Intelligent wireless theranostic contact lens for close-loop electrical sensing and regulation of glaucoma

Engineered closed-loop devices that can wirelessly track intraocular pressure (IOP) and offer feedback-medicine administrations are highly desirable for glaucoma treatments, yet remain difficult to develop. Integrated theranostic systems based on contact lens still confront several challenges, including size limits, requirements of wireless operations, and cross-coupling between multiple functional modulus. Here, for the first time to our knowledge, an integrated wireless theranostic contact lens (WTCL) for in situ electrical sensing and on-demand drug delivery of glaucoma was developed. The WTCL utilized a highly compact circuitry and structural design, which enabled highdegreed integration of IOP sensing and electrically controlled delivery modulus on the curved and limited surface of contact lens. The wireless IOP sensing modulus could ultra-sensitively detect IOP fluctuations, due to the unique cantilever configuration design of LCR circuit with ultra-soft air dielectric film sandwiched between each capacitive sensing plate. The drug delivery modulus employed a highly efficient wireless power transfer circuit, to trigger delivery of anti-glaucoma drug into aqueous chamber via iontophoresis to enhance drug permeation across cornea. The specialized design of frequency separation enabled individual operations of different modules without cross-coupling. The minimally invasive, smart, wireless and closed-loop theranostic features endowed the WTCL as a highly promising system for glaucoma


Introduction
Intelligent point-of-care electrical platforms that could provide real-time health assessment and medical intervention would greatly relieve many acute and stubborn diseases [1][2][3][4][5][6] . Among the diseases, glaucoma and its combined ophthalmic diseases can cause irreversible vision loss of patients 7 , which is often deteriorated by the elevation of intraocular pressure (IOP) due to abnormal circulation of aqueous humor [7][8][9] . Since IOP varies associated with human activities and circadian rhythm 10 , it needs long-term and continuous tracking to analyze the critical IOP fluctuations for identifying optimal therapeutic conditions 11 . At present, many types of ophthalmotonometers (e.g. indentation tonometry, applanation tonometry, rebound tonometry, and dynamic contour tonometry) have provided snapshot measurements of IOP for glaucoma diagnosis in hospitals 12 , yet the operations generally required trained clinicians, and failed to collect many critical IOP fluctuation 13 . On the other hand, clinically medicine administrations for glaucoma treatments have been relying on topical drug delivery via eyedrops to reduce IOP for suspend the deterioration of vision that glaucoma caused 8,12,14 . However, conventional drug deliveries into the anterior chamber remain challenging (low intraocular bioavailability, inevitable side-effects, and poor patient adherence) due to the diffusion barriers of cornea 15 , and lack the possibility of integration with smart biodevices for on-demand drug delivery. Especially for acute angle-closure glaucoma featured with sudden rise of IOP 16 , it is usually accompanied by headache, nausea and vomiting that hinders manually self-administrations by patients 8 , while the delayed reduction of IOP will inevitably causes ischemic infarcts and damage optic nerve 12 .
Besides, controlled ocular drug deliveries mediated via contact lens devices have employed versatile strategies including thermal-responsive, enzyme triggering, and hydrogel layer-controlled drug release 25,26,28,29 . To reduce burst release of drug from devices, Cakmak et al. fabricated a multi-diffusion layers-based contact lens that could achieve stable ophthalmic drug administration with constant rate 29 . However, medicines permeabilities into aqueous chamber by these passive diffusion methodologies are generally compromised due to the physiological barriers of eye, especially the frequent tear clearance and the tightly packed corneal epithelium cells 30 .
While most of the existing strategies for glaucoma applications focus on either sensing or delivery separately, integrated wireless electrical systems for closed-loop IOP monitor and regulation are highly desirable to treat glaucoma, yet rarely developed due to challenges (Supplementary Materials S2).
