Paper has been used by humans for thousands of years. Today paper is a commodity material commonly used for printing and packaging, but the properties of paper make it appropriate for many other uses. Paper, for example, is porous, it wicks liquids, it is flexible, foldable/creasable, biocompatible and biodegradable. We use these unique properties to achieve new uses for paper in areas such as cell biology, robotics, electronics, microelectromechanical systems (MEMS), and microfluidic devices.
Elastomer Composites for Robots
We have used paper to introduce anisotropy into elastomers, and to build soft pneumatic actuators.1 We folded paper into 3D structures following the principles of origami to form a robotic actuator. The folded structures increase the stiffness and anisotropy of elastomeric actuators, while being light in weight (Fig 1). The principles of design lead to actuators that respond to pressurization that are capable of a wide range of motions (bending, extension, contraction, twisting, and others).
Cells in Gels in Paper
In cell biology, it is important to create 3D scaffolds for cells to recapitulate the structure and function of living tissue. We have used hydrophobic patterning to define areas for cell growth on a single sheet of paper. The patterned paper is then impregnated with suspensions of cells in extracellular matrix hydrogel, and layers of paper are stacked to form a layered 3D model of a tissue (Fig 2). 2–4 The cells in gel/paper composite provide a 3D environment for cell growth. Mass transport of gases (e.g. oxygen), and nutrients can be varied between the different layers, to provide control over the environment in 3D. The stacked paper can then be simply destacked and each paper composite layer can be analyzed by imaging, or other techniques, which eliminates the need for sectioning.
Hydrophobic RF Paper and SLIPS
We have fabricated “fluoroalkylated paper” (“RF paper”) by vapor-phase silanization of paper with fluoroalkyl trichlorosilanes5. RF paper is both hydrophobic and oleophobic, but maintains the high permeability to gases and mechanical flexibility of the untreated paper, and can be folded into functional shapes (e.g., microtiter plates and liquid-filled gas sensors). The silanized papers have also been used to build open channel paper microfluidic devices and analytical devices (Fig 3,8). 6,7
When RF paper is impregnated with a perfluorinated oil, it forms a “slippery” surface (paper slippery liquid-infused porous surface, or “paper SLIPS“) capable of repelling liquids with very low surface tensions. The foldability of the paper SLIPS allows the fabrication of channels and flow switches to guide the transport of liquid droplets (Fig 4).
PAPER BASED MICROFLUIDIC DEVICES
Paper Microfluidics Devices with Photolithography or Wax printing
Microfluidic paper-based analytical devices (µPADs) are a new class of point-of-care diagnostic devices that we have developed to be low-cost, and easy to use8–12. µPADs are fabricated by micro patterning hydrophobic regions on paper. These regions define paths for liquids that spontaneously wick through the paper. We have developed two different patterning methods: 1) The photolithography method (Fig 5) uses an epoxy-based negative photoresist (SU-8). Paper is impregnated with photoresist, dried, and exposed to UV light through a transparency mask, which can be printed. The unexposed photoresist can be washed out of the paper to form the hydrophobic microfluidic channels. 13 2) Wax printing14 is a simple and inexpensive method for patterning microfluidic structures in paper using a commercially available printer and hot plate (Fig 6). Patterns of solid wax are printed on the surface of paper, and a hot plate melts the wax so that it permeates through the paper.
Hydrophobic channels patterned into paper wick micro-liter volumes of fluids by capillary action and distribute the fluids into test zones where independent assays take place (Fig 7). It is possible to pattern microfluidic channels in paper with dimensions down to 200 µm in width. It is also possible to pattern different types of paper, such that the properties of the paper can be selected for specific applications (e.g., filtering, wicking fluids, pumping fluids, and storing reagents).
By stacking layers of patterned-paper and double-sided adhesive tape we can generate three dimensional (3D) microfluidic devices10 (Fig 7). 3D devices can distribute fluids within layers of paper and between adjacent layers of paper. Using 3D devices, it is possible to distribute samples from a single entry point into thousands of test spots where assays can take place.
Open Channel Paper Microfluidic Devices
We have fabricated pressure-driven, open-channel microfluidic systems in paper with lateral dimensions down to 45 microns. The open channel microfluidic devices are manufactured by, first, creating patterns by either carving7 or by embossing15 the paper, to create the channels (Fig 8). Vapor phase silanization then renders paper omniphobic, but preserves its high gas permeability and mechanical properties. The paper is then sealed with tape so that the channels form conduits capable of guiding liquid. These devices are compatible with complex fluids such as droplets of water in oil. The porosity of the paper to gases allows processes not possible in devices made using PDMS or other nonporous materials. Droplet generators and phase separators, for example, could be madeâ€¨by embossing “T”-shaped channels on paper. Vertical stacking of embossed, or cut layers, of omniphobic paper can generate 3D systems of microchannels.
