Priscilla Kailian Ang1,2, Wong Cheng Lee3,4, Kian Ping Loh1,2,3 and Chwee Teck Lim2,3,4,5
National University of Singapore
Being the cornerstone of all living organisms, the living cell determines health and sickness, life and death. Therefore, designing an autonomous wearable or implantable smart medical device (SMD) that obtains information from such living entities and conveys it to electronic systems to assist, augment or restore impaired cognitive, cardiac, motor and homeostatic functions holds key to the betterment of mankind – all within the size range of a living cell. In this respect, having a single carbon nanomaterial that could boost performance in the size, operational, communication and energy aspects of such an SMD is highly desirable. In fact, since 2004, scientists are steadily fulfilling this goal with graphene, a two-dimensional, single-atom-thick sheet of sp2 hybridized carbon nanomaterial.
The key question is: how does graphene aid in the development of SMD? Graphene, amidst its carbon counterparts such as fullerene, CNT and diamond, displays superior functionalities stemming from its versatility to tune its electronic, electrochemical, optical, mechanical and thermal properties simply by modifying the lateral dimension, number of layers, stiffness, defect density and chemical composition. This gives rise to various graphene-related materials, such as graphene quantum dots (Lu et al., 2011), graphene nanoparticles (Li et al., 2012), graphene nanoribbon (Parashar et al., 2011), graphene nanosheets (Zhang et al., 2011), few-layer graphene and chemically processed graphene (Ang et al., 2009), which can boost the performance, biocompatibility and chemical stability of SMDs. The striking advantages of pristine graphene hinge on its atomic structure, giving rise to its two-dimensionality, atomic thinness and high electrical conductivity – properties which are advantageous for scaling of nanoelectronic devices (Schwierz 2010). On the other hand, from a chemist’s viewpoint, graphene is a giant “poly-molecule” amenable to a library of chemical reactions (Loh et al., 2010), resulting in composite hybrid materials possessing novel physical, chemical and electrical properties. By tuning its lateral dimension and chemical functional groups, graphene can be used in a broad spectrum of biomedical and engineering applications.
Here, we place a central focus on how graphene can be incorporated in an autonomous SMD. In particular, we witness how the unique properties of graphene and graphene-related materials, such as biocompatibility, chemical stability, mechanical robustness, conformity, lightweight, optical transparency, high surface area, electrical sensitivity, energy storage and harvesting capabilities, bear pivotal importance for the advancement of SMDs.
Sensing applications of graphene
A sensor converts an external physical stimulus, which can take the form of a chemical (ions and molecules), electrical (potential gradient), optical (luminescence) or thermal change, into a distinguishable and processable signal. The fundamental sensitivity limit of the sensor hinges on the intimate coupling with bio-entities and the signal-to-noise ratio. Graphene and its derivatives establish excellent communication between biotic and abiotic system because of its stable interaction with bio-entities (e.g. DNA, lipids, proteins and cells) (Lu et al., 2012; Ryoo et al., 2010; Singh et al., 2012), high adsorption capacity for biorecognition proteins and target molecules (Zhang et al., 2011), and high sensitivity since every carbon atom in graphene responds to changes induced by bio-entities enabling single molecule detection such as each nucleobase in deoxyribonucleic acids (DNA) (Merchant et al., 2010). In particular, graphene accurately detects the presence of electrically charged and electroactive bio-entities (Dong et al., 2010), enables fluorescence molecular detection (Shen et al., 2012), responds precisely to changes in the ionic environment of the cell specific to cellular activity such as the electrical activity of beating cardiomyocytes (Cohen-Karni et al., 2010) and forms a stable interface with neuronal cells (Heo et al., 2011). Capitalizing on the electrical sensitivity of graphene, harmful micro-organisms (Mannoor et al., 2012) and diseased cells (Swierczewska et al., 2012) are also detected. These attributes reinforce the unique selling point of graphene as the sensor unit in SMD.
Graphene electronic circuits
The intelligence of the autonomous SMD is derived from the memory and logic components, which are responsible for data processing, information storage and communication with external devices. As memory and logic devices are expected to be scaled to smaller dimensions and yet achieve nonvolatile memory, large storage density, fast switching speed, high-fidelity transmission of information and low power consumption with minimal heat generation, the scaling and performance of current devices are hitting fundamental limits. However, graphene offers new hopes as performance improvements with added device flexibility are evident for graphene-based memory and logic devices (Sordan et al., 2009; Jeong et al., 2010). On the other hand, wireless communication is an essential feature of SMDs and having an ultra-small communication system is desirable for wireless body area network (BAN). A basic wireless communication system consists of a transmitter and receiver, with the most common operational electromagnetic wavelength in the radio frequency (RF) range.
