Cell-Based Chips for Biotechnology - Introduction to BioMEMS - page 275

that cells need to be fed more oten, or continuously as it happens in vivo. As a matter
of fact, it is extremely unlikely that the optimal feeding schedule for all cell types is
24 hours!
We are proposing a transition from dispensing luids by pipetting (whether manual or
robotic) to dispensing luids through micropumps and microvalves. However, this transition
raises the issue of luid metering. In a microluidic device, although the volumes of microcham-
bers can be known with high precision, the measurement of low rates is challenging because
it requires specialized low visualization techniques; as a result, continuous low systems such
as micromixers are not easily metered. However, stationary microscale volumes (e.g., micro-
chambers closed by microvalves) are straightforwardly known independently (roughly) of their
size and number. he volume of the chamber is easier to predict with “doormat” microvalves
(see Figure 3.41 ) than with Quake's pinch microvalves (see discussion in Section 3.8.1.5). For
example, the smallest chamber in Figure 3.107 is 500 × 220 × 55 μm ≈ 6 nL; because it is possible
to know the dimensions with an error of approximately 1% in each dimension, the volume can
be known within approximately ±3% = ±20 pL. An example of a fully automated microluidic
cell culture system has been demonstrated by a collaborative team led by Christopher Chen at
the University of Pennsylvania and Stephen Quake at Stanford University. he device creates
arbitrary culture media formulations in 96 independent culture chambers and maintains cell
viability for weeks. he team demonstrated osteogenic diferentiation of human embryonic stem
cells as visualized by on-chip alkaline phosphatase assays ( Figure 5.36 ).

Input manifold and mixer
Chambers
Multiplexers
Control channels

a
Input manifold
Chaotic mixer

Chambers

Peristaltic pump

1 cm

Flush
channel

Flow

Input sieve

Output sieve

1 mm

Chambers
(1.12 mm × 0.9 mm × 40 µm)

Mixer flush
output

Cell input

1 mm

Alkaline phosphatase Phase contrast Alkaline phosphatase Phase contrast

b c

Growth medium Osteogenic medium

200 µm 200 µm

FIGURE 5.36 Fully.automated.microluidic.cell.culture.system..(From.R..Gómez-Sjöberg,.A..A..Leyrat,.
D..M..Pirone,.C..S..Chen,.and.S..R..Quake,.“Versatile,.fully.automated,.microluidic.cell.culture.sys-
tem,”. Anal. Chem. 79,.8557-8563,.2007..With.permission..Contributed.by.Stephen.Quake.)