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Bioengineering
Special Issues
Advanced 3D Cell Culture Technologies and Formats
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Advanced 3D Cell Culture Technologies and Formats

A special issue of Bioengineering (ISSN 2306-5354). This special issue belongs to the section "Regenerative Engineering".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 18364

Special Issue Editors

Prof. Dr. Cornelia Kasper

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Guest Editor
Department of Biotechnology, University of Natural Resources and Life Science, Muthgasse 18, A-1190 Vienna, Austria
Interests: 3D cell culture; bioreactors; tissue engineering; biomaterials; stem cells; cell expansion and differentiation; dynamic cultivation; hypoxia
Special Issues, Collections and Topics in MDPI journals
Dr. Dominik Egger

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Guest Editor
Department of Biotechnology, University of Natural Resources and Life Science, Muthgasse 18, A-1190 Vienna, Austria
Interests: biotechnology; bioengineering; bioprocess engineering; 3D cell culture; tissue engineering; bioreactors; stem cell manufacturing; stem cells; biomaterials; scaffolds
Prof. Dr. Fedor Senatov

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Guest Editor
Director of Center for Biomedical Engineering, National University of Science and Technology "MISIS", Moscow, Russia
Interests: biomaterials; biopolymers; bioprinting; biomimetics; implants; hybrid materials; tissue engineering
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Michael Raghunath

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Guest Editor
Center for Cell Biology & Tissue Engineering, Institute for Chemistry and Biotechnology (ICBT), Zurich University of Applied Sciences (ZHAW), Wädenswil, Switzerland
Interests: 3D tissue engineering; biofabrication; in vitro models of fibrosis; angiogenesis; cell-based therapy; extracellular matrix; transglutaminases; microenvironment; macromolecular crowding; adult stem cells; spheroid culture
Special Issues, Collections and Topics in MDPI journals
Dr. Farhad Chariyev-Prinz

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Guest Editor
Department of Biotechnology, University of Natural Resources and Life Science, Muthgasse 18, A-1190 Vienna, Austria
Interests: 3D culture; hydrogel development; bioreactor culture and differentiation; MSC culture and differentiation; MSC immunomodulation; cell based therapies

Special Issue Information

Dear Colleagues,

Approved cells and cellular products (i.e., extracellular vesicles) for cell-based therapy applications carry a huge promise for the treatment of a broad variety of diseases and several (stem) cell therapies. However, the therapeutic potential of cells is not fully exploited at present.

Traditional cell culture conditions do not represent the physiological conditions of the cellular native environment. For example, two-dimensional plastic surfaces are widely used as standard conditions. However, these conditions are proven to result in non-physiological behavior of the cells, cell damage, or genetic instability. By contrast, different 3D culture formats have been found to enhance the therapeutic potential of cells and cellular products for cell-based therapies. However, the generation of 3D cultures requires advanced culture technologies, such as novel culture plates geometries, materials and formats, and scaffold-based and scaffold-free approaches. Some approaches also require integration or combination with dynamic bioreactor systems.

Therefore, the aim of this Special Issue is to highlight these recent advances in 3D cell culture technologies to increase the therapeutic potential of cells and cellular products.

We invite you to contribute original research articles, reviews, and methods regarding novel 3D cell culture technologies that result in increased therapeutic potential of cells and cellular products (e.g., extracellular vesicles) for cell-based therapy applications. This might include but is not limited to:

  • 3D culture approaches (aggregates/spheroids/organoids, influence of biomaterials, and biomaterial functionalization);
  • Novel bioreactor systems or novel applications of existing systems for the generation and culture of 3D cell cultures or production of cells and cell-based products from 3D cultures.

Prof. Dr. Cornelia Kasper
Dr. Dominik Egger
Prof. Dr. Fedor Senatov
Prof. Dr. Michael Raghunath
Dr. Farhad Chariyev-Prinz
Guest Editors

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. Bioengineering 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 2700 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.

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Published Papers (7 papers)

