Application of micromixers - Micromixers Fundamentals Design and Fabrication - page 333

Chaotic advection in the flow increases the amount of particles trapped onto the surface. Using the
mixer, the amount of trapped particles increased by 50% compared to the case of a straight and
smooth channel.
9.2.4 Biological assays
Micromixers in the form of gradient generators have a number of biological applications. The major
biological assays based on a concentration gradient are cancer chemotaxis, immune response, stem
cell differentiation, axon guidance, and angiogenesis [53,54] .
Cancer metastasis is the late stage of the disease where cancer cells spread to other organs.
Metastasis consists of two main steps: intravasation and extravasation. In the first step of intravasation,
cancer cells are transported in the circulatory system. In the second step of extravasation, cancer cells
migrate and spread from blood vessel to the organ tissues. These steps are regulated by a number of
chemoattractants such as growth factors and chemokines, which are chemotactic cytokines. For
instance, chemokine receptor type 4/chemokine (C-X-C motif) ligand 12 (CXCR4/CXCL12),
epidermal growth factor (EGF), and insulin-like growth factor 1 (IGF1) are potent mediators of breast
cancer. The gradient of the above-mentioned chemoattractants significantly affect the migration of
cancer cells. Gradient generators can mimic the environment in tissues under controlled conditions.
Understanding cancer metastasis in gradient generators can lead to the development of new thera-
peutics against cancers.
Wang et al. studied metastasis of breast cancer cells in a concentration gradient of EGF generated
by a parallel lamination generator [55] . The results show that the cancer cells show a more directional
movement in a nonlinear gradient than in a linear one ( Fig. 9.6 ). Abhyankar et al. [56] used a free-
diffusion generator forming an EGF gradient in a 3-D gel matrix to study metastasis of rat mammary
adenocarcinoma cells. The extracellular matrix (ECM) represents an additional controllable factor for
the study. The platform allows detailed investigation of the interaction of the cells with the ECM
substrate in an EGF gradient.
Immune response is affected by chemokines and their receptor. Chemokines recruit leukocytes to
the infection site. Therefore, detailed studies on the ability of immune cells to sense the gradient are
important for the understanding of immune response. Neutrophils or polymorphonuclear neutrophils
(PMNs) are the most abundant type of white blood cells in mammals. During the early phase of
inflammation, neutrophils are one of the first responders to migrate toward the infection site.
Neutrophils migrate through the blood vessels, then through interstitial tissue, following the gradient
of chemoattractants such as interleukin-8 (IL-8), C5a, and leukotriene B4 (LTB4). Jeon et al. [57] used
a parallel lamination generator to investigate chemotaxis of human neutrophils in a concentration
gradient of IL-8. The results show that the behavior of neutrophils depends not only on the gradient but
also on the shape of the concentration distribution. Further investigations on the same platform [58]
reveal that the mean concentration of linear gradients strongly affects the directed motility of
neutrophils.
Axon guidance is important for the regeneration of nerve cells. Chemotaxis of neuronal precursors
and their differentiation are the key processes of axonal regeneration. The concentration gradient of
both diffusible and surface-bound molecules can modulate axon guidance. Dertinger et al. used
a parallel lamination generator to investigate the effect of laminin gradient on the axon specification of
rat hippocampal neurons [59] . Axons were oriented toward the higher concentration of laminin.