Design and Application of Microfluidic Systems for In Vitro Pharmacokinetic Evaluation of Drug Candidates

Abstract

One of the fundamental challenges facing the development of new chemical entities within the pharmaceutical industry is the extrapolation of key in vivo parameters from in vitro cell culture assays and animal studies. Development of microscale devices and screening assays incorporating primary human cells can potentially provide better, faster and more efficient prediction of in vivo toxicity and clinical drug performance. With this goal in mind, large strides have been made in the area of microfluidics to provide in vitro surrogates that are designed to mimic the physiological architecture and dynamics. More recent advancements have been made in the development of in vitro analogues to physiologically-based pharmacokinetic (PBPK) models – a mathematical model that represents the body as interconnected compartments specific for a particular organ. In this review we highlight recent advancements in human hepatocyte microscale culture, and describe the next generation of integrated devices, whose potential allows for the high throughput assessment of drug metabolism, distribution and pharmacokinetics.

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

“…The microfluidic, body-on-a-chip design (Maguire et al, 2009) has potential for creating custom in vitro toxicity evaluations for multiple cells plated onto different parts of the microfluidic plate. This system requires more development, especially to move from a laboratory research device to low to medium throughput.…”

Molecular Surveillance of Viral Processes Using Silicon Nitride Membranes

“…Triple-layered particles (TLPs) in the supernatant were then pelleted through a 35% (w/v) sucrose cushion in TNC buffer (20 mM Tris-HCl pH 8.0, 100 mM NaCl, 1 mM CaCl) at 133,000 × g for 90 min. TLPs were purified by isopycnic centrifugation in CsCl (density of 1.36 g/cm 3 ) at 137,000 × g for 16 h. Purified TLPs were collected in a 500-μL fraction, dialyzed exhaustively against TNC buffer, and stored at 4 °C. Rotavirus DLPs were created by treating TLPs with 20 mM EDTA followed by purification using isopycnic centrifugation in CsCl (density of 1.38 g/cm 3 ).…”

“…TLPs were purified by isopycnic centrifugation in CsCl (density of 1.36 g/cm 3 ) at 137,000 × g for 16 h. Purified TLPs were collected in a 500-μL fraction, dialyzed exhaustively against TNC buffer, and stored at 4 °C. Rotavirus DLPs were created by treating TLPs with 20 mM EDTA followed by purification using isopycnic centrifugation in CsCl (density of 1.38 g/cm 3 ). Purified DLPs were collected in a 500-μL fraction, dialyzed exhaustively against TNE buffer (20 mM Tris-HCl pH 7.5, 50 mM NaCl, 2 mM EDTA) and stored at 4 °C.…”

“…Microscale devices are currently being used to capture rare cells from whole blood [1], to lyse cells [2], to screen for drug candidates [3] and to immobilize living microorganisms [4]. Fluidic chambers composed of silicon nitride (SiN)-based microchips with nanometer-thin windows provide new tools to view the progression of chemical processes using electron microscopy [5,6].…”

Stem Cells for HUMAN Hepatic Tissue Engineering

“…Furthermore, in a static well the system is usually mass transport limited; flow can remedy this by the addition of convective mode of mass transport. A variety of devices have been developed for this purpose [68][69][70], and in particular to determine parameters for multi-compartmental physiologically-based pharmacokinetic (PBPK) models, Figure 6. For example, a multi-tissue compartmental device has been developed that incorporates a large liver compartment for the assessment of drug absorption both in the liver as well as in other metabolizing tissue types [71][72][73].…”