Closed-loop theranostic systems on flexible patches have recently been developed to automatically monitor biomarkers, and respond rapidly to treat these complications 1,3,4,31 . However, in contrast to patch devices worn on skin, closed-loop theranostic systems based on contact lens confront several complicating challenges due to its nature of limited size and requirement of wireless operations. First, contact lens is flexible, lightweight, curved and ultrathin device with extremely limited area 32,33 , which is highly challenging to install intricate theranostic system composited by multimodules, and less compatible with standard 2D micro/nano-fabrication routes. Second, contact lens devices need to operate wirelessly to promote patients' comforts 34 , yet the potential cross-coupling between wireless sensing and delivery modulus on limited device area would interfere to their individual operations. Third, simultaneous satisfactions of detection sensitivity and on-demand drug delivery on a single device are also difficult, since the limited space of contact lens would restrict the sizes of sensor or delivery module to achieve effective operations. showing the structure of the cantilever capacitive sensor, which could be highly sensitive to pressure, allowing drug delivery circuits to integrate in limited space.
In this work, for the first time to our knowledge, an integrated wireless theranostic contact lens (WTCL) was developed, for in situ glaucoma monitoring and electrically triggered drug administration at high-risk IOP conditions (Figure 1a). The WTCL employed a highly compact structural design and circuits layout, which enabled high-degreed integration of IOP sensing and on-demand delivery modulus on the curved and limited surface of contact lens without vision blockage (Figure 1b). The IOP sensing modulus possessed a unique cantilever configuration of LCR circuit, where each capacitive sensing plate sandwiching ultra-soft air dielectric film could ultra-sensitively respond to the IOP changes, producing detectable resonant frequency signals for wireless recording. The drug delivery modulus utilized a highly efficient wireless power transfer (WPT) circuit to drive anti-glaucoma drugs coated on electrode surface to migrate into the aqueous chamber via iontophoresis, which offered an electrical switch for drug delivery and enhancement of drug permeation across cornea ( Figure   1c). The specialized design of wireless sensor and WPT receiver enabled channel separation via different operational frequencies without cross-coupling, ensuring the individual functions of modulus in an integrated closed-loop system. The minimally invasive, smart, wireless and closed-loop theranostic features of the WTCL endowed this platform as a highly promising tool for facilitating glaucoma treatments and preventing acute symptoms.

System design and fabrications of the WTCL
Soft contact lens conformally interface with the cornea could effectively deform to transduce the expansion of the corneal limbus to the integrated sensor circuit when IOP increases, and localize external stimulations (e.g. electricity or chemicals) exerted on the cornea. Double layer-lens structure, a typical design acceptable for contact lens devices 34,35 , was adopted for fabricating WTCL to benefit integration of LCR circuit and drug administration module (Figure 1d) on the extremely limited space of contact lens (Figure 1e). The air film sandwiched between two layers of lens combined with LCR circuit characterized by cantilever structure formed the IOP transducer that could detect pressure fluctuations and transmit it wirelessly 23,36 . At high-risk IOP condition (IOP>21 mmHg), WPT triggered iontophoresis enables in situ drug administration effectively. Key advantages of this device contain: 1) soft, lightweight, re-usable, and minimally invasive features as well as wireless operations are highly compatible with contact lens platform. 2) Compact structural design and circuits layout enable high-degreed integration of IOP monitoring and on-demand delivery modulus in limited area without vision blockage. 3) Rational circuit designs enabled sensitive IOP monitoring by unique cantilever sensor structure, on-demand and effective ocular drug delivery via iontophoresis, individually controlled channel without cross-coupling via frequency separation. 4) the cantilever capacitive sensor is highly sensitive to pressure, which allows drug delivery circuits to integrate in limited space, while maintaining sensitive IOP monitoring performance. Any slight distance displacement or angle displacement of the capacitive plates could easily induce significant electrical signals. Due to the cantilever design that ultra-soft air layer is present between the capacitive plates, the displacement of capacitive plates could be highly responsive to the pressure even the pressure could be partially buffered by the delivery coils on top of the sensor (Figure   1f). 5) The closed-loop system with entirely electrical interface is beneficial for signal collection, processing, feedback, and transmission, as well as programmable ondemand drug administration. 6) Fabrication of the device is compatible with existing large-scale and cost-effective manufacturing process, emphasizing its potential for widespread applications.
