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<p>Due to the lack of an intricate microenvironment, in vitro drug testing based on traditional two-dimensional (2D) cell culture models often fails to predict clinical drug response. Three-dimensional (3D) cell spheroids have emerged as a way of recreating the structure and function of human tissues. However, these models have seldom been vascularized, overlooking the complexities of in vivo physiology. This study reports on the simultaneous vascularization of hundreds of cell spheroids using a scalable microfluidic device for predicting drug response. Utilizing a designed gap between two microfluidic layers, endothelial cells were guided to form a microvascular network on the surface of Matrigel matrix-coated microwells. Huh-7 cell spheroids were then loaded onto the vascular bed and covered by another layer of endothelial cells for vascularization. Unlike conventional 2D and 3D cell culture models, these vascularized tumor spheroids exhibited the lenvatinib resistance commonly encountered in the clinical treatment of hepatocellular carcinoma. We demonstrated that vascularization of the tumor spheroids with endothelial cells activated the epidermal growth factor receptor (EGFR) signaling pathway in Huh-7 cells, and further limited the response to lenvatinib. Therefore, the construction of the tumor perivascular microenvironment could reconstitute tumor behavior with improved fidelity for the evaluation of drug response. The microfluidic approach reported here represents a straightforward strategy for the vascularization of cell spheroids in parallel. With elevated physiological relevance and accuracy, these vascularized cell spheroids may bridge the gap between 2D cell monolayers and living tissues, accelerating the drug screening process.</p>

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Upgrading the Physiological Relevance and Accuracy of 3D Cell Spheroids-based Drug Testing Through Massively Parallel Vascularization

  • 期刊论文

  • 发表日期：

    2025年9月25日

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  • Ziyi Li,
  • Xiahe Han,
  • Qiurui Chen,
  • Tao Zhang,
  • Wu Liu

摘要

Due to the lack of an intricate microenvironment, in vitro drug testing based on traditional two-dimensional (2D) cell culture models often fails to predict clinical drug response. Three-dimensional (3D) cell spheroids have emerged as a way of recreating the structure and function of human tissues. However, these models have seldom been vascularized, overlooking the complexities of in vivo physiology. This study reports on the simultaneous vascularization of hundreds of cell spheroids using a scalable microfluidic device for predicting drug response. Utilizing a designed gap between two microfluidic layers, endothelial cells were guided to form a microvascular network on the surface of Matrigel matrix-coated microwells. Huh-7 cell spheroids were then loaded onto the vascular bed and covered by another layer of endothelial cells for vascularization. Unlike conventional 2D and 3D cell culture models, these vascularized tumor spheroids exhibited the lenvatinib resistance commonly encountered in the clinical treatment of hepatocellular carcinoma. We demonstrated that vascularization of the tumor spheroids with endothelial cells activated the epidermal growth factor receptor (EGFR) signaling pathway in Huh-7 cells, and further limited the response to lenvatinib. Therefore, the construction of the tumor perivascular microenvironment could reconstitute tumor behavior with improved fidelity for the evaluation of drug response. The microfluidic approach reported here represents a straightforward strategy for the vascularization of cell spheroids in parallel. With elevated physiological relevance and accuracy, these vascularized cell spheroids may bridge the gap between 2D cell monolayers and living tissues, accelerating the drug screening process.