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Biomedicines
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3D Cell Culture Systems for Biomedical Research
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3D Cell Culture Systems for Biomedical Research

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Biomedical Engineering and Materials".

Deadline for manuscript submissions: 31 July 2025 | Viewed by 6861

Special Issue Editors

Dr. Agnieszka Rusak

E-Mail Website
Guest Editor
Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
Interests: biomaterials; surface functionalisation; regenerative medicine; targeted therapies in cancer; angiogenesis
Dr. Benita Wiatrak

E-Mail Website
Guest Editor
Department of Pharmacology, Wroclaw Medical University, 50-368 Wroclaw, Poland
Interests: regenerative medicine; neurodegeneration; neuroregeneration; Alzheimer’s disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recently, 3D cell culture systems have become one of the most relevant models in biological research; they are employed in a broad range of studies, particularly in the human health field, and are often chosen over traditional 2D (monolayer) in vitro cell cultures. They have a spatial structure, which enables the possibility of cell–cell interactions, and the model’s scaffold surface can mimic the tissue microenvironment. Three-dimensional cell culture systems may be useful in the development of new biomaterials or for surface functionalisation, which is the basis for tissue engineering. Moreover, some 3D structures may provide alternative solutions for tumour in vitro models and act as a bridge between in vitro and in vivo investigations. 3D models have the potential to depict advanced scaffold-linked pathology conditions in tissues and serve as a model for the design of new therapies. Interdisciplinary techniques are greatly needed to evaluate and visualise these structures and the experimental results.

We hope that this Special Issue will provide significant insight into the most advanced 3D cell culture models and encourage researchers to share their unique research and models to enable us to better understand and project future research with more adequate models.

Dr. Agnieszka Rusak
Dr. Benita Wiatrak
Guest Editors

Manuscript Submission Information

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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. Biomedicines 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

  • 3D
  • scaffolds
  • spheroids
  • biomaterials
  • tumour model
  • bioengineering
  • tissue regeneration
  • regenerative medicine
  • targeted therapies
  • tissue mimics
  • angiogenesis
  • cancerogenesis
  • drug development
  • 3D printing
  • material functionalisation

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Published Papers (6 papers)

