Article Cite This: Acc. Chem. Res. 2019, 52, 73−81
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Wearable and Implantable Soft Bioelectronics Using TwoDimensional Materials Published as part of the Accounts of Chemical Research special issue “Wearable Bioelectronics: Chemistry, Materials, Devices, and Systems”. Changsoon Choi,†,‡,⊥ Youngsik Lee,†,‡,⊥ Kyoung Won Cho,†,§ Ja Hoon Koo,†,§ and Dae-Hyeong Kim*,†,‡,§ †
Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 08826, Republic of Korea School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea § Interdisciplinary Program for Bioengineering, Seoul National University, Seoul 08826, Korea
Acc. Chem. Res. 2019.52:73-81. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/16/19. For personal use only.
‡
CONSPECTUS: Soft bioelectronics intended for application to wearable and implantable biomedical devices have attracted great attention from material scientists, device engineers, and clinicians because of their extremely soft mechanical properties that match with a variety of human organs and tissues, including the brain, heart, skin, eye, muscles, and neurons, as well as their wide diversity in device designs and biomedical functions that can be finely tuned for each specific case of applications. These unique features of the soft bioelectronics have allowed minimal mechanical and biological damage to organs and tissues integrated with bioelectronic devices and reduced side effects including inflammation, skin irritation, and immune responses even after long-term biointegration. These favorable properties for biointegration have enabled long-term monitoring of key biomedical indicators with high signal-to-noise ratio, reliable diagnosis of the patient’s health status, and in situ feedback therapy with high treatment efficacy optimized for the requirements of each specific disease model. These advantageous device functions and performances could be maximized by adopting novel high-quality soft nanomaterials, particularly ultrathin two-dimensional (2D) materials, for soft bioelectronics. Two-dimensional materials are emerging material candidates for the channels and electrodes in electronic devices (semiconductors and conductors, respectively). They can also be applied to various biosensors and therapeutic actuators in soft bioelectronics. The ultrathin vertically layered nanostructure, whose layer number can be controlled in the synthesis step, and the horizontally continuous planar molecular structure, which can be found over a large area, have conferred unique mechanical, electrical, and optical properties upon the 2D materials. The atomically thin nanostructure allows mechanical softness and flexibility and high optical transparency of the device, while the large-area continuous thin film structure allows efficient carrier transport within the 2D plane. In addition, the quantum confinement effect in the atomically thin 2D layers introduces interesting optoelectronic properties and superb photodetecting capabilities. When fabricated as soft bioelectronic devices, these interesting and useful material features of the 2D materials enable unconventional device functions in biological and optical sensing, as well as superb performance in electrical and biochemical therapeutic actuations. In this Account, we first summarize the distinctive characteristics of the 2D materials in terms of the mechanical, optical, chemical, electrical, and biomedical aspects and then present application examples of the 2D materials to soft bioelectronic devices based on each aforementioned unique material properties. Among various kinds of 2D materials, we particularly focus on graphene and MoS2. The advantageous material features of graphene and MoS2 include ultrathin thickness, facile functionalization, large surface-to-volume ratio, biocompatibility, superior photoabsorption, and high transparency, which allow the development of high-performance multifunctional soft bioelectronics, such as a wearable glucose patch, a highly sensitive humidity sensor, an ultrathin tactile sensor, a soft neural probe, a soft retinal prosthesis, a smart endoscope, and a cell culture platform. A brief comparison of their characteristics and performances is also provided. Finally, this Account concludes with a future outlook on next-generation soft bioelectronics based on 2D materials. ultrathin design9−11 that minimize tissue damage and immune responses upon their integration with target organs.12 For example, a silicone-encapsulated soft neural implant could
1. INTRODUCTION Soft bioelectronics, particularly for wearable1−3 and implantable4−6 biomedical applications, has gained special interest from material scientists, device engineers, and clinicians.7,8 The major grounds on which soft bioelectronics bring advantages to biomedical applications is their mechanical softness4,6 and © 2018 American Chemical Society
Received: September 27, 2018 Published: December 26, 2018 73
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Figure 1. Wearable and implantable soft bioelectronics using 2D materials. (A) Schematic illustration and photographs of 2D material-based soft bioelectronics. Reproduced with permission from refs 3, 20, 26, 27, 29, 32, 34, and 35. Copyright 2012, 2014, 2015, 2016, and 2018 Nature Publishing Group and 2015, 2016, and 2017 Wiley-VCH. (B) Scanning electron microscope (SEM) image of the large-area crumpled graphene nanosheet. Reproduced with permission from ref 21. Copyright 2013 Nature Publishing Group. (C) SEM image of MXene. Reproduced with permission from ref 39. Copyright 2018 Nature Publishing Group. (D) Photograph of the stretchable transistor using graphene and carbon nanotube. Reproduced with permission from ref 32. Copyright 2015 Wiley-VCH. (E) Microscope image of cultured myotubes on patterned graphene. Reproduced with permission from ref 28. Copyright 2015 American Chemical Society.
