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Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine

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

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 45590

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Special Issue Editor

Dr. Anna E. Guller

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Guest Editor

1. The Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Australia
2. Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
Interests: disease models; tissue engineering; 3D culture; experimental pathology; regeneration;cancer; nanomedicine; effects of physical factors on tissues
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Special Issue Information

Dear Colleagues,

The overall aim of this Special Issue is to enhance the understanding and present a broad overview of the recent advances in the area of engineered three-dimensional (3D) microenvironments developed during the last five years for innovative cell culture, tissue engineering and regenerative medicine applications. The importance and the role of the complex microenvironments that include different cell types and extracellular matrix, as well as various chemical and physical factors are gradually become recognized as a key for the biologically accurate in vitro modelling and the reconstruction of the functional tissues for the regenerative medicine purposes. At the same time, many challenges in this field are still open. These burning questions include, for example, the structural and functional relevance of the modelled and reconstructed tissues to the native prototypes, the methodology applicable for the characterization and the comparative analysis of such systems, and many other problems.

The Special Issue on the “Engineered microenvironments for 3D cell culture and regenerative medicine” is open for the original papers and reviews exploring the effects of the reconstructed tissue-, organ- or disease-specific microenvironments on cellular growth, differentiation, motility and other biological responses. The broad spectra of 3D engineered microenvironments can be discussed, including 3D organoids, scaffold- and gel-based cultures, cell sheets, tissue barriers models, microfluidic and bioreactor-aided systems.

The topics and themes of this unique collection will include but not limited to, the following:

Quantitative studies revealing the role of multiple controlled interacting factors in cell biological behaviour modulation in the context of normal and pathological tissue growth.
Comparative studies of different types of engineered 3D cell culture microenvironments.
Biological accuracy and relevance of 3D engineered cell culture microenvironments.
Industrial applications and clinical translation of the results obtained using 3D engineered cell culture microenvironments.
Advanced and innovative research applications of 3D engineered cell culture microenvironments.
Reconstruction of functional tissues for regenerative medicine applications.
Methodology for the analysis of the biological, physical, chemical, and material parameters of 3D engineered microenvironments for cell culture and regenerative medicine.

Dr. Anna E. Guller
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. Bioengineering is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

3D cell culture
tissue engineering
modelling
engineered microenvironment
regeneration
cancer
regenerative medicine
extracellular matrix
scaffolds
cell-cell interactions
cell-extracellular matrix interactions

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

8 pages, 569 KiB

Open AccessEditorial

Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine: Challenges, Advances, and Trends

by Anna Guller and Alexandra Igrunkova

Bioengineering 2023, 10(1), 17; https://doi.org/10.3390/bioengineering10010017 - 22 Dec 2022

Cited by 3 | Viewed by 1800

Abstract

The overall goal of regenerative medicine is to restore the functional performance of the tissues and organs that have been severely damaged or lost due to traumas and diseases [...] Full article

(This article belongs to the Special Issue Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine)

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Research

Jump to: Editorial, Review

19 pages, 2333 KiB

Open AccessArticle

The Impact of the Extracellular Matrix Environment on Sost Expression by the MLO-Y4 Osteocyte Cell Line

by Robert T. Brady, Fergal J. O’Brien and David A. Hoey

Bioengineering 2022, 9(1), 35; https://doi.org/10.3390/bioengineering9010035 - 13 Jan 2022

Cited by 3 | Viewed by 3871

Abstract

Bone is a dynamic organ that can adapt its structure to meet the demands of its biochemical and biophysical environment. Osteocytes form a sensory network throughout the tissue and orchestrate tissue adaptation via the release of soluble factors such as a sclerostin. Osteocyte physiology has traditionally been challenging to investigate due to the uniquely mineralized extracellular matrix (ECM) of bone leading to the development of osteocyte cell lines. Importantly, the most widely researched and utilized osteocyte cell line: the MLO-Y4, is limited by its inability to express sclerostin (Sost gene) in typical in-vitro culture. We theorised that culture in an environment closer to the in vivo osteocyte environment could impact on Sost expression. Therefore, this study investigated the role of composition and dimensionality in directing Sost expression in MLO-Y4 cells using collagen-based ECM analogues. A significant outcome of this study is that MLO-Y4 cells, when cultured on a hydroxyapatite (HA)-containing two-dimensional (2D) film analogue, expressed Sost. Moreover, three-dimensional (3D) culture within HA-containing collagen scaffolds significantly enhanced Sost expression, demonstrating the impact of ECM composition and dimensionality on MLO-Y4 behaviour. Importantly, in this bone mimetic ECM environment, Sost expression was found to be comparable to physiological levels. Lastly, MLO-Y4 cells cultured in these novel conditions responded accordingly to fluid flow stimulation with a decrease in expression. This study therefore presents a novel culture system for the MLO-Y4 osteocyte cell line, ensuring the expression of an important osteocyte specific gene, Sost, overcoming a major limitation of this model. Full article

