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A mini-review with 79 references. In this review, the most recent trends in 3D-printed microfluidic devices
are discussed. In addition, a focus is given to the fabrication aspects of these devices, with the ESI†
containing detailed instructions for designing a variety of structures including: a microfluidic channel,
Received 13th June 2016
Accepted 14th July 2016
threads to accommodate commercial fluidic fittings, a flow splitter; a well plate, a mold for PDMS
channel casting; and how to combine multiple designs into a single device. The advantages and
DOI: 10.1039/c6ay01671e
limitations of 3D-printed microfluidic devices are thoroughly discussed, as are some future directions for
www.rsc.org/methods the field.
allows high throughput fabrication of microuidic devices. For Fabrication of 3D-printed microfluidic
example, one can 3D print several identical devices for parallel
experiments or multiple devices with different test parameters devices
at one time.18 3D-printed devices also offer robust structural 3D-printing, also known as additive manufacturing, builds
alternatives to conventional microuidic devices. Some a three-dimensional object, layer by layer.21 There are different
3D-printed devices allow for ow rates as high as hundreds of techniques 3D-printers can utilize to fabricate 3D objects,
mL min 1.17,19 These devices are reusable aer cleaning through among which the most commonly used are polyjet printing and
a chemical wash (i.e., bleach) and/or mechanical sonication, fused deposition molding.16 Polyjet printing overlays liquid
which helps minimize errors arising from using different polymer layers, with each added layer cured by ultraviolet (UV)
devices.19,20 Furthermore, by sharing the design les,
Published on 27 July 2016. Downloaded by Cornell University Library on 28/07/2016 09:19:58.
Inkjet printing34
Solid particles are bonded layer by Acrylonitrile 375 375 790 dpi Evaluating printers for microuidic
layer via adhesive or UV. Support VisiJet crystala fabrication: 200 mm (diameter).74
materials are needed ABSb 68 68 32 mm Microuidic circuitry: 750 mm
ThermoJet 2000c (channel diameter)24
PolyJet printing35
Liquid material is cured by UV layer Verowhited 600 600 1600 dpi Endothelium lysis study: 800 1000
by layer. Support materials are Full Cure 720e (cross section) mm.26
needed Veroclearf 42 42 16 mm Gradient generators and mixers
within channels for biosensing:
114 51 mm (cross section).41
Wall-jet electrochemical detector:
375 375 mm (cross section)19
Stereolithography36,37
Object is cured layer by layer by UV Acrylate resing 454 454 508 dpi Micromixer for pKa determination:
and is placed in a resin bath. Support Modied resin 500 500 mm (cross section).75
materials are needed 56 56 50 mm Immunoassay for bacteria detection:
250 500 mm (cross section).76
Mold to cast PDMS channels:
300 300 mm (cross section)77
reflection of the CAD design. This example shows the fabrication of The resolution of different 3D-printing technologies and the
a flow splitter using 3D-printing.
actual sizes of example devices using the printers can be found
in Table 1.34–39 As long as the CAD design of a device is within
the resolution requirement of a 3D-printer, the printed part
3D-printers can recognize) prior to sending to a printer.33 Based
should be the exact reection of the CAD design (Fig. 1). In
on user demand, certain materials can be chosen to fabricate the
other words, any feature or shape drawn using a CAD soware
device (Table 1). Fig. 1 shows an example of 3D-printing an object
can be achieved by 3D-printing. Therefore, compared to so
following these steps. The design and drawing of a potential
lithography, 3D-printing enables the fabrication of more
device using CAD soware is key to the nal structure and
complicated and functional features on microuidic devices.
function of a microuidic device. Therefore, in this review, the
Fig. 3 shows several published examples of unique 3D-printed
authors chose six examples that can be used for microuidic
functional parts that can be used for microuidic devices.19,40–44
devices and will introduce the detailed design and drawing
process using Autodesk Inventor in the ESI,† which include (1)
Advantageous features of 3D-printed
microfluidic devices
3D-printing can be an efficient method to fabricate structurally
robust microuidic devices. Furthermore, 3D-printing enables
the fabrication of unique but advantageous features integrated
on a microuidic device. Although integrated components have
been created with PDMS devices, it is time consuming and
costly to integrate multiple functional units on one device.45
Because 3D-printing can produce any shape based on users'
demand, complex and functional 3D-printed microuidic
features have been reported.