in each case of biomedical applications and then describe unique properties of 2D materials essential in developing these soft bioelectronics. Among various 2D materials, we particularly focus on graphene and MoS2, which are the most notable 2D materials used as ultrathin conductor and semiconductor, respectively. The deformability and high transparency of graphene, for example, have enabled fabrication of novel neural probes for optogenetics24 and smart endoscopes for theragnosis of cancers.26 Because graphene can be easily functionalized and can form a biocompatible interface with soft tissues, cells, and proteins, it could also be applied to wearable biosensing patches3 and cell culture and monitoring platforms.27,28 In the case of MoS2, it exhibits ultrathin thickness, superior photoabsorption, and piezoresistivity; hence, it could be applied to a high-density curved image sensor array for a soft retinal prosthesis9 and ultrathin wearable tactile sensors.10 Furthermore, the large surface-to-volume ratio and chemically active intrinsic defect sites of MoS2 have enabled a highly sensitive humidity sensor29 and nonvolatile memory.30 Finally, this Account concludes with a brief description of the future prospects for 2D materialbased soft bioelectronics.
facilitate rehabilitation of an animal that had leg motion dysfunction through spinal cord stimulation.6 In another case, a soft retinal prosthesis based on an ultrathin optoelectronic device could effectively stimulate retinal neurons in response to external light illumination to restore the vision of a blind animal.9 As such, the ultimate goal of the soft bioelectronics is to clinically implement deformable devices, whose mechanical properties are similar to soft human tissues, for diagnosis and treatment of diverse diseases.7,13 To achieve this goal, a variety of bioelectronic devices that employ soft materials have been proposed.6,8 Among many material candidates, ultrathin soft two-dimensional (2D) materials have been particularly highlighted,3,9,14 considering their unique mechanical,15,16 electrical,17 optical,18,19 and chemical3,20 properties that can be adapted to specific disease models. The most fascinating feature of 2D materials is their atomically thin nature that provides extraordinary softness and inherent flexibility to the devices.15,21 The quantum confinement effect induced by the atomically thin layered nanostructure also introduces interesting band structure and optoelectronic characteristics.18,22 High transparency23,24 and carrier transport properties25 are additional important advantages of 2D materials. Here, we review recent technological advances in soft bioelectronics using 2D materials with a particular focus on materials and devices. We first discuss device features required 74
DOI: 10.1021/acs.accounts.8b00491 Acc. Chem. Res. 2019, 52, 73−81
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Table 1. Characteristics of 2D Materials, Applications to Soft Bioelectronics, and Performance of the 2D Material-Based Soft Bioelectronic Devices 2D materials graphene
characteristics flexibility
transparency
functionalization large surface/volume ratio
biocompatibility
MoS2
superior photoabsorption softness piezoresistivity large surface/volume ratio
black phosphorus MXene
intrinsic defects hydrophilicity large surface/volume ratio layered structure
soft bioelectronic devices
performance
ref
wearable glucose patch ECoG sensor for optogenetics wearable touch sensor glucose monitoring lens smart endoscope for tumor theragnosis ECoG sensor for optogenetics wearable glucose patch glucose monitoring lens wireless bacteria sensor smart endoscope for tumor theragnosis cell-sheet−graphene hybrid ECoG sensor for optogenetics curved image sensor array soft retinal prosthesis ultrathin tactile sensor MoS2 bilayer strain gauge highly sensitive humidity sensor pH sensor streptavidin biosensor nonvolatile memory selective humidity sensor smart endoscope for tumor theragnosis
