Progress on three-dimensional cell culture technology and their application_Journal of Biomedical Engineering

Authors：

LU Xiaoqin ,  LIU Xiaofeng , ZHONG Hao , ZHANG Wei , YU Shuzhen , GUAN Rongfa

College of Food Science and Technology, Zhejiang University of Technology, Hangzhou 310014, P. R. China;

Corresponding author：

LIU Xiaofeng, Email: lxf0817@zjut.edu.cn

Keywords：

In vitro culture; Three-dimensional cell culture; Active substance; Functional evaluation; Application

DOI：

10.7507/1001-5515.202204062

Video：

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Three-dimensional (3D) cell culture model is a system that co-culture carriers with 3D structural materials and different types of cells in vitro to simulate the microenvironment in vivo. This novel cell culture model has been proved to be close to the natural system in vivo. In the process of cell attachment, migration, mitosis and apoptosis, it could produce biological reactions different from that of monolayer cell culture. Therefore, it can be used as an ideal model to evaluate the dynamic pharmacological effects of active substances and the metastasis process of cancer cells. This paper compared and analyzed the different characteristics of cell growth and development under two-dimensional (2D) and 3D model culture and introduced the establishment method of 3D cell model. The application progress of 3D cell culture technology in tumor model and intestinal absorption model was summarized. Finally, the application prospect of 3D cell model in the evaluation and screening of active substance was revealed. This review is expected to provide reference for the development and application of new 3D cell culture models.

Citation： LU Xiaoqin, LIU Xiaofeng, ZHONG Hao, ZHANG Wei, YU Shuzhen, GUAN Rongfa. Progress on three-dimensional cell culture technology and their application. Journal of Biomedical Engineering, 2023, 40(3): 602-608. doi: 10.7507/1001-5515.202204062 Copy