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Research

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27 pages, 4562 KiB  
Article
Reproducibility and Robustness of a Liver Microphysiological System PhysioMimix LC12 under Varying Culture Conditions and Cell Type Combinations
by Alicia Y. Lim, Yuki Kato, Courtney Sakolish, Alan Valdiviezo, Gang Han, Piyush Bajaj, Jason Stanko, Stephen S. Ferguson, Remi Villenave, Philip Hewitt, Rhiannon N. Hardwick and Ivan Rusyn
Bioengineering 2023, 10(10), 1195; https://doi.org/10.3390/bioengineering10101195 - 14 Oct 2023
Cited by 2 | Viewed by 2655
Abstract
The liver is one of the key organs for exogenous and endogenous metabolism and is often a target for drug- and chemical-driven toxicity. A wide range of experimental approaches has been established to model and characterize the mechanisms of drug- and chemical-induced hepatotoxicity. [...] Read more.
The liver is one of the key organs for exogenous and endogenous metabolism and is often a target for drug- and chemical-driven toxicity. A wide range of experimental approaches has been established to model and characterize the mechanisms of drug- and chemical-induced hepatotoxicity. A number of microfluidics-enabled in vitro models of the liver have been developed, but the unclear translatability of these platforms has hindered their adoption by the pharmaceutical industry; to achieve wide use for drug and chemical safety evaluation, demonstration of reproducibility and robustness under various contexts of use is required. One of these commercially available platforms is the PhysioMimix LC12, a microfluidic device where cells are seeded into a 3D scaffold that is continuously perfused with recirculating cell culture media to mimic liver sinusoids. Previous studies demonstrated this model’s functionality and potential applicability to preclinical drug development. However, to gain confidence in PhysioMimix LC12’s robustness and reproducibility, supplementary characterization steps are needed, including the assessment of various human hepatocyte sources, contribution of non-parenchymal cells (NPCs), and comparison to other models. In this study, we performed replicate studies averaging 14 days with either primary human hepatocytes (PHHs) or induced pluripotent stem cell (iPSC)-derived hepatocytes, with and without NPCs. Albumin and urea secretion, lactate dehydrogenase, CYP3A4 activity, and metabolism were evaluated to assess basal function and metabolic capacity. Model performance was characterized by different cell combinations under intra- and inter-experimental replication and compared to multi-well plates and other liver platforms. PhysioMimix LC12 demonstrated the highest metabolic function with PHHs, with or without THP-1 or Kupffer cells, for up to 10–14 days. iPSC-derived hepatocytes and PHHs co-cultured with additional NPCs demonstrated sub-optimal performance. Power analyses based on replicate experiments and different contexts of use will inform future study designs due to the limited throughput and high cell demand. Overall, this study describes a workflow for independent testing of a complex microphysiological system for specific contexts of use, which may increase end-user adoption in drug development. Full article
(This article belongs to the Special Issue Advanced 3D Cell Culture Technologies and Formats)
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15 pages, 4977 KiB  
Article
Finite Element Evaluation of the Electric Field Distribution in a Non-Homogeneous Environment
by Elisabetta Sieni, Monica Dettin, Annj Zamuner, Maria Teresa Conconi, Bianca Bazzolo, Cristian Balducci, Paolo Di Barba, Michele Forzan, Patrizia Lamberti and Maria Evelina Mognaschi
Bioengineering 2023, 10(9), 1062; https://doi.org/10.3390/bioengineering10091062 - 8 Sep 2023
Cited by 3 | Viewed by 1265
Abstract
Finite element analysis is used in this study to investigate the effect of media inhomogeneity on the electric field distribution in a sample composed of cells and their extracellular matrix. The sample is supposed to be subjected to very high pulsed electric field. [...] Read more.
Finite element analysis is used in this study to investigate the effect of media inhomogeneity on the electric field distribution in a sample composed of cells and their extracellular matrix. The sample is supposed to be subjected to very high pulsed electric field. Numerically computed electric field distribution and transmembrane potential at the cell membrane in electroporation conditions are considered in order to study cell behavior at different degrees of inhomogeneity. The different inhomogeneity grade is locally obtained using a representative model of fixed volume with cell–cell distance varying in the range of 1–283 um. The conductivity of the extracellular medium was varied between plain collagen and a gel-like myxoid matrix through combinations of the two, i.e., collagen and myxoid. An increase in the transmembrane potential was shown in the case of higher aggregate. The results obtained in this study show the effect of the presence of the cell aggregates and collagen on the transmembrane potential. In particular, by increasing the cell aggregation in the two cases, the transmembrane potential increased. Finally, the simulation results were compared to experimental data obtained by culturing HCC1954 cells in a hyaluronic acid-based scaffold. The experimental validation confirmed the behavior of the transmembrane potential in presence of the collagen: an increase in electroporation at a lower electric field intensity was found for the cells cultured in the scaffolds where there is the formation of collagen areas. Full article
(This article belongs to the Special Issue Advanced 3D Cell Culture Technologies and Formats)
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20 pages, 2868 KiB  
Article
Human Patient-Derived Brain Tumor Models to Recapitulate Ependymoma Tumor Vasculature
by Min D. Tang-Schomer, Markus J. Bookland, Jack E. Sargent and Taylor N. Jackvony
Bioengineering 2023, 10(7), 840; https://doi.org/10.3390/bioengineering10070840 - 15 Jul 2023
Cited by 3 | Viewed by 1841
Abstract
Despite in vivo malignancy, ependymoma lacks cell culture models, thus limiting therapy development. Here, we used a tunable three-dimensional (3D) culture system to approximate the ependymoma microenvironment for recapitulating a patient’s tumor in vitro. Our data showed that the inclusion of VEGF in [...] Read more.
Despite in vivo malignancy, ependymoma lacks cell culture models, thus limiting therapy development. Here, we used a tunable three-dimensional (3D) culture system to approximate the ependymoma microenvironment for recapitulating a patient’s tumor in vitro. Our data showed that the inclusion of VEGF in serum-free, mixed neural and endothelial cell culture media supported the in vitro growth of all four ependymoma patient samples. The growth was driven by Nestin and Ki67 double-positive cells in a putative cancer stem cell niche, which was manifested as rosette-looking clusters in 2D and spheroids in 3D. The effects of extracellular matrix (ECM) such as collagen or Matrigel superseded that of the media conditions, with Matrigel resulting in the greater enrichment of Nestin-positive cells. When mixed with endothelial cells, the 3D co-culture models developed capillary networks resembling the in vivo ependymoma vasculature. The transcriptomic analysis of two patient cases demonstrated the separation of in vitro cultures by individual patients, with one patient’s culture samples closely clustered with the primary tumor tissue. While VEGF was found to be necessary for preserving the transcriptomic features of in vitro cultures, the presence of endothelial cells shifted the gene’s expression patterns, especially genes associated with ECM remodeling. The homeobox genes were mostly affected in the 3D in vitro models compared to the primary tumor tissue and between different 3D formats. These findings provide a basis for understanding the ependymoma microenvironment and enabling the further development of patient-derived in vitro ependymoma models for personalized medicine. Full article
