Gas-Permeable, Irritation-Free, Transparent Hydrogel Contact Lens

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Gas-Permeable, Irritation-Free, Transparent Hydrogel Contact Lens Devices with MetalCoated Nanofiber Mesh for Eye Interfacing Shiyuan Wei,†,‡ Rongkang Yin,†,‡,§ Tao Tang,∥,⊥ Yingxiao Wu,# Yang Liu,† Puxin Wang,†,‡ Kai Wang,*,∥,⊥ Ming Mei,∇ Ruqiang Zou,# and Xiaojie Duan*,†,‡ Downloaded via BUFFALO STATE on July 19, 2019 at 00:51:26 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China § Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China ∥ Department of Ophthalmology, Peking University People’s Hospital, Beijing 100044, China ⊥ College of Optometry, Peking University Health Science Center, Beijing 100044, China # Department of Materials Science and Engineering, College of Engineering, Peking University, Beijing 100871, China ∇ WuXi App Tec (Suzhou) Co., Ltd., Suzhou 215104, China ‡

S Supporting Information *

ABSTRACT: An electronic “smart” contact lens device with high gas permeability and optical transparency, as well as mechanical compliance and robustness, offers daily wear capability in eye interfacing and can have broad applications ranging from ocular diagnosis to augmented reality. Most existing contact lens electronics utilize gasimpermeable substrates, electronic components, and interfacial adhesion layers, which impedes them from applications requiring continuous daily wear. Here we report on the design and fabrication of an eye interfacing device with a commercial ocular contact lens as the substrate, metalcoated nanofiber mesh as the conductor, and in situ electrochemically deposited poly(3,4-ethylenedioxythiophene) (PEDOT) /poly(styrene sulfonate) (PSS) as the adhesion material. This hydrogel contact lens device shows high gas permeability, wettability, and level of hydration, in addition to excellent optical transparency, mechanical compliance, and robustness. Using a rabbit model, we found that the animals wearing these hydrogel contact lens devices continuously for 12 hours showed a level of corneal fluorescein staining comparable to those wearing pure hydrogel contact lenses for same period of time, with no obvious corneal abrasion or irritation, indicating their high level of safety for continuous daily wear. Finally, full-field electroretinogram (ERG) recordings on rabbits were carried out to demonstrate the functionality of this device. We believe that the strategy of integrating nanofiber mesh-based electronic components demonstrated here can offer a general platform for hydrogel electronics with the advantages of preserving the physiological and mechanical properties of the hydrogel, thus enabling seamless integration with biological tissues and providing various wearable or implantable sensors with improved biocompatibility for health monitoring or medical treatment. KEYWORDS: hydrogel, seamless biointegration, wearable electronics, bioelectronics, ocular diagnosis, augmented reality diverse bioactive molecules for various purposes.6−9 This may include growth or signaling factors that can guide neural differentiation or regeneration,7 antibiotics and anti-inflammatory drugs to alleviate probe insertion damage,8 and mitotic inhibitors to attenuate the formation of glial scars.9 The resemblance of hydrogels to living tissue opens up many opportunities for a broad range of applications in biomedical

H

ydrogels with physiological and mechanical properties similar to human tissue represent ideal matrix materials for electronics and devices and can help achieve effective and seamless electrical biointegration.1,2 The softness and stretchability of hydrogel electronics render them more comfortable to wear, which greatly enhances the amplitude and fidelity of signals acquired from the biological tissues.3−5 Their high porosity and level of hydration promotes the transport of charges, ions, and molecules, which is critical for applications that require the maintenance of moisture and gas permeability. In addition, the high porosity and hydration level enables preloading of the hydrogel electronics with © XXXX American Chemical Society

Received: March 25, 2019 Accepted: June 25, 2019 Published: June 25, 2019 A

DOI: 10.1021/acsnano.9b02305 ACS Nano XXXX, XXX, XXX−XXX

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Cite This: ACS Nano XXXX, XXX, XXX−XXX

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Figure 1. Gas-permeable, irritation-free, transparent hydrogel contact lens devices based on metalc-NM and in situ electrochemically deposited PEDOT/PSS. (a) Schematic drawing of the device structure. (b) Picture of a Auc-NM/HyCL(PEDOT) device. Scale bar, 5 mm. (c) Schematic illustration of the device fabrication process.

that rely on contact with tear fluid and require large coverage of electronic components. Here we report on a design of contact lens-based eye interfacing devices employing metal-coated nanofiber mesh (metalc-NM) as electronic conductors and commercial hydrogel ocular contact lenses as substrates; both are highly porous, gas-permeable, optically transparent, and soft. An in situ electrochemical deposition of poly(3,4-ethylenedioxythiophene) (PEDOT)/poly(styrene sulfonate) (PSS) with the metalc-NM as the electrode was conducted to improve the adhesion between the metalc-NM and the hydrated hydrogel contact lens substrates (Figure 1). In addition to their high optical transparency, as well as excellent mechanical compliance and robustness, these hydrogel contact lens electronics possess high gas permeability, even for those requiring a large area of electronic conductors. This is different from previous contact lens-based devices using gas-impermeable substrates,14−18 electronic components,13−18 and interfacial adhesion layers.13 We demonstrated that rabbit eyes wearing these gas-permeable, transparent hydrogel contact lens electrodes for 12 hours had no obvious signs of corneal abrasion or irritation, indicating their high safety level for continuous daily wear. Finally, full-field ERG recordings were carried out on rabbits to demonstrate the functionality of this gas-permeable, irritation-free, transparent hydrogel contact lens electrode.