gauge factor ∼2.18 conformal contact to brain relative resistance 80% transparency >70% transparency >90% detection limit ∼10 μM detection limit ∼1 μM detection limit ∼1 bacterium/μL no apoptosis cell culture no apoptosis 12 × 12 imaging without IR noise 0.61 MPa stress to retina gauge factor ∼72.5 gauge factor ∼230 sensitivity ∼104 at 35% RH sensitivity ∼713/pH sensitivity ∼196 at 100 fM retention time ∼10000 s sensitivity ∼104 from 10% to 85% RH gauge factor ∼180.1
3 24 42 40 26 24 3 40 35 26 27 24 9 9 10 44 34 38 38 30 46 47
2. UNIQUE CHARACTERISTICS OF 2D MATERIALS FOR SOFT BIOELECTRONICS Soft bioelectronics are particularly highlighted because of their mechanical softness that matches with target organs and multifunctional sensing capabilities that are optimized for target diseases. Each diseased tissue has different mechanical characteristics and requires specialized biosensing and therapy capabilities. Soft bioelectronic devices, therefore, are optimized for each specific disease case,31 and these features enable precise monitoring of the disease-specific physiological,32 electrophysiological,5,14 and biochemical3,33 signals from the human body under long-term device−organ integration. In this aspect, the unique electrical, mechanical, optical, and chemical properties of 2D materials can be fully used for customizing diagnostic and therapeutic functions of the soft bioelectronics to specific disease models. The 2D material-based soft bioelectronics, therefore, have been highlighted in various wearable3,29,32 and implantable9,34,35 biomedical applications (Figure 1A). In this section, we first describe various functions and performances of the soft bioelectronics, suited for the specific disease model in each location of the body, and then summarize representative properties of 2D materials applied to soft bioelectronics to solve unmet biomedical challenges (Table 1). The human body consists of soft tissues with curvilinear shapes that dynamically move. The continued movement of the tissues, such as heart beating and lung expanding, causes mechanical perturbations to devices integrated with target organs.36 In particular, neural tissues are extremely soft (∼20 kPa) and viscoelastic and can be easily damaged by a stiff implant because of the mechanical mismatch between the tissue and the device.6,9,37 Therefore, conventional rigid and bulky medical devices are difficult to conformally integrate with the soft human body, particularly for long-term biointegration.7,13 In contrast, soft bioelectronic devices, whose mechanical properties are similar to human tissues,
can prevent unwanted mechanical damage by the implant and achieve conformal and robust contacts onto curvilinear and dynamically contorting organs.6,12 Two-dimensional materials are among the softest electronic building blocks for fabricating flexible and stretchable bioelectronic devices because of their atomically thin thickness.9,21 For example, graphene can be flexed and crumpled without deterioration of its original electrical performance, which cannot be achieved in conventional electronic materials (Figure 1B). Softness and flexibility increase as the device thickness decreases, minimizing the mechanical stress to the target tissues by the implanted device.9 Therefore, 2D material-based soft biomedical devices have been developed and were integrated with the curvilinear human body without immune responses.14,34 The graphenebased soft neural implant, for example, has extremely low