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.	楊帆, 劉保一, 劉家河, 等. 體外培養 SD 大鼠關節軟骨細胞原代至第 3 代的形態學特點. 中國組織工程研究, 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. 單細胞三維成球培養對間充質干細胞的優化及相關機理的研究. 合肥: 中國科學技術大學, 2021.
4.	Juki? I, Kolobari? 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.	王亞超. 芯片上的三維細胞培養模型構建及其應用研究. 武漢: 華中科技大學, 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.	張增利. 體外三維非小細胞肺癌原代細胞球模型的建立及該模型在藥物篩查中應用的研究. 蘇州: 蘇州大學, 2018.
18.	?tampar M, Breznik B, Filipi? 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. 旋轉細胞培養系統模擬微重力環境對小鼠成纖維細胞lncRNA表達的影響. 解放軍醫學雜志, 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.	羅升昌, 王穎, 王士斌, 等. 基于微流控技術構建3D腫瘤模型用于藥物篩選. 科學通報, 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.	潘海濤, 張國亮, 錢華, 等. 基于結腸癌HCT116細胞三維培養模型的靈芝水提物抗腫瘤活性研究. 中國現代應用藥學, 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, 唐靚, 王晗, 等. 3D打印肝腫瘤模型及其白術和薏米藥敏試驗. 醫學理論與實踐, 2021, 34(5): 721-725.
35.	郭正昌, 趙澤玉, 張宗耀, 等. 小腸類器官的構建及傳代培養. 中國比較醫學雜志, 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細胞模型的楊梅花色苷納米脂質體抗氧化機制的研究. 杭州: 中國計量大學, 2018.
38.	歐靜, 徐珍妮, 劉登群, 等. 3D培養體系中不同腸上皮細胞株形成腸類器官潛能的比較及應用. 第三軍醫大學學報, 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. 楊帆, 劉保一, 劉家河, 等. 體外培養 SD 大鼠關節軟骨細胞原代至第 3 代的形態學特點. 中國組織工程研究, 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. 單細胞三維成球培養對間充質干細胞的優化及相關機理的研究. 合肥: 中國科學技術大學, 2021.
4. Juki? I, Kolobari? 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. 王亞超. 芯片上的三維細胞培養模型構建及其應用研究. 武漢: 華中科技大學, 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. 張增利. 體外三維非小細胞肺癌原代細胞球模型的建立及該模型在藥物篩查中應用的研究. 蘇州: 蘇州大學, 2018.
18. ?tampar M, Breznik B, Filipi? 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. 旋轉細胞培養系統模擬微重力環境對小鼠成纖維細胞lncRNA表達的影響. 解放軍醫學雜志, 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. 羅升昌, 王穎, 王士斌, 等. 基于微流控技術構建3D腫瘤模型用于藥物篩選. 科學通報, 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. 潘海濤, 張國亮, 錢華, 等. 基于結腸癌HCT116細胞三維培養模型的靈芝水提物抗腫瘤活性研究. 中國現代應用藥學, 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, 唐靚, 王晗, 等. 3D打印肝腫瘤模型及其白術和薏米藥敏試驗. 醫學理論與實踐, 2021, 34(5): 721-725.
35. 郭正昌, 趙澤玉, 張宗耀, 等. 小腸類器官的構建及傳代培養. 中國比較醫學雜志, 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細胞模型的楊梅花色苷納米脂質體抗氧化機制的研究. 杭州: 中國計量大學, 2018.
38. 歐靜, 徐珍妮, 劉登群, 等. 3D培養體系中不同腸上皮細胞株形成腸類器官潛能的比較及應用. 第三軍醫大學學報, 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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