areas,3,10−13 including wearable electronics for diseases diagnosis13 and implantable bioelectrodes for neural activity recording12 and modulation.3 Electronics on contact lenses have recently attracted substantial attention from the scientific community.13−19 Contact lens-type wearable devices have been developed for the diagnosis of glaucoma and diabetes by measuring intraocular pressure or glucose composition of tears.13,15,16 Electroretinogram (ERG) recording with contact lens electrodes is widely used in ophthalmic diagnostic testing to assess the functional integrity of the retina.17,20 A see-through contact lens display can be used to overlay computer-generated visual information on the real world, providing immediate and handsfree access to information.18 Many existing contact lens electronics utilize transparent electronic components such as graphene17,19 or a graphene/metal nanowire hybrid13 to obtain unobstructed vision and lens-shaped plastic substrates14−18 for high softness to obtain conformal interfacing with eyes and also enhance the device’s reliability upon repeated eye blinks. However, the low oxygen permeability of these devices limits their safe use for long periods of time in humans. A recent study used actual hydrogel ocular contact lenses as substrates.13 But the use of gas-impermeable graphene-based electronic components and a parylene interfacial adhesion layer between the electronics and hydrogel substrate undercut the advantage of the hydrogel’s high gas permeability. This gas impermeability issue will become more important for applications where a large coverage of electronic components is required. In addition, the poor wettability of the graphenebased electronic components brings problems in fit and causes liplike deposits,21 as well as poses challenges in applications

RESULTS AND DISCUSSION Fabrication and Characterization of the Electrodes. The metalc-NM used as the electronic conductor of the gaspermeable, irritation-free hydrogel contact lens devices here was made through sputtering a thin layer of gold on a sparse, randomly oriented polyacrylonitrile (PAN) nanofiber mesh B


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Figure 2. Characterization of the hydrogel contact lens devices. (a) SEM micrograph of Auc-NM prepared with different PAN electrospinning time (marked in the upper left corners). Scale bar, 5 μm. (b) Optical transmittance of Auc-NM prepared with different PAN electrospinning time. The sheet resistance of each Auc-NM is shown in the inset. (c) Sheet resistance versus optical transmission (at 550 nm) for various transparent conductive materials including Auc-NM, device-grade ITO, graphene, PEDOT, gold thin film, solution-processed silver nanowires (AgNWs), carbon nanotubes (CNTs), lithography-fabricated silver patterns (Ag pattern), and gold nanotrough. (d) ESEM images of Auc-NM/HyCL devices without PEDOT:PSS deposition and with PEDOT:PSS deposition for 100 and 1000 s. Scale bar, 2 μm. (e) Optical transmittance of Auc-NM/HyCL and Auc-NM/HyCL(PEDOT) devices. Both are measured under fully hydrated state. (f, g) EIS (f) and cyclic voltammograms (g) of Auc-NM/HyCL and Auc-NM/HyCL(PEDOT) devices. (h) Impedance magnitude of a Auc-NM/ HyCL(PEDOT) device after multiple cycles of dehydration−hydration. (i) Relative change of resistance of various materials under stretching strain. R0 and R denote the resistance values before and after stretching. Strain is defined as (L − L0)/L0; L0 and L denote the length of devices before and after stretching.

film prepared by electrospinning (Figure 1c). This resulted in a uniform network of intertwined gold-coated PAN nanofibers (Figure 2a). The sputtering provided a homogeneous conformal gold coating all over the surface of the PAN nanofibers, resulting in a PAN/Au core−shell structure (Figure S1a, Supporting Information). Close examination of the network with scanning electron microscopy (SEM) showed that individual gold-coated nanofibers are naturally interconnected at their junctions during gold deposition (Figure S1b, Supporting Information). This is important in order to avoid the creation of large junction resistance and to ensure a high electrical conductivity of the nanofiber mesh. The PAN nanofibers had diameters in the range of 160−360 nm with the peak distribution at ∼220 nm (Figure S1c, Supporting Information); a gold thickness of ∼110 nm was used in this

study. The highly uniform, interconnected gold-coated nanofiber mesh (Auc-NM) showed excellent optical transparency in the visible spectrum range (Figure 2b). Increasing the electrospinning time resulted in a higher density of nanofibers, decreased void area size, enhanced electrical conductivity, and decreased optical transparency (Figure 2a,b), which is consistent with the prediction from percolation theory.22 The Auc-NM exhibited a sheet resistance of ∼8.87 Ω/sq at T = 88.4%, ∼30.73 Ω/sq at T = 93.2%, and ∼51.23 Ω/sq at T = 95.1% (all at 550 nm). This performance is superior to many other transparent conducting materials, including those based on graphene,23 carbon nanotube films,24,25 solution-processed or lithography-fabricated silver nanowires or patterns,26,27 thin metal films,28 and conducting polymers29 (Figure 2c). Although the performance is not as good as the state-of-theC


