ABSTRACT
A functional, multi-organ, serum-free system was developed for the culture of P. falciparum in an attempt to establish innovative platforms for therapeutic drug development. It contains 4 human organ constructs including hepatocytes, splenocytes, endothelial cells, as well as recirculating red blood cells which allow for infection with the parasite. Two strains of P. falciparum were used: the 3D7 strain, which is sensitive to chloroquine; and the W2 strain, which is resistant to chloroquine. The maintenance of functional cells was successfully demonstrated both in healthy and diseased conditions for 7 days in the recirculating microfluidic model. To demonstrate an effective platform for therapeutic development, systems infected with the 3D7 strain were treated with chloroquine which significantly decreased parasitemia, with recrudescence observed after 5 days. Conversely, when the W2 systems were dosed with chloroquine, parasitemia levels were moderately decreased when compared to the 3D7 model. The system also allows for the concurrent evaluation of off-target toxicity for the anti-malarial treatment in a dose dependent manner which indicates this model could be utilized for therapeutic index determination. The work described here establishes a new approach to the evaluation of anti-malarial therapeutics in a realistic human model with recirculating blood cells for 7 days.
Subject(s)
Antimalarials , Malaria, Falciparum , Malaria , Humans , Antimalarials/pharmacology , Endothelial Cells , Parasitemia/drug therapy , Malaria/drug therapy , Chloroquine/pharmacology , Malaria, Falciparum/drug therapy , Lab-On-A-Chip DevicesABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and strongly correlates with the growing incidence of obesity and type II diabetes. We have developed a human-on-a-chip model composed of human hepatocytes and adipose tissue chambers capable of modeling the metabolic factors that contribute to liver disease development and progression, and evaluation of the therapeutic metformin. This model uses a serum-free, recirculating medium tailored to represent different human metabolic conditions over a 14-day period. The system validated the indirect influence of adipocyte physiology on hepatocytes that modeled important aspects of NAFLD progression, including insulin resistant biomarkers, differential adipokine signaling in different media and increased TNF-α-induced steatosis observed only in the two-tissue model. This model provides a simple but unique platform to evaluate aspects of an individual factor's contribution to NAFLD development and mechanisms as well as evaluate preclinical drug efficacy and reassess human dosing regimens.
Subject(s)
Adipocytes/drug effects , Drug Discovery/instrumentation , Hepatocytes/drug effects , Hypoglycemic Agents/pharmacology , Lab-On-A-Chip Devices , Metformin/pharmacology , Non-alcoholic Fatty Liver Disease/drug therapy , Adipocytes/metabolism , Adipose Tissue, White/cytology , Cell Communication , Cells, Cultured , Culture Media/pharmacology , Culture Media, Serum-Free/pharmacology , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP3A/metabolism , Equipment Design , Fatty Acids/metabolism , Fatty Acids/pharmacology , Glucose/pharmacology , Hepatocytes/metabolism , Humans , Inflammation , Insulin/pharmacology , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
A piezoelectric biomedical microelectromechanical system (bioMEMS) cantilever device was designed and fabricated to act as either a sensing element for muscle tissue contraction or as an actuator to apply mechanical force to cells. The sensing ability of the piezoelectric cantilevers was shown by monitoring the electrical signal generated from the piezoelectric aluminum nitride in response to the contraction of iPSC-derived cardiomyocytes cultured on the piezoelectric cantilevers. Actuation was demonstrated by applying electrical pulses to the piezoelectric cantilever and observing bending via an optical detection method. This piezoelectric cantilever device was designed to be incorporated into body-on-a-chip systems.
