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Micromachines
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Microfluidic Brain-on-a-Chip
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Microfluidic Brain-on-a-Chip

A special issue of Micromachines (ISSN 2072-666X). This special issue belongs to the section "B：Biology and Biomedicine".

Deadline for manuscript submissions: closed (10 March 2021) | Viewed by 31749

Special Issue Editor

Dr. Regina Luttge

E-Mail Website
Guest Editor
Chair Neuro-Nanoscale Engineering, Microsystems Section, Department of Mechanical Engineering, Institute of Complex Molecular Systems (ICMS), Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands
Interests: micro- and nanoscale assisted neuroscience and technology; micro- and nanofabrication; microfluidic applications; 3D brain-on-a-chip; organ-on-a-chip platforms; systems engineering
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Microfluidic brain-on-a-chip entails research on in vitro mimicking and investigating brain organization and function by applying micro-and nanofabricated features. The chip format stands for integrated technologies that yield an understanding of all types of processes involved during interrogation of neurons either in a natural source of tissue or cultured from cells, keeping in mind the efficiency of the implementation of such techniques. The latter is particularly important for robust biomedical research and industrial applications. This Special Issue collects publications discussing the underlying design requirements, constraints, and preferences to fabricate, vascularize, and manipulate biohybrid constructs. Microfluidic brain-on-a-chip is motivated by a multi-disciplinary perspective shedding light on the complex neurophysiology encompassing perfusion and cell differentiation processes and includes the molecular and cellular neurobiology machinery responsible for creating neural circuits, networks of neurons, and hierarchical brain systems standing at the basis of actions that are central to cognition and behavior. Moreover, the design of microfluidic brain-on-a-chip systems using cells from human origin provides us with a technology for discovering and testing novel therapeutic interventions in a safe, ethically sound, and highly representative manner. The concept of brain-on-a-chip may extend to the entire nervous system as a cornerstone in conquering brain diseases and stimulating systems thinking.

I highly welcome your submissions of research manuscripts, short communications including technical notes on chip fabrication methods and microfluidic cell-handling protocols, as well as reviews to be considered for inclusion in the Special Issue: Microfluidic Brain-on-a-Chip.

Prof. Dr. Regina Luttge
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Micromachines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Microchip fabrication methods and technology
  • Microfluidic-assisted in vitro brain research
  • Flow-induced gradients and stimuli
  • BioMEMS
  • Integrative biology
  • In vitro brain models
  • Nervous systems science and technology
  • Experimental neuro(electro)physiology
  • Microelectrode arrays
  • Micro- and mesoscale total analysis systems
  • Lab-on-a-chip
  • Neuroprobes
  • Neuro-sensors and actuators (including optogenetics, dynamic stimuli, and dyes as biomarkers)
  • Neuroengineering
  • Stem cell technology for brain research
  • Soft tissue engineering
  • Microenvironments to host microtissues and cell cultures
  • Organoid technology
  • Brain organoids
  • Biohybrids
  • Neurobiology
  • Neuronal processes
  • Mechanotransduction
  • Integrated data-harvesting technology including automation and robotics control
  • Artificial intelligence applications emerging from microfluidic brain-on-a-chip

Published Papers (7 papers)

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Editorial

Jump to: Research, Review, Other

6 pages, 195 KiB  
Editorial
Editorial for the Special Issue on Microfluidic Brain-on-a-Chip
by Regina Luttge
Micromachines 2021, 12(9), 1100; https://doi.org/10.3390/mi12091100 - 13 Sep 2021
Viewed by 1876
Abstract
A little longer than a decade of Organ-on-Chip (OoC) developments has passed [...] Full article
(This article belongs to the Special Issue Microfluidic Brain-on-a-Chip)