The IOP monitoring circuit employed a unique snowflake-shaped layout design (Figure   2a), where each capacitive sensing plate (totally 6 plates) was then aligned with reference plate (Figure 2b) by folding to form a cantilever configuration (Figure 2c).
The reference plates and 5 coils of inductance were embedded in the upper lens ( Figure   2d), while dangling sensing plates contacting the front surface of the lower lens, with a dielectric air film between the reference and sensing plates forming a variable capacitor ( Figure S3.1). The capacitance combined with inductance coil formed a LCR circuit for wirelessly IOP monitoring. The deformation of corneal curvature caused by increased IOP compresses the thickness of air dielectric layer (Δd), leading to the rise of capacitance (CSR) and reduction of resonant frequency of LCR circuit that could be recorded by reading coil of integrated antenna (Figure 2e) wirelessly 23,36 . Due to the ultra-soft (ultra-low elastic modulus and zero viscoelasticity) feature of the sandwiched air film, the variable capacitors formed by cantilever configuration can ultra-sensitively respond according to the change of pressure (Figure S3.2). The cantilever design effectively avoids the issues of redundant serial capacitors, and complicated device fabrication process especially the wire bonding step that have been encountered in previous reported strategies 36,37 . On the other hand, the drug delivery circuit utilized a flower-shaped layout design (Figure 2f) that enables robust interlocking mechanically between the flexible circuit and the lower layer of contact lens (Figure 2g) 38 . The front side of circuit embedded in the lower lens possessed coils (Figure 2f-IV and Figure   S3.1) connected with chip capacitor for wireless power harvest, while the drugs-coated iontophoretic electrodes on the bottom side of delivery circuit were exposed and would be in contact with the cornea. Anti-glaucoma drugs, brimonidine, was loaded in a hydrogel layer coated on the iontophoretic electrode, which could be delivered into the aqueous humor via wirelessly iontophoresis to reduce IOP. The iontophoresis not only offered non-mechanical switch for drug delivery in a low-power consummation manner, but also facilitate drug penetration across cornea via electrophoresis effects 39 (Figure 2h). For the delivery module, similar to the sensing module, Cu was electro-deposited on PI substrate and patterned as coils features via photolithography and wet etching to form the WPT receiver. A second layer of PI was spinning coated on top of the coils, and another Cu layer was prepared according to the iontophoretic electrode pattern, which was connected to the coils at the bottom side by through-holes. The electrodes were further covered with Ni/Au, and capacitors were soldered onto the front side of circuit to tune the WPT operation frequency, followed by embedding the circuit into the lower PDMS lens via cast-molding. The delivery electrode of lower lens was coated with a thin layer of drugs-loaded hydrogel, and assembled with the upper lens to form the final WTCL (Figure 2i). The compact layout and double layer lens design enables sensors and WPT receiver to be embedded inside contact lens, avoiding direct contact of these components to the ocular surface that might cause potential irritations to eye. The

In-vitro performance of wireless IOP monitoring
The sensing performance of the WTCL was tested in vitro using porcine eyeballs, where porcine eyeballs' features similar with human eyeball have been widely employed in many physiological experiments. The IOP in porcine eye was tuned by controlled infusion of saline solution into the anterior chamber via microinfusion pump, with a pressure gauge to monitor the reference IOP. The IOP reading coil (diameter: 17 mm, turns: 1) of the integrated antenna connected to a network analyzer was positioned on top of the WTCL to monitoring the resonance frequency (Figure 3a). The static sensing performance was conducted by stepwise increase of IOP, while the resonance frequency of WTCL at each IOP condition was recorded. The reflection spectra of six representative WTCL devices worn on the porcine eyeball at different IOP  were recorded and analyzed (Figure 3b and Figure S4.1a), where the resonant frequency of IOP monitoring module was found to shift to the lower frequency at higher IOP.
