharmaceutical sciences.

[207]  G. Lajoie,et al.  Matrigel: A complex protein mixture required for optimal growth of cell culture , 2010, Proteomics.

[208]  Douglas H. Smith,et al.  Mechanical breaking of microtubules in axons during dynamic stretch injury underlies delayed elasticity, microtubule disassembly, and axon degeneration , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[209]  Zhigang He,et al.  Intrinsic Control of Axon Regeneration , 2010, Neuron.

[210]  M Edbladh,et al.  Environmental factors contribute to the enhanced regeneration of frog sciatic sensory axons by a conditioning lesion. , 1989, Acta physiologica Scandinavica.

[211]  T. Bowden,et al.  Enhanced neuronal differentiation in a three‐dimensional collagen‐hyaluronan matrix , 2007, Journal of neuroscience research.

[212]  Min Zhao,et al.  Electrical fields in wound healing-An overriding signal that directs cell migration. , 2009, Seminars in cell & developmental biology.

[213]  M Edbladh,et al.  Regeneration in vitro of the adult frog sciatic sensory axons. , 1990, Restorative neurology and neuroscience.

[214]  J. Ghajar,et al.  Fluid percussion barotrauma chamber: a new in vitro model for traumatic brain injury. , 1991, The Journal of surgical research.

[215]  Xavier Navarro,et al.  In vitro comparison of motor and sensory neuron outgrowth in a 3D collagen matrix , 2011, Journal of Neuroscience Methods.

[216]  R. Campenot,et al.  Local control of neurite development by nerve growth factor. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[217]  Mohammad A. Qasaimeh,et al.  Integration of Shallow Gradients of Shh and Netrin-1 Guides Commissural Axons , 2015, PLoS biology.

[218]  John W Haycock,et al.  Development of a bioreactor for evaluating novel nerve conduits , 2008, Biotechnology and bioengineering.

[219]  François Berthod,et al.  In vitro study of axonal migration and myelination of motor neurons in a three‐dimensional tissue‐engineered model , 2008, Glia.

[220]  Katherine Ellen Foley,et al.  Organoids: a better in vitro model , 2017, Nature Methods.

[221]  Michael Chopp,et al.  Mesenchymal Stromal Cells Promote Axonal Outgrowth Alone and Synergistically with Astrocytes via tPA , 2016, PloS one.

[222]  Vivek Gupta,et al.  Microfluidics‐based 3D cell culture models: Utility in novel drug discovery and delivery research , 2016, Bioengineering & translational medicine.

[223]  C. Cotman,et al.  A microfluidic culture platform for CNS axonal injury, regeneration and transport , 2005, Nature Methods.

[224]  Yvonne Höller,et al.  Rodent, large animal and non-human primate models of spinal cord injury. , 2017, Zoology.

[225]  Jiwoon Kwon,et al.  High-strain-rate brain injury model using submerged acute rat brain tissue slices. , 2012, Journal of neurotrauma.

[226]  Roger D Kamm,et al.  A high-throughput microfluidic assay to study neurite response to growth factor gradients. , 2011, Lab on a chip.

[227]  J. Kessler,et al.  Transforming growth factor beta has neurotrophic actions on sensory neurons in vitro and is synergistic with nerve growth factor. , 1992, Developmental biology.

[228]  Phillip G. Popovich,et al.  Extracellular matrix regulation of inflammation in the healthy and injured spinal cord , 2014, Experimental Neurology.

[229]  D. Stein Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials , 2015, Brain injury.

[230]  B. Kieseier,et al.  A reliable in vitro model for studying peripheral nerve myelination in mouse , 2013, Journal of Neuroscience Methods.

[231]  Xi-ping Cheng,et al.  De-differentiation Response of Cultured Astrocytes to Injury Induced by Scratch or Conditioned Culture Medium of Scratch-Insulted Astrocytes , 2009, Cellular and Molecular Neurobiology.

[232]  M. Chopp,et al.  Angiogenesis, neurogenesis and brain recovery of function following injury. , 2010, Current opinion in investigational drugs.

[233]  Jae-Woong Jeong,et al.  Microfluidic neural probes: in vivo tools for advancing neuroscience. , 2017, Lab on a chip.

[234]  A. Nistri,et al.  The volatile anesthetic methoxyflurane protects motoneurons against excitotoxicity in an in vitro model of rat spinal cord injury , 2015, Neuroscience.

[235]  Jeffrey T. Borenstein,et al.  Biomaterials-based microfluidics for engineered tissue constructs , 2010 .

[236]  J. Kapfhammer,et al.  Spontaneous regeneration of intrinsic spinal cord axons in a novel spinal cord slice culture model , 2008, The European journal of neuroscience.

[237]  Vito Paolo Pastore,et al.  Sphingomyelin as a myelin biomarker in CSF of acquired demyelinating neuropathies , 2017, Scientific Reports.

[238]  Roger D. Kamm,et al.  Microfluidic device for the formation of optically excitable, three-dimensional, compartmentalized motor units , 2016, Science Advances.

[239]  Sameer B. Shah,et al.  Mouse hippocampal explant culture system to study isolated axons , 2014, Journal of Neuroscience Methods.

[240]  Adrian Ranga,et al.  Neural tube morphogenesis in synthetic 3D microenvironments , 2016, Proceedings of the National Academy of Sciences.

