Abstract
Microphysiological systems (MPSs) are in vitro models that capture facets of in vivo organ function through use of specialized culture microenvironments, including 3D matrices and microperfusion. Here, we report an approach to co-culture multiple different MPSs linked together physiologically on re-useable, open-system microfluidic platforms that are compatible with the quantitative study of a range of compounds, including lipophilic drugs. We describe three different platform designs – “4-way”, “7-way”, and “10-way” – each accommodating a mixing chamber and up to 4, 7, or 10 MPSs. Platforms accommodate multiple different MPS flow configurations, each with internal re-circulation to enhance molecular exchange, and feature on-board pneumatically-driven pumps with independently programmable flow rates to provide precise control over both intra- and inter-MPS flow partitioning and drug distribution. We first developed a 4-MPS system, showing accurate prediction of secreted liver protein distribution and 2-week maintenance of phenotypic markers. We then developed 7-MPS and 10-MPS platforms, demonstrating reliable, robust operation and maintenance of MPS phenotypic function for 3 weeks (7-way) and 4 weeks (10-way) of continuous interaction, as well as PK analysis of diclofenac metabolism. This study illustrates several generalizable design and operational principles for implementing multi-MPS “physiome-on-a-chip” approaches in drug discovery.
Highlights
The failure of pre-clinical cell culture and animal models to predict drug safety and efficacy in humans results in billions of wasted dollars each year and slows development of treatments for needy patients[1,2,3,4]
Standard hepatocyte-centric in vitro liver models fail to capture the deleterious interplay between the immune-targeting drug Tocilizumab and metabolism of small molecule drugs that emerged after Tocilizumab entered the clinic[20]
We focus on pharmacological testing and interrogation of Microphysiological systems (MPSs) crosstalk, illustrating the use of quantitative systems pharmacology (QSP) modeling for integrating experimental design and interpretation with platform design and operation
Summary
The failure of pre-clinical cell culture and animal models to predict drug safety and efficacy in humans results in billions of wasted dollars each year and slows development of treatments for needy patients[1,2,3,4] These gaps have driven an explosion of approaches to capture complex human physiology in vitro, merging several parallel threads of science and technology, including pluripotent stem cell (PSC) and organoid biology; design principles and tools for 3D tissue and organ culture; microfluidic and mesofluidic approaches to controlling perfusion flow; and quantitative systems pharmacology models[5]. Technical challenges in building functional multi-MPS platforms include: (i) creation and maintenance of MPSs that exhibit sufficiently representative and robust physiological function over extended culture periods, typically requiring resource-intensive procurement and preparation of primary cells or pluripotent-stem cells (PSCs) to reach functional maturity in specialized microenvironments; (ii) design and fabrication of platform hardware that can accommodate and sustain the relevant MPSs – including transfer from off-platform to on-platform for MPSs requiring disparate maturation times and complex maturation media – while fluidically linking them together in a manner that is permissive for quantitative analysis of biological phenomena involving drug fate or disease phenomena; (iii) selection of a medium composition compatible with the different MPSs on the platform; (iv) a variety of other practical and translational aspects including flow partitioning, flow rates, physiological sensors, sampling frequency, and sample volume, among others
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