1.	杨帆, 刘保一, 刘家河, 等. 体外培养 SD 大鼠关节软骨细胞原代至第 3 代的形态学特点. 中国组织工程研究, 2021, 25(14): 2161-2165.
2.	Davies M, Peramuhendige P, King L, et al. Evaluation of in vitro models for assessment of human intestinal metabolism in drug discovery. Drug Metabolism and Disposition, 2020, 48(11): 169-1182.
3.	徐中娟. 单细胞三维成球培养对间充质干细胞的优化及相关机理的研究. 合肥: 中国科学技术大学, 2021.
4.	Jukić I, Kolobarić N, Stupin A, et al. Carmosine, small but mighty-prospect of use as functional ingredient for functional food formulation. Antioxidants, 2021, 10(7): 1037.
5.	Nguyen T, Lestienne F, Cousy A, et al. Effective inhibition of Th17/Th22 pathway in 2D and 3D human models of psoriasis by celastrol enriched plant cell culture extract. Journal of the European Academy of Dermatology and Venereology, 2020, 34(6): 3-9.
6.	王亚超. 芯片上的三维细胞培养模型构建及其应用研究. 武汉: 华中科技大学, 2019.
7.	Albogami S, Hassan A M. Assessment of the efficacy of olive leaf (Olea europaea L.) extracts in the treatment of colorectal cancer and prostate cancer using in vitro cell models. Molecules, 2021, 26(13): 4069.
8.	Li B L, Hu J J, Xie J D, et al. Rosanortriterpenes A-B, two promising agents from rosa laevigata var. leiocapus, alleviate inflammatory responses and liver fibrosis in in vitro cell models. Evidence-based Complementary and Alternative Medicine, 2020, 2020: 8872945.
9.	Jiang G J, Li Y, You X G, et al. Establish an in vitro cell model to explore the impacts of UVA on human corneal endothelial wound healing. Current Eye Research, 2020, 45(9): 1065-1073.
10.	Khalifa O, Al-Akl N S, Errafii K, et al. Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway. Scientific Reports, 2022, 12(1): 2226.
11.	Pan Q, Wang L, Liu Y, et al. Knockdown of POLQ interferes the development and progression of hepatocellular carcinoma through regulating cell proliferation, apoptosis and migration. Cancer Cell International, 2021, 21(1): 482.
12.	Kawai K, Negoro R, Yamashita T, et al. Establishment of SLC15A1/PEPT1-Knockout human-induced pluripotent stem cell line for intestinal drug absorption studies. Molecular Therapy-Methods & Clinical Development, 2020, 17: 49-57.
13.	Paniushkina L, Grueso-Navarro E, Cheng X, et al. Three-dimensional cell models for extracellular vesicles production, isolation, and characterization. Methods in enzymology, 2020, 645: 209-230.
14.	Reale O, Huguet A, Fessard V. Co-culture model of Caco-2/HT29-MTX cells: a promising tool for investigation of phycotoxins toxicity on the intestinal barrier. Chemosphere, 2020, 273: 128497.
15.	Suenaga H, Kagaya N, Kawada M, et al. Phenotypic screening system using three-dimensional (3D) culture models for natural product screening. The Journal of Antibiotics, 2021, 74(10): 660-666.
16.	Jensen C, Teng Y. Is it time to start transitioning from 2D to 3D cell culture?. Frontiers in Molecular Biosciences, 2020, 7: 33.
17.	张增利. 体外三维非小细胞肺癌原代细胞球模型的建立及该模型在药物筛查中应用的研究. 苏州: 苏州大学, 2018.
18.	Štampar M, Breznik B, Filipič M, et al. Characterization of in vitro 3D cell model developed from human hepatocellular carcinoma (HepG 2) cell line. Cells, 2020, 9(12): 2257.
19.	王占宇, 姜福全, 徐冰心, 等. 旋转细胞培养系统模拟微重力环境对小鼠成纤维细胞lncRNA表达的影响. 解放军医学杂志, 2017, 42(10): 876-882.
20.	Miller C P, Tsuchida C, Zheng Y, et al. A 3D human renal cell carcinoma-on-a-chip for the study of tumor angiogenesis. Neoplasia, 2018, 20(6): 610-620.
21.	Koroleva A, Deiwick A, El-Tamer A, et al. In vitro development of human iPSC-derived functional neuronal networks on laser-fabricated 3D scaffolds. ACS Applied Materials & Interfaces, 2021, 13(7): 7839-7853.