The return loss (S11) values at different frequencies and IOP conditions were plotted as heatmap diagrams, where the S11 value exhibited a linear pattern in the frequency-IOP heatmap (Figure 3c). The relation of resonance frequency and IOP of each device was analyzed (Figure 3d and Figure S4 MHz/mmHg, which was superior or comparable to other wireless IOP sensors (Table   S2). This is likely due to the specific cantilever design of sensor, where the ultra-soft air film sandwiched between the sensing capacitive plates is highly mobile, so that the variable capacitors formed by cantilever configuration can respond to the change of pressure in a highly sensitive manner. The linear range of WTCL was wider than 5-50 mmHg, which were desirable for glaucoma monitoring applications. The measured IOP values by the six WTCL devices were derived from the recorded values of resonant frequency, and compared to the reference IOP measured by pressure gauge for analyzing the sensor's static accuracy via error grid analysis ( Figure 3f). The percentage of data points at different error range was quantified, where >50% recording was found to be within error<10%, and >75% recording was found to be within error<20%. The continuous recording of IOP via WTCL was also examined by measuring the resonant frequency and reference IOP via pressure gauge, respectively, where saline solution was injected into anterior chamber at t=0 s and 883 s intending to induce IOP spikes ( Figure   3g). The measured resonant frequency ( Figure S4  Region A+B, C and D referred to errors <20%, 20-40% and >40%, respectively.

The studies on WPT, cross-coupling and drug delivery
Magnetic resonance coupling-based WPT has been a competing technique for wireless bioelectronics due to its relatively high power transfer efficiency and resistance to environmental inference 40 . To achieve optimal coupling performance, four types of WPT receivers with 2, 5, 9, and 17 coils-design (namely Rec#2, Rec#5, Rec#9, and Rec#17, respectively) were designed with other circuit parameters accordingly modified ( Figure S5.1 and Table S3). In order to evaluate the power transfer performance, the optimal coupling frequency and acceptable radiation distance between WPT receiver and transmitter were examined. During experiments, the WPT transmitter of the integrated antenna connected to a waveform generator and a network analyzer was aligned over the WTCL with identical axis (Figure 4a), while the WPT receivers were connected to an oscilloscope to monitored the generated voltages. The Reflection coefficient spectra from four receivers at different radiation distance were recorded (Figure 4b and Figure S5.2), where the resonant frequency of transmitter and all receivers were observed to be at ~850 kHz according to the circuit designs. The channel separation between IOP monitoring (~3.8 GHz) and WPT (~850 kHz) was sufficiently large to avoid cross-coupling, which might prevent unexpected activation of a nontargeted wireless channel in the closed-loop glaucoma diagnosis and treatment 41 . The return loss (S11) reveals that most of the energy carried by electromagnetic wave could be radiated rather than dissipated in the frequency range of 837.38 kHz to 867.45 kHz), with a bandwidth of transmitter about 30 kHz 42 . The S21 under 850 kHz of all receivers decreased linearly with the increase of radiation distance (Figure 4c). Considering that certain distance between transmitting coils and contact lens is required to avoid interference to human eyes in practical applications, 6 mm was chosen as optimal distance between transmitting coils and WTCL in experiments.
Sequentially, a series of square wave (20 Vpp) with different frequencies (500 kHz to 1200 kH, 50 kHz step) or different distances (0 mm to 15 mm, 1 mm step) were wirelessly exerted on the transmitter, to further verify the optimized coupling frequency and distance. The generated sinusoidal voltages on the receivers were recorded by oscilloscope (Figure 4d, Figure 4e and Figure S5 at SinWave voltage were similar to that at SquWave, where 850 kHz was close to the optimal frequency. Moreover, the Vpp induced by the SquWave voltage wave was slightly higher than the that by SinWave (Figure 4i and Figure 4j), likely due to the fact that SquWave signals with more steeper edges created more rapidly changed magnetic field that is more favorable for WPT performance, compared to the SinWave at identical conditions.