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Research

25 pages, 4466 KiB  
Article
Biomanufacturing and Curcumin-Loading of Human Choroid Plexus Organoid-Derived Extracellular Vesicles from a Vertical-Wheel Bioreactor to Alleviate Neuro-Inflammation
by Justice Ene, Laureana Muok, Vanessa Gonzalez, Nicolas Sanchez, Aakash Nathani, Falak Syed, Zixiang Leonardo Liu, Mandip Singh, Tristan Driscoll and Yan Li
Biomedicines 2025, 13(5), 1069; https://doi.org/10.3390/biomedicines13051069 - 28 Apr 2025
Viewed by 31
Abstract
Background: Choroid plexus is a complex structure in the human brain that is responsible for the secretion of extracellular vesicles (EVs) in cerebrospinal fluid. Few studies to date have generated choroid plexus (ChP) organoids differentiated from human induced pluripotent stem cells (hiPSCs) and [...] Read more.
Background: Choroid plexus is a complex structure in the human brain that is responsible for the secretion of extracellular vesicles (EVs) in cerebrospinal fluid. Few studies to date have generated choroid plexus (ChP) organoids differentiated from human induced pluripotent stem cells (hiPSCs) and analyzed their secreted EVs. The scalable Vertical-Wheel bioreactors (VWBRs) provide low shear stress and a controlled environment. Methods: This study utilized VWBRs for the differentiation of hiPSCs into ChP organoids and generation of the secreted EVs compared to a static culture. Additionally, this study loaded curcumin into ChP organoid-derived EVs, performed EV lyophilization, and determined the ability of the re-hydrated EVs to alleviate neuro-inflammation. Results: The results demonstrated that the VWBR culture exhibited more aerobic metabolism and active glucose and glutamine consumption than the static control. Consequently, the ChP markers and Endosomal Sorting Complexes Required for Transport-dependent and -independent EV biogenesis genes were significantly upregulated (2–3-fold) in the VWBR, producing four-fold-higher EVs per mL media than the static control. The EVs retained similar size and zeta potential after lyophilization and re-hydration. The cells exposed to amyloid beta 42 oligomers and treated with the curcumin-loaded re-hydrated EVs showed high viability and the reduced inflammatory response determined by TNF-α and IL-6 expression. Conclusions: This study demonstrates a scalable bioreactor system to promote ChP organoid differentiation and generation of EV-based cell-free therapeutics to treat neural inflammation in various neurological disorders. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems for Biomedical Research)
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16 pages, 2030 KiB  
Article
Sonidegib Inhibits the Adhesion of Acute Myeloid Leukemia to the Bone Marrow in Hypoxia: An Optical Tweezer Study
by Katarzyna Gdesz-Birula, Sławomir Drobczyński, Krystian Sarat and Kamila Duś-Szachniewicz
Biomedicines 2025, 13(3), 578; https://doi.org/10.3390/biomedicines13030578 - 25 Feb 2025
Viewed by 509
Abstract
Background: Acute myeloid leukemia (AML) is a heterogeneous disease highly resistant to chemotherapeutic agents. Leukemia stem cells (LSCs) can enter a dormant state and avoid apoptosis in the protective niche of the bone marrow (BM) microenvironment. Moreover, bone marrow stromal cells protect leukemia [...] Read more.
Background: Acute myeloid leukemia (AML) is a heterogeneous disease highly resistant to chemotherapeutic agents. Leukemia stem cells (LSCs) can enter a dormant state and avoid apoptosis in the protective niche of the bone marrow (BM) microenvironment. Moreover, bone marrow stromal cells protect leukemia cells by promoting pro-survival signaling pathways and drug resistance. Therefore, attenuating interactions between leukemia cells and BM cells may have a positive therapeutic effect. Objectives: In this work, we hypothesized that sondages may inhibit the adhesion of leukemia cells to the bone marrow by inhibiting the Hedgehog (Hh) signaling pathway. The Hedgehog pathway is a key therapeutic target in AML due to its role in leukemic cell growth and survival. Methods: We investigated the effects of sonidegib on the adhesion of individual OCI-AML3 cells to a bone marrow stromal spheroid derived from the HS-5 cell line. For this purpose, we precisely determined the minimum cell-to-cell adhesion time using optical tweezers under normoxic (21% of O2) and hypoxic (1% of O2) conditions. Results: Our results demonstrated that sonidegib significantly increased the minimum cell-to-cell adhesion time necessary for leukemic cells to establish adhesive bonds with bone marrow stromal cells, thereby indicating a reduction in their adhesive properties. Additionally, we showed that sonidegib is particularly effective at hypoxic oxygen concentrations. Conclusions: The results obtained in this study suggest that sonidegib, through its modulation of the Hedgehog signaling pathway, holds promise as a potential therapeutic approach to target leukemic cell adhesion within the bone marrow microenvironment. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems for Biomedical Research)
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14 pages, 3208 KiB  
Article
Advancing Hydrogel-Based 3D Cell Culture Systems: Histological Image Analysis and AI-Driven Filament Characterization
by Lucio Assis Araujo Neto, Alessandra Maia Freire and Luciano Paulino Silva
Biomedicines 2025, 13(1), 208; https://doi.org/10.3390/biomedicines13010208 - 15 Jan 2025
Viewed by 962
Abstract
Background: Machine learning is used to analyze images by training algorithms on data to recognize patterns and identify objects, with applications in various fields, such as medicine, security, and automation. Meanwhile, histological cross-sections, whether longitudinal or transverse, expose layers of tissues or tissue [...] Read more.
