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Bioengineering
Special Issues
3D Cell Culture Systems: Current Technologies and Applications
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3D Cell Culture Systems: Current Technologies and Applications

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

Deadline for manuscript submissions: 30 June 2026 | Viewed by 7304

Special Issue Editor

Dr. Peggy Stock

E-Mail Website
Guest Editor
Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany
Interests: 3D cell culture; tissue engineering; liver diseases; liver regenerative medicine; MSC; hepatocytes; toxicology; cell isolation; bioreactor culture

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to our Special Issue on "3D Cell Culture Systems: Current Technologies and Applications". The field of 3D cell culture systems has seen significant advancements in recent years, providing more physiologically relevant models compared to traditional 2D cultures. These systems are crucial for better understanding cell behavior, drug responses, and tissue engineering applications. The importance of this research area lies in its potential to revolutionize biomedical research and therapeutic development, offering more accurate models for studying diseases and testing new treatments.

This Special Issue aims to compile a comprehensive collection of papers that highlight the latest advancements, methodologies, and applications in the realm of 3D cell culture systems. By gathering contributions from leading researchers in the field, we seek to provide a platform for disseminating innovative technologies and novel applications that push the boundaries of current knowledge. Our goal is to establish a collection of at least 10 articles that will be of significant interest to scholars and practitioners. Should this number be reached, this Special Issue may be printed in book form, further broadening its impact.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • The development and optimization of 3D cell culture technologies;
  • Applications of 3D cell cultures in drug discovery and development;
  • Comparative studies between 2D and 3D cell culture systems;
  • Advances in biomaterials and scaffolds for 3D cultures;
  • The use of 3D cultures in cancer research, tissue engineering, and regenerative medicine;
  • High-throughput screening and imaging technologies for 3D cultures.

We look forward to receiving your contributions and working together to create a valuable resource that will benefit researchers, scholars, and practitioners alike.

Dr. Peggy Stock
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 250 words) can be sent to the Editorial Office for assessment.

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.

Keywords

  • 3D cell culture
  • tissue engineering
  • biomaterials
  • drug discovery
  • cancer research
  • regenerative medicine
  • scaffold technology
  • high-throughput screening
  • organoids
  • in vitro models

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • Reprint: MDPI Books provides the opportunity to republish successful Special Issues in book format, both online and in print.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (5 papers)