stiffness, and hence it can minimize mechanical damage to the neural tissues while forming conformal integration to the brain (i; Figure 1A).24,34 In another example, an ultrathin graphenebased biosensor successfully detected bacteria at a single-cell level, as implemented on curved teeth (ii; Figure 1A).35 The human body secretes various biofluids containing biochemicals that provide diverse information about metabolism and chronic diseases.33 Biosensors monitor these biochemicals by measuring electrical signal changes induced by biochemicals at the sensor surface functionalized with receptors sensitive to target molecules.38 In these biosensors, the sensitivity needs to be improved to detect trace amounts of target biochemicals for accurate disease diagnosis. In general, the sensitivity depends on the surface-to-volume ratio of the biosensor. A larger surface-to-volume ratio leads to larger changes in electrical signals induced by adsorption of biochemicals.29 The adsorbed biochemicals to receptors on 2D materials induce larger signal changes than conventional bulky materials because 2D materials have an atom-level thickness (Figure 1C).39 Consequently, 2D material-based biosensors can detect the tiny amount of biochemicals with 75
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Figure 2. Characteristics of graphene and applications to soft bioelectronics. (A) Schematic illustration of soft graphene (left), photograph of flexible graphene-based neural probes (middle), and optogenetic stimulation through graphene-based neural probes (right). Reproduced with permission from ref 24. Copyright 2014 Nature Publishing Group. (B) Schematic illustration of transparent graphene (left), optical transparency of graphene, Ag nanowire, and graphene−Ag nanowire hybrid (middle), and tumor images captured by the camera in an endoscope with graphenebased and metal-based bioelectronic devices (right). Reproduced with permission from refs 26 and 40. Copyright 2015 and 2017 Nature Publishing Group. (C) Schematic illustration showing the functionalized surface of graphene (left), SEM image of graphene functionalized with metal-based dopant and functional polymer (middle), and photograph of graphene-based multifunctional sensors for diabetes patients (right). Reproduced with permission from ref 3. Copyright 2016 Nature Publishing Group. (D) Schematic illustration showing biocompatibility of graphene (left), microscopic image of aligned C2C12 myoblasts on buckled mesh-patterned graphene electrodes (middle), and hematoxylin and eosin stain histology of the hind limb implanted with the cell sheet−graphene hybrid (right). Reproduced with permission from ref 27. Copyright 2016 WileyVCH.
endoscope (v; Figure 1A).26 The sensors and ablation electrodes are transparent; thus, a surgeon can diagnose colon cancer and perform therapies without spatial misalignment. Meanwhile, wearable strain gauges using graphene and MoS2 have enabled transparent skin electronics, which quantitatively analyze dynamic daily body motion (vi; Figure 1A).10,32 Biocompatibility is also an important issue for long-term biointegration.12 Biocompatible interfaces between the implanted devices and the tissues enable continuous monitoring of biosignals with high signal-to-noise ratio under long-term biointegration by preventing the progressive increase in impedance caused by immune responses. Every material composing bioelectronic devices, therefore, should be biocompatible to avoid chronic immune responses.20 Graphene and MoS2 show good biocompatibility and form intimate interfaces with biological tissues (Figure 1E).20,28 For example, the excellent interface between the tissue and the graphenebased device enables high-quality biosensing and stimulation.