To comprehensively evaluate the optimal conditions of WPT, receiver designs and the voltage transfer conditions (the coupling frequency, the radiation distance, and the waveforms) were systematically analyzed (Figure S5.3-5.8) and summarized in two heatmap diagram (Figure 4k). Although the WPT efficiency was higher at shorter radiation distance, 6 mm was selected as optimal distance between transmitting coils and WTCL since the contact lens needs certain separation from the transmitting coils in practical applications. The maximum transferred Vpp was observed on the optimal receiver Rec#17 at the applied SquWave with frequency of 850 kHz, which were identified as the optimal conditions for the final WTCL. The cross-coupling between multiple wireless channels is a significant concern since it may disturb the independent control over the in situ sensing and delivery modulus (Figure 5d). Conventional strategy to spatially avoid cross-coupling is less compatible with contact lens devices due to their limited space for spatially separation of channels 44 .
Here we employed a specialized technique of radio frequency separation to solve the cross-coupling issue, based on a compact design of device to accommodate distinguished wireless circuits on the limited area of contact lens. Firstly, the IOP reading coil and WPT transmitter were coupled with the WPT receiver (using Rec#17) at a set distance of 6 mm, respectively, and the S21 indicating the coupling efficiency and the generated voltages on receiver were separately measured. The coupling between WPT transmitter and receiver exhibited S21 higher than -40 dB and reached its maximum value (-15.6 dB) at around 850 kHz, and apparent sinusoidal voltage waveform with 6 Vpp was recorded. The coupling between reading coil and WPT receiver displayed ultra-low S21 (<-60 dB), and generated negligible voltage that was close to blank group of uncoupled receiver, suggested cross-coupling between IOP reading coil and WPT receiver rarely occurred.
The WTCL was placed on porcine eye at different IOP (0-50 mmHg), and the reading signals were recorded with or without the presence of radiation from WPT transmitter ( Figure S7.1). The S11-freqency spectra appeared to be overlapping well disregard of the presence of WPT radiation, where a typical example at 30 mmHg IOP was shown in Figure 5f-I. The resonance frequency and the peak S11 at different IOP were quantitatively analyzed (Figure 5f-II), where the radiation of WPT transmitter did not significantly influent the IOP monitoring, indicating cross-coupling between IOP sensor and WPT transmitter was negligible.    (Figure 6a) showed that the dye molecule was continuously released at a higher rate when higher voltages were applied, likely due to the fact that the electric field facilitated the diffusion of dye out of the hydrogel layer. Ex vivo experiments on porcine eyes were performed to examine the influence of iontophoresis on delivery across cornea, where rhodamine B was utilized as the medicines analog to facilitate visualization of distribution in tissue. The WTCL was worn on porcine eyes, and voltages with 6 Vpp at 850 kHz (the determined optimal WPT operation frequency) was applied to facilitate dye delivery via iontophoresis, and the anterior tissue was then fixed and sectioned for fluorescence visualization via microscope. Iontophoresis at other frequencies (650 and 1 MHz) or passive free diffusion were tested to optimize the iontophoresis conditions, and the fluorescence intensity and distribution area in the anterior tissues were analyzed.

In vivo performance of the integrated WTCL
Red fluorescence was clearly observed in the tissues of ciliary body and anterior chamber angle for all the samples treated via iontophoresis (Figure 6b), while the group of free diffusion exhibited significantly (> 3-folds) lower fluorescence intensity and less (>3-folds) fluorescence distribution compared to the iontophoresis groups ( Figure   6c). Of note, the ciliary body and anterior chamber angle have been proven to be the target sites for suppressing IOP by brimonidine through reducing aqueous humor production and increasing uveoscleral outflow. These results suggested the coupled iontophoresis could facilitate the delivery of drug analog molecules into anterior segment, and effectively work at the determined optimal WPT operation frequency of 850 kHz.