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Research

Jump to: Review, Other

21 pages, 5000 KB  
Article
Immortalized Rat Tendon-Derived Stem Cells for Tendon Tissue Engineering
by Kat Tik Lau, Hui Wang, Jinxiang Zhang, Dan Michelle Wang and Dai Fei Elmer Ker
Bioengineering 2026, 13(3), 354; https://doi.org/10.3390/bioengineering13030354 - 18 Mar 2026
Viewed by 311
Abstract
Tendon-derived stem cells (TDSCs) are a unique cell population found in tendons, exhibiting both mesenchymal stem cell (MSC)-like phenotypes and tendon-specific markers. They have emerged as a promising research tool in tendon-related tissue engineering studies. However, there is currently no well-characterized TDSC line [...] Read more.
Tendon-derived stem cells (TDSCs) are a unique cell population found in tendons, exhibiting both mesenchymal stem cell (MSC)-like phenotypes and tendon-specific markers. They have emerged as a promising research tool in tendon-related tissue engineering studies. However, there is currently no well-characterized TDSC line with MSC-related phenotypes for investigating tendon biology or developing therapeutics. Here, we established an immortalized monoclonal TDSC, named iTDSC#6, from the Achilles tendon of an adult male Sprague-Dawley rat. Cell clones were characterized for MSC-associated cell surface markers, colony formation capacity, and trilineage differentiation potentials, tenogenic potential and SV40LT expression at both early (passage < 10) and late (passage > 30) stages. iTDSC#6 showed stable expression of Simian virus 40 large T antigen (SV40LT) and demonstrated similar MSC-like phenotypes as its wild-type counterpart at both early and late passages, including colony formation capability and multi-lineage differentiation potentials. iTDSC#6 was positive for the MSC markers CD90, CD44, CD29 and CD73 (≥95%) and negative for the hematopoietic markers CD34 and CD45 (<1%). Regarding its utility for basic research and therapeutic development, iTDSC#6 showed potential for modelling cells with increased levels of senescence-associated beta-galactosidase activity in response to hydrogen peroxide and for bioengineering scaffold-free, tendon-like 3D constructs as evidenced by its upregulation of tendon-related markers, high nuclear aspect ratio, and aligned collagen organization. In conclusion, an immortalized TDSC line was successfully established that shows promise as a useful research tool to study tendon biology and aid the development of therapeutics for tissue engineering and regenerative medicine. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems: Current Technologies and Applications)
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20 pages, 2068 KB  
Article
Establishment of a 3D Multicellular HCC Tumor Spheroid Model to Unravel Nrf2’s Influence on the Tumor Immune Microenvironment
by Nicole Böttcher, Philipp Krumm, Rosanna Huchzermeier, Lara Berschkeit, Johanna Vollmer, Julie Dick, Thomas Pufe and Athanassios Fragoulis
Bioengineering 2026, 13(3), 336; https://doi.org/10.3390/bioengineering13030336 - 13 Mar 2026
Viewed by 305
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death, yet adequate in vitro models mimicking the tumor immune microenvironment (TIME) are rare. Specifically, the role of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in modulating interactions between tumor cells [...] Read more.
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death, yet adequate in vitro models mimicking the tumor immune microenvironment (TIME) are rare. Specifically, the role of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in modulating interactions between tumor cells and tumor-associated macrophages (TAMs) is not fully understood. We established a 3D multicellular tumor spheroid (MCT) model using murine N-HCC25 cells with CRISPR/Cas9-mediated knockouts of Nrf2 and its negative regulator Kelch-like ECH-associated protein 1 (Keap1), the latter mimicking constitutive activation. N-HCC25 cells were co-cultured with bone marrow-derived macrophages (BMDMs) isolated from wild-type and Nrf2-knockout C57BL/6J mice. We compared co-culture setups (conditioned media, transwell systems, direct contact) using RT-qPCR, flow cytometry, and invasion assays. 3D spheroid systems better preserved stemness than 2D cultures and revealed functional Nrf2-dependent effects such as increased Vegf-α secretion in Keap1-deficient spheroids. Among the different co-cultivation models, the most profound effects were observed in the MCT model. Macrophages successfully integrated into the spheroids and triggered invasive outgrowth, whereas MCTs containing Nrf2-deficient macrophages displayed markedly reduced tumor spheroid growth and lower programmed cell death ligand-1 expression. These findings demonstrate that Nrf2 signaling in macrophages fosters an immunosuppressive and pro-invasive microenvironment. The established MCT model provides a suitable platform to further unravel Nrf2-dependent mechanisms in the HCC TIME. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems: Current Technologies and Applications)
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Review