22.	Dasgupta S, Barui A. 3D cell culture for pharmaceutical application. Advances and Challenges in Pharmaceutical Technology. India: Indian Institute of Engineering Science and Technology, 2021: 261-282.
23.	Liu H, Liu J, Qi C, et al. Thermosensitive injectable in-situ forming carboxymethyl chitin hydrogel for three-dimensional cell culture. Acta Biomaterialia, 2016, 35: 228-237.
24.	Saleh N A, Rode M P, Sierra J A, et al. Three-dimensional multicellular cell culture for anti-melanoma drug screening: focus on tumor microenvironment. Cytotechnology, 2021, 73(1): 35-48.
25.	Turtoi M, Anghelache M, Bucatariu S M, et al. A novel platform for drug testing: biomimetic three-dimensional hyaluronic acid-based scaffold seeded with human hepatocarcinoma cells. International Journal of Biological Macromolecules, 2021, 185: 604-619.
26.	Zhang J, Penny J, Lu J R. Development of a novel in vitro 3D intestinal model for permeability evaluations. International Journal of Food Sciences and Nutrition, 2020, 71(5): 549-562.
27.	Betriu N, Andreeva A, Semino C E. Erlotinib promotes ligand-induced EGFR degradation in 3D but not 2D cultures of pancreatic ductal adenocarcinoma cells. Cancers, 2021, 13(18): 4504.
28.	Grunewald L, Lam T, Andersch L, et al. A reproducible bioprinted 3D tumor model serves as a preselection tool for CAR-T cell therapy optimization. Frontiers in Immunology, 2021, 12: 689697.
29.	罗升昌, 王颖, 王士斌, 等. 基于微流控技术构建3D肿瘤模型用于药物筛选. 科学通报, 2021, 66(34): 4395-4410.
30.	Loessner D, Holzapfel M, Clements J A. Engineered microenvi-ronments provide new insights into ovarian and prostate cancer progression and drug responses. Advanced drug delivery reviews. 2014, 79-80: 193-213.
31.	Zhu J, Zheng S, Liu H, et al. Evaluation of anti-tumor effects of crocin on a novel 3D tissue-engineered tumor model based on sodium alginate/gelatin microbead. International Journal of Biological Macromolecules, 2021, 174: 339-351.
32.	潘海涛, 张国亮, 钱华, 等. 基于结肠癌HCT116细胞三维培养模型的灵芝水提物抗肿瘤活性研究. 中国现代应用药学, 2021, 38(13): 1550-1558.
33.	Milazzo L, Vulcano F, Macioce G, et al. Silk fibroin scaffolds as biomaterials for 3D mesenchymal stromal cells cultures. Applied Sciences, 2021, 11: 11345.
34.	徐怡朦, 唐靓, 王晗, 等. 3D打印肝肿瘤模型及其白术和薏米药敏试验. 医学理论与实践, 2021, 34(5): 721-725.
35.	郭正昌, 赵泽玉, 张宗耀, 等. 小肠类器官的构建及传代培养. 中国比较医学杂志, 2021, 31(1): 1-6.
36.	Xu P, Elamin E, Elizalde M, et al. Modulation of intestinal epithelial permeability by plasma from patients with Crohn's disease in a three-dimensional cell culture model. Scientific Reports, 2019, 9(1): 2030.
37.	梁提松. 基于3D细胞模型的杨梅花色苷纳米脂质体抗氧化机制的研究. 杭州: 中国计量大学, 2018.
38.	欧静, 徐珍妮, 刘登群, 等. 3D培养体系中不同肠上皮细胞株形成肠类器官潜能的比较及应用. 第三军医大学学报, 2020, 42(1): 31-38.
39.	Kandilogiannakis L, Filidou E, Drygiannakis I, et al. Development of a human intestinal organoid model for in vitro studies on gut inflammation and fibrosis. Stem Cells Int, 2021, 2021: 9929461.
40.	Lin T Y, Ki C S, Lin C C. Manipulating hepatocellular carcinoma cell fate in orthogonally cross-linked hydrogels. Biomaterials, 2014, 35(25): 6898-6906.
41.	Quan R, Zheng X, Xu S, et al. Gelatin-chondroitin-6-sulfate-hyaluronic acid scaffold seeded with vascular endothelial growth factor 165 modified hair follicle stem cells as a three-dimensional skin substitute. Stem Cell Res Ther, 2014, 5(5): 118.
42.	Zhang M, Yan S, Xu X, et al. Three-dimensional cell-culture platform based on hydrogel with tunable microenvironmental properties to improve insulin-secreting function of MIN6 cells. Biomaterials, 2021, 270: 120687.

