Optical pressure treatment through electrical stimulation

Abstract

An arrangement for reducing intraocular pressure includes a pulse signal source, a probe coupling, and at least one electrode. The probe coupling is configured to be supported on a portion of a living eye. The electrodes are supported on the probe coupling. The electrodes are operably coupled to receive a pulse signal from the pulse signal source.

Claims

1. A system comprising: a contact lens configured to be positioned on an exterior surface of a mammalian eye and comprising at least one electrode configured to be positioned adjacent to a ciliary body of the mammalian eye when the contact lens is positioned on the exterior surface of the mammalian eye; and a sensor disposed inside the contact lens; and a stimulation signal source coupled to the contact lens and configured to provide a pulsed electrical signal to the electrode when positioned adjacent to the mammalian eye, wherein the pulsed electrical signal causes a reduction in an intraocular pressure within an anterior chamber of the mammalian eye; wherein the sensor is coupled to the stimulation signal source and the stimulation signal source provides the pulsed electrical signal to the at least one electrode in response to a signal received from the sensor.

2. The system of claim 1, wherein the at least one electrode is configured to be disposed adjacent to a nerve associated with a ciliary body of the mammalian eye.

3. The system of claim 1, wherein the at least one electrode is disposed on or in the contact lens.

4. The system of claim 1, wherein the stimulation signal source is sized and configured to be mounted on a pair of eye-glasses frames.

5. The system of claim 1, wherein the at least one electrode is configured to be disposed in or around a ciliary body of the mammalian eye such that the at least one electrode hyperpolarizes non-pigmented epithelium of the ciliary body of the mammalian eye.

6. The system of claim 1, wherein the sensor is configured to measure the intraocular pressure of the mammalian eye.

7. The system of claim 1, wherein the stimulation source and the sensor form a closed-loop regulation system.

8. The system of claim 1, wherein the sensor is disposed proximate a surface of the exterior surface of the mammalian eye.

9. The system of claim 1, wherein the at least one electrode comprises one or more ring electrodes.

10. A system comprising: means for positioning at least one electrode on an exterior surface of a mammalian eye adjacent to the mammalian eye; means for measuring an aspect of the mammalian eye at the exterior surface of the mammalian eye; and means for generating a pulsed electrical signal and applying the pulsed electrical signal to the at least one electrode when positioned adjacent to the mammalian eye, wherein the pulsed electrical signal causes a reduction in an intraocular pressure within an anterior chamber of the mammalian eye.

11. The system of claim 10, wherein the at least one electrode is configured to be disposed adjacent to a nerve associated with a ciliary body of the mammalian eye.

12. The system of claim 10, wherein the at least one electrode is disposed on or in a contact lens.

13. The system of claim 10, wherein the means for generating the pulsed electrical signal is sized and configured to be mounted on a pair of eye-glasses frames.

14. The system of claim 10, wherein the at least one electrode is configured to be disposed in or around a ciliary body such that the at least one electrode hyperpolarizes non-pigmented epithelium of the ciliary body of the mammalian eye.

15. The system of claim 10, wherein the means for measuring the aspect of the mammalian eye is a means for measuring an intraocular pressure, and the means for measuring an intraocular pressure is disposed outside the mammalian eye.

16. The system of claim 15, wherein the pulsed electrical signal is provided to the at least one electrode in response to the intraocular pressure measurement.

17. A system comprising: a contact lens configured to be positioned on an exterior surface of a mammalian eye and comprising at least one electrode configured to be positioned adjacent to the mammalian eye when the contact lens is positioned on an exterior surface of the mammalian eye, the contact lens comprising a sensor configured to measure an intraocular pressure of the mammalian eye; and a pair of eye-glasses frames comprising a stimulation signal source coupled to the contact lens and configured to provide a pulsed electrical signal to the at least one electrode when positioned adjacent to the mammalian eye and in response to the intraocular pressure measurement, wherein the pulsed electrical signal reduces the intraocular pressure within an anterior chamber of the mammalian eye.

18. The system of claim 17, wherein the at least one electrode is configured to be disposed adjacent to a nerve associated with a ciliary body of the mammalian eye.

19. The system of claim 17, wherein the at least one electrode is disposed on or in the contact lens.

20. The system of claim 17, wherein the at least one electrode is configured to be disposed in or around a ciliary body such that the at least one electrode hyperpolarizes non-pigmented epithelium of the ciliary body of the mammalian eye.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows a schematic block diagram of an exemplary arrangement for modulating intraocular pressure according to a first embodiment of the invention;

(2) FIG. 2 shows a timing diagram of a stimulation signal that may be selectively applied in accordance with embodiments of the present invention;

(3) FIG. 3 shows a schematic block diagram of an exemplary stimulation circuit of the arrangement of FIG. 1;

(4) FIG. 4 shows an exemplary set of electrodes affixed to a cuff for use in the arrangement of FIG. 1;

(5) FIG. 5 shows a representative diagram of the set of electrodes and cuff of FIG. 4 implemented in a human eye in a first exemplary arrangement;

