Nguyen Huu Tuan, Tirpakova Zuzana, Peirsman Arne, Maity Surjendu, Falcone Natashya, Kawakita Satoru, Jeon Keuna, Khorsandi Danial, Rashad Ahmad, Farhadi Neda, Mandal Kalpana, Ermis Menekse, Herculano Rondinelli Donizetti, Najafabadi Alireza Hassani, Dokmeci Mehmet Remzi, De Barros Natan Roberto, Khademhosseini Ali, Jucaud Vadim
Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90064, United States of America.
Department of Biology and Physiology, University of Veterinary Medicine and Pharmacy in Kosice, Komenskeho 73, 04181 Kosice, Slovakia.
Biofabrication. 2025 Sep 29;17(4). doi: 10.1088/1758-5090/adfbc3.
Blood vessel embolization is a well-established treatment modality for liver cancer. Novel shear-thinning hydrogels (STH) have been developed to address the need for safer and more effective local delivery of embolic agents and therapeutics. However, embolization therapies are currently optimized in animal models, which often differ from humans at the cellular, tissue, and organ levels. We aim to evaluate the efficacy of novel embolic agents such as STH using a human-relevantmodel that recapitulates human hepatocellular carcinoma capillary networks. A vascularized human liver-tumor-on-a-chip model was developed to assess embolic agent performance. The effects of drug-eluting STH (DESTH) on tumor cell viability, surface marker expression, vasculature morphology, and cytokine responses were evaluated. To study the effects of embolization on microvasculature morphology independent of the chemotherapy compound, we evaluated the effect of different drug-free embolic agents on the vascular tumor microenvironment under flow conditions. DESTH treatment induced tumor cell death, downregulated the expression of epithelial cell adhesion molecules in HepG2, increased levels of cytokines such as interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor, and vascular endothelial growth factor, and decreased albumin secretion. Furthermore, different embolic agents exert distinct effects on microvascular morphology, with STH causing complete regression of the microvascular networks. This vascularized liver tumor-on-a-chip model enables human-relevant, real-time assessment of embolic agent efficacy and vascular response and can be applied for the development of innovative and effective embolization therapies for liver cancer.
血管栓塞是一种成熟的肝癌治疗方式。新型剪切变稀水凝胶（STH）已被开发出来，以满足更安全、更有效地局部递送栓塞剂和治疗药物的需求。然而，栓塞疗法目前在动物模型中得到优化，而动物模型在细胞、组织和器官水平上往往与人类不同。我们旨在使用一种模拟人类肝细胞癌毛细血管网络的与人类相关的模型来评估新型栓塞剂（如STH）的疗效。我们开发了一种血管化的人源芯片上肝肿瘤模型来评估栓塞剂的性能。评估了载药STH（DESTH）对肿瘤细胞活力、表面标志物表达、血管形态和细胞因子反应的影响。为了研究栓塞对微血管形态的影响而不考虑化疗化合物，我们评估了不同的无药栓塞剂在流动条件下对肿瘤血管微环境的影响。DESTH治疗诱导肿瘤细胞死亡，下调HepG2中上皮细胞粘附分子的表达，增加白细胞介素-4（IL-4）、粒细胞-巨噬细胞集落刺激因子和血管内皮生长因子等细胞因子的水平，并减少白蛋白分泌。此外，不同的栓塞剂对微血管形态有不同的影响，STH可导致微血管网络完全消退。这种血管化的芯片上肝肿瘤模型能够对栓塞剂疗效和血管反应进行与人类相关的实时评估，并可用于开发创新有效的肝癌栓塞疗法。
