Figure 1
Correlation of the number of scientific publications over the years concerning microbioreactor technology (blue) and microfluidics technology (orange). This search was carried out using the analytical search tool from the Scopus platform (Elsevier B.V.) by the following strategies: “(microbioreactor*) OR (microfermentor*) OR (miniaturized AND bioreactor*) OR (microfluidic AND bioreactor*)” for article title, abstract and keywords; and “(microfluidic*)” for article title, abstract and keywords.
Figure 2
Example of a patterning protocol using soft lithography for the fabrication of micropatterned slabs using PDMS as substrate. Uniformization of photoresist by coating on a silicon wafer (A and B). The mask is placed over the photoresist (C). The system is exposed to UV light and non-polymerized photoresist is washed out by a solvent, rising the master piece (D). The substrate (PDMS) is applied over the master and cured thermally (E). The final piece is peeled away with the microstructures embossed into its surface (F). Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Microbiology (Weibel et al., 2007Weibel, D.B.; Diluzio, W.R.; and Whitesides, G.M., Microfabrication meets microbiology. Nature Reviews Microbiology, 5, 209–18 (2007).), copyright 2007.
Figure 3
Microfluidic devices based on microarrays: (A) microfluidic system with parallel arrays for the fluidfluid diffusional contact study for biochemical reactions. [Reproduced from Ismagilov et al. (2001)Ismagilov, R.F.; Ng, J.M.K.; Kenis, P.J.A.; and Whitesides, G.M., Microfluidic arrays of fluid-fluid diffusional contacts as detection elements and combinatorial tools. Analytical Chemistry, 73, 5207–5213 (2001). with permission of the American Chemical Society]. (B) schematic design of a microfluidic network of channels for the concomitant transportation of reactants from peripheric macroscopic pads to a central microchannel where detectors are located. [Reproduced with permission from Delamarche et al. (1998)Delamarche, E.; Schmid, H.; Bietsch, A.; Michel, B.; and Biebuyck, H., Microfluidic Networks for Chemical Patterning of Substrates. Journal of the American Chemical Society, 7863, 1–9 (1998). with permission of the American Chemical Society] (C) microfluidic system with 1536 chambers for mood-disorders-related-serological studies based on chemi-luminescent immunoassays as illustrated in the bottom right corner. A photo of the system is provided at the bottom left corner. [Reproduced from Zhao and Dong (2013)Zhao, X.; and Dong, T., Design and fabrication of low-cost 1536-chamber microfluidic microarrays for mood-disorders-related serological studies. Sensors (Basel), 13(11), 14570–14582 (2013)., published under Creative Commons Attribution License (CC BY 3.0)].
Figure 4
Concentration gradient microfluidic devices: (A) scheme of a concentration gradient-based microdevice composed of two inlets, a sink channel (lower or no concentration) and a source channel (higher or total concentration), along with red regions where nonlinear gradients are formed due to the asymmetric configurations. [Reproduced with permission from Mosadegh et al. (2007)Mosadegh, B.; Huango, C.; Park, J.W.; Shin, H.S.; Chung, B.G.; Hwang, S.K.; Lee, K.H.; Kim, H.J.; Brody, J.; and Jeon, N.L., Generation of stable complex gradients across two-dimensional surfaces and three-dimensional gels. Langmuir, 23, 10910–10912 (2007).. Copyright 2007 American Chemical Society]. (B) microfluidic cell culture device combining both array and concentration gradient approaches, composed of inlets and outlet of media (left and right ports) and inlet and outlet of cells and reagents (top and bottom ports). (C) colorimetric record of the concentration gradient formed by the device. [Reproduced with permission from Hung et al. (2005)Hung, P.J.; Lee, P.J.; Sabounchi, P.; Lin, R.; and Lee, L.P., Continuous perfusion microfluidic cell culture array for high-throughput cell-based assays. Biotechnology and Bioengineering, 89(1), 1–8 (2005).. Copyright 2005 Wiley Periodicals].
Figure 5
Single-cell trapping-based approaches: single cell trapping array: (A) photograph of the device, indicating the flow direction containing cell and media to the distribution through the trapping chambers. (B) schematic 3D diagram of the device illustrating the principle of the mechanism of cell entrapment. (C) a bright-field micrograph of the trapping chambers showing entrapped cells, where in some cases two cells are found to be entrapped together. [Reproduced from Di Carlo, Wu, and Lee (2006)Di Carlo, D.; Wu, L.Y.; and Lee, L.P., Dynamic single cell culture array. Lab on a Chip, 6, 1445–1449 (2006). with permission of The Royal Society of Chemistry].
Figure 6
Droplet microfluidic devices: (A). bright-field micrography of algal cells (black arrows) encapsulated in droplets. The cell suspension and oil flow are indicated by white arrows. [Reproduced from Pan et al. (2011)Pan, J.; Stephenson, A.L.; Kazamia, E.; Huck, W.T.S.; Dennis, J.S.; Smith, A.G.; and Abell, C., Quantitative tracking of the growth of individual algal cells in microdroplet compartments. Integrative Biology, 3, 1043-1051 (2011). with permission of The Royal Society of Chemistry]. (B) illustration of the formation of droplets with different concentration of NaCl as its flow rate decreases, resulting in a different microenvironment in each droplet applied to the crystallization of proteins. [Reproduced with permission from Zheng, Roach, and Ismagilov (2003)Zheng, B.; Roach, L.S.; and Ismagilov, R.F., Screening of protein crystallization conditions on a microfluidic chip using nanoliter-size droplets. Journal of the Americal Chemical Society, 125, 11170–11171 (2003)., Copyright 2003 American Chemical Society].
Figure 7
Microbioreactors as tools for continuous culture assays: (A) microbioreactor for continuous culture of single-cells, integrated with computer-controlled pressure regulators and syringe pumps for valve pressure and media delivery, respectively; a thermal plate equipped with thermocouple for temperature control and an inverted microscope equipped with fluorescent and phase-contrast imaging. The device is also equipped with a sample inlet. [Reproduced from Johnson-Chavarria et al. (2014)Johnson-Chavarria, E.M.; Agrawal, U.; Tanyeri, M.; Kuhlman, T.E.; and Schroeder, C.M., Automated single cell microbioreactor for monitoring intracellular dynamics and cell growth in free solution. Lab on a Chip, ,14, 1–10 (2014). with permission of The Royal Society of Chemistry]. (B) schematic illustration of a microbioreactor for continuous culture of mammalian cells in microcarriers. (i) detailed dimensions of each piece that assemble the microbioreactor. (ii) illustration highlighting the porous membrane between the two PMMA pieces. (iii) scheme illustrating the principle of the microbioreactor, where the upper channel hosts mammalian cells consuming the substrate while the lower channel provides fresh medium by diffusion though the porous membrane. [Reproduced from Abeille et al. (2014)Abeille, F.; Mittler, F.; Obeid, P.; Huet, M.; Kermarrec, F.; Dolega, M.E.; Navarro, F.; Pouteau, P.; Icard, B.; Gidrol, X.; Agache, V.; and Picollet-D’hahan, N., Continuous microcarrier-based cell culture in a benchtop microfluidic bioreactor. Lab on a Chip, 14, 3510–3518 (2014). with permission of The Royal Society of Chemistry].