Fig. 3 Examples of unique features that can be realized by 3D-printing. (A) A 3D-printed microfluidic device with wall-jet electrochemical
configuration. Threaded ports that fit commercial finger tight adapters were 3D-printed on the device. A sample can be introduced through the
inlet, which then hits the electrode housed in the “electrode insert” to achieve wall-jet detection (adapted from ref. 19 with permission from The
Royal Society of Chemistry). (B) Luer adapters were 3D-printed on a microfluidic device for easy connection with tubing and syringes (adapted
from ref. 40 with permission from John Wiley & Sons, Inc). (C) O-rings can be 3D-printed with rubber-like materials on a fluidic device. In this
example, the authors used the printed O-ring to connect different chips (adapted from ref. 41 with permission from The Royal Society of
Chemistry). (D) A 3D-printed gradient generator. With 3D-printing, complicated channels were fabricated in this example (adapted from ref. 42
with permission from The American Chemical Society). (E) A 3D-printed microfluidic mixer. By fabricating zigzag channels and vales, two liquids
can be mixed well using the device (adapted from ref. 44 with permission from Elsevier). (F) A 3D-printed pneumatic valve. The “membrane” is
a thin layer (200 mm) of 3D-printed structure. When proper air pressure is applied through the nozzle, the membrane can deform to open or
close the channel on the right side (adapted from ref. 43 with permission from The Royal Society of Chemistry).
Complex ow regulating components microuidic devices to enhance mixing of owing reagents.52–54
3D-printing can also achieve complicated structures with just
Precise and efficient ow control is an important factor to
a few steps. For example, Lee and colleagues developed
consider when designing a microuidic device. On the micro
a 3D-printed channel with twists and turns, as well as a separate
scale, uids typically exhibit laminar ow that may cause
unit to mix the ows for alpha-fetoprotein biomarker detection.
insufficient mixing between reagents if needed.49 On-chip mix-
As the authors have proved, these devices were 3D-printed in
ing mechanisms have been integrated on PDMS devices
through complex fabrication.50,51 For example, R. F. Ismagilov's a straight forward, rapid and user friendly way.41 3D-printed
valves and pumps, a common technique for uid manipulation
group have developed multiple PDMS-based droplet
in PDMS devices, have also been achieved (Fig. 3F).28,43
reported a method to embed an electrode in a hollow plastic and in vivo microenvironment mimicking (i.e., shear stress).58
tting, which can then be integrated into a threaded port in the Although a number of PDMS cells-on-a-chip models have been
device.20 The electrodes can be removed by unscrewing to be reported, 3D-printing can enhance the multiplexity, versatility
cleaned for reuse. With 3D-printing, more complicated elec- and reusability of such models. Chen reported a 3D-printed
trochemical conguration can also be easily achieved. Munshi system that combined pancreatic b-cells, endothelial cells and
et al. reported a microuidic wall-jet electrochemical detector a blood ow mimic. This platform enabled multiple studies
with detachable and adjustable electrodes (Fig. 3A), which has such as endocrine secretions, hormone transportation and cell-
proven to be highly sensitive for multiple applications.19 Bou- to-cell interactions. Such a device cannot be easily achieved
telle's group recently described a 3D-printed integrative system using PDMS. Furthermore, most of the reported PDMS cells-on-
that contained microdialysis probes for continuous monitoring a-chip systems contained only one or two cell types.59 Another
of glucose and lactate in humans. As shown in Fig. 4, the dial- important advantage includes the integration of transwell
ysis outlet (c) that collects dialysate from a human was con- inserts for exible cell culture on the 3D-printed device. Inserts
nected to the inlet of a 3D-printed microuidic chip (e). with pre-cultured cells can be inserted and removed from the
Electrochemistry based needle biosensors (f) were housed in uidic base as needed. When an insert was contaminated or the
two 3D-printed adapters (g), which can screw into the micro- cells were not cultured correctly, the insert can be replaced
uidic channel for detection. The inset (h) is the real picture of rather than failure of the entire device. Though the authors
a housed electrode and the black part was printed using a so tested three cell types of interest, in theory, any other cell type
material for tight sealing. With this system, online monitoring can be integrated in the system by this method.