high sensitivity. For example, the wearable graphene-based glucose sensor can detect glucose concentrations of 10 μM (iii; Figure 1A),3 and the MoS2-based humidity sensor shows a high sensitivity of more than 104 (iv; Figure 1A).29 Another material property useful for soft bioelectronics is transparency.21,34 Opaque wearable electronics attached to the skin cause visual discomfort to the user.37 In addition, metalbased devices integrated on minimally invasive surgical tools, such as the surgical endoscope, may disturb the camera vision because of opaqueness of the mounted device, and hence cause a spatial misalignment between the tissues observed through the camera and the characterized or stimulated tissues by the sensors and actuators during surgical procedures.26 Instead of opaque electronic materials, 2D materials, which are transparent because of their atomically thin thickness, can be used (Figure 1D).32 Most of the incoming light is transmitted without absorption. Graphene-based transparent bioelectronic devices, including tumor, pH, and viability sensors, for example, have been integrated on the camera lens of a surgical 76
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Accounts of Chemical Research The graphene electrodes were integrated with C2C12 cell sheets and formed a biocompatible interface for electrophysiological sensing and electropharmaceutical actuation (vii; Figure 1A).27 In another example, biodegradable sensors using MoS2 monolayer were applied to the transient electronic system. This MoS2-based biodegradable sensor monitored intracranial pressure, temperature, strain, and motion of animals and then disappeared through hydrolysis in biofluids without any side effects due to its low toxicity (viii; Figure 1A).20
Much effort has been made to realize biosensing systems detecting an extremely small amount of biomolecules and classifying many different types of target molecules.33 Various surface functionalization methods using target-specific receptors such as antibodies,35 enzymes,33 and pH-responsive oxides or polymers,3 as well as various sensing mechanisms such as sensing of impedance, capacitance, resistance, and open-circuit potential and field-effect transistor (FET)-type amplified sensing can be easily adapted to graphene-based biosensors. This is because of π−π orbital interactions between graphene’s carbon hexagonal rings and external functional groups for biosensing (Figure 2C, left). Furthermore, graphene is compatible with conventional semiconductor device fabrication processes, which enables mass production. Many studies have shown that different types of functionalization methods and sensing mechanisms have improved the sensitivity and detection limit of graphene-based biosensors (Figure 2C, middle).3 For example, graphene-based multifunctional biosensors show high sensitivities and hence detect a trace amount of glucose in sweat accurately (Figure 2C, right).3 These flexible and stretchable biosensors have huge potential to monitor various biochemical concentrations directly from the human body to diagnose the conditions of patients in real time. Biocompatibility is one of the most important issues for bioelectronic devices. Conventional electronic devices may cause tissue damage, such as scars or inflammation, upon biointegration mainly caused by their rigid and bulky features and material toxicity. However, graphene hardly induces such harmful responses in contact with the biological tissues because it is extremely thin, soft, and biocompatible (Figure 2D, left). For example, muscle cells could be cultured on graphene electrodes with buckled topology. The line-and-space specific pattern of graphene can induce alignment of cultured cells, which is similar to native biological tissues (Figure 2D, middle).27 The graphene electrodes integrated with a cultured cell sheet offer an improved interface of the implanted device with tissues near the implantation site (Figure 2D, right).27 This cell-sheet−graphene hybrid was transplanted into the target muscle of the animal, successfully measured electromyogram without immune responses, and electrically stimulated the tissue for long-term therapy.
