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传统的癌症研究是通过观察实验小白鼠的活体组织切片了解肿瘤的形成及癌症的各阶段发展情况，相比于活体实验，癌细胞的体外实验因为可以灵活地操控实验变量和实时观测癌细胞生长和发育的特点从而得以快速发展. 但进一步的研究发现，在诸如培养皿二维环境中培养的细胞的行为在很大程度上与其实际所处的三维环境中的细胞行为有着巨大的差异. 因此借助于微加工和微流体技术以及近年来蓬勃发展的生物3D打印技术、飞秒激光直写技术和水凝胶的紫外光固化等技术，越来越多的癌细胞体外三维实验模型得以制造并用于癌症的研究. 但同时，现有的技术也面临着精度与速度的矛盾和模型材料的生物相容性等问题. 本文讨论了二维及三维癌细胞体外侵袭转移实验的模型及制造技术的优缺点，简要介绍了最新的研究进展，分析提出了未来几年三维实验模型成型技术的发展方向，为相关研究提供新的实验思路.
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关键词:
- 癌细胞侵袭转移实验模型 /
- 三维结构成型技术 /
- 癌症生物物理
Traditional cancer researches focus on the analyses of the mice biopsy in order to understand the formation of cancer and the stage of cancer development. In contrast to in vivo experiments, in vitro investigation of cancer cells provides the flexible manipulation of the experimental parameters and the real time observation of the growth and reproduction of cancer cells, thus has been developing rapidly. However, further studies have demonstrated that cells' behavior in a two-dimensional (2D) environment, e.g. Petri dish, is dramatically different from that in a three-dimensional (3D) environment. Therefore, with assistance of bio-microfluidic chips, 3D bio-printing, direct femtosecond laser writing technology and UV curing hydrogel technology, an increasing number of 3D models have been developed to investigate the behaviors of cancer cells in vitro. Nevertheless, the existing technology is also facing the contradiction between accuracy and speed requirements, as well as the biocompatibility and biodegradability of scaffold materials in use. In this paper, we first summarize and compare present 2D models, e. g. Agar Plate and Boyden Assay, and the developing 3D models in vitro experimental approaches as mentioned above, and discuss the merits of these fabricating technologies. Then we focus on the recent progress and achievements of 3D bio-techniques, especially the successful applications in probing the invasion behaviors of cancer cells. Though significant progress has been made from 2D to 3D approaches and these in vitro experimental models are becoming more flawless in simulating the in vivo environment of cells, the following challenges remain: 1) biocompatible material with the appropriate mechanic properties simulating the environment in vivo; 2) the viability of cells in the complex 3D model with of biomaterial, especially during the laser or UV-assisted gelation of hydrogels; 3) the speed and resolution of the present 3D fabrication technologies; 4) the in situ observation and control of cells. Nevertheless, with the development of 3D bio-technologies, breakthroughs can be expected in solving those problems, and thus will guide the 3D experimental models for the invasion of cancer cells in next few years. This will eventually help people in the war towards cancers, and at the same time provide new experimental approaches for other relevant researches in the interdisciplinary fields of biology, physics, chemistry, materials and engineering.-
Keywords:
- invasion and metastasis experimental models of tumor cell /
- 3D shape molding technology /
- cancer biophysical
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[18] Wu P H, Giri A, Sun S X, Wirtz D 2014 Proc. Natl. Acad. Sci. USA 111 3949
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[21] Zorlutuna P, Annabi N, Camci-Unal G, Nikkhah M, Cha J M, Nichol J W, Manbachi A, Bae H, Chen S, Khademhosseini A 2012 Adv. Mater. 24 1782
[22] Xu T, Zhao W, Zhu J M, Albanna M Z, Yoo J J, Atala A 2013 Biomaterials 34 130
[23] Ahn S, Lee H, Lee E J, Kim G H 2014 J. Mater. Chem. B 2 2773
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[25] Gill A A, Ortega I, Kelly S, Claeyssens F 2015 Biomed. Microdevices 17 27
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[27] Wang J, Auyeung R C, Kim H, Kim H, Charipar N A, Pique A 2010 Adv. Mater. 22 4462
[28] Buckmann T, Stenger N, Kadic M, Kaschke J, Frolich A, Kennerknecht T, Eberl C, Thiel M, Wegener M 2012 Adv. Mater. 24 2710