Next, in vivo experiments were conducted on rabbits, while the size of WTCL was proportionally scaled down to fit the rabbits' eyes. The WTCL was worn on the anesthetized rabbits' eyes, while the signals recording of WTCL and WPT operation were conducted by the integrated antenna (Figure 6d). The rabbits' IOP were monitored with either WTCL or commercial tonometry as a standard reference, and brimonidine delivery via wirelessly powered iontophoresis of WTCL was performed to reduce the IOP and compared to that via eyedrop. The initial IOP of rabbits exhibited slight fluctuation within the range of 10-15 mmHg as measured by Tonopen (Figure   6e), which rapidly (< 0.5 h) dropped by 39.2±10.3% (Figure S9.1) after brimonidine delivery via wirelessly powered iontophoresis (at 6 Vpp, 850 kHz, for 30 min), and the IOP reduction remained above 20% for the prolonged period (~2 h) after delivery ( Figure S9.2). In contrast, brimonidine delivery via free diffusion (for 30 min) from WTCL only slightly reduced IOP by 12.4±14.3% within 0.5 h after delivery (Figure 6f and Figure S9.1), and produced negligible effects (6.85+14.7%) within 2 h ( Figure   S9.3). These results suggested that the slow diffusion of brimonidine from WTCL might form a basal delivery to stabilize the IOP, while iontophoresis was able to facilitate a bolus delivery to more effectively reduce IOP spikes. Simultaneous IOP sensing and drug delivery using a single WTCL device were next performed (Figure 6g). The rabbit's IOP were wirelessly monitored with the WTCL for the first hour, then in situ brimonidine delivery via wireless iontophoresis on the same WTCL was conducted to reduce IOP, which were still continuously monitored by the WTCL (Figure 9.4 and the results confirmed that the iontophoresis via WTCL rapidly reduce the IOP with pronounced and prolonged effects that was desirable for regulating glaucoma. At the end, since WPT operation at high frequency is likely to produce thermal effects that are harmful to animal eyes, the temperatures of rabbits' eye surface (cornea) and WTCL were monitored via infrared thermal camera during the process of WPT operation (Figure 6j and Figure S10.1). The temperature of the and cornea was not increased, while the temperature of WTCL was observed to increase only by <3 o C (Figure 6k), respectively, during WPT for 30 min, suggesting negligible thermal effects produced by WTCL.

Conclusion
In this work, a soft, minimally invasive and battery-free WTCL system for in situ IOP tracking and on-demand medicines administration was developed. The delicate design for structure, circuits layout of the device enabled highly integration on limited area and curved surface without causing vision blockage as well as potential irritations. The where L1, L2 represent the inductance value of coil integrated in WPT transmitter and receiver circuit, respectively. k, denotes the magnetic coupling coefficient, means the link of magnetic flux between the WPT transmitter and receiver side 43 . The parameter is approximately equal to the following equation when the radiation distance is comparable to coils dimension 43 .
where d refers to distance between WPT transmitter and receiver circuit. Furthermore, r1, r2 denote radius of inductance coil of transmitter and receiver circuit.
According to these two equations mentioned above, the M was inversely proportional to the radiation distance for these two coaxial coils of transmitter and receiver circuit.
According to Kirchhoff's voltage law, the equation of the WPT system could be described as Where Us, RPT, LPT, CPT, IPT refer to the alternating voltage supplied for the transmitter, parasitic resistance, inductor, capacitor and alternating current in transmitter.
Correspondingly, RPR, LPR, CPR, RL denote the parasitic resistance, inductor, capacitor and electric load in receiver circuit. IPR represents the total alternating current in receiver circuit. IL is the alternating current flow through electric load.