3. SOFT BIOELECTRONICS USING GRAPHENE Graphene is one of the most highlighted 2D materials in soft bioelectronics. The unique characteristics of graphene, such as softness,24 flexibility,32 transparency,26,40 facile functionalization,3 and biocompatibility,27 enable extraordinary and unconventional device performance. This section discusses characteristics of graphene and its application to soft bioelectronics. Graphene consists of layers of a uniform hexagonal structure of carbon atoms, whose individual layer thickness is only a few angstroms.25 Graphene has a unique band structure in which the valence and conduction band have an overlap at the Dirac point; thus, it simultaneously presents characteristics of a metal and a semiconductor (i.e., a zero-gap semiconductor), which also induces extremely fast carrier mobility. In addition, higher electrical and thermal conductivity can be obtained by controlling the thickness of graphene and applying doping to graphene. Also, graphene exhibits low stiffness (i.e., excellent flexibility) because of its ultrathin thickness, thereby showing exceptional mechanical softness that is a huge advantage for wearable and implantable biomedical applications (Figure 2A, left and middle).32,41 Because of the mechanical softness and deformability of graphene, graphene-based devices achieve conformal biointegration with target organs, such as the brain,34 skin,42 and eyes,41 without mechanical distortion and chronic immune responses (Figure 2A, right). The high signalto-noise ratio based on the low impedance caused by conformal integration and the efficient signal transmission based on high electrical conductivity allow high-quality recording of electrophysiological signals from the brain with high temporal and spatial resolution.34 The graphene-based devices can also measure other biological signals, including electrocardiogram, electromyogram, tissue strain, and biochemicals like glucose levels, with a high signal-to-noise ratio for a long period.3,24 Graphene shows high optical transparency of over 95% because most photons pass through ultrathin graphene layers without absorption (Figure 2B, left and middle).40 Although bulk graphene (i.e., graphite) has high opacity because of its low energy conical band structure, single layer graphene’s ultrathin thickness makes it optically transparent. Therefore, graphene-based devices have been recently applied for transparent bioelectronic devices that need to measure biosignals while avoiding visual disturbance on a camera module. For example, clear images of tumor tissues could be obtained through the camera lens with graphene-based sensors and actuators for tumor diagnosis and treatment, which is not available for metal-based devices (Figure 2B, right).26 In another example, a smart contact lens integrated with graphene-based biosensors monitors the glucose concentration within tears, as well as the intraocular pressure, without obstructing the vision.40,41
4. SOFT BIOELECTRONICS USING MoS2 Graphene is used as a flexible and transparent conductor for soft bioelectronic applications because of its high carrier mobility. However, the relatively low on/off ratio of graphene FET derived from zero-gap structure limits its applicability in biomedical devices that require semiconducting properties such as high on/off ratio. In this regard, MoS2 has been highlighted as a resourceful 2D material for soft bioelectronics because of its band gap (1.8 eV for monolayer and 1.2 eV for bulk), which provides unique optical18 and electrical17 properties hardly found in graphene. This section discusses distinctive material features of MoS2 and its application to soft bioelectronics and optoelectronics. One advantage of layered transition metal dichalcogenides for optoelectronic applications is the strong light−matter interaction upon irradiation by an optical source, which results in superior photoabsorption and photocurrent generation.22 This interaction is due to the spatial confinement effect and reduced screening effect caused by the 2D confined nanostructure.18 In particular, 2D layers of MoS2 exhibit 77
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Figure 3. Characteristics of MoS2 and applications to soft bioelectronics. (A) Schematic illustration showing superior photoabsorption of MoS2 (left), transfer curve of the MoS2-based phototransistor under different irradiation intensities (middle), and photograph of a high-density curved image sensor array based on the MoS2−graphene heterostructure (right). The inset shows the image captured by the curved image sensor array. Reproduced with permission from ref 9. Copyright 2017 Nature Publishing Group. (B) Schematic showing the band gap modulation in the bilayer MoS2 by tensile strain (left), characteristic curve of the MoS2-based tactile sensor under different pressures (middle), and photograph of the ultrathin MoS2-based tactile sensor attached on the fingertip (right). Reproduced with permission from ref 10. Copyright 2016 Wiley-VCH. (C) Schematic illustration showing the large surface-to-volume ratio of MoS2 (left), real-time humidity sensing of the MoS2 FET (middle), and schematic illustration of the MoS2-based biosensor (right). Reproduced with permission from refs 29 and 38. Copyright 2017 Wiley-VCH and 2014 American Chemical Society. (D) Schematic illustration of the intrinsic defects presented in the layered MoS2 (left), conductive atomic force microscope analysis of the MoS2−MoOx heterostructure (middle), and photograph of flexible MoS2 RRAM (right). Reproduced with permission from ref 30. Copyright 2016 Wiley-VCH.