Background: Machine learning is used to analyze images by training algorithms on data to recognize patterns and identify objects, with applications in various fields, such as medicine, security, and automation. Meanwhile, histological cross-sections, whether longitudinal or transverse, expose layers of tissues or tissue mimetics, which provide crucial information for microscopic analysis. Objectives: This study aimed to employ the Google platform “Teachable Machine” to apply artificial intelligence (AI) in the interpretation of histological cross-section images of hydrogel filaments. Methods: The production of 3D hydrogel filaments involved different combinations of sodium alginate and gelatin polymers, as well as a cross-linking agent, and subsequent stretching until rupture using an extensometer. Cross-sections of stretched and unstretched filaments were created and stained with hematoxylin and eosin. Using the Teachable Machine platform, images were grouped and trained for subsequent prediction. Results: Over six hundred histological cross-section images were obtained and stored in a virtual database. Each hydrogel combination exhibited variations in coloration, and some morphological structures remained consistent. The AI efficiently identified and differentiated images of stretched and unstretched filaments. However, some confusion arose when distinguishing among variations in hydrogel combinations. Conclusions: Therefore, the image prediction tool for biopolymeric hydrogel histological cross-sections using Teachable Machine proved to be an efficient strategy for distinguishing stretched from unstretched filaments. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems for Biomedical Research)
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14 pages, 4014 KiB  
Article
Unexpected and Synergistical Effects of All-Trans Retinoic Acid and TGF-β2 on Biological Aspects of 2D and 3D Cultured ARPE19 Cells
by Megumi Higashide, Megumi Watanabe, Tatsuya Sato, Toshifumi Ogawa, Araya Umetsu, Soma Suzuki, Masato Furuhashi, Hiroshi Ohguro and Nami Nishikiori
Biomedicines 2024, 12(10), 2228; https://doi.org/10.3390/biomedicines12102228 - 30 Sep 2024
Cited by 1 | Viewed by 979
Abstract
Objectives: To study the effects of all-trans retinoic acid (ATRA) on TGF-β2-induced effects of human retinal pigment epithelium cells under normoxia and hypoxia conditions. Methods: Two-dimensionally (2D) and three-dimensionally (3D) cultured ARPE19 cells were subjected to cellular functional analyses by transepithelial electrical resistance [...] Read more.
Objectives: To study the effects of all-trans retinoic acid (ATRA) on TGF-β2-induced effects of human retinal pigment epithelium cells under normoxia and hypoxia conditions. Methods: Two-dimensionally (2D) and three-dimensionally (3D) cultured ARPE19 cells were subjected to cellular functional analyses by transepithelial electrical resistance (TEER) and an extracellular flux assay (2D), measurement of levels of reactive oxygen species (ROS), gene expression analyses of COL1, αSMA, Zo-1, HIF1α, and PGC1α (2D), and physical property analyses (3D). Results: Under a normoxia condition, treatment with 100 nM ATRA substantially decreased barrier function regardless of the presence of 5 ng/mL TGF-β2 in 2D ARPE19 monolayer cells. Under a hypoxia condition, treatment with ATRA conversely increased barrier function, but the effect was masked by a marked increase in effects induced by TGF-β2. Although ATRA alone did not affect cellular metabolism and ROS levels in 2D ARPE cells, treatment with ATRA under a hypoxia condition did not affect ROS levels but shifted cellular metabolism from mitochondrial respiration to glycolysis. The changes of cellular metabolism and ROS levels were more pronounced with treatment of both ATRA and TGF-β2 independently of oxygen conditions. Changes in mRNA expressions of some of the above genes suggested the involvement of synergistical regulation of cellular functions by TGF-β2 and hypoxia. In 3D ARPE spheroids, the size was decreased and the stiffness was increased by either treatment with TGF-β2 or ATRA, but these changes were unexpectedly modulated by both ATRA and TGF-β2 treatment regardless of oxygen conditions. Conclusions: The findings reported herein indicate that TGF-β2 and hypoxia synergistically and differentially induce effects in 2D and 3D cultured ARPE19 cells and that their cellular properties are significantly altered by the presence of ATRA. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems for Biomedical Research)
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17 pages, 10148 KiB  
Article
Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Reversing Hepatic Fibrosis in 3D Liver Spheroids
by Giulia Chiabotto, Armina Semnani, Elena Ceccotti, Marco Guenza, Giovanni Camussi and Stefania Bruno
Biomedicines 2024, 12(8), 1849; https://doi.org/10.3390/biomedicines12081849 - 14 Aug 2024
Cited by 1 | Viewed by 2096
Abstract
Hepatic fibrosis, arising from prolonged liver injury, entails the activation of hepatic stellate cells (HSCs) into myofibroblast-like cells expressing alpha-smooth muscle actin (α-SMA), thereby driving extracellular matrix deposition and fibrosis progression. Strategies targeting activated HSC reversal and hepatocyte regeneration show promise for fibrosis [...] Read more.
Hepatic fibrosis, arising from prolonged liver injury, entails the activation of hepatic stellate cells (HSCs) into myofibroblast-like cells expressing alpha-smooth muscle actin (α-SMA), thereby driving extracellular matrix deposition and fibrosis progression. Strategies targeting activated HSC reversal and hepatocyte regeneration show promise for fibrosis management. Previous studies suggest that extracellular vesicles (EVs) from mesenchymal stromal cells (MSCs) can suppress HSC activation, but ensuring EV purity is essential for clinical use. This study investigated the effects of MSC-derived EVs cultured in chemically defined conditions on liver spheroids and activated HSCs. Umbilical cord- and bone marrow-derived MSCs were expanded in chemically defined media, and EVs were isolated using filtration and differential ultracentrifugation. The impact of MSC-EVs was evaluated on liver spheroids generated in Sphericalplate 5D™ and on human HSCs, both activated by transforming growth factor beta 1 (TGF-β1). MSC-EVs effectively reduced the expression of profibrotic markers in liver spheroids and activated HSCs induced by TGF-β1 stimulation. These results highlight the potential of MSC-EVs collected under chemically defined conditions to mitigate the activated phenotype of HSCs and liver spheroids, suggesting MSC-EVs as a promising treatment for hepatic fibrosis. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems for Biomedical Research)
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Graphical abstract

