Collaborative Research: Mimicking Stress-Mediated Invasive Solid Tumor Using Bioprinted Microtissue and Acoustofluidics

在实体肿瘤中，化学和物理信号导致癌细胞侵入附近的组织和血管系统。一个众所周知的物理信号是肿瘤区域的间质液体压力，现有的肿瘤模型很难调节这样的体积压力。众所周知，高间质压力的肿瘤区域通常会抵抗抗癌药物和治疗药物的输送。这个项目的目标是创造和研究间质压力如何在仿生(生物模拟)肿瘤模型中调节肿瘤细胞的反应。将使用生物打印技术和水凝胶工程来构建模型。肿瘤微环境将通过控制细胞球体的形成来引入。物理力将由声波诱导，并将研究它们在药物质量传输和肿瘤细胞转移行为中的作用。这种模式的成功开发将代表着癌症社区的范式转变，它将改善患者的生活质量，潜在地延长生存时间，并开辟新的临床试验来测试各种新药配方。教育目标是扩大代表不足的少数群体在STEM领域的参与。这将通过各种教育活动来实现，将研究纳入本科生的基于项目的教育活动，并为人数不足的学生进行暑期实习。肿瘤微环境(TME)是高度复杂的，具有独特的细胞外基质成分和泄漏的血管，调节肿瘤细胞的成瘤功能。研究人员假设，声学驱动、流体诱导压力、水凝胶生物印迹和理论模拟可以用于复制TME相关的压力梯度和肿瘤细胞侵袭行为的低氧条件。提出了一种在细胞微组织模型中利用声场来调节生物物理压力的新方法。将开发一种装有肿瘤球体的微流控设备，配备叉指换能器，产生表面声波，并用于验证这一假设。通过数字光处理生物打印，该项目旨在创建具有硬度和孔径大小空间梯度的高分辨率血管微组织。然后，将产生大范围的声场(在兆赫范围内)，以在肿瘤球体上诱导压力场，并表征肿瘤细胞的侵袭标记。最后，将开发一种多物理理论和数值方法来帮助量化流体饱和的孔弹性环境中声辐射力的变化并估计诱导压力场。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

In solid tumors, chemical and physical signals lead to cancer cells invading nearby tissue and vascularized systems. A well-known physical signal is the interstitial fluid pressure in the tumor region, and existing tumor models have difficulties regulating such a volumetric pressure. It is known that tumor regions with high interstitial pressure typically resist the delivery of the anti-cancer drugs and therapeutics. The goal of this project is to create and study how interstitial pressure can regulate the tumor cell response in a biomimetic (biology mimicking) tumor model. Bioprinting technology and hydrogel engineering will be used to construct the model. The tumor microenvironment will be introduced using the controlled formation of cell spheroids. Physical forces will be induced by acoustic waves, and their role in drug mass transport and the metastatic behavior of tumor cells will be studied. Successful development of such a model will represent a paradigm shift in the cancer community by improving patients’ quality of life, potentially prolonging survival, and opening up new clinical trials to test various new drug formulations. The educational objective is to broaden the participation of underrepresented minorities in STEM fields. This will be accomplished through various educational activities by integrating the research into project-based educational activities for undergraduate students and summer internships for underrepresented students. The tumor microenvironment (TME) is highly complex, with a distinct extracellular matrix composition and leaky vasculature that regulate the tumorigenic function of tumor cells. The investigators hypothesize that acoustic-driven, flow-induced pressure, hydrogel bioprinting, and theoretical simulation could be employed to replicate TME-associated pressure gradients and hypoxic conditions for an invasion behavior in tumor cells. A novel way is proposed for regulating biophysical pressure using the acoustic field in cell-laden microtissue models. A tumor-spheroid-laden microfluidic device equipped with interdigital transducers that generate surface acoustic waves will be developed and used to test the hypothesis. Through digital light processing bioprinting, the project aims to create a high-resolution vascular microtissue with spatial gradients of stiffness and pore sizes. Then, a wide range of acoustic fields (in the megahertz regime) will be made to induce pressure fields onto the tumor spheroids and characterize the tumor cells' invasion markers. Finally, a multi-physics theoretical and numerical approach will be developed to help quantify the variation of acoustic radiation forces within a fluid-saturated poroelastic environment and estimate the induced pressure field.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.