Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
Sci Rep. 2017 Mar 31;7:45424. doi: 10.1038/srep45424.
The malaria liver stage is an attractive target for antimalarial development, and preclinical malaria models are essential for testing such candidates. Given ethical concerns and costs associated with non-human primate models, humanized mouse models containing chimeric human livers offer a valuable alternative as small animal models of liver stage human malaria. The best available human liver chimeric mice rely on cellular transplantation into mice with genetically engineered liver injury, but these systems involve a long and variable humanization process, are expensive, and require the use of breeding-challenged mouse strains which are not widely accessible. We previously incorporated primary human hepatocytes into engineered polyethylene glycol (PEG)-based nanoporous human ectopic artificial livers (HEALs), implanted them in mice without liver injury, and rapidly generated human liver chimeric mice in a reproducible and scalable fashion. By re-designing the PEG scaffold to be macroporous, we demonstrate the facile fabrication of implantable porous HEALs that support liver stage human malaria (P. falciparum) infection in vitro, and also after implantation in mice with normal liver function, 60% of the time. This proof-of-concept study demonstrates the feasibility of applying a tissue engineering strategy towards the development of scalable preclinical models of liver stage malaria infection for future applications.
疟原虫肝期是抗疟药物开发的一个有吸引力的靶点，临床前疟疾模型对于测试这些候选药物至关重要。鉴于非人类灵长类动物模型存在伦理问题和成本，含有嵌合人肝脏的人源化小鼠模型作为肝期人类疟疾的小型动物模型提供了一个有价值的替代方案。目前最好的人肝嵌合小鼠依赖于将细胞移植到具有基因工程肝损伤的小鼠中，但这些系统涉及漫长且可变的人源化过程，成本高昂，并且需要使用广泛无法获得的具有繁殖挑战的小鼠品系。我们之前将原代人肝细胞整合到工程化的聚乙二醇（PEG）基纳米多孔人异位人工肝脏（HEAL）中，在没有肝损伤的小鼠中植入它们，并以可重复和可扩展的方式快速生成人肝嵌合小鼠。通过重新设计 PEG 支架为大孔，我们证明了可植入多孔 HEAL 的简便制造，该支架支持体外肝期人类疟疾（疟原虫）感染，并且在正常肝功能的小鼠中植入后，60%的时间也支持感染。这项概念验证研究证明了应用组织工程策略开发可扩展的肝期疟疾感染临床前模型的可行性，以用于未来的应用。