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ACS Nano art device-grade indium tin oxide (ITO),30 Auc-NM has the advantage of being flexible. The existence of the nanofiber core in Auc-NM compared to Au nanotrough mesh31 resulted in decreased optical transparency under the same electrical conductance but with the gain of higher mechanical strength and robustness, both of which are critical for hydrogel-based wearable or implantable bioelectronic devices. The replacement of Au with Cu can further improve the performance of the metalc-NM in terms of electrical conductivity under certain optical transparency, but Cu-coated nanofiber mesh cannot be used in implantable devices due to the toxicity of the copper.32 Throughout this study, we used Auc-NM with a sheet resistance of ∼10 Ω/sq and an optical transparency of ∼90% at 550 nm (corresponding electrospinning time of 20 s) for hydrogel devices. The Auc-NM with electrospinning time of 60 s showed a decreased void area size to around the same scale as the visible light wavelengths. Previous work on a similar gold nanomesh structure showed that it is only ∼3% for the portion scattered out of the solid angle ∼0.2 sr (when transmittance exceeds 80%).33 The Auc-NM used in this study had a void area size around ∼1−6 μm, which is larger than the wavelengths of visible light. Under this condition, we believe that the change of light wavefront and distortion of the field of view should be negligible. The Auc-NM is mechanically flexible and robust, which allows it to be transferred easily onto various substrates, including the curved hydrated hydrogel. However, we found that Auc-NM directly laminated on the hydrated hydrogel detaches easily. The adhesion of the electronic components and the hydrated hydrogel is a common problem for hydrogel bioelectronics, especially for applications involving repeated motions.4 To increase adhesion between the Auc-NM and the hydrated hydrogel, following the mesh transfer a electrochemical deposition of PEDOT:PSS was performed using the Auc-NM on the hydrogel substrate as the electrode. We transferred Auc-NM (with an area of ∼1.94 cm2, which covers the entire surface of the hydrogel contact lens; same for below unless specified) onto commercially available daily disposable hydrogel contact lenses (Auc-NM/HyCL) and conducted in situ electrochemical deposition of PEDOT:PSS. The environmental SEM (ESEM) images clearly show the PEDOT:PSS shell on the gold-coated nanofibers after 100 s deposition (Figure 2d). Adhesion between the Auc-NM and the hydrated hydrogel was significantly improved after the PEDOT:PSS deposition, making the hydrogel devices fully functional and robust when working in aqueous environments. We attribute the improvement of adhesion to the outgrowth of PEDOT:PSS from the gold-coated nanofibers to the hydrogel matrix, a structure that provides a strong anchor for the fibers onto the hydrogel.34,35 When the PEDOT:PSS deposition time was increased, thick PEDOT:PSS flakes could be found on the surface of the hydrogel substrate (Figure 2d). This not only severely decreased the optical transparency of the final devices but also reduced their oxygen permeability due to the blockage of gas passage. We found that a deposition time of 100 s, which resulted in a ∼200 nm thick PEDOT:PSS shell on the nanofibers, provided sufficient adhesion between the Auc-NM and the hydrogel matrix, while still preserving high optical transparency (Figure 2e) as well as oxygen and water vapor permeability of the final hydrogel devices (as will be shown later). This deposition condition was used throughout our study.

Figure 2e shows representative optical transmission spectra of an Auc-NM/HyCL with [Auc-NM/HyCL(PEDOT)] (Figure 1b) and without PEDOT:PSS deposition (Auc-NM/ HyCL). The Auc-NM/HyCL(PEDOT) exhibited high optical transparency (81.1% at 550 nm, under hydration), and the application of PEDOT:PSS only led to a slight decrease of optical transmission across the visible spectrum (versus 89.4% at 550 nm for Au c -NM/HyCL). The application of PEDOT:PSS had profound effects on the electrochemical interfacial properties of the hydrogel devices. We measured the electrochemical impedance spectra (EIS) of the Auc-NM/ HyCL and Auc-NM/HyCL(PEDOT) electrodes. The deposition of PEDOT:PSS significantly decreased the electrochemical impedance and resulted in a more resistive phase angle at the low-frequency range (Figure 2f), consistent with the Faradaic and non-Faradaic reactions at the PEDOT− electrolyte interface.36 The cyclic voltammogram (CV) of the Auc-NM/HyCL(PEDOT) showed an increased anodic and cathodic current with peaks at −0.29 and −0.47 V (Figure 2g), which corresponded to the reduction and oxidation of PEDOT.37 This improved electrochemical interfacial property will be beneficial to many applications including ocular electrophysiology measurements. To examine the mechanical durability of our hydrogel contact lens devices, we performed multiple cycles of dehydration−hydration tests with EIS monitored after each cycle. The impedance of the Auc-NM/HyCL(PEDOT) showed an increase after the first dehydration−hydration cycle (∼34.9 Ω versus ∼110.3 Ω at 1 kHz and ∼37.8 Ω versus ∼158.1 Ω at 100 Hz) and then remained nearly constant for the following four dehydration−hydration cycles until the end of the test (Figure 2h). The hydrogel contact lenses used here have an equilibrium water content (EWC) of ∼62.7% (defined as the percentage of the water weight relative to the total weight of the hydrated hydrogel38); there was a large volume change between the hydrated and dehydrated state. In addition, the shrinkage of the hydrogel during the dehydration process always leads to wrinkles or folding, which are associated with extreme strain (conditions). We believe that the increase in impedance after the first round of dehydration reflects an adaptation of the Auc-NM film onto the contact lens. The impedance remained modest and nearly constant upon the application of extreme strain for the following dehydration−-hydration cycles, reflecting the stability and high mechanical durability of our hydrogel devices after this adaptation. The Auc-NM can also sustain large stretching deformation. The resistance was only increased by ∼237% when it was stretched uniaxially to a 200% strain (Figure 2i). This stretchability is superior to many other stretchable conductive materials (Figure 2i).33,39−43 The possible mechanism for this excellent stretching capacity is that the binding of adjacent nanofibers by metal sputtering protected the nanofiber junctions from complete separation during sliding and rotating under strain.31,44 The deposition of PEDOT:PSS further increased the stretch tolerance of the Auc-NM with only a ∼89.2% increase in resistance at a strain of 200% (Figure 2i). This is possibly because the PEDOT coating further strengthens the binding of the adjacent nanofibers at the junctions.45 The excellent mechanical durability and robustness ensures high reliability for hydrogel bioelectronics applications during normal, everyday motions of living tissues. D


