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3D-printing and microfluidics
           3D-printing’s unique ability to monolithically create 3D   membrane  were  5  mm  and  100  µm,  respectively.  The
           structures  to  realize  true  3D  microfluidic  architectures   membrane  would  deflect  by  ~200  µm  under  2.9  psi
           that were unattainable by the traditional microfabrication   pressure. Due to the large Young’s modulus, the size of the
           techniques. Lee et al. fabricated a helical channel using   membrane was considerably larger than the PDMS-based
           SLA  for  inertia-based  bacteria  separation  (Figure  1).   valve to achieve the required deflection for valve closure.
           The  helical  channel  spiraled  up  in  the  z-direction  and   A similar circular membrane valve was demonstrated by
           formed a true 3D microchannel with a trapezoid cross-  Gong et al.  By pushing the thickness of the membrane
                                                                        [34]
           section .  The  3D  helical  design  significantly  reduced   down to ~20 µm, they were able to reduce the diameter
                 [27]
           the device footprint compared to the planer spiral design.   of the membrane to ~1 mm and pack the valves into a
           Shallan  et  al.  used  a  liquid  resin-based  3D  printer  to   dense array. The required diameter of the membrane in
           fabricate  3D  microchannels  for  more  efficient  passive   the  valve  at  various  membrane  thickness  was  studied
           mixing . Monaghan et al. developed a 3D microfluidic   by  Rogers  et  al.   The  same  design  was  also  used  as
                                                                             [35]
                 [28]
           device coupled with optical fibers to monitor chemical   an  active  Micropump  in  3D-printed  microfluidics .
                                                                                                            [34]
           synthesis . The group used the same approach to fabricate   A 3D-printed Quake valve was demonstrated by Keating
                  [29]
           a 3D tree-like chemical gradient generator with reduced   et al. using an inkjet-based technique that is capable of
           footprint  and  high  portability .  Cabot  et  al.  used  a   printing  multiple  materials .  Tangoplus,  a  rubber-like
                                     [28]
                                                                                      [36]
           similar 3D-printed microfluidic passive mixer to improve   flexible material was used to print the membrane while
           sample mixing in a capillary electrophoresis assay that   other parts of the microfluidic device were printed with
           measured  the  pK a [30] . A  highly  complex  interconnected   rigid  plastic  material.  Nonetheless, Tangoplus  was  less
           3D microfluidic network was fabricated by casting epoxy   flexible  than  PDMS,  and  the  dimension  of  the  control
           or agarose against a 3D-printed sacrificial mold . After   channel was in the millimeter range. In addition to active
                                                   [31]
           casting, the mold made of isomalt was dissolved to clear   valves, passive valves were also created  in 3D-printed
           space for microfluidic channels. 3D-printing also enabled   microfluidic devices. These were usually one-way check
           easy integration of chip-user interface that coupled the   valves similar to those in silicon-based MEMS device.
           external fluid into the microfluidic chip. A good example   Sochol et al. printed microfluidic circuitry components,
           was demonstrated by Anderson et al. who fabricated a   such as fluidic diodes and transistors, by incorporating
           microfluidic  drug  screening  platform  that  incorporated   these designs . Chen et al. incorporated these passive
                                                                          [37]
           standard  membrane  devices  for  the  cell  culture  and   valves to prevent backflow in a 3D-printed microfluidic
           standard  thread  fitting  for  the  coupling  of  tubing .   multi-chamber  cell  culture  device  that  modeled  the
                                                        [32]
           Another  example  was  demonstrated  by Au  et  al.  who   circulatory system .
                                                                              [38]
           printed a Luer lock fitting on the microfluidic device as a   Another  enhancement  brought  to  microfluidics  by
           standard fluid connector .                          3D-printing  is  device  modulation.  With  3D-printing
                               [33]
             One  of  the  reasons  for  PDMS  being  so  popular  in   technology,  it  is  straightforward  to  fabricate  individual
           microfluidics  is  due  to  its  high  flexibility  that  enables   modules,  each  of  which  contains  a  single  microfluidic
           the  fabrication  of  multilayer  pneumatic  valves  and   component and to incorporate standard connectors on
           pumps.  Each  multilayer  pneumatic  valve  consists  of   the  individual  modules  for  easy  assembly.  Bhargava
           two  overlapping  crisscross  microchannels  separated  by   et  al.  3D-printed  cubes  with  a  female  port  and  a  male
           a thin PDMS membrane at the intersection. One of the   connector (Figure 3) . These cubes, which functioned
                                                                                [39]
           microchannels carries the sample fluid, and the other one   as  microfluidic  modules,  created  elastic  reversible
           carries the control fluid (sometimes just air). When the   liquid-tight  seals  when  coupled  together.  Microfluidic
           control channel is pressurized, the thin PDMS membrane   components, such as straight channels, helical channels,
           deflects, creating a bulge that blocks the fluidic channel.   and reaction chambers, were embedded in these modules.
           The  enabling  factor  of  the  multilayer  pneumatic  valve   Non-fluidic  components,  such  as  optical  components,
           is  the  low  Young’s  modulus  of  PDMS,  which  allows   were  also  introduced  into  individual  modules.  A  fully
           the  thin  membrane  to  deflect  easily.  In  contrast,  most   functional  3D  microfluidic  network  was  constructed
           3D-printed  plastic  materials  have  Young’s  modulus   by  plug-and-play.  Lee  et  al. developed  a 3D-printed
           hundreds or thousands of times larger than PDMS, which   modular  microfluidic  system  assembled  together  with
           makes it difficult to pneumatically deflect the 3D-printed   horseshoe-shaped pins that functioned somewhat like a
           membrane. Nevertheless, using relatively flexible plastic,   stapler bullet . To prevent leakage, O-rings were used
                                                                          [40]
           active  valving  has  been  demonstrated  in  a  3D-printed   at the fluidic interface between the modules. Nie et al.
           monolithic microfluidic device (Figure 2). In this work,   designed  lego-like  microfluidic  modules  with  press-fit
           Au  et  al.  printed  a  multilayer  membrane  valve  using   connectors along the edge of each modular block. Due
           watershed (a biocompatible resin) with Young’s modulus   to the poor sealing, this system was only designed for
           of 2.7 GPa . The diameter and thickness of the circular   capillary-driven flow and could not operate under high
                    [20]
           64                          International Journal of Bioprinting (2019)–Volume 5, Issue 2
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