We produced a novel three-dimensional (3D) bone tumor model (BTM) to study the interactions between healthy and tumor cells in a tumor microenvironment, the migration tendency of the tumor cells, and the efficacy of an anticancer drug, Doxorubicin, on the cancer cells. The model consisted of two compartments: (a) a healthy bone tissue mimic, made of poly(lactic acid-co-glycolic acid) (PLGA)/beta-tricalcium phosphate (β-TCP) sponge seeded with human fetal osteoblastic cells (hFOB) and human umbilical vein endothelial cells (HUVECs), and (b) a tumor mimic, made of lyophilized collagen sponge seeded with human osteosarcoma cells (Saos-2). The tumor mimic component was placed into a central cavity created in the healthy bone mimic and together they constituted the complete 3D bone tumor model (3D-BTM). The porosities of both sponges were higher than 85% and the diameters of the pores were 199 ± 52 μm for the PLGA/TCP and 50-150 μm for the collagen scaffolds. The compression Young's modulus of the PLGA/TCP and the collagen sponges were determined to be 4.76 MPa and 140 kPa, respectively. Cell proliferation, morphology, calcium phosphate forming capacity and alkaline phosphatase production were studied separately on both the healthy and tumor mimics. All cells demonstrated cellular extensions and spread well in porous scaffolds indicating good cell-material interactions. Confocal microscopy analysis showed direct contact between the cells present in different parts of the 3D-BTM. Migration of HUVECs from the healthy bone mimic to the tumor compartment was confirmed by the increase in the levels of angiogenic factors vascular endothelial growth factor, basic fibroblast growth factor, and interleukin 8 in the tumor component. Doxorubicin (2.7 μg.ml-1) administered to the 3D-BTM caused a seven-fold decrease in the cell number after 24 h of interaction with the anticancer drug. Caspase-3 enzyme activity assay results demonstrated apoptosis of the osteosarcoma cells. This novel 3D-BTM has a high potential for use in studying the metastatic capabilities of cancer cells, and in determining the effective drug types and combinations for personalized treatments.

中文翻译：

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两室骨肿瘤模型，用于研究健康细胞与肿瘤细胞之间的相互作用。

我们制作了一种新型的三维（3D）骨肿瘤模型（BTM），以研究肿瘤微环境中健康细胞与肿瘤细胞之间的相互作用，肿瘤细胞的迁移趋势以及抗癌药物阿霉素的作用。癌细胞。该模型由两个部分组成：（a）一种健康的骨组织模拟物，由植入人胎儿成骨细胞（hFOB）的聚乳酸-乙醇酸（PLGA）/β-磷酸三钙（β-TCP）海绵制成）和人脐静脉内皮细胞（HUVEC），以及（b）一种肿瘤模拟物，由冻干的胶原海绵制成，并植入人骨肉瘤细胞（Saos-2）。将肿瘤模拟成分放入健康的骨骼模拟物中创建的中央腔中，它们共同构成了完整的3D骨肿瘤模型（3D-BTM）。两种海绵的孔隙率均高于85％，PLGA / TCP的孔直径为199±52μm，胶原蛋白支架的孔直径为50-150μm。测定PLGA / TCP和胶原海绵的压缩杨氏模量分别为4.76MPa和140kPa。在健康和肿瘤模拟物上分别研究了细胞增殖，形态，磷酸钙形成能力和碱性磷酸酶产生。所有细胞均表现出细胞扩展并在多孔支架中良好散布，表明良好的细胞材料相互作用。共聚焦显微镜分析表明存在于3D-BTM不同部分的细胞之间直接接触。HUVEC从健康的骨模拟物向肿瘤区隔的迁移通过肿瘤成分中血管生成因子，血管内皮生长因子，碱性成纤维细胞生长因子和白介素8含量的增加来证实。与抗癌药相互作用24小时后，向3D-BTM给药的阿霉素（2.7μg.ml-1）导致细胞数量减少了7倍。Caspase-3酶活性测定结果表明骨肉瘤细胞凋亡。这种新颖的3D-BTM在研究癌细胞的转移能力以及确定有效的药物类型和个性化治疗组合方面具有很高的潜力。与抗癌药相互作用24小时后，给予3D-BTM的ml-1）导致细胞数量减少了7倍。Caspase-3酶活性测定结果表明骨肉瘤细胞凋亡。这种新颖的3D-BTM在研究癌细胞的转移能力以及确定有效的药物类型和个性化治疗组合方面具有很高的潜力。与抗癌药相互作用24小时后，给予3D-BTM的ml-1）导致细胞数量减少了7倍。Caspase-3酶活性测定结果表明骨肉瘤细胞凋亡。这种新颖的3D-BTM具有很高的潜力，可用于研究癌细胞的转移能力，以及确定个性化治疗的有效药物类型和组合。