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Figure 3. Gas permeability, wettability, and biocompatibility tests. (a) Water vapor transmission of open bottle (none), pure hydrogel ocular contact lens (HyCL), Auc-NM/HyCL, and Auc-NM/HyCL(PEDOT) devices, and Ecoflex film as a function of elapsed time. (b) EWC and Dk values of HyCL, Auc-NM/HyCL, and Auc-NM/HyCL(PEDOT). Error bars show SD, n = 4. ns, p > 0.05, one-way ANOVA. (c) Water contact angle on HyCL, Auc-NM/HyCL, and Auc-NM/HyCL(PEDOT). Error bars show SD, n = 3. (d) Slit lamp micrographs of corneal fluorescein stained rabbit eyes after wearing Auc-NM/HyCL(PEDOT) and HyCL continuously for 12 h and parylene-C contact lens of 10 μm thickness continuously for 9 h. The intensity of fluorescence represents the level of corneal damage. Scale bars, 5 mm.

One feature of metalc-NM compared to other transparent conductive films such as graphene and its hybrid with nanowires is that it is highly porous, which will preserve the gas permeability of the underlying hydrogel substrate, even for applications that require large-area electronic conductors. We calculated the water vapor transmission rates at room temperature by measuring the weight loss of water in a container with its opening covered by various samples. The water vapor transmission rates of a pure hydrogel contact lens (HyCL), Auc-NM/HyCL, and Auc-NM/HyCL(PEDOT) are ∼69.2, ∼60.7, and ∼46.2 mg·cm−2·day−1, respectively, compared to ∼95.9 mg·cm−2·day−1 of an open bottle and ∼7.98 mg·cm−2·day−1 of a gas-impermeable Ecoflex film with a thickness of 80 μm (Figure 3a). The Auc-NM/HyCL(PEDOT) retained high water vapor permeability, which we attribute to the use of porous Auc-NM as electronic conductors and in situ electrochemically deposited PEDOT:PSS as the adhesion material. Using controlled conditions, the PEDOT:PSS was deposited on and around the gold-coated nanofibers, which would not block the pores or gas passage in Auc-NM or in the underlying hydrogel substrate. This is distinct from previous work, which used a gas-impermeable solid interfacial adhesion layer. Oxygen permeability of the contact lens-based eye interfacing devices is critical for applications requiring longterm wear in order to avoid oxygen deprivation of the cornea and to alleviate any discomfort.,46 For conventional hydrogel ocular contact lenses, oxygen permeability essentially depends on EWC in hydrogels because oxygen has the capability to diffuse through water rather than through the gel.38 In the contact lens industry, the oxygen permeability is characterized as “Dk”, where ‘D’ is the diffusivity of the lens and ‘k’ is the oxygen solubility in the lens material. The relationship between the water content and Dk is Dk = 1.67 e 0.0397EWC

EWC is defined as m EWC = × 100% mtot

(2)

where m is the water weight and mtot is the total weight of the hydrated contact lenses.38 We found that there is no statistically significant difference in EWC and calculated Dk between HyCL, Au c -NM/HyCL, and Au c -NM/HyCL(PEDOT) (Figure 3b). This result indicates that the oxygen diffusion inside the hydrogel contact lens devices showed no difference from the pure hydrogel contact lenses. The previous results from the water-transmission tests showed that the existence of Auc-NM and PEDOT:PSS adhesion material on the device surface will not block the gas passage. We reason that the hydrogel devices with Auc-NM as electronic conductors and in situ electrochemically deposited PEDOT:PSS as the adhesion material have oxygen permeability as high as that of pure hydrogel lenses. In recent years, silicone hydrogel has been utilized to make contact lenses for extended wear, due to its higher oxygen permeability.38 In silicone hydrogel contact lenses, silicone rather than water becomes the main vehicle for the passage of oxygen through the lens.47 Since the porous Auc-NM and PEDOT:PSS deposition is confined at/around the surface of the hydrogel matrix and will not alter the polymer chains inside the lenses, we speculated that the integration of them will not obviously reduce the oxygen permeability of the silicone hydrogel contact lenses either. In addition, we found that the PEDOT:PSS deposition can significantly improve the wettability, with the contact angle of water changing from ∼64.6° (HyCL) and ∼82.1° (Auc-NM/ HyCL) to ∼12.2° [Auc-NM/HyCL(PEDOT)] (Figure 3c). The improved wettability facilitates the spreading of tears and increases the capability to produce a stable uniform tear film layer between the contact lens and the cornea, which not only helps achieve a good fit and facilitates the exchange of tears

