Biomimetic design of human induced pluripotent stem cells on a chip

描述（由申请人提供）：在美国，肝脏相关疾病是发病率和死亡率的主要原因。美国每年约有40，000人死于急性或慢性肝病。肝组织工程已经在建立用于药物筛选的体外肝模型以及用于药物筛选的体内构建体方面取得了重大进展。 解决了对移植来源的大量临床需求。然而，细胞来源仍然是体内和体外肝脏模型的重大挑战。人类诱导多能干细胞（iPSC）是再生医学中一项很有前途的技术，因为它们可以自体来源，保持高增殖能力，并表现出巨大的分化潜力，同时还减轻了与使用胚胎干细胞（ESC）相关的伦理问题。然而，iPSCs在体外功能性组织模型中的应用仍在很大程度上处于开发中，用于体内移植的组织工程化构建体尚未完全实现。为了解决这些具有挑战性的问题，我们建议通过使用新型3D生物打印技术封装预分化的iPSC来开发功能性体外微肝模型。该模型随后将通过添加生理相关组分（即与支持细胞共培养）来增强，以提供可以进一步研究的先进的肝芯片模型。将系统地检查肝脏芯片模型的肝脏相关功能。在具体目标1中，我们将通过将iPSC衍生的肝祖细胞封装在3D仿生支架内来开发肝脏芯片模型。在具体目标2中，我们建议将生物学相关的支持细胞类型并入肝脏中。 片上模型。为了实现我们的目标，我们聚集了三位专家的合作人才，包括生物制造和组织工程的Chen，iPSCs的Wang和肝细胞功能和肝脏生物学的Feng。我们设想，我们的患者特异性肝芯片模型可以作为一个可靠的和具有成本效益的体外平台，以促进药物代谢研究，临床前药物筛选和基础肝病学研究。

DESCRIPTION (provided by applicant): In the U.S., liver associated diseases are major contributors to morbidity and mortality. Approximately 40,000 people in the U.S. die each year from acute or chronic liver diseases. Liver tissue engineering has made significant progress towards the creation of in vitro liver models for drug screening, as well as in vivo constructs for addressing the large clinical need for transplant sources. However, cell sourcing remains a significant challenge for both in vivo and in vitro liver models. Human induced pluripotent stem cells (iPSCs) are a promising technology in regenerative medicine as they can be autologously derived, maintain high proliferative capacity, and demonstrate enormous differentiation potential, while also mitigating the ethical concerns associated with the use of embryonic stem cells (ESCs). However, the application of iPSCs towards functional in vitro tissue models is still largely under development, and tissue-engineered constructs for in vivo transplantation have yet to be fully realized. To address these challenging issues, we propose to develop a functional in vitro micro-liver model via encapsulation of pre-differentiated iPSCs using a novel 3D bioprinting technique. This model will be subsequently enhanced through the addition of physiologically related components (i.e. co-cultures with supportive cells) to provide an advanced liver-on-a-chip model that can be studied further. The liver associated functions of the liver-on-a-chip models will be systematically examined. In Specific Aim 1, we will develop a liver-on-a-chip model by encapsulating iPSC-derived hepatic progenitor cells within 3D biomimetic scaffolds. In Specific Aim 2, we propose to incorporate biologically related supportive cell types into the liver on-a-chip model. To accomplish our goal, we have assembled the collaborative talents of three experts, including Chen for biofabrication and tissue engineering, Wang for iPSCs, and Feng for hepatocellular function and liver biology. We envision that our patient specific liver-on-a chip model can be explored as a reliable and cost-efficient in vitro platform to facilitate drug metabolism studies, preclinical drug screening, and fundamental hepatology research.