Tricinci Omar, De Pasquale Daniele, Marino Attilio, Battaglini Matteo, Pucci Carlotta, Ciofani Gianni
Smart Bio-Interfaces, Istituto Italiano di Tecnologia, Viale Rinaldo Piaggio 34, Pontedera 56025, Italy.
Adv Mater Technol. 2020 Aug 23;5(10):2000540. doi: 10.1002/admt.202000540. eCollection 2020 Oct.
The modeling of the pathological microenvironment of the central nervous system (CNS) represents a disrupting approach for drug screening for advanced therapies against tumors and neuronal disorders. The in vitro investigations of the crossing and diffusion of drugs through the blood-brain barrier (BBB) are still not completely reliable, due to technological limits in the replication of 3D microstructures that can faithfully mimic the in vivo scenario. Here, an innovative 1:1 scale 3D-printed realistic biohybrid model of the brain tumor microenvironment, with both luminal and parenchyma compartments, is presented. The dynamically controllable microfluidic device, fabricated through two-photon lithography, enables the triple co-culture of hCMEC/D3 cells, forming the internal biohybrid endothelium of the capillaries, of astrocytes, and of magnetically-driven spheroids of U87 glioblastoma cells. Tumor spheroids are obtained from culturing glioblas-toma cells inside 3D microcages loaded with superparamagnetic iron oxide nanoparticles (SPIONs). The system proves to be capable in hindering dextran diffusion through the bioinspired BBB, while allowing chemotherapy-loaded nanocarriers to cross it. The proper formation of the selective barrier and the good performance of the anti-tumor treatment demonstrate that the proposed device can be successfully exploited as a realistic in vitro model for high-throughput drug screening in CNS diseases.
中枢神经系统（CNS）病理微环境的建模是一种用于针对肿瘤和神经疾病的先进疗法进行药物筛选的突破性方法。由于在复制能够忠实地模拟体内情况的三维微观结构方面存在技术限制，药物通过血脑屏障（BBB）的穿越和扩散的体外研究仍然不完全可靠。在此，提出了一种创新的1:1比例的脑肿瘤微环境三维打印逼真生物杂交模型，该模型具有管腔和实质区室。通过双光子光刻制造的动态可控微流控装置能够实现hCMEC/D3细胞、星形胶质细胞以及U87胶质母细胞瘤细胞的磁性驱动球体的三重共培养，hCMEC/D3细胞形成毛细血管的内部生物杂交内皮。肿瘤球体是通过在装载有超顺磁性氧化铁纳米颗粒（SPIONs）的三维微笼中培养胶质母细胞瘤细胞获得的。该系统被证明能够阻碍葡聚糖通过仿生血脑屏障的扩散，同时允许载有化疗药物的纳米载体穿过它。选择性屏障的正确形成和抗肿瘤治疗的良好性能表明，所提出的装置可以成功地用作中枢神经系统疾病高通量药物筛选的逼真体外模型。