(This article belongs to the Special Issue Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine)

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12 pages, 3330 KiB

Open AccessArticle

Human iPSC-Derived Vascular Smooth Muscle Cells in a Fibronectin Functionalized Collagen Hydrogel Augment Endothelial Cell Morphogenesis

by Kaiti Duan, Biraja C. Dash, Daniel C. Sasson, Sara Islam, Jackson Parker and Henry C. Hsia

Bioengineering 2021, 8(12), 223; https://doi.org/10.3390/bioengineering8120223 - 18 Dec 2021

Cited by 11 | Viewed by 4654

Abstract

Tissue-engineered constructs have immense potential as autologous grafts for wound healing. Despite the rapid advancement in fabrication technology, the major limitation is controlling angiogenesis within these constructs to form a vascular network. Here, we aimed to develop a 3D hydrogel that can regulate angiogenesis. We tested the effect of fibronectin and vascular smooth muscle cells derived from human induced pluripotent stem cells (hiPSC-VSMC) on the morphogenesis of endothelial cells. The results demonstrate that fibronectin increases the number of EC networks. However, hiPSC-VSMC in the hydrogel further substantiated the number and size of EC networks by vascular endothelial growth factor and basic fibroblast growth factor secretion. A mechanistic study shows that blocking αvβ3 integrin signaling between hiPSC-VSMC and fibronectin impacts the EC network formation via reduced cell viability and proangiogenic growth factor secretion. Collectively, this study set forth initial design criteria in developing an improved pre-vascularized construct. Full article

(This article belongs to the Special Issue Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine)

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17 pages, 4063 KiB

Open AccessArticle

Guided Self-Assembly of ES-Derived Lung Progenitors into Biomimetic Tube Structures That Impact Cell Differentiation

by John P. Soleas, Linwen Huang, Elisa D’Arcangelo, Maria Cristina Nostro, Thomas K. Waddell, Alison P. McGuigan and Golnaz Karoubi

Bioengineering 2021, 8(12), 209; https://doi.org/10.3390/bioengineering8120209 - 10 Dec 2021

Cited by 2 | Viewed by 2802

Abstract

Chemically directed differentiation of pluripotent stem cells (PSCs) into defined cell types is a potent strategy for creating regenerative tissue models and cell therapies. In vitro observations suggest that physical cues can augment directed differentiation. We recently demonstrated that confining human PSC-derived lung progenitor cells in a tube with a diameter that mimics those observed during lung development results in the alteration of cell differentiation towards SOX2⁻SOX9⁺ lung cells. Here we set out to assess the robustness of this geometric confinement effect with respect to different culture parameters in order to explore the corresponding changes in cell morphometry and determine the feasibility of using such an approach to enhance directed differentiation protocols. Culture of progenitor cells in polydimethylsiloxane (PDMS) tubes reliably induced self-organization into tube structures and was insensitive to a variety of extracellular matrix coatings. Cellular morphology and differentiation status were found to be sensitive to the diameter of tube cells that were cultured within but not to seeding density. These data suggest that geometric cues impose constraints on cells, homogenize cellular morphology, and influence fate status. Full article

(This article belongs to the Special Issue Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine)

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14 pages, 3387 KiB

Open AccessArticle

Facile Fabrication of Three-Dimensional Hydrogel Film with Complex Tissue Morphology

by Young-Hyeon An and Su-Hwan Kim

Bioengineering 2021, 8(11), 164; https://doi.org/10.3390/bioengineering8110164 - 27 Oct 2021