Graphene has made significant strides in RF communications (Moon et al., 2012). Unlike organic semiconductors plagued by low carrier mobility, graphene is good for high frequency low noise amplifiers (Das et al., 2011), which are used for fast communicating devices with low power consumption. The ambipolarity of graphene is also explored in RF mixed-signal applications such as full wave rectifiers (Han et al., 2009), frequency multipliers (Han et al., 2010) and mixers (Han et al., 2010). Prior to the discovery of graphene, these RF mixed-signal applications would require a full bridge circuit and several conventional diodes (Sung-Yong et al., 2006) for zero-volt rectification (Palacios et al., 2010). Besides facilitating a wireless sensing readout, in which changes in conductance can be correlated to changes in frequency and bandwidth of the sensor resonance, RF communication also enables battery-free powering of the SMD by inductive coupling between RF antennas and transmitters (Mannoor et al., 2012). Recently, the terahertz (1012 Hz or THz) region is gaining interest. With relatively small wavelengths in the millimeter to micrometer range, antennas built on THz technology will dramatically decrease in size. Electrically tunable THz modulation is of particular advantage in wireless communications and this can be easily achieved by graphene, unlike metal gates. Besides modulating THz transmission, graphene plasmons are more easily tunable than metallic ones, thus enables frequency selection of optical antennas with the added advantage of stronger electric field enhancement factor (Liu et al., 2012). Additionally, THz radiation is found to be emitted from the electron-hole plasma in optically pumped graphene and this makes graphene a viable source for THz emission (Prechtel et al., 2012).
Graphene-based energy sources
Continuous monitoring systems built into SMDs heavily rely on a continuous supply of energy for long-term powering. Other than conventional energy sources such as batteries and supercapacitors (Sun et al., 2011), emerging technologies that derive energy from body fluids (e.g. graphene-based biofuel cells (Sharma et al., 2011)), body heat (e.g. graphene-based thermoelectric generators (Xiao et al., 2011)) and body movements (e.g. graphene-based piezoelectric generators (Ong et al., 2012)) are also viable energy sources. Because the size of SMDs is mainly constrained by the size of their energy sources, approaches that can scale energy sources and deliver higher power density are been actively pursued. Graphene is positioned as a key material for this quest. Being extremely light and thin, it could deliver the highest gravimetric energy density (J/g) and the highest volumetric energy density (J/cm3), respectively. The energy storage capability of graphene and its derivatives has been capitalized in the construction of lithium (Li) ion batteries and supercapacitors. The two-dimensional membrane structure, flexibility, electrical conductivity and chemical versatility, coupled with easy integration with nanoparticles (Wu et al., 2012) or nanopillars (Ji et al., 2011) and easy engineering of porosity (Zhao et al., 2011) resulting in high in-plane and edge defect density, are attributes of graphene to create Li ion batteries that exhibit highly reversible specific capacity, enhanced rate capability and charge/discharge cycling stability, with added incentives of flexibility and printability (Wei et al., 2011). Graphene and its related materials are particularly attractive for a battery-supercapacitor hybrid energy source since they can be chemically functionalized to increase surface area for charge storage (Brownson et al., 2011).
It is highly desirable to create a miniaturized and autonomous graphene-based system-on-a-chip SMD that could periodically check the health of cells and report cellular activities to an external monitoring system to prevent the onset of diseases and improve the quality of life. We believe that scaling of a fully functional and flexible system comprising the sensing electrode, memory and logic unit, communication antennas and transmitters as well as energy sources could be realized with the incorporation of graphene. Graphene bioelectronics will certainly revolutionize the landscape of electronics and the medical industry in the years to come.
1 Department of Chemistry, National University of Singapore
2 NUS Graphene Research Centre
3 NGS Graduate School, National University of Singapore
4 Department of Bioengineering, National University of Singapore
5 Mechanobiology Institute, National University of Singapore
- Cohen-Karni, T., Qing, Q., Li, Q., Fang, Y., and Lieber, C.M. (2010). Graphene and nanowire transistors for cellular interfaces and electrical recording. Nano Lett 10, 1098-1102.
- Gao, C., Guo, Z., Liu, J.-H., and Huang, X.-J. (2012). The new age of carbon nanotubes: An updated review of functionalized carbon nanotubes in electrochemical sensors. Nanoscale 4, 1948-1963.
- Jha, N. and Ramaprabhu, S. (2010). Development of Au nanoparticles dispersed carbon nanotube-based biosensor for the detection of paraoxon. Nanoscale 2, 806-810.