of the metabolites with high temporal resolution can be ach-
ieved.56 Also, the ability of 3D-printing to mold any design Limitations of current 3D-printed
enables the device shape to t commercial detectors. For
example, Chen and colleagues developed a device in the format
microfluidic devices
of a standard 96-well plate that is amenable to plate readers for As a new, rapidly evolving technology, 3D-printing also
high throughput analysis.33 Other detection techniques such as possesses some limitations. Currently, these include but are not
limited to resolution, surface properties, and compatibility
issues.
Resolution
Although the resolution of many 3D-printers has been claimed
to be as low as a few tens of microns, the smallest 3D-printed
open channel acquired so far is approximately 200 mm wide.60
Most of currently reported 3D-printed microuidic devices
have channel sizes from hundreds of microns to a few milli-
meters.33,41,43,59 This is partially because the printers with the
highest resolution usually need supporting materials to ll the
void spaces (i.e., a channel) during the printing process
(Fig. 5A), which typically needs to be removed manually.16
Unfortunately, it is almost impossible to remove all the waxy
Fig. 4 An integrated 3D-printed microfluidic system for metabolite
supporting materials from a very small channel. Even if some
detection. Part (a) is the outlet of a dialysis probe that collects samples
from a human being. Via part (b), which is a 3D-printed adapter, (a) can micron scale mechanical methods may be applied to remove
be connected to the 3D-printed microfluidic device (c). Two elec- the supporting materials, the removal efficiency will still be
trodes (d) were housed in 3D-printed adapters (e), which can be questionable. Any le-over material in a channel may
screwed into the microfluidic channel with a good sealing. When adversely alter the ow pattern and/or affect the owing
a sample is collected and flowing through the channel, glucose and
reagents by absorption or even reaction. Most of the sup-
lactate can then be electrochemically detected. (f) is a real picture of
a housed electrode and the black part was 3D-printed using a rubber- porting materials have similar chemical composition with the
like material for tight sealing (adapted from ref. 56 with permission construction materials,61 which makes it impossible to use
from The American Chemical Society). harsh solvents for cleaning. Mild solvents such as isopropanol
Fig. 5 The SEM images of a 3D-printed channel before and after removing supporting material. (A) Upon printed, the channel was completely
filled with the supporting material, which is commonly used in high resolution 3D-printers. (B) After removal of the supporting material, rough
surfaces can be seen on the inner wall of the channel. The scale bars in the images represent 200 mm (adapted from ref. 26 with permission from
The American Chemical Society).
(IPA) have been tried by the authors and others, which turned Compatibility issues
out to push this situation into a dilemma: IPA treatment for
Cell integration on microuidic devices is popular. However,
a short time cannot remove much of the material; while too
the biocompatibility of most of the 3D-printing resins and
long treatment causes expansion of the bulk material and plastics remains unknown. 3D-printing materials are usually
resulting in channel deformation or even clogging.20,59 This complex mixtures. Even though the major composition is non-
limitation currently prohibits 3D-printed microuidic devices
toxic, other components such as commonly used photo-
from being used in applications that require small channels,
initiators may adversely affect cells.63 Biocompatible
such as cell/particle gating and electrophoresis. Moreover,
3D-printing materials are being developed that are expected to
most of currently reported 3D-printed microuidic devices
be non-toxic to cells.64 However, most of these studies are still in
have straight channels, because of the difficulty to remove
development. Solvent compatibility is another concern in
supporting materials from a fully closed channel with sharp
3D-printing. Some 3D-printing materials may swell in aqueous
bends. However, if a channel with such complicated structures systems, which can cause ow problems.65 Organic solvents are
as twists and turns must be fabricated, the channel may not be also commonly used in microuidics (i.e., oils for droplet
printed as fully closed. Instead, it can be fabricated as an
microuidics66); but the solvent compatibility of 3D-printing
engraved slab, which can then be sealed onto another
materials still remains a concern.