Cited by 2 | Viewed by 2820

Abstract

In this study, we proposed a simple and easy method for fabricating a three-dimensional (3D) structure that can recapitulate the morphology of a tissue surface and deliver biological molecules into complex-shaped target tissues. To fabricate the 3D hydrogel film structure, we utilized a direct tissue casting method that can recapitulate tissue structure in micro-/macroscale using polydimethylsiloxane (PDMS). A replica 3D negative mold was manufactured by a polyurethane acrylate (PUA)-based master mold. Then, we poured the catechol-conjugated alginate (ALG-C) solution into the mold and evaporated it to form a dried film, followed by crosslinking the film using calcium chloride. The ALG-C hydrogel film had a tensile modulus of 725.2 ± 123.4 kPa and maintained over 95% of initial weight after 1 week without significant degradation. The ALG-C film captured over 4.5 times as much macromolecule (FITC-dextran) compared to alginate film (ALG). The cardiomyoblast cells exhibited high cell viability over 95% on ALG-C film. Moreover, the ALG-C film had about 70% of surface-bound lentivirus (1% in ALG film), which finally exhibited much higher viral transfection efficiency of GFP protein to C2C12 cells on the film than ALG film. In conclusion, we demonstrated a 3D film structure of biofunctionalized hydrogel for substrate-mediated drug delivery, and this approach could be utilized to recapitulate the complex-shaped tissues. Full article

(This article belongs to the Special Issue Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine)

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12 pages, 3543 KiB

Open AccessArticle

Engineering and Monitoring 3D Cell Constructs with Time-Evolving Viscoelasticity for the Study of Liver Fibrosis In Vitro

by Ludovica Cacopardo and Arti Ahluwalia

Bioengineering 2021, 8(8), 106; https://doi.org/10.3390/bioengineering8080106 - 27 Jul 2021

Cited by 12 | Viewed by 3679

Abstract

Liver fibrosis is generally associated with an over-production and crosslinking of extracellular matrix proteins, causing a progressive increase in both the elastic and viscous properties of the hepatic tissue. We describe a strategy for mimicking and monitoring the mechano-dynamics of the 3D microenvironment associated with liver fibrosis. Cell-laden gelatin hydrogels were crosslinked with microbial transglutaminase using a purpose-designed cytocompatible two-step protocol, which allows for the exposure of cells to a mechanically changing environment during culturing. A bioreactor was re-engineered to monitor the mechanical properties of cell constructs over time. The results showed a shift towards a more elastic (i.e., solid-like) behaviour, which is likely related to an increase in cell stress. The method effectively mimics the time-evolving mechanical microenvironment associated with liver fibrosis and could provide novel insights into pathophysiological processes in which both elastic and viscous properties of tissues change over time. Full article

(This article belongs to the Special Issue Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine)

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Review

Jump to: Editorial, Research

17 pages, 1842 KiB

Open AccessReview

Engineering Extracellular Microenvironment for Tissue Regeneration

by Dake Hao, Juan-Maria Lopez, Jianing Chen, Alexandra Maria Iavorovschi, Nora Marlene Lelivelt and Aijun Wang

Bioengineering 2022, 9(5), 202; https://doi.org/10.3390/bioengineering9050202 - 8 May 2022

Cited by 9 | Viewed by 3944

Abstract

The extracellular microenvironment is a highly dynamic network of biophysical and biochemical elements, which surrounds cells and transmits molecular signals. Extracellular microenvironment controls are of crucial importance for the ability to direct cell behavior and tissue regeneration. In this review, we focus on the different components of the extracellular microenvironment, such as extracellular matrix (ECM), extracellular vesicles (EVs) and growth factors (GFs), and introduce engineering approaches for these components, which can be used to achieve a higher degree of control over cellular activities and behaviors for tissue regeneration. Furthermore, we review the technologies established to engineer native-mimicking artificial components of the extracellular microenvironment for improved regenerative applications. This review presents a thorough analysis of the current research in extracellular microenvironment engineering and monitoring, which will facilitate the development of innovative tissue engineering strategies by utilizing different components of the extracellular microenvironment for regenerative medicine in the future. Full article

(This article belongs to the Special Issue Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine)

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13 pages, 1838 KiB

Open AccessReview

High-Resolution Imaging for the Analysis and Reconstruction of 3D Microenvironments for Regenerative Medicine: An Application-Focused Review

by Michail E. Klontzas and Alexandros Protonotarios

Bioengineering 2021, 8(11), 182; https://doi.org/10.3390/bioengineering8110182 - 10 Nov 2021

