2.1 Development of the multi-organ microphysiological system
(MO–MPS)
We developed a multi-organ microphysiological system (MO–MPS)
integrated with a liver part having metabolic functions based on
pharmacokinetics and a lung cancer part as a drug target. The bloodin vivo is dispensed to the organs by the heart after
assimilating the oxygen from the lung. The blood flow ratio between
liver, heart, and lung is 1:3.3:3.3(Fig. 1A).(Takahashi, (1989)) A
stirrer-based micropump, which we had developed previously, was
integrated for medium perfusion on the MO–MPS.(Nakayama et al., (2014))
The flow ratio was controlled by the resistance of a bypass-channel
installed onto the MO–MPS to be similar in vivo (Fig. 1B). The
design of the bypass channel was optimized using ANSYS 17.1 (ANSYS Inc.,
USA), a fluidic simulation software by the finite element method (Fig.
1C). The dimensions of the chambers of the lung and the liver cancer
parts were 15 mm2 and 50 mm2,
respectively. The height of the channel and cell culture chambers were
380 µm and 770 µm, respectively.
The MO–MPS was fabricated by conventional photolithography and soft
lithography methods.(McDonald and Whitesides, (2002)) A chromium mask
for photolithography, which was used to fabricate microstructure, was
designed using a computer-aided design software (AutoCAD, Autodesk, USA)
and fabricated using a micro-pattern generator (μPG101, Heidelberg
instruments Inc., Germany). A negative photoresist (SU-8 2010, MicroChem
Corp., USA) was spin-coated onto a silicon wafer. After baking, the
microchannel pattern was formed on the substrate using ultraviolet lamp.
The stepped structures of the microchannels and the cell culture
chambers were fabricated similarly. The substrate was used as a master
mold for polydimethysiloxane (PDMS, SILPOT 184, Dow Corning Toray,
Japan), the material of the MO–MPS. A 10:1 mixture of PDMS and a
polymerization agent was poured onto the master mold and heat cured in
an oven at 75 ˚C for 2 h. The cured PDMS was peeled from the master mold
to produce a PDMS chip as to which the channel pattern was transferred.
The surface of the PDMS was coated with CYTOP (CTL-107MK, AGC, Japan) to
spin the stirrer bar smoothly. A 7% CYTOP solution was casted onto the
micropump chamber and baked at 65 ℃ for 30 min and 100 ℃ for 60 min. The
PDMS surfaces were activated using a plasma cleaner (PDC-32G, Harrick
Plasma, USA). After setting the stirrer bar into the chamber, the
MO–MPS was assembled to permanently bond the PDMS chips (Fig. 1D).