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Bio-Design and Manufacturing  2021 Vol.4 No.4 P.842-850

http://doi.org/10.1007/s42242-021-00141-8


Porous hydrogel arrays for hepatoma cell spheroid formation and drug resistance investigation


Author(s):  Xin Lei, Changmin Shao, Xin Shou, Keqing Shi, Liang Shi, Yuanjin Zhao

Affiliation(s):  Translational Medicine Laboratory, The First Afliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; more

Corresponding email(s):   shaocm@wiucas.ac.cn, shiliang3@mail.sysu.edu.cn, yjzhao@seu.edu.cn

Key Words:  Drug resistance, Hydrogel, Porous, Spheroid, Hepatoma


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Xin Lei, Changmin Shao, Xin Shou, Keqing Shi, Liang Shi, Yuanjin Zhao. Porous hydrogel arrays for hepatoma cell spheroid formation and drug resistance investigation[J]. Journal of Zhejiang University Science D, 2021, 4(4): 842-850.

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author="Xin Lei, Changmin Shao, Xin Shou, Keqing Shi, Liang Shi, Yuanjin Zhao",
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Abstract: 
drug resistance is one of the major obstacles in the drug therapy of cancers. Eforts in this area in pre-clinical research have focused on developing novel platforms to evaluate and decrease drug resistance. In this paper, inspired by the structure of hives where swarms live and breed, we propose porous hydrogel arrays with a uniform pore structure for the generation of hepatoma cell spheroids and the investigation of drug resistance. The porous hydrogel arrays were fabricated using polyethylene glycol diacrylate (PEGDA) hydrogel to negatively replicate a well-designed template. Benefting from the elaborate processing of the template, the prepared porous hydrogel arrays possessed a uniform pore structure. Due to their anti-adhesion properties and the excellent biocompatibility of the PEGDA hydrogel, the hepatoma cells could form well-defned and uniform hepatoma cell spheroids in the porous hydrogel arrays. We found that the resistant hepatoma cell spheroids showed more signifcant Lenvatinib resistance and a migratory phenotype compared with a two-dimensional (2D) cell culture, which reveals the reason for the failure of most 2D cell-selected drugs for in vivo applications. These features give such porous hydrogel arrays promising application prospects in the investigation of tumor cell spheroid culture and in vitro drug resistance.

南京大学鼓楼医院赵远锦等 | 多孔水凝胶阵列用于肝癌细胞球体形成及耐药性研究

本研究论文聚焦多孔水凝胶阵列用于肝癌细胞球体形成及耐药性研究。耐药是影响肿瘤化疗疗效最大的障碍。尽管肿瘤治疗取得了很大进展,但这一问题仍然普遍存在。为了提高对化疗药物治疗的反应性,已开发了多种用于耐药性研究的体外模型和平台。近年来3D细胞球体的培养方法取得突飞猛进的发展,尤其以水凝胶为代表的仿生材料因其具有优良的仿生微环境,被广泛用于细胞球体的培养。受蜂群生活和繁殖的蜂巢结构的启发,本文作者借助PEGDA水凝胶构建多孔水凝胶阵列用于培养肝癌细胞球体。研究结果发现在多孔水凝胶阵列中形成了大量致密、清晰的3D肝癌细胞球体,所建立的细胞球体大小均一且形态完整,接近体内实体瘤的形态。同时,与传统2D培养的细胞相比,肝癌亲本和耐药细胞产生的3D细胞球体对仑伐替尼的耐药性和迁移能力显著增加。此外,与2D模型相比,3D模型中P-gp蛋白表达水平显著升高,E-cadherin蛋白表达水平明显降低;更有趣的是,在仑伐替尼治疗48小时后,3D模型中P-gp蛋白表达水平下降,E-cadherin蛋白表达增加。而在2D模型中,只有P-gp的表达下降,这证实了3D模型在耐药性研究中的优越性。我们相信,本研究设计制备的多孔水凝胶阵列将有助于开发各种类型的三维组织模型,并为研究体外药物试验提供一个有价值的平台,在肿瘤细胞球体培养和体外耐药研究中具有广阔的应用前景。

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