[29] Kim S, Qiu F, Kim S, Ghanbari A, Moon C, Zhang L, Nelson B J, Choi H 2013 Adv. Mater. 25 5863
[30] Cha C, Soman P, Zhu W, Nikkhah M, Camci-Unal G, Chen S, Khademhosseini A 2014 Biomater. Sci. 2 703
[31] Hong S, Sycks D, Chan H F, Lin S, Lopez G P, Guilak F, Leong K M, Zhao X 2015 Adv. Mater. 27 4035
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[34] Liu L, Sun B, Pedersen J N, Yong K A, Getzenberg R H, Stone H A, Austin R H 2011 Proc. Natl. Acad. Sci. USA 108 6853
[35] Han W, Chen S, Yuan W, Fan Q, Tian J, Wang X, Chen L, Zhang X, Wei W, Liu R, Qu J, Jiao Y, Austin R H, Liu L 2016 Proc. Natl. Acad. Sci. USA doi: 10.1073/pnas.1610347113
[36] A. Sydney Gladman, Matsumoto E A, Nuzzo R G, Mahadevan L, Lewis J A 2016 Nature. Mater. 15 413
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[1] Sleeman J, Steeg P S 2010 Eur. J. Cancer 46 1177
[2] Steeg P S, Theodorescu D 2008 Nat. Clin. Pract. Onco. 5 206
[3] Hanahan D, Weinberg R A 2011 Cell 144 646
[4] Frisch S M, Ruoslahti E 1997 Curr. Opin. Cell Biol. 9 701
[5] Xu W, Mezencev R, Kim B, Wang L, McDonald J, Sulchek T 2012 PLoS One 7 e46609
[6] Discher D E, Janmey P, Wang Y L 2005 Science 310 1139
[7] Liu W F, Nelson C M, Pirone D M, Chen C S 2006 J. Cell Biol. 173 431
[8] Pishvaian M J, Feltes C M, Thompson P, Bussemakers M J, Schalken J A, Byers S W 1999 Cancer Res. 59 947
[9] Nieman M T, Prudoff R S, Johnson K R, Wheelock M J 1999 J. Cell Biol. 147 631
[10] Poincloux R, Collin O, Lizarraga F, Romao M, Debray M, Piel M, Chavrier P 2011 Proc. Natl. Acad. Sci. USA 108 1943
[11] Chabottaux V, Noel A 2007 Clin. Exp. Metastasis 24 647
[12] Hegedus L, Cho H, Xie X, Eliceiri G L 2008 J. Cell Physiol. 216 480
[13] Pampaloni F, Reynaud E G, Stelzer E H 2007 Nat. Rev. Mol. Cell Biol. 8 839
[14] Meyer A S, Hughes-Alford S K, Kay J E, Castillo A, Wells A, Gertler F B, Lauffenburger D A 2012 J. Cell Biol. 197 721
[15] Sung K E, Su X, Berthier E, Pehlke C, Friedl A, Beebe D J 2013 PLoS One 8 e76373
[16] Trepat X, Wasserman M R, Angelini T E, Millet E, Weitz D A, Butler J P, Fredberg J J 2009 Nat. Phys. 5 426
[17] Irimia D, Toner M 2009 Integr. Biol. 1 506
[18] Wu P H, Giri A, Sun S X, Wirtz D 2014 Proc. Natl. Acad. Sci. USA 111 3949
[19] Malda J, Visser J, Melchels F P, Jungst T, Hennink W E, Dhert W J A, Groll J, Hutmacher D W 2013 Adv. Mater. 25 5011
[20] Derby B 2012 Science 338 921
[21] Zorlutuna P, Annabi N, Camci-Unal G, Nikkhah M, Cha J M, Nichol J W, Manbachi A, Bae H, Chen S, Khademhosseini A 2012 Adv. Mater. 24 1782
[22] Xu T, Zhao W, Zhu J M, Albanna M Z, Yoo J J, Atala A 2013 Biomaterials 34 130
[23] Ahn S, Lee H, Lee E J, Kim G H 2014 J. Mater. Chem. B 2 2773
[24] Kang H W, Lee S J, Ko I K, Kengla C, James J, Yoo J, Atala A 2016 Nat. Biotechnol. 34 312
[25] Gill A A, Ortega I, Kelly S, Claeyssens F 2015 Biomed. Microdevices 17 27
[26] Selimis A, Mironov V, Farsari M 2015 Microelectron. Eng. 132 83
[27] Wang J, Auyeung R C, Kim H, Kim H, Charipar N A, Pique A 2010 Adv. Mater. 22 4462
[28] Buckmann T, Stenger N, Kadic M, Kaschke J, Frolich A, Kennerknecht T, Eberl C, Thiel M, Wegener M 2012 Adv. Mater. 24 2710
[29] Kim S, Qiu F, Kim S, Ghanbari A, Moon C, Zhang L, Nelson B J, Choi H 2013 Adv. Mater. 25 5863
[30] Cha C, Soman P, Zhu W, Nikkhah M, Camci-Unal G, Chen S, Khademhosseini A 2014 Biomater. Sci. 2 703
[31] Hong S, Sycks D, Chan H F, Lin S, Lopez G P, Guilak F, Leong K M, Zhao X 2015 Adv. Mater. 27 4035
[32] Soman P, Kelber J A, Lee J W, Wright T N, Vecchio K S, Klemke R L, Chen S 2012 Biomaterials 33 7064
[33] Soman P, Fozdar D Y, Lee J W, Phadke A, Varghese S, Chen S 2012 Soft Matter 8 4946
[34] Liu L, Sun B, Pedersen J N, Yong K A, Getzenberg R H, Stone H A, Austin R H 2011 Proc. Natl. Acad. Sci. USA 108 6853
[35] Han W, Chen S, Yuan W, Fan Q, Tian J, Wang X, Chen L, Zhang X, Wei W, Liu R, Qu J, Jiao Y, Austin R H, Liu L 2016 Proc. Natl. Acad. Sci. USA doi: 10.1073/pnas.1610347113
[36] A. Sydney Gladman, Matsumoto E A, Nuzzo R G, Mahadevan L, Lewis J A 2016 Nature. Mater. 15 413
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