1. 杨帆, 刘保一, 刘家河, 等. 体外培养 SD 大鼠关节软骨细胞原代至第 3 代的形态学特点. 中国组织工程研究, 2021, 25(14): 2161-2165.
2. Davies M, Peramuhendige P, King L, et al. Evaluation of in vitro models for assessment of human intestinal metabolism in drug discovery. Drug Metabolism and Disposition, 2020, 48(11): 169-1182.
3. 徐中娟. 单细胞三维成球培养对间充质干细胞的优化及相关机理的研究. 合肥: 中国科学技术大学, 2021.
4. Jukić I, Kolobarić N, Stupin A, et al. Carmosine, small but mighty-prospect of use as functional ingredient for functional food formulation. Antioxidants, 2021, 10(7): 1037.
5. Nguyen T, Lestienne F, Cousy A, et al. Effective inhibition of Th17/Th22 pathway in 2D and 3D human models of psoriasis by celastrol enriched plant cell culture extract. Journal of the European Academy of Dermatology and Venereology, 2020, 34(6): 3-9.
6. 王亚超. 芯片上的三维细胞培养模型构建及其应用研究. 武汉: 华中科技大学, 2019.
7. Albogami S, Hassan A M. Assessment of the efficacy of olive leaf (Olea europaea L.) extracts in the treatment of colorectal cancer and prostate cancer using in vitro cell models. Molecules, 2021, 26(13): 4069.
8. Li B L, Hu J J, Xie J D, et al. Rosanortriterpenes A-B, two promising agents from rosa laevigata var. leiocapus, alleviate inflammatory responses and liver fibrosis in in vitro cell models. Evidence-based Complementary and Alternative Medicine, 2020, 2020: 8872945.
9. Jiang G J, Li Y, You X G, et al. Establish an in vitro cell model to explore the impacts of UVA on human corneal endothelial wound healing. Current Eye Research, 2020, 45(9): 1065-1073.
10. Khalifa O, Al-Akl N S, Errafii K, et al. Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway. Scientific Reports, 2022, 12(1): 2226.
11. Pan Q, Wang L, Liu Y, et al. Knockdown of POLQ interferes the development and progression of hepatocellular carcinoma through regulating cell proliferation, apoptosis and migration. Cancer Cell International, 2021, 21(1): 482.
12. Kawai K, Negoro R, Yamashita T, et al. Establishment of SLC15A1/PEPT1-Knockout human-induced pluripotent stem cell line for intestinal drug absorption studies. Molecular Therapy-Methods & Clinical Development, 2020, 17: 49-57.
13. Paniushkina L, Grueso-Navarro E, Cheng X, et al. Three-dimensional cell models for extracellular vesicles production, isolation, and characterization. Methods in enzymology, 2020, 645: 209-230.
14. Reale O, Huguet A, Fessard V. Co-culture model of Caco-2/HT29-MTX cells: a promising tool for investigation of phycotoxins toxicity on the intestinal barrier. Chemosphere, 2020, 273: 128497.
15. Suenaga H, Kagaya N, Kawada M, et al. Phenotypic screening system using three-dimensional (3D) culture models for natural product screening. The Journal of Antibiotics, 2021, 74(10): 660-666.
16. Jensen C, Teng Y. Is it time to start transitioning from 2D to 3D cell culture?. Frontiers in Molecular Biosciences, 2020, 7: 33.
17. 张增利. 体外三维非小细胞肺癌原代细胞球模型的建立及该模型在药物筛查中应用的研究. 苏州: 苏州大学, 2018.
18. Štampar M, Breznik B, Filipič M, et al. Characterization of in vitro 3D cell model developed from human hepatocellular carcinoma (HepG 2) cell line. Cells, 2020, 9(12): 2257.
19. 王占宇, 姜福全, 徐冰心, 等. 旋转细胞培养系统模拟微重力环境对小鼠成纤维细胞lncRNA表达的影响. 解放军医学杂志, 2017, 42(10): 876-882.
20. Miller C P, Tsuchida C, Zheng Y, et al. A 3D human renal cell carcinoma-on-a-chip for the study of tumor angiogenesis. Neoplasia, 2018, 20(6): 610-620.
21. Koroleva A, Deiwick A, El-Tamer A, et al. In vitro development of human iPSC-derived functional neuronal networks on laser-fabricated 3D scaffolds. ACS Applied Materials & Interfaces, 2021, 13(7): 7839-7853.