To simplify the matrix, ZPT and ZPR were introduced as the impedance of transmitter and receiver circuit and expressed as Therefore, equation (1) could be transformed as And the current consumed by load illustrated as The power transfer efficiency was regarded to be the ratio of the real power dissipated in the load impedance to the power supplied from the source side , As regards high frequency circuit, alternating high-frequency currents tend to distributed toward the surface of conductor. This phenomenon, known as skin effect, will increase the resistance of the conductor and reduce the effective electric power exerted on load. The effective cross-section of the conductor for alternating currents was defined as skin depth that could be expressed by the following equation: where , , , , and represent skin depth in meters, frequency of the alternating current in Hz, relative magnetic permeability of the conductive matter, permeability of free space (4π×10 -7 H/m), and conductivity of conductor. Detailed parameters (relative magnetic permeability and conductivity of the conductive matter) were listed in Table S4.  University. For all in vivo experiment process, the rabbits were deeply anesthetized with pentobarbital sodium solution (0.8 ml/kg body weight). To minimize side effects, the administration of anesthetic solution was separately into three times through ear venous and twice intramuscular injection every ten minutes successively. Moreover, Isoflurane and oxygen were supplied through gas anaesthesia machine for rabbit to obtain prolonged anesthesia effects. Propivacaine hydrochloride eye drops (S. A. ALCON-COUVREUR N.V. Belgium) were dropped onto the rabbit cornea surface for topical anesthesia to avoid ocular movement including blink, facilitate WTCL wearing and IOP measurement by commercial ophthalmotonometer.
In vivo experiments of WTCL performance. Pentobarbital sodium (Nembutal, Ovation Pharmaceuticals Inc. Deerfield, USA) solution in saline (0.3 wt%) was prepared. New Zealand white rabbit (3 kg) was initially anesthetized with an appropriate dose of pentobarbital sodium solution (0.8 ml/kg body weight), and continuously anesthetized with Isoflurane anesthesia machine. To avoid unexpected situations, the administration of anesthetic solution was divided into three times through ear venous and twice intramuscular injection every ten minutes successively. After anesthesia, the rabbits were covered with blanket to maintain body temperature.
Propivacaine hydrochloride eye drops were dropped onto the rabbit cornea surface for local anesthesia to further avoid of ocular movement including blink. Commercial applanation tonometer (Tono-Pen Avia; Reichert, Inc., Depew, NY) was applied to acquire IOP measurement as reference. WTCL was worn on rabbit's eye, and oscilloscope was connected to the WTCL to monitor the Vpp between delivery and counter electrode during WPT process. Integrated antenna connected to network analyzer and waveform generator was posited above WTCL with the distance of 6 mm.
Sequentially, measurements of return loss by IOP reading coil was collected by network analyzer to wirelessly detect IOP. After one hour, square voltage with 20 Vpp at 850 kHz produced from waveform generator was exerted on WPT transmitter to trigger iontophoretic delivery wirelessly. Meanwhile, wireless IOP monitoring was continuously performed until the end of experiments.
Thermal characterization. New Zealand white rabbit (3 kg) was anesthetized with an appropriate dose of pentobarbital sodium solution (0.8 ml/kg body weight) through ear venous injections. After general anesthesia, the rabbits were covered with blanket to maintain body temperature. Then anesthesia machine was further adopted to supply isoflurane and oxygen via facemask for the rabbit, which could obtain prolonged anesthesia effects. WTCL was worn on rabbit's eye, and integrated antenna connected to waveform generator was posited above WTCL with the distance of 6 mm. Square voltage with 20 Vpp at 850 kHz produced from waveform generator was exerted on WPT transmitter. Infrared camera (T650sc, FLIR Systems, Wilsonille, OR, USA) was exploited to monitor thermal changes of ocular surface tissue, WTCL, and integrated antenna during the experimental process.