Research

Jump to: Editorial, Review, Other

13 pages, 2289 KiB  
Article
Analyzing Developing Brain-On-Chip Cultures with the CALIMA Calcium Imaging Tool
by Elles A. L. Raaijmakers, Nikki Wanders, Rob M. C. Mestrom and Regina Luttge
Micromachines 2021, 12(4), 412; https://doi.org/10.3390/mi12040412 - 08 Apr 2021
Cited by 2 | Viewed by 2449
Abstract
Brain-on-chip (BoC) models are tools for reproducing the native microenvironment of neurons, in order to study the (patho)physiology and drug-response of the brain. Recent developments in BoC techniques focus on steering neurons in their activity via microfabrication and via computer-steered feedback mechanisms. These [...] Read more.
Brain-on-chip (BoC) models are tools for reproducing the native microenvironment of neurons, in order to study the (patho)physiology and drug-response of the brain. Recent developments in BoC techniques focus on steering neurons in their activity via microfabrication and via computer-steered feedback mechanisms. These cultures are often studied through calcium imaging (CI), a method for visualizing the cellular activity through infusing cells with a fluorescent dye. CAlciumImagingAnalyser 2.0 (CALIMA 2.0) is an updated version of a software tool that detects and analyzes fluorescent signals and correlates cellular activity to identify possible network formation in BoC cultures. Using three previous published data sets, it was demonstrated that CALIMA 2.0 can analyze large data sets of CI-data and interpret cell activity to help study the activity and maturity of BoC cultures. Last, an analysis of the processing speed shows that CALIMA 2.0 is sufficiently fast to process data sets with an acquisition rate up to 5 Hz in real-time on a medium-performance computer. Full article
(This article belongs to the Special Issue Microfluidic Brain-on-a-Chip)
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11 pages, 3928 KiB  
Article
Stiff-to-Soft Transition from Glass to 3D Hydrogel Substrates in Neuronal Cell Culture
by Gulden Akcay and Regina Luttge
Micromachines 2021, 12(2), 165; https://doi.org/10.3390/mi12020165 - 08 Feb 2021
Cited by 7 | Viewed by 3591
Abstract
Over the past decade, hydrogels have shown great potential for mimicking three- dimensional (3D) brain architectures in vitro due to their biocompatibility, biodegradability, and wide range of tunable mechanical properties. To better comprehend in vitro human brain models and the mechanotransduction processes, we [...] Read more.
Over the past decade, hydrogels have shown great potential for mimicking three- dimensional (3D) brain architectures in vitro due to their biocompatibility, biodegradability, and wide range of tunable mechanical properties. To better comprehend in vitro human brain models and the mechanotransduction processes, we generated a 3D hydrogel model by casting photo-polymerized gelatin methacryloyl (GelMA) in comparison to poly (ethylene glycol) diacrylate (PEGDA) atop of SH-SY5Y neuroblastoma cells seeded with 150,000 cells/cm2 according to our previous experience in a microliter-sized polydimethylsiloxane (PDMS) ring serving for confinement. 3D SH-SY5Y neuroblastoma cells in GelMA demonstrated an elongated, branched, and spreading morphology resembling neurons, while the cell survival in cast PEGDA was not supported. Confocal z-stack microscopy confirmed our hypothesis that stiff-to-soft material transitions promoted neuronal migration into the third dimension. Unfortunately, large cell aggregates were also observed. A subsequent cell seeding density study revealed a seeding cell density above 10,000 cells/cm2 started the formation of cell aggregates, and below 1500 cells/cm2 cells still appeared as single cells on day 6. These results allowed us to conclude that the optimum cell seeding density might be between 1500 and 5000 cells/cm2. This type of hydrogel construct is suitable to design a more advanced layered mechanotransduction model toward 3D microfluidic brain-on-a-chip applications. Full article
(This article belongs to the Special Issue Microfluidic Brain-on-a-Chip)
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13 pages, 4083 KiB  
Article
Gaining Micropattern Fidelity in an NOA81 Microsieve Laser Ablation Process
by Rahman Sabahi-Kaviani and Regina Luttge
Micromachines 2021, 12(1), 21; https://doi.org/10.3390/mi12010021 - 27 Dec 2020
Cited by 5 | Viewed by 2515
Abstract
We studied the micropattern fidelity of a Norland Optical Adhesive 81 (NOA81) microsieve made by soft-lithography and laser micromachining. Ablation opens replicated cavities, resulting in three-dimensional (3D) micropores. We previously demonstrated that microsieves can capture cells by passive pumping. Flow, capture yield, and [...] Read more.
We studied the micropattern fidelity of a Norland Optical Adhesive 81 (NOA81) microsieve made by soft-lithography and laser micromachining. Ablation opens replicated cavities, resulting in three-dimensional (3D) micropores. We previously demonstrated that microsieves can capture cells by passive pumping. Flow, capture yield, and cell survival depend on the control of the micropore geometry and must yield high reproducibility within the device and from device to device. We investigated the NOA81 film thickness, the laser pulse repetition rate, the number of pulses, and the beam focusing distance. For NOA81 films spin-coated between 600 and 1200 rpm, the pulse number controls the breaching of films to form the pore’s aperture and dominates the process. Pulse repetition rates between 50 and 200 Hz had no observable influence. We also explored laser focal plane to substrate distance to find the most effective ablation conditions. Scanning electron micrographs (SEM) of focused ion beam (FIB)-cut cross sections of the NOA81 micropores and inverted micropore copies in polydimethylsiloxane (PDMS) show a smooth surface topology with minimal debris. Our studies reveal that the combined process allows for a 3D micropore quality from device to device with a large enough process window for biological studies. Full article
(This article belongs to the Special Issue Microfluidic Brain-on-a-Chip)
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Review

