Microfluidic Platform For Biomimetic Construction Of Toxicology Evaluation System And Applications

Pharmaceutical development is greatly hindered by the poor predictive power of existing in vitro models for drug efficacy and toxicity testing.It has resulted in numerous clinical trial failures and high drug development costs.The rapid development of microfluidic technology may provide a good solution to simulate the complex in vivo-like physical environment in vitro.It may provide a promising and cost-effective alternative in vitro method for drug testing and development.In this study,we take the microfluidics as the key technology to present a series of functional microfluidic organ models,providing a new way for toxicology evaluation.The detailed work in this thesis includes:First,we developed a glomerular model to examine Cd-induced nephrotoxicity.Cd induced significant cytotoxicity and increased the permeability of the endothelial layer to large molecules in a dose-dependent manner.The model enables direct visualization and quantitative analysis of endothelial responses to Cd in real time.It may provide a micro-scale platform for nephrotoxicity testing under varying environmental exposure.Second,we present a novel integrated liver-kidney chip that facilitates the evaluation of drug-induced nephrotoxicity following liver metabolism.Ifosfamide and verapamil were used as drug models and the metabolites triggered significantly distinct nephrotoxic effects.This in vitro model is simple and scalable,and maybe widely applicable to the evaluation of drug metabolism and safety during the early phases of drug developmentThird,we presented a novel intestine-kidney chip,which recapitulated drug absorption in the intestine and its resultant drug toxicity on the kidney.In agreement with clinical observations,our data demonstrated that DIG-induced nephrotoxicity was enhanced combined with VER but weakened with COL.All of these findings suggest that the established microdevice might provide a useful and cost-effective platform in vitro for testing drug absorption and nephrotoxicity in preclinical trials during new drug development.Final,we proposed a new and multilayer organs-on-a-chipdevice that allows for the assessment of drug metabolism,and its resultant drug efficacy and cytotoxicity in different organ-specific cells simultaneously.CAP exhibited strong cytoxicity on breast cancer and lung cancer cells,but not in normal gastric cells,which suggesting the metabolism-dependent drug efficacy in different tissues as exisits in vivo.This in vitro model facilitate the assessment of drug bioactivity on various target tissues in a simple way,indicating the utility of this model for applications in drug efficacy and toxicity testing.