- Occhipinti, E., Verderio, P., Natalello, A., Galbiati, E., Colombo, M., Mazzucchelli, S., Salvade, A., Tortora, P., Doglia, S.M., and Prosperi, D. (2011). Investigating the structural biofunctionality of antibodies conjugated to magnetic nanoparticles. Nanoscale 3, 387-390.
- Thalhammer, A., Edgington, R.J., Cingolani, L.A., Schoepfer, R., and Jackman, R.B. (2010). The use of nanodiamond monolayer coatings to promote the formation of functional neuronal networks. Biomaterials 31, 2097-2104.
- Kuila, T., Bose, S., Khanra, P., Mishra, A.K., Kim, N.H., and Lee, J.H. (2011). Recent advances in graphene-based biosensors. Biosens Bioelectron 26, 4637-4648.
- Zhang, Y., Nayak, T.R., Hong, H., and Cai, W. (2012). Graphene: a versatile nanoplatform for biomedical applications. Nanoscale
- Lu, J., Yeo, P.S.E., Gan, C.K., Wu, P., and Loh, K.P. (2011). Transforming C60 molecules into graphene quantum dots. Nat Nano 6, 247- 252.
- Li, J.-L., Bao, H.-C., Hou, X.-L., Sun, L., Wang, X.-G., and Gu, M. (2012). Graphene Oxide Nanoparticles as a Nonbleaching Optical Probe for Two-Photon Luminescence Imaging and Cell Therapy. Angewandte Chemie International Edition 51, 1830-1834.
- Parashar, U.K., Bhandari, S., Srivastava, R.K., Jariwala, D., and Srivastava, A. (2011). Single step synthesis of graphene nanoribbons by catalyst particle size dependent cutting of multiwalled carbon nanotubes. Nanoscale 3, 3876-3882.
- Zhang, S., Xiong, P., Yang, X., and Wang, X. (2011). Novel PEG functionalized graphene nanosheets: enhancement of dispersibility and thermal stability. Nanoscale 3, 2169-2174.
- Ang, P.K., Wang, S., Bao, Q., Thong, J.T., and Loh, K.P. (2009). High-throughput synthesis of graphene by intercalation-exfoliation of graphite oxide and study of ionic screening in graphene transistor. ACS Nano 3, 3587-3594.
- Schwierz, F. (2010). Graphene transistors. Nat. Nanotechnol. 5, 487-496.
- Loh, K.P., Bao, Q., Ang, P.K., and Yang, J. (2010). The chemistry of graphene. Journal of Materials Chemistry 20, 2277-2289.
- Lu, B., Li, T., Zhao, H., Li, X., Gao, C., Zhang, S., and Xie, E. (2012). Graphene-based composite materials beneficial to wound healing. Nanoscale 4, 2978-2982.
- Ryoo, S.-R., Kim, Y.-K., Kim, M.-H., and Min, D.-H. (2010). Behaviors of NIH-3T3 Fibroblasts on Graphene/Carbon Nanotubes: Proliferation, Focal Adhesion, and Gene Transfection Studies. ACS Nano 4, 6587-6598.
- Singh, S.K., Singh, M.K., Kulkarni, P.P., Sonkar, V.K., Grácio, J.J.A., and Dash, D. (2012). Amine-Modified Graphene: Thrombo-Protective Safer Alternative to Graphene Oxide for Biomedical Applications. ACS Nano 6, 2731-2740.
- Zhang, M., Yin, B.-C., Wang, X.-F., and Ye, B.-C. (2011). Interaction of peptides with graphene oxide and its application for real-time monitoring of protease activity. Chemical Communications 47, 2399-2401.
- Merchant, C.A., Healy, K., Wanunu, M., Ray, V., Peterman, N., Bartel, J., Fischbein, M.D., Venta, K., Luo, Z., Johnson, A.T.C., and Drndic, M. (2010). DNA Translocation through Graphene Nanopores. Nano Letters 10, 2915-2921.
- Dong, X., Shi, Y., Huang, W., Chen, P., and Li, L.-J. (2010). Electrical Detection of DNA Hybridization with Single-Base Specificity Using Transistors Based on CVD-Grown Graphene Sheets. Advanced Materials 22, 1649-1653.
- Shen, J., Zhu, Y., Yang, X., and Li, C. (2012). Graphene quantum dots: emergent nanolights for bioimaging, sensors, catalysis and photovoltaic devices. Chemical Communications 48, 3686-3699.
- Heo, C., Yoo, J., Lee, S., Jo, A., Jung, S., Yoo, H., Lee, Y.H., and Suh, M. (2011). The control of neural cell-to-cell interactions through non-contact electrical field stimulation using graphene electrodes. Biomaterials 32, 19-27.
