Assessing functional connectivity across 3D tissue engineered axonal tracts using calcium fluorescence imaging

Dhobale, Anjali; Adewole, Dayo O.; Chan, Andy Ho Wing; Marinov, Toma; Serruya, Mijail; Kraft, Reuben H.; Cullen, D. Kacy

doi:10.1088/1741-2552/aac96d

Cited by 17 publications

(11 citation statements)

References 70 publications

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“…15,19 To date, micro-TENNs have been fabricated using dorsal root ganglia neurons, cerebral cortical neurons (e.g., mixed glutamatergic and GABAergic), embryonic rodent ventral mesencephalic dopaminergic neurons, and human ESC-derived dopaminergic neurons. 5,125,126,129,[141][142][143][144] As our understanding of PD pathophysiology expands, it is possible that multiple micro-TENNs could be transplanted to reconnect different damaged regions, comprised of alternative neuronal phenotypes, such as noradrenergic, serotoninergic, and cholinergic cell types. However, it is difficult to predict how transplant therapies, including either transplanted cells or pathways, such as micro-TENNs, could be used to recapitulate widely dispersed innervation of cerebral cortex from cholinergic, serotonergic, or noradrenergic brainstem nuclei.…”

Section: Tissue Engineering: Combining Cells and Scaffoldsmentioning

confidence: 99%

Emerging regenerative medicine and tissue engineering strategies for Parkinson’s disease

Harris

Burrell

Struzyna

et al. 2020

npj Parkinsons Dis.

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Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease, affecting 1–2% of people over 65. The classic motor symptoms of PD result from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a loss of their long axonal projections to the striatum. Current treatment strategies such as dopamine replacement and deep brain stimulation (DBS) can only minimize the symptoms of nigrostriatal degeneration, not directly replace the lost pathway. Regenerative medicine-based solutions are being aggressively pursued with the goal of restoring dopamine levels in the striatum, with several emerging techniques attempting to reconstruct the entire nigrostriatal pathway—a key goal to recreate feedback pathways to ensure proper dopamine regulation. Although many pharmacological, genetic, and optogenetic treatments are being developed, this article focuses on the evolution of transplant therapies for the treatment of PD, including fetal grafts, cell-based implants, and more recent tissue-engineered constructs. Attention is given to cell/tissue sources, efficacy to date, and future challenges that must be overcome to enable robust translation into clinical use. Emerging regenerative medicine therapies are being developed using neurons derived from autologous stem cells, enabling the construction of patient-specific constructs tailored to their particular extent of degeneration. In the upcoming era of restorative neurosurgery, such constructs may directly replace SNpc neurons, restore axon-based dopaminergic inputs to the striatum, and ameliorate motor deficits. These solutions may provide a transformative and scalable solution to permanently replace lost neuroanatomy and improve the lives of millions of people afflicted by PD.

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Section: Tissue Engineering: Combining Cells and Scaffoldsmentioning

confidence: 99%

Emerging regenerative medicine and tissue engineering strategies for Parkinson’s disease

Harris

Burrell

Struzyna

et al. 2020

npj Parkinsons Dis.

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“…In the case of bidirectional living electrodes for recording, activity from host neurons must be conveyed across at least two synapses, making them potentially useful for recording local fields but likely hindering the ability to isolate single neurons from the output activity at the brain surface. Computer models of living electrodes may provide predictions of synaptogenesis and signal propagation to better inform design choices and interpret neuronal activity (Dhobale et al, 2018). Clinical bio-fabrication will also be a significant challenge for translation, including starting biomass, quality assurance, and safety monitoring.…”

Section: Micro-tissue Engineered “Living Electrodes”mentioning

confidence: 99%

Bioactive Neuroelectronic Interfaces

et al. 2019

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Within the neural engineering field, next-generation implantable neuroelectronic interfaces are being developed using biologically-inspired and/or biologically-derived materials to improve upon the stability and functional lifetime of current interfaces. These technologies use biomaterials, bioactive molecules, living cells, or some combination of these, to promote host neuronal survival, reduce the foreign body response, and improve chronic device-tissue integration. This article provides a general overview of the different strategies, milestones, and evolution of bioactive neural interfaces including electrode material properties, biological coatings, and “decoration” with living cells. Another such biohybrid approach developed in our lab uses preformed implantable micro-tissue featuring long-projecting axonal tracts encased within carrier biomaterial micro-columns. These so-called “living electrodes” have been engineered with carefully tailored material, mechanical, and biological properties to enable natural, synaptic based modulation of specific host circuitry while ultimately being under computer control. This article provides an overview of these living electrodes, including design and fabrication, performance attributes, as well as findings to date characterizing in vitro and in vivo functionality.

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“…Among them are micro-tissue engineered neural networks (micro- 37 TENNs), which are three-dimensional (3D) living constructs comprised of long-projecting axonal 38 tracts and discrete neuronal populations within a microscopic, hollow hydrogel cylinder 39 (microcolumn) filled with an extracellular matrix (ECM) [1]. Preformed clusters of neuronal cell 40 bodies (aggregates) are housed at one or both ends of the microcolumn, with axons growing 41 longitudinally through the hydrogel lumen (Figure 1). This segregation of long axonal tracts and 42 neuronal cell bodies approximates the network architecture of the central nervous system by 43…”

Section: Introduction 35mentioning

confidence: 99%

“…research group has begun [41]. The neuronal growth patterns will be used to serve as the input 468 of a spiking model to study the firing patterns within micro-TENNs and, following implantation, at 469 the distal ends of micro-TENNs upon integration with the host brain neurons.…”

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confidence: 99%

A Computational Model of Bidirectional Axonal Growth in Micro-Tissue Engineered Neuronal Networks (micro-TENNs)

Marinov

Yuchi

Adewole

et al. 2018

Preprint

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AbstractMicro-Tissue Engineered Neural Networks (Micro-TENNs) are living three-dimensional constructs designed to replicate the neuroanatomy of white matter pathways in the brain, and are being developed as implantable microtissue for axon tract reconstruction or as anatomically-relevant in vitro experimental platforms. Micro-TENNs are composed of discrete neuronal aggregates connected by bundles of long-projecting axonal tracts within miniature tubular hydrogels. In order to help design and optimize micro-TENN performance, we have created a new computational model including geometric and functional properties. The model is built upon the three-dimensional diffusion equation and incorporates large-scale uni- and bi-directional growth that simulates realistic neuron morphologies. The model captures unique features of 3D axonal tract development that are not apparent in planar outgrowth, and may be insightful for how white matter pathways form during brain development. The processes of axonal outgrowth, branching, turning and aggregation/bundling from each neuron are described through functions built on concentration equations and growth time distributed across the growth segments. Once developed we conducted multiple parametric studies to explore the applicability of the method and conducted preliminary validation via comparisons to experimentally grown micro-TENNs for a range of growth conditions. Using this framework, this model can be applied to study micro-TENN growth processes and functional characteristics using spiking network or compartmental network modeling. This model may be applied to improve our understanding of axonal tract development and functionality, as well as to optimize the fabrication of implantable tissue engineered brain pathways for nervous system reconstruction and/or modulation.

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Assessing functional connectivity across 3D tissue engineered axonal tracts using calcium fluorescence imaging

Cited by 17 publications

References 70 publications

Emerging regenerative medicine and tissue engineering strategies for Parkinson’s disease

Emerging regenerative medicine and tissue engineering strategies for Parkinson’s disease

Bioactive Neuroelectronic Interfaces

A Computational Model of Bidirectional Axonal Growth in Micro-Tissue Engineered Neuronal Networks (micro-TENNs)

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