strong light absorption because of the strong exciton binding (Figure 3A, left).18 In addition, by forming a heterostructure of MoS2 and graphene, a high-quality contact can be made because of the narrow van der Waals gap at the heterointerface, which enables good photoresponsivity (∼4.3 A W−1).9 The ultrathin thickness of MoS2 also allows fabrication of soft optoelectronic or bioelectronic devices.43 For example, a highdensity hemispherically curved image sensor array that mimics the human eye was developed by adopting atomically thin MoS2−graphene heterostructure and strain-releasing device designs (Figure 3A, middle and right).9 This curved image sensor array was integrated with ultrathin neural-interfacing electrodes using an anisotropic conductive film and was applied to a soft retinal prosthesis, aiding restoration of vision. The soft retinal prosthesis using MoS2−graphene heterostructure successfully visualizes external images and applies the corresponding electrical stimulation to the retina without mechanical stress and immune responses to the neural tissues nearby the retinal implant.9
Piezoresistivity is another unique characteristic of MoS2, whereby the resistivity is changed as a result of modulation in the band gap by applied strains (Figure 3B, left).44 Using the piezoresistive property of MoS2, a highly sensitive strain gauge was developed, showing a much higher gauge factor (∼230) than those of metal-based (∼1−5) and graphene-based (∼2) strain gauges.45 One interesting point is that the piezoresistive effect of the bilayer MoS2 is larger than that of the monolayer MoS2.44 The piezoresistive effect of MoS2 is determined by overlap and hybridization between the out-of-plane Mo dz2 orbitals. Because monolayer MoS2 has a single Mo layer, its Mo dz2 orbitals remain unaffected by strain. In the bilayer MoS2, on the other hand, Poisson contraction by tensile strain causes strong interaction between Mo dz2 orbitals of stacked layers, which leads to large piezoresistive effect. And using bilayer MoS2, a skin-like ultrathin tactile sensor array was developed.10 This tactile sensor has an ultrathin thickness of 75 nm and exhibits a high gauge factor of 72.5 (Figure 3B, middle). Therefore, it could achieve conformal contact to the 78
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Accounts of Chemical Research rough human fingertip and map external pressures applied to the skin with high fidelity (Figure 3B, right). To enhance sensitivity and detection limit of biosensors, it is important that the active material has a high surface-to-volume ratio. Because the bonding between each MoS2 layer is weak, an atomically thin film of MoS2, which has a high surface-tovolume ratio can be easily obtained (Figure 3C, left). In addition, the band gap of MoS2 allows fabrication of FET-type biosensors with significantly improved sensitivity, which graphene cannot provide.29,38 Therefore, the MoS2 FETbased biosensors can effectively detect various biosignals, such as humidity29 and biochemicals38 (Figure 3C, middle). A humidity sensor using the MoS2 FET shows remarkably high sensitivity above 104 when the relative humidity changes from 0% to 35%.29 A MoS2 FET-type sensor can also monitor pH and biomolecules by detecting the current changes caused by adsorption of charged molecules on the gate dielectric surface (Figure 3C, right).38 Changes in the surface charge result in a significant threshold voltage shift. The MoS2-based pH sensor achieves a high sensitivity of 713 for a change of one pH unit. Accordingly, 100 fM streptavidin could be measured with sensitivity of 196 by functionalizing the gate dielectric with biotin. MoS2 layers naturally contain numerous types of intrinsic defects within their lattice (e.g., sulfur vacancies and oxidized MoS2 layer), which are generated during the synthesis or posttreatment processes (Figure 3D, left). Among the various kinds of defects, the oxygen vacancies in the MoS 2 −MoO x heterostructure allow the resistance switching behavior, which can be found in resistive random-access memory (RRAM).30 The migration and alignment of the oxygen vacancies form a conducting filament, indicating a lowresistance state (Figure 3D, middle). Meanwhile, this conducting filament can be ruptured via Joule-heating, turning to a high-resistance state. Using this approach, a flexible nonvolatile memory has been developed by introducing the MoS2−MoOx heterostructure to the surface of the synthesized MoS2 (Figure 3D, right).30 This MoS2 RRAM showed waferscale uniformity and an extremely high on/off ratio and was integrated with a pressure sensor array and a quantum dot light-emitting diode array to realize a flexible biosensing, data storage, and in situ display system.