- Mannoor, M.S., Tao, H., Clayton, J.D., Sengupta, A., Kaplan, D.L., Naik, R.R., Verma, N., Omenetto, F.G., and McAlpine, M.C. (2012). Graphene-based wireless bacteria detection on tooth enamel. Nature Communications 3, 763.
- Swierczewska, M., Liu, G., Lee, S., and Chen, X. (2012). High-sensitivity nanosensors for biomarker detection. Chemical Society Reviews 41, 2641-2655.
- Sordan, R., Traversi, F., and Russo, V. (2009). Logic gates with a single graphene transistor. Applied Physics Letters 94, 073305-073303.
- Jeong, H.Y., Kim, J.Y., Kim, J.W., Hwang, J.O., Kim, J.-E., Lee, J.Y., Yoon, T.H., Cho, B.J., Kim, S.O., Ruoff, R.S., and Choi, S.-Y. (2010). Graphene Oxide Thin Films for Flexible Nonvolatile Memory Applications. Nano Letters 10, 4381-4386.
- Moon, J.S., Antcliffe, M., Seo, H.C., Lin, S.C., Schmitz, A., Milosavljevic, I., McCalla, K., Wong, D., Gaskill, D.K., Campbell, P.M., Lee, K.M., and Asbeck, P. (2012) Graphene review: An emerging RF technology. In Silicon Monolithic Integrated Circuits in RF Systems (SiRF), 2012 IEEE 12th Topical Meeting on, pp. 199-202
- Das, S. and Appenzeller, J. (2011) An all-graphene radio frequency low noise amplifier. In Radio Frequency Integrated Circuits Symposium (RFIC), 2011 IEEE, pp. 1-4
- Han, W., Nezich, D., Jing, K., and Palacios, T. (2009). Graphene Frequency Multipliers. Electron Device Letters, IEEE 30, 547-549.
- Han, W., Hsu, A., Ki Kang, K., Jing, K., and Palacios, T. (2010) Gigahertz ambipolar frequency multiplier based on CVD graphene. In Electron Devices Meeting (IEDM), 2010 IEEE International, pp. 23.26.21-23.26.24
- Han, W., Hsu, A., Wu, J., Jing, K., and Palacios, T. (2010). Graphene-Based Ambipolar RF Mixers. Electron Device Letters, IEEE 31, 906- 908.
- Sung-Yong, C., Ronghua, Y., Niu, J., Si-Young, P., Berger, P.R., and Thompson, P.E. (2006). Si/SiGe resonant interband tunnel diode with fr0 20.2 GHz and peak current density 218 kA/cm2 for K-band mixed-signal applications. Electron Device Letters, IEEE 27, 364-367.
- Palacios, T., Hsu, A., and Han, W. (2010). Applications of graphene devices in RF communications. Communications Magazine, IEEE 48, 122-128.
- Liu, P., Cai, W., Wang, L., Zhang, X., and Xu, J. (2012). Tunable terahertz optical antennas based on graphene ring structures. Applied Physics Letters 100, 153111-153115.
- Prechtel, L., Song, L., Schuh, D., Ajayan, P., Wegscheider, W., and Holleitner, A.W. (2012). Time-resolved ultrafast photocurrents and terahertz generation in freely suspended graphene. Nat Commun 3, 646.
- Sun, Y., Wu, Q., and Shi, G. (2011). Graphene based new energy materials. Energy & Environmental Science 4, 1113-1132.
- Sharma, T., Hu, Y., Stoller, M., Feldman, M., Ruoff, R.S., Ferrari, M., and Zhang, X. (2011). Mesoporous silica as a membrane for ultra-thin implantable direct glucose fuel cells. Lab on a Chip 11, 2460-2465.
- Xiao, N., Dong, X., Song, L., Liu, D., Tay, Y., Wu, S., Li, L.-J., Zhao, Y., Yu, T., Zhang, H., Huang, W., Hng, H.H., Ajayan, P.M., and Yan, Q. (2011). Enhanced Thermopower of Graphene Films with Oxygen Plasma Treatment. ACS Nano 5, 2749-2755.
- Ong, M.T. and Reed, E.J. (2012). Engineered Piezoelectricity in Graphene. ACS Nano 6, 1387-1394.