22. Dasgupta S, Barui A. 3D cell culture for pharmaceutical application. Advances and Challenges in Pharmaceutical Technology. India: Indian Institute of Engineering Science and Technology, 2021: 261-282.
23. Liu H, Liu J, Qi C, et al. Thermosensitive injectable in-situ forming carboxymethyl chitin hydrogel for three-dimensional cell culture. Acta Biomaterialia, 2016, 35: 228-237.
24. Saleh N A, Rode M P, Sierra J A, et al. Three-dimensional multicellular cell culture for anti-melanoma drug screening: focus on tumor microenvironment. Cytotechnology, 2021, 73(1): 35-48.
25. Turtoi M, Anghelache M, Bucatariu S M, et al. A novel platform for drug testing: biomimetic three-dimensional hyaluronic acid-based scaffold seeded with human hepatocarcinoma cells. International Journal of Biological Macromolecules, 2021, 185: 604-619.
26. Zhang J, Penny J, Lu J R. Development of a novel in vitro 3D intestinal model for permeability evaluations. International Journal of Food Sciences and Nutrition, 2020, 71(5): 549-562.
27. Betriu N, Andreeva A, Semino C E. Erlotinib promotes ligand-induced EGFR degradation in 3D but not 2D cultures of pancreatic ductal adenocarcinoma cells. Cancers, 2021, 13(18): 4504.
28. Grunewald L, Lam T, Andersch L, et al. A reproducible bioprinted 3D tumor model serves as a preselection tool for CAR-T cell therapy optimization. Frontiers in Immunology, 2021, 12: 689697.
29. 罗升昌, 王颖, 王士斌, 等. 基于微流控技术构建3D肿瘤模型用于药物筛选. 科学通报, 2021, 66(34): 4395-4410.
30. Loessner D, Holzapfel M, Clements J A. Engineered microenvi-ronments provide new insights into ovarian and prostate cancer progression and drug responses. Advanced drug delivery reviews. 2014, 79-80: 193-213.
31. Zhu J, Zheng S, Liu H, et al. Evaluation of anti-tumor effects of crocin on a novel 3D tissue-engineered tumor model based on sodium alginate/gelatin microbead. International Journal of Biological Macromolecules, 2021, 174: 339-351.
32. 潘海涛, 张国亮, 钱华, 等. 基于结肠癌HCT116细胞三维培养模型的灵芝水提物抗肿瘤活性研究. 中国现代应用药学, 2021, 38(13): 1550-1558.
33. Milazzo L, Vulcano F, Macioce G, et al. Silk fibroin scaffolds as biomaterials for 3D mesenchymal stromal cells cultures. Applied Sciences, 2021, 11: 11345.
34. 徐怡朦, 唐靓, 王晗, 等. 3D打印肝肿瘤模型及其白术和薏米药敏试验. 医学理论与实践, 2021, 34(5): 721-725.
35. 郭正昌, 赵泽玉, 张宗耀, 等. 小肠类器官的构建及传代培养. 中国比较医学杂志, 2021, 31(1): 1-6.
36. Xu P, Elamin E, Elizalde M, et al. Modulation of intestinal epithelial permeability by plasma from patients with Crohn's disease in a three-dimensional cell culture model. Scientific Reports, 2019, 9(1): 2030.
37. 梁提松. 基于3D细胞模型的杨梅花色苷纳米脂质体抗氧化机制的研究. 杭州: 中国计量大学, 2018.
38. 欧静, 徐珍妮, 刘登群, 等. 3D培养体系中不同肠上皮细胞株形成肠类器官潜能的比较及应用. 第三军医大学学报, 2020, 42(1): 31-38.
39. Kandilogiannakis L, Filidou E, Drygiannakis I, et al. Development of a human intestinal organoid model for in vitro studies on gut inflammation and fibrosis. Stem Cells Int, 2021, 2021: 9929461.
40. Lin T Y, Ki C S, Lin C C. Manipulating hepatocellular carcinoma cell fate in orthogonally cross-linked hydrogels. Biomaterials, 2014, 35(25): 6898-6906.
41. Quan R, Zheng X, Xu S, et al. Gelatin-chondroitin-6-sulfate-hyaluronic acid scaffold seeded with vascular endothelial growth factor 165 modified hair follicle stem cells as a three-dimensional skin substitute. Stem Cell Res Ther, 2014, 5(5): 118.
42. Zhang M, Yan S, Xu X, et al. Three-dimensional cell-culture platform based on hydrogel with tunable microenvironmental properties to improve insulin-secreting function of MIN6 cells. Biomaterials, 2021, 270: 120687.

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