ELECTRONIC AND ELECTROCHEMICAL DEVICES
Printed Electrochemical Devices
We have developed microfluidic paper-based electrochemical devices (µPEDs) that are comparable in function to commercial electrochemical cells, but are a fraction of the cost, and disposable. µPEDs comprise paper microfluidic channels that direct the liquid to printed carbon and Ag/AgCl electrodes for electrochemical detection. We have created µPEDs with reference electrodes that allow well-defined electrochemical potentials16, for accurate voltammetric measurements (Fig 9), and potentiometric measurements.17
µPEDs are capable of quantitatively detecting various analytes (e.g., heavy metals, glucose, and various ions) in aqueous solutions, including biological fluids such as urine, serum and blood. These one time use disposable systems can be easily interfaced with other electronic devices, such as commercial glucometers or proprietary designed electronics to perform measurements and transmit data18,19.
We have fabricated flexible electronic circuits on paper (Fig10,11,12). The circuits comprise typically patterned metallic wires on paper, and discrete surface-mountable electronic components that are fastened directly to the wires with conductive adhesive. Four examples of our work in this area are:
1) Paper touch pads were constructed from a commercially available, metallized paper.20
2) Electronic display that is fabricated by patterning electrically conductive wires (heaters) on one side of paper, and thermochromic ink on the opposite side.21
3) Paper-based three-dimensional electronic circuits (Fig 10) that are thin and lightweight; they should be useful for applications in consumer electronics and packaging, and for disposable systems. Unlike printed circuit boards, paper can be folded and creased, to form complex 3D structures, and disposed of by incineration22.
4) Hydrophobic (“RF paper”) was used as a substrate for inkjet printing of aqueous inks that are the precursors of electrically conductive patterns (Fig 11). By controlling the surface chemistry of the paper, it is possible to print high resolution, conductive patterns that remain conductive after folding and exposure to common solvents23.
Paper Microelectromechanical Systems (MEMS)
By combining the mechanical properties of paper with electronic control or feedback we developed paper MEMS. We have fabricated force sensors that were constructed using paper as the structural material. The working principle of the sensors are based on the piezoresistive effect generated by conductive materials patterned on a paper substrate24. We have fabricated force sensors, paper-based weighing balance24, and cantilever-type MEMS deflection sensors (Fig 12).23
- Martinez, R. V, Fish, C. R., Chen, X. & Whitesides, G. M. "Elastomeric Origamiâ€¯: Programmable Paper-Elastomer Composites as Pneumatic Actuators", 1376–1384 (2012). doi:10.1002/adfm.201102978
- Mosadegh, B., Dabriri.B.E., Lockett.M., Derda.R., Campbell.P., Parker.K.K., and Whitesides.G.M., "Three-Dimensional Paper-Based Model for Cardiac Ischemia", 1036–1043 (2014). doi:10.1002/adhm.201300575
- Derda, R., Tang.S.K.Y., Laromaine.A., Mosadegh.B., Hong.E., Thuo.M.M., Mammoto.A., Ingber.D.E., and Whitesides.G.M., "Multizone Paper Platform for 3D Cell Cultures", PLoS ONE, 2011, 6, e18940.
- Mosadegh, B., Lockett.M.R., Minn.K.T., Simon.K.A., Gilbert.K., Hillier.S., Newsome.D., Li.H., Hall.A.B., Boucher.D.M., Eustace.B.K., and Whitesides.G.M., "A paper-based invasion assayâ€¯: Assessing chemotaxis of cancer cells in gradients of oxygen", Biomaterials 52, 262–271 (2015).
- Glavan, A., Martinez.R.V., Subramaniam.A.B., Yoon.H.J., Nunes.R.M.D., Lange.H., Thuo.M.M., and Whitesides.G.M., "Omniphobic ‘rF paper’ produced by silanization of paper with fluoroalkyltrichlorosilanes", Adv. Funct. Mater. 24, 60–70 (2014).
- Glavan, A., Christodouleas.D.C, Mosadegh.B., Yu.H., Smith.B., Lessing.J., Fernandez-Abedul.M.T, and Whitesides.G.M, "Folding Analytical Devices for Electrochemical ELISA in Hydrophobic RH Paper", Analytical Chemistry, 2014, 86, 11999-12007. (2014).