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Figure 4. Full-field ERG recordings. (a) Schematic illustration of full-field ERG recording with Ganzfeld stimulation from albino rabbits. (b) Photograph of an albino rabbit eye wearing a Auc-NM/HyCL(PEDOT) device. The black dashed circle marks the edge of the device. Scale bar, 5 mm. (c) Photograph (left, scale bar, 5 mm) and anterior segment OCT images (scale bar, 500 μm) of a rabbit eye wearing a Auc-NM/ HyCL(PEDOT). The anterior segment OCT cross-sectional images are on corneal meridian along the directions marked by the arrows in the upper right corners of the anterior segment OCT images. (d) Slit lamp micrograph of a rabbit eye wearing a Auc-NM/HyCL(PEDOT) device with tear film stained with sodium fluorescein. The intensity of fluorescence represents the thickness of the tear film. Scale bar, 5 mm. (e−j) Representative full-field ERG signals recorded with a Auc-NM/HyCL(PEDOT) device from an albino rabbit eye, following the guidelines set by the ISCEV. (e, f, h) Scotopic (dark-adapted) ERG responses under 0.01, 3.0, and 10.0 cd·s/m2. (f) Scotopic oscillatory potentials recorded under 3.0 cd·s/m2. N1, N2, N3, P1, P2, P3, etc. label the wavelets in oscillatory potentials. (i) Photopic (light-adapted) ERG responses under 3.0 cd·s/m2. (j) Photopic 30 Hz flicker ERG responses under 3.0 cd·s/m2. Different categories are presented here according to the order of recording. The dashed lines in (j) mark the midpoints of the stimulus flashes.

behind the lens and the removal of metabolites48 but is also critical for applications involving the detection of physiological changes in tear fluids for the diagnosis of diseases.21 This improvement in wettability will be especially beneficial for silicone hydrogel lenses, which normally have poor wettability due to the use of hydrophobic siloxane moieties. The mesh electronics based on lithographically patterned ultrathin polymer substrate and metal lines has been successfully demonstrated in single-neuron chronic recording from the retina in awake mice49 and in forming a structurally and functionally stable interface with the neuronal and glial networks in brain.50 We believe that with shared similarities with the metalc-NM in high softness and porosity, the mesh electronics can also be a promising candidate to be incorporated onto contact lens for interfacing with retina, provided that the metal width is reduced to ensure optical transparency and uniformity. The metalc-NM here is prepared by simple electrospinning and metal sputtering, which is helpful for mass production and reducing metal line width to sub-1 μm. But the lithography based mesh electronics would be advantageous when a high-density electrode array is required.

Biosafety Test. For many applications, such as glucose level monitoring or see-through contact lens display, contact lens devices must be worn for an extended period of time. Oxygen transmission is critical for these applications in order to avoid the development of corneal hypoxia, a phenomenon that can compromise corneal health and result in poor patient outcomes.51,52 We used rabbits, a common model for studying contact-lens-associated corneal hypoxia,52,53 to test the safety of our devices for daily wear. After continuous 12 h wear of the Auc-NM/HyCL(PEDOT), the rabbits’ eyes did not show any obvious sign of corneal abrasion or irritation. Corneal fluorescein staining showed a very low level of fluorescence (Figure 3d), comparable to rabbit eyes wearing pure HyCL for the same duration (Figure 3d and S2, Supporting Information). In addition, during the 12 h period of wearing the AucNM/HyCL(PEDOT), the animals displayed no abnormal behavior, such as rubbing of the eyes (Supplementary Movies 1−3). We believe that these results indicate that our hydrogel devices caused minimal disturbance to the rabbits. In significant contrast, after 9 h of wearing oxygen impermeable parylene C contact lenses (10 μm thick), the rabbits’ eyes showed severe symptoms of corneal hypoxia including limbal redness and corneal swelling (Figure S3, Supporting F


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ACS Nano Information). Dramatic fluorescein staining was observed on the corneal surface (Figure 3d), indicating severe epithelial cell damage from oxygen deficiency. These results indicate that our gas-permeable hydrogel contact lens devices made with AucNM as conductors and in situ electrochemically deposited PEDOT:PSS as the adhesion material do not irritate the cornea and can be worn continuously on a daily basis with a high level of safety. For prolonged wear, a week to a month, silicone hydrogel contact lenses with extended wear capability could be used to replace the daily wear contact lenses here as substrates. ERG Recordings. We tested the functionality of our gaspermeable, irritation-free, transparent hydrogel contact lens electrodes via corneal ERG measurements in rabbit eyes. These electrodes were in their fully hydrated state, as those worn by human beings on daily basis. The ERG signal is generated at the corneal surface by various neuronal and nonneuronal cells in the retina in response to a light stimulus and is widely used in ophthalmic diagnostic testing to assess the functional integrity of the retina.20 The usual testing time for an ERG in clinical settings is approximately tens of minutes to 1 h. Although oxygen permeability is not necessary for this short period of time, it can enhance the comfort of the recording process. In addition, the high compliance and optical transparency of ERG electrodes may confer substantial benefits including conformal and stable interfacing with eyes, preserved eye refraction, minimal corneal irritation, and full-cornea access.17 Furthermore, the use of the daily wear ocular contact lens-based ERG electrodes is less frightening from the patient’s point of view. We conducted full-field ERG recordings from the cornea of ophthalmologically normal albino rabbits using the Auc-NM/ HyCL(PEDOT) devices (Figure 4a); these devices have an impedance value of ∼158.1 Ω at 100 Hz, which meets the requirement of most commercial ERG recording amplifiers. The photograph taken of a rabbit eye wearing an electrode show that the thin, transparent Auc-NM/HyCL(PEDOT) closely conformed to the front surface of the eye due to its compliant nature (Figure 4b). The anterior segment optical coherence tomography (OCT) studies of the electrode− cornea interfaces indicated that the Auc-NM/HyCL(PEDOT) formed a conformal and tight interface with the cornea (Figure 4c), with no thick or inhomogeneous tear film observed between them (Figure 4d). The ERG recordings were carried out using ganzfeld full-field stimulation on a commercial Retiport/scan21 system (Roland Consult, Germany), following the guidelines set by the International Society for Clinical Electrophysiology of Vision (ISCEV).54 The Auc-NM/HyCL(PEDOT) can successfully record various full-field ERG signals, including scotopic ERG responses at different luminous strengths, oscillatory potentials, photopic ERG responses, and light-adapted 30-Hz flicker ERG responses (Figure 4e−j). These responses reflect activities from different cells in the retina and can be used for the diagnosis of various forms of retinal degeneration.20 All these recorded ERG signals show high signal-to-noise ratio and well-defined features characteristic of standard ERGs in albino rabbits (Figure S5, Supporting Information). These results indicate the capability of our hydrogel contact lens devices for high-efficacy recording of full-field ERG responses. It is noted that the full-field ERG signals recorded with the Auc-NM/HyCL(PEDOT) showed comparable amplitude to those recorded with the Jet electrodes (Figures S4 and S5, Supporting Information),

