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

合作研究：利用生物打印微组织和声流控技术模拟压力介导的侵袭性实体瘤

• 批准号: 2243507
• 负责人: Chen Shen
• 金额: $ 18.9万
• 依托单位: Rowan University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2243507&HistoricalAwards=false
• 关键词: Collaborative; Research; Mimicking; Stress; Mediated

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.

在实体瘤中，化学和物理信号导致癌细胞侵入附近的组织和血管系统。众所周知的物理信号是肿瘤区域中的间质流体压力，并且现有的肿瘤模型难以调节这样的体积压力。已知具有高间质压的肿瘤区域通常抵抗抗癌药物和治疗剂的递送。该项目的目标是创建和研究间质压力如何在仿生（生物学模拟）肿瘤模型中调节肿瘤细胞反应。生物打印技术和水凝胶工程将用于构建模型。将使用细胞球状体的受控形成来引入肿瘤微环境。物理力将由声波引起，并将研究它们在药物质量运输和肿瘤细胞转移行为中的作用。这种模型的成功开发将通过改善患者的生活质量，潜在地延长生存期，并开辟新的临床试验来测试各种新的药物制剂，代表癌症社区的范式转变。教育目标是扩大代表性不足的少数群体在STEM领域的参与。这将通过各种教育活动来实现，将研究纳入基于项目的本科生教育活动和代表性不足的学生的暑期实习。肿瘤微环境（TME）是高度复杂的，具有独特的细胞外基质组成和渗漏的血管系统，调节肿瘤细胞的致瘤功能。研究人员假设，声学驱动、流动诱导压力、水凝胶生物打印和理论模拟可以用于复制TME相关的压力梯度和缺氧条件，以实现肿瘤细胞的侵袭行为。提出了一种在载有细胞的微组织模型中使用声场调节生物物理压力的新方法。将开发一种装有叉指换能器的肿瘤球体微流体装置，该叉指换能器产生表面声波，并用于测试该假设。通过数字光处理生物打印，该项目旨在创建具有刚度和孔径空间梯度的高分辨率血管微组织。然后，将产生宽范围的声场（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，将开发一种多物理场理论和数值方法，以帮助量化流体饱和多孔弹性环境中声辐射力的变化，并估计诱导的压力场。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

项目成果

Underwater double vortex generation using 3D printed acoustic lens and field multiplexing

• DOI: 10.1063/5.0201781
• 发表时间: 2024-03
• 期刊: APL Materials
• 影响因子: 6.1
• 作者: Chadi Ellouzi;Ali Zabihi;Farhood Aghdasi;Aidan Kayes;Milton Rivera;Jiaxin Zhong;Amir Miri;Chen Shen