Microfluidic Droplet-Assisted Fabrication of Vessel-Supported Tumors for Preclinical Drug Discovery.
Microfluidic Droplet-Assisted Fabrication of Vessel-Supported Tumors for Preclinical Drug Discovery.
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DOI：
10.1021/acsami.2c23305
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发表时间：
2023-03-29
影响因子：
9.5
通讯作者：
Liu, Yaling
中科院分区：
文献类型：
--
作者：
Wu, Yue;Zhao, Yuwen;Zhou, Yuyuan;Islam, Khayrul;Liu, Yaling
关键词：
高保真的体外肿瘤模型对于临床前药物发现过程是重要的。目前，最常用的体外药物测试模型仍然是二维（2D）细胞单层。然而，天然的体内肿瘤微环境（TME）由细胞外基质（ECM）、支持基质细胞和血管系统组成。它们不仅参与肿瘤的进展，而且阻碍药物递送和对肿瘤细胞的有效性。在这里，我们报告了一个集成的工程系统，以产生血管支持的肿瘤临床前药物筛选。首先，选择明胶-甲基丙烯酰（GelMA）水凝胶来模拟肿瘤细胞外基质（ECM）。采用微流控液滴技术将HCT-116肿瘤细胞包封到单个微GelMA珠中，以模拟体外肿瘤-ECM相互作用。然后，将正常人肺成纤维细胞与肿瘤细胞混合以模拟肿瘤-基质相互作用。肿瘤细胞和成纤维细胞在单个GelMA微珠中重构，形成具有核-壳结构的仿生异型肿瘤模型。接下来，将载有细胞的珠粒结合成功能性芯片上血管网络平台，以恢复肿瘤-肿瘤微环境（TME）相互作用。之后，抗癌药物紫杉醇在个体和血管支持的肿瘤模型上进行了测试。在药物筛选实验中证明，血管相关的TME赋予显著的额外耐药性。所报道的系统有望实现各种细胞组成的血管支持异型肿瘤模型的大规模制造。它被认为是有前途的大规模制造仿生体外肿瘤模型，并可能是有价值的，以提高效率的临床前药物发现过程。
High-fidelity in vitro tumor models are important for preclinical drug discovery processes. Currently, the most commonly used model for in vitro drug testing remains the two-dimensional (2D) cell monolayer. However, the natural in vivo tumor microenvironment (TME) consists of extracellular matrix (ECM), supporting stromal cells and vasculature. They not only participate in the progression of tumors but also hinder drug delivery and effectiveness on tumor cells. Here, we report an integrated engineering system to generate vessel-supported tumors for preclinical drug screening. First, gelatin-methacryloyl (GelMA) hydrogel was selected to mimic tumor extracellular matrix (ECM). HCT-116 tumor cells were encapsulated into individual micro-GelMA beads with microfluidic droplet technique to mimic tumor–ECM interactions in vitro. Then, normal human lung fibroblasts were mingled with tumor cells to imitate the tumor–stromal interaction. The tumor cells and fibroblasts reconstituted in the individual GelMA microbead and formed a biomimetic heterotypic tumor model with a core–shell structure. Next, the cell-laden beads were consociated into a functional on-chip vessel network platform to restore the tumor–tumor microenvironment (TME) interaction. Afterward, the anticancer drug paclitaxel was tested on the individual and vessel-supported tumor models. It was demonstrated that the blood vessel-associated TME conferred significant additional drug resistance in the drug screening experiment. The reported system is expected to enable the large-scale fabrication of vessel-supported heterotypic tumor models of various cellular compositions. It is believed to be promising for the large-scale fabrication of biomimetic in vitro tumor models and may be valuable for improving the efficiency of preclinical drug discovery processes.
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DOI：
10.1016/j.mattod.2015.05.002
发表时间：
2015-12
期刊：
Materials today (Kidlington, England)
影响因子：
--
作者：
Asghar W;El Assal R;Shafiee H;Pitteri S;Paulmurugan R;Demirci U
通讯作者：
Demirci U
影响因子：
17.1
作者：
Agarwal P;Wang H;Sun M;Xu J;Zhao S;Liu Z;Gooch KJ;Zhao Y;Lu X;He X
通讯作者：
He X
影响因子：
14
作者：
Hajal C;Ibrahim L;Serrano JC;Offeddu GS;Kamm RD
通讯作者：
Kamm RD
影响因子：
3.5
作者：
Chen, Keke;Sui, Chenxi;Guo, Feng
通讯作者：
Guo, Feng
影响因子：
6.8
作者：
Gonzalez-Estefan, Juan H.;Gonidec, Mathieu;Chastanet, Guillaume
通讯作者：
Chastanet, Guillaume