17 pages, 11336 KiB  
Article
Three-Dimensional-Printed Modular Titanium Alloy Plates for Osteosynthesis of the Jawbone
by Maciej Dobrzyński, Maria Szymonowicz, Joanna Nowicka, Magdalena Pajączkowska, Anna Nikodem, Piotr Kuropka, Magdalena Wawrzyńska and Agnieszka Rusak
Biomedicines 2024, 12(7), 1466; https://doi.org/10.3390/biomedicines12071466 - 2 Jul 2024
Viewed by 1580
Abstract
Backgrounds: The titanium–aluminum–vanadium alloy (Ti-6Al-4V) is frequently used in implantology due to its biocompatibility. The use of 3D printing enables the mechanical modification of implant structures and the adaptation of their shape to the specific needs of individual patients. Methods: The titanium alloy [...] Read more.
Backgrounds: The titanium–aluminum–vanadium alloy (Ti-6Al-4V) is frequently used in implantology due to its biocompatibility. The use of 3D printing enables the mechanical modification of implant structures and the adaptation of their shape to the specific needs of individual patients. Methods: The titanium alloy plates were designed using the 3D CAD method and printed using a 3D SLM printer. Qualitative tests were performed on the material surface using a microcomputed tomography scanner. The cytotoxicity of the modular titanium plates was investigated using the MTT assay on the L929 cell line and in direct contact with Balb/3T3 cells. Cell adhesion to the material surface was evaluated with hFOB1.19 human osteoblasts. Microbial biofilm formation was investigated on strains of Lactobacillus rhamnosus, Staphylococcus epidermidis, Streptococcus mutans and Candida albicans using the TTC test and scanning electron microscopy (SEM). Results: The surface analysis showed the hydrophobic nature of the implant. The study showed that the titanium plates had no cytotoxic properties. In addition, the material surface showed favorable properties for osteoblast adhesion. Among the microorganisms tested, the strains of S. mutans and S. epidermidis showed the highest adhesion capacity to the plate surface, while the fungus C. albicans showed the lowest adhesion capacity. Conclusions: The manufactured modular plates have properties that are advantageous for the implantation and reduction in selected forms of microbial biofilm. Three-dimensional-printed modular titanium plates were investigated in this study and revealed the potential clinical application of this type of materials, regarding lack of cytotoxicity, high adhesion properties for osteoblasts and reduction in biofilm formation. The 3D CAD method allows us to personalise the shape of implants for individual patients. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems for Biomedical Research)
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