which are extensively used for clinical full-field ERG recording and are reported to give the highest signal amplitude among commercially available ERG electrodes.54 Previously we observed that soft and transparent graphene contact lens electrodes gave higher signal amplitude than Jet electrodes in full-field ERG recordings.17 We suspect that the difference in electrode size between the hydrogel and graphene contact lens electrodes might account for their signal difference in full-field ERG recordings. The Auc-NM/HyCL(PEDOT) electrodes we used here had a size 2× that of rabbit cornea. A large portion of the hydrogel electrodes interfaced with the region outside the cornea, which had much weaker ERG signal. The average between the signal on and outside cornea might lead to a decrease in signal amplitude compared to those recorded with the graphene contact lens electrodes. The ability to wear the Auc-NM/HyCL(PEDOT) electrodes for extended periods of time without any interference with corneal physiology or discomfort may enable other types of ERG investigation, such as continuous long-term ERG monitoring for drug screening.

CONCLUSIONS In summary, compared to existing contact lens devices made of gas-impermeable substrates, electronic components, and interfacial adhesion layers, our work represents a breakthrough as it was achieved by using hydrogel ocular contact lenses as substrates, porous metalc-NM as conductors, and in situ electrochemically deposited PEDOT:PSS as the adhesion material. This design provides gas-permeable, irritation-free, transparent contact lens devices with daily wear capability and holds substantial promise for broad applications ranging from next-generation ocular diagnostics to augmented reality. The idea of using nanofiber-mesh-based electronic components could be expanded from metal to semiconductors; combined with patterning using lithography or with shadow mask, various complex functional hydrogel circuits could be fabricated, which preserve the gas permeability, moisture, mechanical compliance, and durability, as well as the optical transparency of the hydrogel matrix. We believe that this will offer a general platform for seamless biointegration and provide wearable or implanted sensors with improved biocompatibility for health monitoring or medical treatment. METHODS Auc-NM Preparation and Characterization. The polymer nanofiber mesh was produced using electrospinning. Briefly, the precursor solution was made by adding polyacrylonitrile (PAN, Sigma-Aldrich) powder to dimethylformamide (DMF) at a concentration of 10 wt %, and then stirring at 60 °C for 12 h. The precursor solution was poured into a plastic syringe (5 mL volume) with a flat blunt #20 needle for electrospinning. A stainless-steel ring (circle or rectangular) was placed coaxially with and 15 cm away from the needle as the collector for free-standing polymer nanofiber mesh. A positive voltage of 13 kV was applied to the needle, and a negative voltage of −2 kV was applied to the collector (SS-2535H, Ucalery, China). The precursor solution was delivered from the needle at a constant velocity (0.15 mm/min), and nanofibers were spun out of the needle to form a PAN nanofiber mesh. The density of nanofibers could be controlled by altering the electrospinning time. The nanofiber mesh used in this study was electrospun for 20 s, unless specifically stated. Gold-coated nanofiber mesh (Auc-NM) was prepared by sputtering a thin film of gold onto the free-standing PAN nanofiber mesh (PVD75, Kurt J. Lesker, USA), at base pressure of 3 mTorr and power of 100 W for 8 min. This gives a uniform coating of ∼110 nm thick gold on the nanofibers. Scanning electron microscopy (SEM, S-4800, Hitachi, Japan) operated at 1−5 kV G