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27 pages, 3312 KB  
Review
Influence of Structure–Property Relationships of Polymeric Biomaterials for Engineering Multicellular Spheroids
by Sheetal Chowdhury and Amol V. Janorkar
Bioengineering 2025, 12(8), 857; https://doi.org/10.3390/bioengineering12080857 - 9 Aug 2025
Cited by 3 | Viewed by 1906
Abstract
Two-dimensional cell culture systems lack the ability to replicate the complex, three-dimensional (3D) architecture and cellular microenvironments found in vivo. Multicellular spheroids (MCSs) present a promising alternative, with the ability to mimic native cell–cell and cell–matrix interactions and provide 3D architectures similar to [...] Read more.
Two-dimensional cell culture systems lack the ability to replicate the complex, three-dimensional (3D) architecture and cellular microenvironments found in vivo. Multicellular spheroids (MCSs) present a promising alternative, with the ability to mimic native cell–cell and cell–matrix interactions and provide 3D architectures similar to in vivo conditions. These factors are critical for various biomedical applications, including cancer research, tissue engineering, and drug discovery and development. Polymeric materials such as hydrogels, solid scaffolds, and ultra-low attachment surfaces serve as versatile platforms for 3D cell culture, offering tailored biochemical and mechanical cues to support cellular organization. This review article focuses on the structure–property relationships of polymeric biomaterials that influence MCS formation, growth, and functionality. Specifically, we highlight their physicochemical properties and their influence on spheroid formation using key natural polymers, including collagen, hyaluronic acid, chitosan, and synthetic polymers like poly(lactic-co-glycolic acid) and poly(N-isopropylacrylamide) as examples. Despite recent advances, several challenges persist, including spheroid loss during media changes, limited viability or function in long-term cultures, and difficulties in scaling for high-throughput applications. Importantly, the development of MCS platforms also supports the 3R principle (Replacement, Reduction, and Refinement) by offering ethical and physiologically relevant alternatives to animal testing. This review emphasizes the need for innovative biomaterials and methodologies to overcome these limitations, ultimately advancing the utility of MCSs in biomedical research. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems: Current Technologies and Applications)
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16 pages, 1273 KB  
Review
The Risks Associated with Inhalation Exposure to Cosmetics and Potential for Assessment Using Lung Organoids
by Yiguang Li, Xin Luo, Rong Hu, Lifeng Tang and Qi Xiang
Bioengineering 2025, 12(6), 652; https://doi.org/10.3390/bioengineering12060652 - 13 Jun 2025
Cited by 1 | Viewed by 2621
Abstract
This review addresses the exposure risks associated with the inhalation of aerosolized cosmetic products and explores the utility of lung organoids in assessing these risks. Aerosolized cosmetics such as sprays pose potential health hazards through inhalation, necessitating a thorough evaluation of exposure levels. [...] Read more.
This review addresses the exposure risks associated with the inhalation of aerosolized cosmetic products and explores the utility of lung organoids in assessing these risks. Aerosolized cosmetics such as sprays pose potential health hazards through inhalation, necessitating a thorough evaluation of exposure levels. Traditional methods for assessing inhalation risks have limitations, prompting the exploration of more sophisticated models. Lung organoids, three-dimensional structures derived from stem cells, offer a biologically relevant model for studying lung responses to inhaled substances. This review discusses the construction of lung organoids, their characteristics, and the advantages that they provide over conventional models. Furthermore, it examines existing studies that have employed lung organoids to evaluate the effects of cosmetic inhalation exposure, highlighting the potential of this approach to enhance the safety assessments of cosmetic products. We aim to establish lung organoids as a reliable tool for future research, ensuring the safety and regulatory compliance of cosmetics. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems: Current Technologies and Applications)
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Other

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14 pages, 2733 KB  
Protocol
A Protocol for the In Vitro Culturing of Vascularized Pancreatic Islet Organoids
by Pengkun Song, Yue Wang, Junya Peng, Lei Liu and Lei Du
Bioengineering 2025, 12(11), 1222; https://doi.org/10.3390/bioengineering12111222 - 9 Nov 2025
Viewed by 1258
Abstract
This study presents a protocol for co-culturing pancreatic islet cell clusters derived from pancreatic tissue with human umbilical vein endothelial cells (HUVECs) on Matrigel using a specialized culture medium to form vascularized pancreatic islet organoids. We established a novel culture system for vascularized [...] Read more.
This study presents a protocol for co-culturing pancreatic islet cell clusters derived from pancreatic tissue with human umbilical vein endothelial cells (HUVECs) on Matrigel using a specialized culture medium to form vascularized pancreatic islet organoids. We established a novel culture system for vascularized pancreatic islet organoids and compared the survival and insulin secretion capabilities of pancreatic islet cells in the presence and absence of glucose stimulation. Our results indicate that matrix adhesive materials can effectively facilitate the self-assembly of the vascularized endothelial cell–pancreatic islet organoids complex. Vascularized HUVEC prolongs the survival of pancreatic islet organoids in vitro. Moreover, the interaction between vascularized HUVEC and pancreatic islets significantly enhances the insulin secretion ability in response to glucose stimulation. This study reports a protocol for the long-term in vitro culture of pancreatic islet organoids, offering methods for the vascularization of pancreatic islet organoids on Matrigel. These data contribute to the understanding of how vascularization impacts the fate and function of pancreatic islet organoids, although the specific mechanism still requires further clarification. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems: Current Technologies and Applications)
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