(This article belongs to the Special Issue Advanced 3D Cell Culture Technologies and Formats)
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16 pages, 4717 KiB  
Article
Towards Ready-to-Use Iron-Crosslinked Alginate Beads as Mesenchymal Stem Cell Carriers
by Timothée Baudequin, Hazel Wee, Zhanfeng Cui and Hua Ye
Bioengineering 2023, 10(2), 163; https://doi.org/10.3390/bioengineering10020163 - 26 Jan 2023
Cited by 3 | Viewed by 2263
Abstract
Micro-carriers, thanks to high surface/volume ratio, are widely studied as mesenchymal stem cell (MSCs) in vitro substrate for proliferation at clinical rate. In particular, Ca-alginate-based biomaterials (sodium alginate crosslinked with CaCl2) are commonly investigated. However, Ca-alginate shows low bioactivity and requires [...] Read more.
Micro-carriers, thanks to high surface/volume ratio, are widely studied as mesenchymal stem cell (MSCs) in vitro substrate for proliferation at clinical rate. In particular, Ca-alginate-based biomaterials (sodium alginate crosslinked with CaCl2) are commonly investigated. However, Ca-alginate shows low bioactivity and requires functionalization, increasing labor work and costs. In contrast, films of sodium alginate crosslinked with iron chloride (Fe-alginate) have shown good bioactivity with fibroblasts, but MSCs studies are lacking. We propose a first proof-of-concept study of Fe-alginate beads supporting MSCs proliferation without functionalization. Macro- and micro-carriers were prepared (extrusion and electrospray) and we report for the first time Fe-alginate electrospraying optimization. FTIR spectra, stability with various mannuronic acids/guluronic acids (M/G) ratios and size distribution were analyzed before performing cell culture. After confirming literature results on films with human MSCs, we showed that Macro-Fe-alginate beads offered a better environment for MSCs adhesion than Ca-alginate. We concluded that Fe-alginate beads showed great potential as ready-to-use carriers. Full article
(This article belongs to the Special Issue Advanced 3D Cell Culture Technologies and Formats)
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14 pages, 2781 KiB  
Article
Engineering Human Mesenchymal Bodies in a Novel 3D-Printed Microchannel Bioreactor for Extracellular Vesicle Biogenesis
by Richard Jeske, Xingchi Chen, Logan Mulderrig, Chang Liu, Wenhao Cheng, Olivia Z. Zeng, Changchun Zeng, Jingjiao Guan, Daniel Hallinan, Xuegang Yuan and Yan Li
Bioengineering 2022, 9(12), 795; https://doi.org/10.3390/bioengineering9120795 - 13 Dec 2022
Cited by 9 | Viewed by 2381
Abstract
Human Mesenchymal Stem Cells (hMSCs) and their derived products hold potential in tissue engineering and as therapeutics in a wide range of diseases. hMSCs possess the ability to aggregate into “spheroids”, which has been used as a preconditioning technique to enhance their therapeutic [...] Read more.
Human Mesenchymal Stem Cells (hMSCs) and their derived products hold potential in tissue engineering and as therapeutics in a wide range of diseases. hMSCs possess the ability to aggregate into “spheroids”, which has been used as a preconditioning technique to enhance their therapeutic potential by upregulating stemness, immunomodulatory capacity, and anti-inflammatory and pro-angiogenic secretome. Few studies have investigated the impact on hMSC aggregate properties stemming from dynamic and static aggregation techniques. hMSCs’ main mechanistic mode of action occur through their secretome, including extracellular vesicles (EVs)/exosomes, which contain therapeutically relevant proteins and nucleic acids. In this study, a 3D printed microchannel bioreactor was developed to dynamically form hMSC spheroids and promote hMSC condensation. In particular, the manner in which dynamic microenvironment conditions alter hMSC properties and EV biogenesis in relation to static cultures was assessed. Dynamic aggregation was found to promote autophagy activity, alter metabolism toward glycolysis, and promote exosome/EV production. This study advances our knowledge on a commonly used preconditioning technique that could be beneficial in wound healing, tissue regeneration, and autoimmune disorders. Full article
(This article belongs to the Special Issue Advanced 3D Cell Culture Technologies and Formats)
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13 pages, 2750 KiB  
Article
Glucose-Dependent Insulin Secretion from β Cell Spheroids Is Enhanced by Embedding into Softer Alginate Hydrogels Functionalised with RGD Peptide
by Md Lutful Amin, Kylie Deng, Hien A. Tran, Reena Singh, Jelena Rnjak-Kovacina and Peter Thorn
Bioengineering 2022, 9(12), 722; https://doi.org/10.3390/bioengineering9120722 - 23 Nov 2022
Cited by 1 | Viewed by 2631
Abstract
Type 1 diabetes results from the loss of pancreatic β cells, reduced insulin secretion and dysregulated blood glucose levels. Replacement of these lost β cells with stem cell-derived β cells, and protecting these cells within macro-device implants is a promising approach to restore [...] Read more.
Type 1 diabetes results from the loss of pancreatic β cells, reduced insulin secretion and dysregulated blood glucose levels. Replacement of these lost β cells with stem cell-derived β cells, and protecting these cells within macro-device implants is a promising approach to restore glucose homeostasis. However, to achieve this goal of restoration of glucose balance requires work to optimise β cell function within implants. We know that native β cell function is enhanced by cell–cell and cell–extracellular matrix interactions within the islets of Langerhans. Reproducing these interactions in 2D, such as culture on matrix proteins, does enhance insulin secretion. However, the impact of matrix proteins on the 3D organoids that would be in implants has not been widely studied. Here, we use native β cells that are dispersed from islets and reaggregated into small spheroids. We show these β cell spheroids have enhanced glucose-dependent insulin secretion when embedded into softer alginate hydrogels conjugated with RGD peptide (a common motif in extracellular matrix proteins). Embedding into alginate–RGD causes activation of integrin responses and repositioning of liprin, a protein that controls insulin secretion. We conclude that insulin secretion from β cell spheroids can be enhanced through manipulation of the surrounding environment. Full article
(This article belongs to the Special Issue Advanced 3D Cell Culture Technologies and Formats)
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Review