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ACS Nano acceleration voltage was used to characterize the Auc-NM. The optical transmittance measurements were conducted using a UV/vis spectrophotometer (Lambda 950, PerkinElmer, USA). The sheet resistance was measured using a four-point probe (ResMap 178, CDE, USA). Auc-NM/HyCL Electrodes Fabrication and Characterization. Daily disposable hydrogel ocular contact lenses (HyCL, Ocufilcon D) of −1.00 diopter and −2.00 diopter were purchased from www.JD. com, with central thicknesses of 100 and 90 μm, respectively. The diameter is ∼14 mm, and the base curve is ∼8.6 mm. The freestanding Auc-NM with a total area of ∼1.94 cm2 was directly laminated on the curved surface of the hydrated HyCL, followed by a drop of ethanol to enhance the physical attachment. Copper wire was connected onto the Auc-NM at the edge with the assistance of silver paste, followed by connection point insulation with epoxy resin. For PEDOT:PSS deposition, electrolyte consisting of 0.014 M 3,4ethylenedioxythiophene (EDOT) (Sigma-Aldrich, USA) and 0.025 M sodium PSS (Sigma-Aldrich, USA) aqueous solution was used. The electrochemically polymerized reaction was performed in a threeelectrode cell under galvanostatic conditions on a CHI600e electrochemical workstation (CH Instruments, USA). A platinum foil was used as the counter electrode, and a Ag/AgCl electrode was used as the reference electrode. The Auc-NM/HyCL electrode acting as the working electrode was immersed into precursor electrolyte with care to avoid the peeling off of the Auc-NM. After waiting for ∼5 min until the electrolyte solution completely exchanged with the water and filled in the hydrogel, the electrochemical polymerization started under the galvanostatic mode with a constant current density of ∼0.5 mA/cm2. A positive transient potential of 0.85−1.05 V was accompanied by the deposition. The electrodes had a surface area of ∼1.94 cm2. The 100 s polymerization time gave a total charge of ∼0.015 C. The total charge and thickness of the PEDOT/PSS can be controlled by changing the deposition time. After PEDOT−PSS deposition, samples were kept immersed in deionized water for 2 h to remove the impurities and excess EDOT. An environmental scanning electron microscope (ESEM, Quanta 450FEG, FEI Company, USA) operated at 20 kV acceleration voltage was used to image the AucNM/HyCL(PEDOT). The optical transmittance measurements of all HyCL and hydrogel devices were conducted under hydrated state using UV/vis spectrophotometer (Lambda 950, PerkinElmer, USA) with integrating sphere mode. The electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) measurements were conducted using a CHI600e electrochemical workstation (CH Instruments, USA). A threeelectrode configuration was used, with the potentials referenced to a Ag/AgCl electrode, a large surface area platinum wire as counter electrode, and the tested sample as working electrode. The measurements were performed in 1× phosphate buffered saline (PBS) at pH 7.4 at room temperature. CV tests were conducted by sweeping the potential of the electrode between the voltage limits of −0.9 to 0.5 V at a scan rate of 50 mV/s. For cyclic dehydration− hydration tests, the Auc-NM/HyCL(PEDOT) devices were dehydrated from naturally drying in air at room temperature and moisture for ∼5 h. Obvious volume shrinkage was observed. After immersion in 1× PBS for ∼1 h, the electrodes became fully swelled and finished one cycle of dehydration−hydration. The EIS was measured after each dehydration−hydration cycle. The stretchability of Auc-NM and Auc-NM(PEDOT) was tested on a mechanics testing unit (AGS-X, SHIMADZU, Japan). Planar stretchable Ecoflex film (Ecoflex 00-30, SMOOTH-ON, 1A:1B), and hydrated polyacrylamide (PAAM)/alginate hydrogel prepared as previously described55 were used as substrates for Auc-NM and AucNM with PEDOT:PSS deposition, respectively. The stretching strain was applied to the samples from the mechanics testing unit at a strain rate of 1 mm/min, and resistance between two sides of the film was measured simultaneously using a Keithley 2400A source meter at a frequency of 10 Hz. Water-vapor transmission rates were measured at room temperature and moisture by measuring the weight loss of water in a container with its opening covered by various samples. Briefly, the