substrate.44
Other issues
Surface properties PDMS devices can be completely transparent for optical detec-
The resolution limitation of current 3D-printers can also tion. Although “clear materials” are available for 3D-printing,
cause rough surface proles in a 3D-printed micro channel. they are typically translucent/semi-transparent. Labor-intensive
Gross reported a microuidic device fabricated using a high polishing can make the outside of a device transparent and
resolution (30 mm on X and Y axes and 16 mm on Z axis as said smooth; but the inner wall of a small, fully-sealed channel
by the manufacturer) 3D-printer.26 As shown in Fig. 5, aer cannot be polished. In other words, it is almost impossible to
removal of the supporting material, large rough ridges can be optically observe the inside of a channel without certain treat-
clearly seen around the inner wall, which may cause issues ments.67 Most of the 3D-printing materials are not gas perme-
such as dead volumes and inconsistent surface modica- able, which makes them not suitable for long-term cell culture
tions. Absorption and adsorption are another concern about inside a channel without additional gas exchange supporting
surface properties of 3D-printed devices. Though the exact units. In addition, 3D-printers with high resolutions (tens of
composition of the 3D-printing materials is proprietary, most microns) are relatively expensive at the moment,68 which may
of them are acrylate and acrylonitrile butadiene styrene (ABS) limit its application in many laboratories. Furthermore, routine
based. These polymers absorb such molecules as proteins maintenance and calibration are needed for a 3D-printer to
and lipids, which may reduce the concentration of analytes of ensure printing quality.
interest, and thereby altering the detected signal.62 The
unpredicted rough channel surface may even increase Future directions
adsorption. To avoid the biotoxicity concern of 3D-printed
devices and to reduce channel roughness, some coating 3D-printing of microuidic devices and components has many
protocols can be applied. For example, Gross successfully benets. Ho and coworkers concluded that 3D-printing can
coated a layer of PDMS on the inside of a 3D-printed channel facilitate the eld of microuidics to nd its “killer applica-
for endothelial cell culture and subsequent microscopic tions”.69 Au and colleagues predicted that 3D-printing can
observation.26 potentially replace so lithography to fabricate microuidic
devices.60 However, in the authors' opinion, due to the limitations 3 D. J. Harrison, A. Manz, Z. H. Fan, H. Ludi and
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Published on 27 July 2016. Downloaded by Cornell University Library on 28/07/2016 09:19:58.
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Acknowledgements 2016, 20, 1–15.
24 R. D. Sochol, E. Sweet, C. C. Glick, S. Venkatesh, A. Avetisyan,
Support for RSM from the National Institute of General Medical K. F. Ekman, A. Raulinaitis, A. Tsai, A. Wienkers, K. Korner,
Sciences (Award Number R15GM084470-04) is acknowledged. K. Hanson, A. Long, B. J. Hightower, G. Slatton,
This paper, as well as another paper from our group (Chen et al., D. C. Burnett, T. L. Massey, K. Iwai, L. P. Lee, K. S. J. Pister
Analyst, 2016, DOI: 10.1039/C6AN01282E) is dedicated to the and L. Lin, Lab Chip, 2016, 16, 668–678.
memory of Craig Lunte, an outstanding scientist and mentor. 25 J. C. McDonald, M. L. Chabinyc, S. J. Metallo, J. R. Anderson,
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