2.3 Drug Development
The drug development process comprises of two phases i.e., drug discovery and
drug testing. The first phase includes the target selection, lead identification, and
preclinical studies, while the development stage includes clinical trials,
manufacturing, and product lifecycle management [ 22 ]. Miniaturized MF devices
being small sized in nature are emerging as useful tools for the study of target
selection, lead identification and optimization and preclinical test and dosage
development [ 23 ]. Recreation of complex pharmacological and pharmacokinetic
interactions occurring in living organisms is a major challenge in toxicology as the
toxic effect of drugs in one tissue often depends on the metabolic activity of another
tissue. Caviglia et al. developed a MF cytotoxicity assay for studying the impact of
anticancer drugs doxorubicin and oxaliplatin (Fig.8.3A)[ 24 ]. The targeted drug
delivery tested the cytotoxicity and was evaluated using real-time impedance
monitoring. The time-dependent effect of doxorubicin on the HeLa cells was
monitored and found to have a delayed onset of cytotoxicity in MF compared
with static culture conditions. Although, the cell-basedin-vitrotests, can provide
useful preliminary data but animal tests are still required to verify the pharmaco-
logical properties of the drug. To mimic these interactions, organ-on-chip devices
i.e. MF system containing a network of interconnected chambers have proved to be
very useful. Sung et al. developed a device using hydrogel cell culture for
pharmacokinetics–pharmacodynamics (PBPK) studies of the three cell lines that
represents the liver, tumor and marrow for testing drug toxicity [ 25 ]. These cell
lines were grown in the three-chambers of device to test the toxicity of an antican-
cer drug, 5-fluorouracil. The device is assembled by sandwiching a cell culture
chamber layer and a fluidic channel layer between a bottom aluminum frame and a
Plexiglass top frame (Fig.8.3B). Gravity-induced flow achieved the recirculation of
cell culture medium and tilting of the device results in the flow of liquid from one
well to the other well, where the flow rate through the conduits was calculated. The
rocking platform changes the angle, and the medium flows in the opposite direction
in almost 3 min. The gravity induced circulation offers several advantages over
pump circulation like reduction of the total space occupied by the device, lowering
of cost, elimination of the possibility of unwanted binding, and prevention of air
bubble formation. Prabhakarpandian et al. designed a synthetic tumor to test in vivo
delivery efficiencies of the drug vehicles [ 23 ]. A pre-digitized MF-based artificial
vasculature assay was used to mimic the tumor microenvironment for in vivo
observation. The MF device recreates the in vivo tumor microenvironment of
circulatory flow in the vessels, transport across the leaky vessel walls between the
vascular and the tumor cells, and delivery to the 3D culture of tumor cells across the
interstitial space. The combination of these features distinguishes the present
synthetic tumor network model from other in vitro models. Several organs on
chips devices are reported to be utilized for drug development purpose (discussed
in the preceding subsection).
198 S. Solanki and C.M. Pandey