openings (∼7 mm diameter) of vials containing 1 mL of deionized water were covered with dehydrated commercial HyCL, Auc-NM/ HyCL, and Auc-NM/HyCL(PEDOT) and strictly sealed with epoxy resin. As a comparison, open vials and vials covered with gasimpermeable Ecoflex film, 80 μm thick, were tested at the same time. Dehydrated samples were used in order to eliminate the interference of evaporation of water in samples. Mass loss was measured at different time points for water-vapor transmission rate calculation. For EWC measurements, pure HyCL, Auc-NM/HyCL, and AucNM/HyCL(PEDOT) were immersed in saline solution for thorough hydration. Absorbent papers and nitrogen purging were used to absorb large water drops and remove the excess water on the surface, respectively. Then the mass of the hydrated samples was measured. The samples were dried in an oven at 60 °C for ∼2 days until the mass remain unchanged. The EWC was calculated as EWC = m/mtot × 100%, where m is the water weight and mtot is the total weight of the hydrated contact lenses. The oxygen permeability (Dk value) was calculated as Dk = 1.67 e0.0397EWC. One-way ANOVA was used for the statistics tests (n = 4). Daily Wear Safety Test. Ophthalmologically normal albino rabbits of 2.0−2.5 kg body weight were used for animal tests in this study. All procedures of handling animals used in this work were approved by the Peking University Committee on the Use and Care of Animals and were performed in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. The daily wear safety tests were conducted on awake male albino rabbits. Pure HyCL and Auc-NM/HyCL(PEDOT) were worn by rabbits continuously for 12 h, and parylene-C contact lenses (10 μm thick) were worn by rabbits continuously for 9 h. After removing the contact lenses, sodium fluorescein was instilled into the inferior sclera of rabbit eyes with normal saline moistened fluorescein sodium strips (Tianjin jingming New technological development Co.,Ltd., Tianjin, China). Slit-lamp microscopy (SL- 8Z, Topcon Corp., Tokyo, Japan) with a cobalt-blue filter was used to examine the eyes. The regions showing fluorescence higher than the background were identified as damaged regions, and their area was calculated using Image-Pro Plus software (Media Cybernetics, Inc., Silver Spring MD, USA). The total damaged area Adamage is the summation of these areas. The degree of corneal damage is characterized as Adamage/Atotal, where Atotal is the area covered by the contact lens devices or contact lenses. Full-Field ERG Recording. The animals were anesthetized by intraperitoneal injection of 10 wt % chloral hydrate (4 mL/kg). The pupils were then fully dilated with topical cyclopentolate hydrochloride 1% (Cyclogyl). Two subcutaneous platinum needle electrodes served as reference and ground electrodes. One of them was placed 0.5 cm posterior to the lateral canthus over the zygomatic arch, and the other was placed on the back of neck. The Auc-NM/ HyCL(PEDOT) electrodes in fully hydrated state were applied to the topically anesthetized cornea. The electrodes were treated with one cycle of dehydration−hydration to obtain stable impedance values before the application on rabbit eyes. After checking the electrode impedance, full-field ERG recordings were performed using a commercial Reti-port/scan21 system (Roland Consult, Germany), following the guidelines set by the ISCEV. A ganzfeld sphere, which presented the eye with an extensive and evenly illuminated field of view for both short flashes and steady background illumination was used to provide the full-field stimulation. Jet electrodes were used to record full-field ERG from the same rabbit eyes for comparison. The sequence of hydrogel contact lens and jet electrode recording was randomly chosen to minimize the potential influence of the light stimulation sequence on the comparison of the ERG responses from different electrode types, and thus yielded a meaningful result. Scotopic ERGs were recorded in the dark with single ganzfeld flashes (2 ms) stimulation of white light and a wide-band filter (−3 dB at 0.3 and 300 Hz) after 30 min of dark adaptation. Scotopic ERG oscillatory potentials were obtained by applying an overall band-pass filter from 75 to 300 Hz on the scotopic ERG waveforms under 3.0 cd·s/m2. Before photopic ERG recordings, 10 min light adaptation was carried out. The same single full-field flashes and filtering as scotopic ERG were used for photopic ERG recordings, which were H


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ACS Nano taken under luminous energy of 3.0 cd·s/m2. A train of brief (5 ms), full-field white light flashes of 3.0 cd·s/m2 at 30 Hz was applied for the 30 Hz flicker ERG recordings. The same filtering of 0.3−300 Hz was used. Three recordings were repeated and averaged for all ERG responses. The anterior segment OCT tests were conducted on RTVue XR100-2 (Optovue, Inc., Gremont, CA, USA) on male albino rabbits. Superluminescent diodes (840 nm) were used as light source for the system. The observations were performed under pachymetric scan mode. During each scan, the operator captured each cross-sectional corneal image with the light beam at the midpoint of the cornea to ensure a centralized scan location. For tear film staining, sodium fluorescein was instilled into the inferior sclera of rabbit eyes with normal saline moistened fluorescein sodium strips. The fluorescein solution was then mixed in the tear film by several eye blinks. The eyes were examined with slit-lamp microscopy 3 min after the sodium fluorescein instillation.

thank Jinsong Hu for assistance with metal sputtering, Yingying Zhang for assistance with stretching performance characterization, and Yifeng Jiang and Yiquan Liu for their technical assistance in ESEM sample preparation and image analysis at the Core Facilities of College of Life Science, Peking University.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.9b02305. Additional figures for characterization of the Auc-NM, comparison of rabbit corneal damage after wearing AucNM/HyCL(PEDOT) and pure HyCL, micrograph of a rabbit eye after wearing the parylene-C contact lens for 9 h, representative full field ERG signals recorded with a Auc-NM/HyCL(PEDOT) device (red) and a Jet electrode (blue) from the same eye of a rabbit, and summary of the implicit times and amplitudes of various ERG responses recorded on albino rabbits (PDF) Movie S1, taken of a rabbit after wearing the Auc-NM/ HyCL(PEDOT) device for 1.5 h (MP4) Movie S2, taken of a rabbit after wearing the Auc-NM/ HyCL(PEDOT) device for 4.5 h (MP4) Movie S3, taken of a rabbit after wearing the Auc-NM/ HyCL(PEDOT) device for 12 h (MP4)

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Ruqiang Zou: 0000-0003-0456-4615 Xiaojie Duan: 0000-0001-7799-3897 Author Contributions

X.D. and S.W. conceived and designed the experiments. S.W., R.Y., Y.W., Y.L., and R.Z. fabricated and characterized the devices, S.W., T.T., P.W., and K.W. conducted the biosafety tests. S.W., T.T., P.W., K.W., and M.M. did the ERG recordings. X.D. supervised the project. X.D. and S.W. wrote the manuscript. All of the authors discussed the results and commented on the manuscript. Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS X.D. acknowledges support by grants from the National Natural Science Foundation of China (No. 91648207, 21422301) and the National Basic Research Program of China (No. 2016YFA0200103, 2014CB932500). K.W. acknowledges support by grant from the National Natural Science Foundation of China (No. 81870684). The authors I


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Gas-Permeable, Irritation-Free, Transparent Hydrogel Contact Lens

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