ABSTRACT
The drug development pipeline is severely limited by a lack of reliable tools for prediction of human clinical safety and efficacy profiles for compounds at the pre-clinical stage. Here we present the design and implementation of a platform technology comprising multiple human cell-based tissue models in a portable and reconfigurable format that supports individual organ function and crosstalk for periods of up to several weeks. Organ perfusion and crosstalk are enabled by a precision flow control technology based on electromagnetic actuators embedded in an arrayed format on a microfluidic platform. We demonstrate two parallel circuits of connected airway and liver modules on a platform containing 62 electromagnetic microactuators, with precise and controlled flow rates as well as functional biological metrics over a two week time course. Technical advancements enabled by this platform include the use of non-sorptive construction materials, enhanced scalability, portability, flow control, and usability relative to conventional flow control modes (such as capillary action, pressure heads, or pneumatic air lines), and a reconfigurable and modular organ model format with common fluidic port architecture. We demonstrate stable biological function for multiple pairs of airway-liver models for periods of 2 weeks in the platform, with precise control over fluid levels, temperature, flow rate and oxygenation in order to support relevant use cases involving drug toxicity, efficacy testing, and organ-organ interaction.
Subject(s)
Microfluidics/methods , Bronchi/cytology , Cells, Cultured , Coculture Techniques , Cytochrome P-450 CYP3A/metabolism , Drug Discovery , Epithelial Cells/cytology , Epithelial Cells/metabolism , Hepatocytes/cytology , Hepatocytes/metabolism , Humans , Magnetic Fields , Microfluidics/instrumentation , Microscopy, FluorescenceABSTRACT
The purpose of this investigation was to examine the regulation of exercise intensity by using Ratings of Perceived Exertion (RPE). The RPE equivalent to 50% and 70% VO2max was estimated by using standard clinical protocols on a treadmill and cycle ergometer. Subjects then produced the target RPEs on these modalities. Physiological validity of perceptually regulated exercise intensity was determined by comparing VO2 and heart rate between estimation and production trials at the same relative intensity. With one exception, RPE was found to be a valid means of regulating exercise intensity both intra- and intermodally at 50% and 70% VO2max. Perceptual regulation of intramodal treadmill exercise was not valid at 70% VO2max in that both VO2 and heart rate were significantly lower during production than estimation. The present results also indicate that target RPE estimated during a cycle ergometer graded exercise test is more accurate for regulating exercise intensity than when the target RPE is estimated during a treadmill test. The lower accuracy found for treadmill production at the higher exercise intensity may have been caused by the use of a test protocol during the estimation trial that included relatively slow speeds and large inclines. In general, RPE provide a physiologically valid method of regulating exercise intensity.