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36 pages, 2624 KiB  
Review
Review of Design Considerations for Brain-on-a-Chip Models
by Tiffany Cameron, Tanya Bennet, Elyn M. Rowe, Mehwish Anwer, Cheryl L. Wellington and Karen C. Cheung
Micromachines 2021, 12(4), 441; https://doi.org/10.3390/mi12040441 - 15 Apr 2021
Cited by 24 | Viewed by 6444
Abstract
In recent years, the need for sophisticated human in vitro models for integrative biology has motivated the development of organ-on-a-chip platforms. Organ-on-a-chip devices are engineered to mimic the mechanical, biochemical and physiological properties of human organs; however, there are many important considerations when [...] Read more.
In recent years, the need for sophisticated human in vitro models for integrative biology has motivated the development of organ-on-a-chip platforms. Organ-on-a-chip devices are engineered to mimic the mechanical, biochemical and physiological properties of human organs; however, there are many important considerations when selecting or designing an appropriate device for investigating a specific scientific question. Building microfluidic Brain-on-a-Chip (BoC) models from the ground-up will allow for research questions to be answered more thoroughly in the brain research field, but the design of these devices requires several choices to be made throughout the design development phase. These considerations include the cell types, extracellular matrix (ECM) material(s), and perfusion/flow considerations. Choices made early in the design cycle will dictate the limitations of the device and influence the end-point results such as the permeability of the endothelial cell monolayer, and the expression of cell type-specific markers. To better understand why the engineering aspects of a microfluidic BoC need to be influenced by the desired biological environment, recent progress in microfluidic BoC technology is compared. This review focuses on perfusable blood–brain barrier (BBB) and neurovascular unit (NVU) models with discussions about the chip architecture, the ECM used, and how they relate to the in vivo human brain. With increased knowledge on how to make informed choices when selecting or designing BoC models, the scientific community will benefit from shorter development phases and platforms curated for their application. Full article
(This article belongs to the Special Issue Microfluidic Brain-on-a-Chip)
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50 pages, 11413 KiB  
Review
Electrophysiology Read-Out Tools for Brain-on-Chip Biotechnology
by Csaba Forro, Davide Caron, Gian Nicola Angotzi, Vincenzo Gallo, Luca Berdondini, Francesca Santoro, Gemma Palazzolo and Gabriella Panuccio
Micromachines 2021, 12(2), 124; https://doi.org/10.3390/mi12020124 - 24 Jan 2021
Cited by 25 | Viewed by 8768
Abstract
Brain-on-Chip (BoC) biotechnology is emerging as a promising tool for biomedical and pharmaceutical research applied to the neurosciences. At the convergence between lab-on-chip and cell biology, BoC couples in vitro three-dimensional brain-like systems to an engineered microfluidics platform designed to provide an in [...] Read more.
Brain-on-Chip (BoC) biotechnology is emerging as a promising tool for biomedical and pharmaceutical research applied to the neurosciences. At the convergence between lab-on-chip and cell biology, BoC couples in vitro three-dimensional brain-like systems to an engineered microfluidics platform designed to provide an in vivo-like extrinsic microenvironment with the aim of replicating tissue- or organ-level physiological functions. BoC therefore offers the advantage of an in vitro reproduction of brain structures that is more faithful to the native correlate than what is obtained with conventional cell culture techniques. As brain function ultimately results in the generation of electrical signals, electrophysiology techniques are paramount for studying brain activity in health and disease. However, as BoC is still in its infancy, the availability of combined BoC–electrophysiology platforms is still limited. Here, we summarize the available biological substrates for BoC, starting with a historical perspective. We then describe the available tools enabling BoC electrophysiology studies, detailing their fabrication process and technical features, along with their advantages and limitations. We discuss the current and future applications of BoC electrophysiology, also expanding to complementary approaches. We conclude with an evaluation of the potential translational applications and prospective technology developments. Full article
(This article belongs to the Special Issue Microfluidic Brain-on-a-Chip)
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Other

18 pages, 2426 KiB  
Perspective
Glioma-on-a-Chip Models
by Merve Ustun, Sajjad Rahmani Dabbagh, Irem Sultan Ilci, Tugba Bagci-Onder and Savas Tasoglu
Micromachines 2021, 12(5), 490; https://doi.org/10.3390/mi12050490 - 26 Apr 2021
Cited by 20 | Viewed by 5012
Abstract
Glioma, as an aggressive type of cancer, accounts for virtually 80% of malignant brain tumors. Despite advances in therapeutic approaches, the long-term survival of glioma patients is poor (it is usually fatal within 12–14 months). Glioma-on-chip platforms, with continuous perfusion, mimic in vivo [...] Read more.
Glioma, as an aggressive type of cancer, accounts for virtually 80% of malignant brain tumors. Despite advances in therapeutic approaches, the long-term survival of glioma patients is poor (it is usually fatal within 12–14 months). Glioma-on-chip platforms, with continuous perfusion, mimic in vivo metabolic functions of cancer cells for analytical purposes. This offers an unprecedented opportunity for understanding the underlying reasons that arise glioma, determining the most effective radiotherapy approach, testing different drug combinations, and screening conceivable side effects of drugs on other organs. Glioma-on-chip technologies can ultimately enhance the efficacy of treatments, promote the survival rate of patients, and pave a path for personalized medicine. In this perspective paper, we briefly review the latest developments of glioma-on-chip technologies, such as therapy applications, drug screening, and cell behavior studies, and discuss the current challenges as well as future research directions in this field. Full article
(This article belongs to the Special Issue Microfluidic Brain-on-a-Chip)
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