[241]  Shaojun Liu,et al.  Establishment and assessment of a simple and easily reproducible incision model of spinal cord neuron cells in vitro , 2011, In Vitro Cellular & Developmental Biology - Animal.

[242]  Alex A. Pollen,et al.  Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia. , 2017, Cell stem cell.

[243]  S. Ramakrishna,et al.  Electrospinning of nano/micro scale poly(L-lactic acid) aligned fibers and their potential in neural tissue engineering. , 2005, Biomaterials.

[244]  Michel Salzet,et al.  Comparison of dynamic behavior and maturation of neural multipotent cells derived from different spinal cord developmental stages: an in vitro study. , 2015, Acta neurobiologiae experimentalis.

[245]  J. Leach,et al.  Three-Dimensional Environment Sustains Morphological Heterogeneity and Promotes Phenotypic Progression During Astrocyte Development. , 2016, Tissue engineering. Part A.

[246]  Dave Speijer,et al.  Injury Response of Resected Human Brain Tissue In Vitro , 2015, Brain pathology.

[247]  Digant P. Dave,et al.  Neuro-optical microfluidic platform to study injury and regeneration of single axons. , 2009, Lab on a chip.

[248]  A. Logan,et al.  Angiogenesis , 1993, The Lancet.

[249]  John A. Kessler,et al.  Transforming growth factor β has neurotrophic actions on sensory neurons in vitro and is synergistic with nerve growth factor , 1992 .

[250]  Michelle C LaPlaca,et al.  High rate shear strain of three-dimensional neural cell cultures: a new in vitro traumatic brain injury model. , 2005, Journal of biomechanics.

[251]  Dan Li,et al.  Graphene Functionalized Scaffolds Reduce the Inflammatory Response and Supports Endogenous Neuroblast Migration when Implanted in the Adult Brain , 2016, PloS one.

[252]  P. Honegger,et al.  Differentiation of rat striatal embryonic stem cells in vitro: monolayer culture vs. three‐dimensional coculture with differentiated brain cells , 2000, Journal of neuroscience research.

[253]  Emma East,et al.  Engineering an integrated cellular interface in three-dimensional hydrogel cultures permits monitoring of reciprocal astrocyte and neuronal responses. , 2012, Tissue engineering. Part C, Methods.

[254]  Mieke Dewerchin,et al.  Vascular endothelial growth factor: a neurovascular target in neurological diseases , 2016, Nature Reviews Neurology.

[255]  Zin Z. Khaing,et al.  High molecular weight hyaluronic acid limits astrocyte activation and scar formation after spinal cord injury , 2011, Journal of neural engineering.

[256]  Emma East,et al.  A versatile 3D culture model facilitates monitoring of astrocytes undergoing reactive gliosis , 2009, Journal of tissue engineering and regenerative medicine.

[257]  S. Margulies,et al.  Premedication with meloxicam exacerbates intracranial haemorrhage in an immature swine model of non-impact inertial head injury , 2012, Laboratory animals.

[258]  Eitan Erez Zahavi,et al.  A compartmentalized microfluidic neuromuscular co-culture system reveals spatial aspects of GDNF functions , 2015, Journal of Cell Science.

[259]  Yuhui Jiang,et al.  Neural Stem Cells in the Immature, but Not the Mature, Subventricular Zone Respond Robustly to Traumatic Brain Injury , 2014, Developmental Neuroscience.

[260]  Lars Olson,et al.  Rat models of spinal cord injury: from pathology to potential therapies , 2016, Disease Models & Mechanisms.

[261]  Catherine A Gorrie,et al.  Severity of spinal cord injury in adult and infant rats after vertebral dislocation depends upon displacement but not speed. , 2013, Journal of neurotrauma.

[262]  Gregory A Petsko,et al.  When failure should be the option , 2010, BMC Biology.

[263]  V. Fazan,et al.  Effects of laser therapy in peripheral nerve regeneration , 2013, Acta ortopedica brasileira.

[264]  Fábio Gonçalves Teixeira,et al.  Modulation of the Mesenchymal Stem Cell Secretome Using Computer-Controlled Bioreactors: Impact on Neuronal Cell Proliferation, Survival and Differentiation , 2016, Scientific Reports.

[265]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[266]  David I Shreiber,et al.  Neurite growth in 3D collagen gels with gradients of mechanical properties , 2009, Biotechnology and bioengineering.

[267]  D. Shreiber,et al.  Microfluidic generation of haptotactic gradients through 3D collagen gels for enhanced neurite growth. , 2011, Journal of neurotrauma.

[268]  T. Palmer,et al.  Vascular niche for adult hippocampal neurogenesis , 2000, The Journal of comparative neurology.

[269]  Jean-Louis Viovy,et al.  Axon diodes for the reconstruction of oriented neuronal networks in microfluidic chambers. , 2011, Lab on a chip.

[270]  Yana Pigareva,et al.  Design of Cultured Neuron Networks in vitro with Predefined Connectivity Using Asymmetric Microfluidic Channels , 2017, Scientific Reports.

[271]  Margaret H Magdesian,et al.  Rewiring Neuronal Circuits: A New Method for Fast Neurite Extension and Functional Neuronal Connection. , 2017, Journal of visualized experiments : JoVE.

[272]  Rebecca Kuntz Willits,et al.  Short‐duration, DC electrical stimulation increases chick embryo DRG neurite outgrowth , 2006, Bioelectromagnetics.