Cited by 11 | Viewed by 2850

Abstract

The rapid evolution of regenerative medicine and its associated scientific fields, such as tissue engineering, has provided great promise for multiple applications where replacement and regeneration of damaged or lost tissue is required. In order to evaluate and optimise the tissue engineering techniques, visualisation of the material of interest is crucial. This includes monitoring of the cellular behaviour, extracellular matrix composition, scaffold structure, and other crucial elements of biomaterials. Non-invasive visualisation of artificial tissues is important at all stages of development and clinical translation. A variety of preclinical and clinical imaging methods—including confocal multiphoton microscopy, optical coherence tomography, magnetic resonance imaging (MRI), and computed tomography (CT)—have been used for the evaluation of artificial tissues. This review attempts to present the imaging methods available to assess the composition and quality of 3D microenvironments, as well as their integration with human tissues once implanted in the human body. The review provides tissue-specific application examples to demonstrate the applicability of such methods on cardiovascular, musculoskeletal, and neural tissue engineering. Full article

(This article belongs to the Special Issue Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine)

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15 pages, 769 KiB

Open AccessReview

How Do Mechanics Guide Fibroblast Activity? Complex Disruptions during Emphysema Shape Cellular Responses and Limit Research

by Mathew N. Leslie, Joshua Chou, Paul M. Young, Daniela Traini, Peta Bradbury and Hui Xin Ong

Bioengineering 2021, 8(8), 110; https://doi.org/10.3390/bioengineering8080110 - 5 Aug 2021

Cited by 7 | Viewed by 4698

Abstract

The emphysema death toll has steadily risen over recent decades, causing the disease to become the third most common cause of death worldwide in 2019. Emphysema is currently incurable and could be due to a genetic condition (Alpha-1 antitrypsin deficiency) or exposure to pollutants/irritants, such as cigarette smoke or poorly ventilated cooking fires. Despite the growing burden of emphysema, the mechanisms behind emphysematous pathogenesis and progression are not fully understood by the scientific literature. A key aspect of emphysematous progression is the destruction of the lung parenchyma extracellular matrix (ECM), causing a drastic shift in the mechanical properties of the lung (known as mechanobiology). The mechanical properties of the lung such as the stiffness of the parenchyma (measured as the elastic modulus) and the stretch forces required for inhalation and exhalation are both reduced in emphysema. Fibroblasts function to maintain the structural and mechanical integrity of the lung parenchyma, yet, in the context of emphysema, these fibroblasts appear incapable of repairing the ECM, allowing emphysema to progress. This relationship between the disturbances in the mechanical cues experienced by an emphysematous lung and fibroblast behaviour is constantly overlooked and consequently understudied, thus warranting further research. Interestingly, the failure of current research models to integrate the altered mechanical environment of an emphysematous lung may be limiting our understanding of emphysematous pathogenesis and progression, potentially disrupting the development of novel treatments. This review will focus on the significance of emphysematous lung mechanobiology to fibroblast activity and current research limitations by examining: (1) the impact of mechanical cues on fibroblast activity and the cell cycle, (2) the potential role of mechanical cues in the diminished activity of emphysematous fibroblasts and, finally, (3) the limitations of current emphysematous lung research models and treatments as a result of the overlooked emphysematous mechanical environment. Full article

(This article belongs to the Special Issue Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine)

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24 pages, 3463 KiB

Open AccessReview

Single-Use Bioreactors for Human Pluripotent and Adult Stem Cells: Towards Regenerative Medicine Applications

by Diogo E.S. Nogueira, Joaquim M.S. Cabral and Carlos A.V. Rodrigues

Bioengineering 2021, 8(5), 68; https://doi.org/10.3390/bioengineering8050068 - 17 May 2021

Cited by 19 | Viewed by 11239

Abstract

Research on human stem cells, such as pluripotent stem cells and mesenchymal stromal cells, has shown much promise in their use for regenerative medicine approaches. However, their use in patients requires large-scale expansion systems while maintaining the quality of the cells. Due to their characteristics, bioreactors have been regarded as ideal platforms to harbour stem cell biomanufacturing at a large scale. Specifically, single-use bioreactors have been recommended by regulatory agencies due to reducing the risk of product contamination, and many different systems have already been developed. This review describes single-use bioreactor platforms which have been used for human stem cell expansion and differentiation, along with their comparison with reusable systems in the development of a stem cell bioprocess for clinical applications. Full article

(This article belongs to the Special Issue Engineered Microenvironments for 3D Cell Culture and Regenerative Medicine)

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