Microfluidic Liver Array for Drug Metabolite Profiling

描述(由申请人提供)：Cellasic已经开发出一种新的微流控技术，将32个生物反应器集成在一个标准的96孔板上，用于对具有长期活性和肝酶功能的原代人类肝细胞进行多重灌流培养。这一阶段的SBIR将利用这项技术开发和验证肝脏特异性药物代谢物图谱的体外筛选平台。模型化合物将用于评估代谢活动，通过LC-MS/MS与我们在BD Biosciences的合作者进行分析。一旦验证完成，该公司就可以迅速将产品推向市场。在过去的十年里，随着人们认识到药物代谢与药物安全性密切相关，利用原代人肝细胞进行药物代谢谱分析变得越来越重要。FDA最近发布了关于药物相互作用测试以及药物代谢物药物安全性测试的指南。此外，在美国和欧洲，减少动物试验和开发改进的体外技术的运动也很强烈。然而，最先进的体外药物代谢模型只能预测大约50%的体内代谢物，部分原因是原代肝细胞在培养过程中迅速降解，失去了肝酶功能。 与公共健康相关：Cellasic正在开发一种微流控肝脏阵列(MLA)系统，该系统将使生物制药公司能够在临床和动物研究之前更准确地预测新药化合物对人体肝脏的不利影响。主要好处包括临床药物更安全，降低每个数据点的成本，在早期阶段获得更多临床相关数据，减少对动物试验的依赖，以及提高对毒性机制的理解。

DESCRIPTION (provided by applicant): CellASIC has developed a novel microfluidic technology to integrate 32 bioreactors on a standard 96-well plate for multiplexed perfusion culture of primary human hepatocytes with demonstrated long-term viability and liver-enzymatic function. This Phase 1 SBIR will utilize this technology to develop and validate an in vitro screening platform for liver-specific drug metabolite profiling. Model compounds will be used to assess metabolic activities, with analysis via LC-MS/MS with our collaborators at BD Biosciences. Once the validation is complete, the company positioned to quickly make the product available to the marketplace. Drug metabolite profiling using primary human hepatocytes has gained more importance in the past decade as it has become recognized that drug metabolism is closely related to drug safety. The FDA has recently issued guidance on drug-drug interaction tests as well as drug safety testing of drug metabolites. Additionally, there is a strong movement in the US as well as in Europe to reduce animal trials and develop improved in vitro technologies. However, the state-of-the-art in vitro drug metabolism models only predict around 50% of the in vivo metabolites, partly because primary hepatocytes rapidly degrade in culture and lose their liver-enzymatic functions. PUBLIC HEALTH RELEVANCE: CellASIC is developing a microfluidic liver array (MLA) system that will allow biopharmaceutical companies to more accurately predict the adverse effects of new drug compounds on human liver prior to clinical and animal studies. Key benefits include safer drugs in the clinic, reduced cost per data point, more clinically relevant data at an earlier stage, reduced reliance on animal testing, and improved understanding of toxicity mechanisms.