- Glavan, A., Martinez.R.V., Maxwell.E.J., Subramaniam.A.B., Nunes.R.M.D., Soh.S., and Whitesides.G.M., "Rapid fabrication of pressure-driven open-channel microfluidic devices in omniphobic R(F) paper", Lab Chip 13, 2922–30 (2013).
- Maxwell, E. J., Mazzeo, A. D. & Whitesides, G. M. "Paper-based electroanalytical devices for accessible diagnostic testing", MRS Bull. 38, 309–314 (2013).
- Martinez, A. W., Phillips, S. T., Whitesides, G. M. & Carrilho, E. "Diagnostics for the developing world: microfluidic paper-based analytical devices", Anal. Chem. 82, 3–10 (2010).
- Martinez, A. W., Phillips, S. T. & Whitesides, G. M. "Three-dimensional microfluidic devices fabricated in layered paper and tape", Proc. Natl. Acad. Sci. U. S. A. 105, 19606–11 (2008).
- Ellerbee, A.K., Phillips, S.T., Siegel, A.C., Mirica, K.A., Martinez, A.W., Striehl, P., Jain, N., Prentiss, M., and Whitesides, G.M., "Quantifying colorimetric assays in paper-based microfluidic devices by measuring the transmission of light through paper", Anal. Chem. 81, 8447–8452 (2009).
- Martinez, A.W., Phillips, S.T., Nie, Z., Cheng, C., Carrilho, E., Wiley, B.J., and Whitesides, G.M., "Programmable diagnostic devices made from paper and tape", Lab Chip 10, 2499–2504 (2010).
- Martinez, A. W., Phillips, S. T., Wiley, B. J., Gupta, M. & Whitesides, G. M. "FLASHâ€¯: A rapid method for prototyping paper-based microfluidic devices" . Lab on a Chip, 2008, 8, 2146-2150. doi:10.1039/b811135a
- Carrilho, E., Martinez, A. W. & Whitesides, G. M. "Understanding wax printing: a simple micropatterning process for paper-based microfluidics", Anal. Chem. 81, 7091–5 (2009).
- Thuo, M.M., Martinez.R.V., Lan.W., Liu.X., Barber.J.R., Atkinson.M.B.J., Bandarage.D.C., Bloch.J., and Whitesides.G.M., "Fabrication of low-cost paper-based microfluidic devices by embossing or cut-and-stack methods", Chem. Mater. 26, 4230–4237 (2014).
- Lan, W., Maxwell.E.J., Parolo.C., Bwambok.D.K., Subramaniam.A.B., and Whitesides.G.M., "Paper-based electroanalytical devices with an integrated, stable reference electrode", Lab Chip 13, 4103–8 (2013).
- Lan, W., Zou.X.U, Hamedi.M.M, Hu.J., Parolo.C., Maxwell.E.J, Buhlmann.P., and Whitesides.G.M, "Paper-Based Potentiometric Ion Sensing", Anal. Chem. 86, 9548−9553, (2014).
- Nie, Z., Deiss, F., Liu, X., Akbulut, O. & Whitesides, G. M. "Integration of paper-based microfluidic devices with commercial electrochemical readers", Lab Chip 10, 3163–9 (2010).
- Nemiroski, A., Christodouleas.D.C, Hennek.J.W, Kumar.A.A, Maxwell.E.J, Fernandez-Abedul.M.T, and Whitesides.G.M., "Universal mobile electrochemical detector designed for use in resource-limited applications", Proc. Natl. Acad. Sci. 111, 11984-11989 (2014).
- Mazzeo, A.D., Kalb.W.B., Chan.L., Killian.M.G., Bloch.J-F., Mazzeo.B.A., and Whitesides.G.M.,"Paper-Based , Capacitive Touch Pads", 2850–2856 (2012). doi:10.1002/adma.201200137
- Siegel, A. C., Phillips, S. T., Wiley, J. & Whitesides, G. M. "Thin , lightweight , foldable thermochromic displays on paper", Lab on a Chip, 9, 2775-2781 (2009).
- Siegel, A.C., Phillips, S.T., Dickey, M.D., Lu, N., Suo, Z., and Whitesides, G.M., "Foldable printed circuit boards on paper substrates", Adv. Funct. Mater. 20, 28–35 (2010).
- Lessing, J., Glavan.A., Walker.S.B., Keplinger.C., Lewis.J.A., and Whitesides.G.M., "Inkjet printing of conductive inks with high lateral resolution on omniphobic ‘R(F) paper’ for paper-based electronics and MEMS", Adv. Mater. 26, 4677–82 (2014).
- Liu, X., Mwangi, M., Li, X., O’Brien, M. & Whitesides, G. M. "Paper-based piezoresistive MEMS sensors", Lab Chip 11, 2189–96 (2011).