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21 pages, 1762 KiB  
Review
In Vitro 3D Modeling of Neurodegenerative Diseases
by Aurélie Louit, Todd Galbraith and François Berthod
Bioengineering 2023, 10(1), 93; https://doi.org/10.3390/bioengineering10010093 - 10 Jan 2023
Cited by 11 | Viewed by 4295
Abstract
The study of neurodegenerative diseases (such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or amyotrophic lateral sclerosis) is very complex due to the difficulty in investigating the cellular dynamics within nervous tissue. Despite numerous advances in the in vivo study of these diseases, [...] Read more.
The study of neurodegenerative diseases (such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or amyotrophic lateral sclerosis) is very complex due to the difficulty in investigating the cellular dynamics within nervous tissue. Despite numerous advances in the in vivo study of these diseases, the use of in vitro analyses is proving to be a valuable tool to better understand the mechanisms implicated in these diseases. Although neural cells remain difficult to obtain from patient tissues, access to induced multipotent stem cell production now makes it possible to generate virtually all neural cells involved in these diseases (from neurons to glial cells). Many original 3D culture model approaches are currently being developed (using these different cell types together) to closely mimic degenerative nervous tissue environments. The aim of these approaches is to allow an interaction between glial cells and neurons, which reproduces pathophysiological reality by co-culturing them in structures that recapitulate embryonic development or facilitate axonal migration, local molecule exchange, and myelination (to name a few). This review details the advantages and disadvantages of techniques using scaffolds, spheroids, organoids, 3D bioprinting, microfluidic systems, and organ-on-a-chip strategies to model neurodegenerative diseases. Full article
(This article belongs to the Special Issue Advanced 3D Cell Culture Technologies and Formats)
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