Interconnected Microphysiological Systems for Quantitative Biology and Pharmacology Studies

TLDR

Microphysiological systems emulate organ function in vitro using 3D matrices and microperfusion. The study presents a method to physiologically link multiple distinct MPSs on reusable, open microfluidic platforms for quantitative compound testing. The authors developed 4-way, 7-way, and 10-way open microfluidic platforms with internal recirculation, pneumatically driven pumps, and programmable flow rates to enable precise intra- and inter‑MPS fluid exchange. The platforms accurately predicted liver protein distribution, maintained phenotypic markers for up to four weeks, operated reliably across 4‑, 7‑, and 10‑MPS systems, and enabled PK analysis of diclofenac, demonstrating generalizable design principles for physiome‑on‑a‑chip drug discovery.

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.