potentially be used for soft wearable and implantable bioelectronics. These novel features can be customized for each organ or specific disease models that require specialized biomedical sensing and therapy capabilities. There are several challenges in applying 2D materials to bioelectronics. First, some layered 2D materials (e.g., black phosphorus) can be easily oxidized under ambient conditions, which severely degrades the device performances.46 Surface passivation using hexagonal boron nitride or organic molecules can be used to prevent the oxidation. In addition, lack of etch selectivity between 2D materials limits the formation of their heterostructures with complex device patterns. Therefore, it is necessary to develop novel patterning and integration technologies that hardly cause damage to other layered materials. Extensive studies to optimize soft bioelectronics by utilizing the unique features of 2D materials would offer unprecedented opportunities for personalized health care. For example, longterm biocompatibility and robust interfacial adhesion will allow conformal attachment between the devices and the target organs without chronic immune responses under long-term biointegration. A soft bioelectric system that integrates multifunctional sensors and therapeutic actuators with energy harvesting devices and wireless modules will enable continuous monitoring of clinically important information and effective therapeutic feedback. Advances in 2D material-based soft bioelectronics would pave the way for high-quality diagnosis and highly effective treatment of various diseases through a long-term conformal biointegration.
5. CONCLUSION In this Account, we have reviewed the recent progress in soft bioelectronics using 2D materials with a special focus on their unique mechanical, optical, chemical, and electrical properties and wearable and implantable biomedical device applications. The use of 2D materials has led to significant advances in soft bioelectronics because of distinctive characteristics of 2D materials that are hardly found in their bulk counterparts. In particular, 2D material-based soft bioelectronics show exceptional mechanical softness and flexibility, superior sensitivity, and unconventional biomedical functions, useful for clinical applications. Along with these advances, many new technologies are being reported in the field of soft bioelectronics using 2D materials. For example, novel distinctive device features using other layered 2D materials (e.g., black phosphorus46 and MXene47) are reported. New material properties, such as superb hydrophilicity and controllability of the interlayer spacing, can be used for development of water-selective humidity sensors46 or high-performance tactile sensors,47 which can
Biographies
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Dae-Hyeong Kim: 0000-0002-4722-1893 Author Contributions ⊥
C.C. and Y.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
C. Choi received his B.S. degree (2012) from the Department of Material Science and Engineering at the Seoul National University and his M.S. degree (2014) from the School of Chemical and Biological Engineering at the Seoul National University. Under the supervision of Prof. Dae-Hyeong Kim, he is working on soft optoelectronic devices using 2D materials. Y. Lee received his B.S. degree (2013) from the School of Chemical and Biological Engineering at Seoul National University. Under the supervision of Prof. Dae-Hyeong Kim, he is working on minimally invasive bioelectronics for implantable biomedical applications. K. W. Cho received his B.S. degree (2012) from the Department of Biological and Environmental Engineering at Cornell University and his M.S. degree (2016) from the School of Chemical and Biological Engineering at Seoul National University. Under the supervision of Prof. Dae-Hyeong Kim, he is working on the fabrication of in vitro sensors and actuators. J. H. Koo received his B.S. (2010) and M.S. (2013) degrees in Electrical and Electronics Engineering from Yonsei University. Under 79
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Accounts of Chemical Research
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the supervision of Prof. Dae-Hyeong Kim, he is working on nanomaterial-based electronic and optoelectronic devices. D.-H. Kim received his B.S. (2000) and M.S. (2002) degrees from the School of Chemical Engineering at Seoul National University. He obtained his Ph.D. (2009) from the department of Materials Science and Engineering at University of Illinois Urbana−Champaign. Since joining the faculty of the School of Chemical and Biological Engineering at Seoul National University in 2011, he has focused on wearable and implantable bioelectronics.
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ACKNOWLEDGMENTS This research was supported by IBS-R006-A1. REFERENCES
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DOI: 10.1021/acs.accounts.8b00491 Acc. Chem. Res. 2019, 52, 73−81
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DOI: 10.1021/acs.accounts.8b00491 Acc. Chem. Res. 2019, 52, 73−81