- Wu, Z.-S., Xue, L., Ren, W., Li, F., Wen, L., and Cheng, H.-M. (2012). A LiF Nanoparticle-Modified Graphene Electrode for High-Power and High-Energy Lithium Ion Batteries. Advanced Functional Materials
- Ji, L., Tan, Z., Kuykendall, T., An, E.J., Fu, Y., Battaglia, V., and Zhang, Y. (2011). Multilayer nanoassembly of Sn-nanopillar arrays sandwiched between graphene layers for high-capacity lithium storage. Energy & Environmental Science 4, 3611-3616.
- Zhao, X., Hayner, C.M., Kung, M.C., and Kung, H.H. (2011). Flexible Holey Graphene Paper Electrodes with Enhanced Rate Capability for Energy Storage Applications. ACS Nano 5, 8739-8749.
- Wei, D., Andrew, P., Yang, H., Jiang, Y., Li, F., Shan, C., Ruan, W., Han, D., Niu, L., Bower, C., Ryhanen, T., Rouvala, M., Amaratunga, G.A.J., and Ivaska, A. (2011). Flexible solid state lithium batteries based on graphene inks. Journal of Materials Chemistry 21, 9762-9767.
- Brownson, D.A.C., Kampouris, D.K., and Banks, C.E. (2011). An overview of graphene in energy production and storage applications. Journal of Power Sources 196, 4873-4885.
- Yan, L., Zhao, F., Li, S., Hu, Z., and Zhao, Y. (2011). Low-toxic and safe nanomaterials by surface-chemical design, carbon nanotubes, fullerenes, metallofullerenes, and graphenes. Nanoscale 3, 362-382.
About the Authors
Lim Chwee Teck is a Professor of Bioengineering at the National University of Singapore. His research interest is in micro- and nanobiotechnology. Prof Lim has authored more than 200 journal papers and delivered more than 190 invited talks. He has also won several awards and honors including the Wall Street Journal Asian Innovation Award (finalist), TechVenture Most Disruptive Innovation Award and Asian Entrepreneurship Award in 2012, President’s Technology Award in 2011 and IES Prestigious Engineering Achievement Award in 2010. His research was featured by the MIT Technology Review magazine as one of the top ten emerging technologies of 2006 that will “have a significant impact on business, medicine or culture”.
Kian Ping Loh is a Professor and also Department Head of Chemistry at the National University of Singapore. He works on functional carbon materials research and focuses on solar cell, optical and biomedical applications of diamond and graphene. The expertise in his group includes large area fabrication of graphene films by chemical vapor deposition, synthesis of solution-processed and printable graphene electronics. He has published more than 250 journal papers including in Nature Communications, Nature Nanotechnology and Nature Photonics. Prof Loh has received numerous awards including the Faculty Young Scientist Award 2007, University Young Scientist Award 2008, Faculty Outstanding Scientist Award in 2011 and the University Outstanding Researcher Award 2012.He has an established track record on functional carbon materials research, focusing on solar cell and optical applications of diamond and graphene. The expertise of his group ranges from optical studies of advanced functional carbon materials, design and synthesis of organic dyes, molecular electronics to solar cells and surface science. The expertise in his group now includes the large area fabrication of graphene films by chemical vapor deposition, synthesis of solution-processed and printable graphene electronics, synthesis of organic dye-derivatized graphene, graphene-titania composites, with a view towards applications in solar cells.
Breakthroughs in his research include the fabrication of organic solar cell on transparent and conducting, large area graphene electrodes, and the first demonstration of wide band mode locking on atomic layer graphene. He has won the University Young Researcher Award in 2008 and the Outstanding Chemist Award in 2009.
Priscilla Kailian Ang obtained her Doctor of Philosophy and Bachelor of Science degree (First Class Honours) in Chemistry from the National University of Singapore in 2012 and 2008, respectively. She received the Outstanding Undergraduate Researcher Prize in 2008. She has worked with Professor Kian Ping Loh and Professor Chwee Teck Lim on developing dual-mode optical and electrical detection for toxic haemolytic agents and diseased cells on carbon platforms such as diamond and graphene. Her research interests focus on understanding the intricate interfacial interaction between graphene and biological entities and incorporating graphene in biomedical applications for the advancement of medical science.
Jacky Wong Cheng Lee obtained his Bachelor of Engineering degree (Upper Second Class Honours) in Bioengineering from the National University of Singapore in 2009. He is currently a graduate student under the NUS Graduate School for Integrative Sciences and Engineering program. He has won the Most Innovative Undergraduate Bioengineering Design Award in 2007 and the Engineering Innovation and Research Award in 2009. He has authored 8 peer-reviewed articles and 6 conference abstracts. His research interests include microfluidics cell separation for elucidating intrinsic heterogeneity in complex cell populations and nano-materials for improving stem cell differentiation for various tissue engineering applications.
Click here for the complete issue.