(6) FIG. 6 shows a representative diagram of the set of electrodes and cuff of FIG. 4 implemented in a human eye in a second exemplary arrangement;

(7) FIG. 7 shows a second exemplary set of electrodes for use in the arrangement of FIG. 1;

(8) FIG. 8 shows a frequency accuracy chart from an experimental prototype of the arrangement of FIG. 1;

(9) FIG. 9 shows a frequency error chart from an experimental prototype of the arrangement of FIG. 1;

(10) FIG. 10 shows a duty cycle or pulse width accuracy chart from an experimental prototype of the arrangement of FIG. 1;

(11) FIG. 11 shows a duty cycle or pulse width error chart from an experimental prototype of the arrangement of FIG. 1; and

(12) FIG. 12 shows a screen display of an oscilloscope showing a pulse train generated by an experimental prototype of the arrangement of FIG. 1.

DETAILED DESCRIPTION

(13) At least some embodiments of the present invention use electrical stimulation to modulate intraocular pressure in the eye. Electrical stimulation has been observed on other muscle groups on subjects at a variety of ages. By utilizing electrical muscle stimulation devices the researchers have been able to increase muscular strength, decrease body weight and body fat, and improve the firmness and tone in their subjects. [5] Another study discloses a circuit that circuit provides a low frequency stimulation (around 100 Hz) and a voltage up to about 50V. Included in this is variable pulse rate, width, and amplitude. [6]

(14) FIG. 1 shows a block diagram of a first embodiment of an arrangement 100 for reducing intraocular pressure that includes an electrical signal source 102, at least one electrode 104, and a intraocular pressure measurement or IOP sensor 108. The arrangement 100 is shown in context operably coupled to eye-related tissue 106. The electrical signal source 102 is a circuit or group of circuits that is operably coupled to receive an intraocular pressure measurement from the IOP sensor 108 and is configured to generate a controlled electrical signal based on the intraocular pressure measurement. The at least one electrode 104 is operably coupled to receive the electrical signal from the electrical signal source, and configured to be attached to a portion of an eye or eye-related tissue 106 of a living being. The IOP sensor is disposed proximate the eye-related tissue 106 and is configured to sense and generate the intraocular pressure measurement for the eye-related tissue 106.

(15) In the embodiment of FIG. 1, the electrical signal source 102 comprises a controller 110, a stimulation circuit 112, and a power source 114. In at least some embodiments, the electrical signal source 102 includes a hermetically sealed enclosure 116 to allow implantation. In this embodiment the controller 110 may suitably be a microcontroller that is operably coupled to receive a value representative of the measured IOP from the IOP sensor 108, and is configured to selectively cause the stimulation circuit 112 to generate (or not generate) the electrical stimulation signals based on whether the value representative of the measured IOP is above a threshold. The threshold represents a value of IOP above which electrical stimulation is deemed necessary or at least beneficial for the purpose of reducing the IOP. Thus, the controller 110 is configured to cause the stimulation circuit 112 to generate the stimulation signals responsive to the IOP measurement value exceeding the threshold, and to cause the stimulation circuit 112 to stop generating the stimulation signals when the IOP measurement falls below the threshold, or falls below a second, lower threshold (to allow for hysteresis). In this manner, the controller 110 is configured to cause application of electrical stimulation to the eye tissue 106 only when the IOP becomes excessively high.

(16) In some embodiments, the controller 110 may suitably be configured to also cause the stimulation circuit 112 to provide stimulation signals when the measured IOP value falls below a threshold value, and to stop the stimulation signals when the measure IOP value exceeds that threshold, or another, higher threshold (to allow for hysteresis).

(17) In general, to cause the stimulation circuit 112 to selectively provide or not provide stimulation signals, the controller 110 is operably coupled to provide control signals to the stimulation circuit 112. In some cases, the control signals further include signals that control the amplitude, pulse frequency, and/or pulse width of the stimulation signals generated by the stimulation circuit 112.

(18) The stimulation circuit 112 is a circuit that is configured to receive control signals from the controller 110 and generate electrical stimulation signals therefrom. In general, the stimulation circuit 112 produces stimulation signals in the form of electrical pulses in a pulse train, or pulse burst. FIG. 2, for example shows a timing diagram of an output voltage generated by the stimulation circuit 112 that includes an exemplary stimulation signal 200 and a no signal output 202. The stimulation signal 200 lasts from a time t.sub.0 to a time t.sub.1, and no signal is produced from the time t.sub.1 through and beyond the time t.sub.2. As discussed above, the control signals from the controller determine when the signal 200 is produced and when no signal 202 is produced.

(19) As also discussed above, the pulse frequency, pulse width and amplitude may be varied. The stimulation circuit 112 may suitably be configured for manual adjustment of such values or automatic adjustment of the values via the controller 110.

(20) FIG. 3 shows an exemplary stimulation circuit 300 that may be used as the stimulation circuit 112. The stimulation circuit 300 is based on a conventional 555 timer-style integrated circuit (“timer IC”) 302, and is configured for manual adjustment via variable resistors 304, 306, and 308. The circuit 300 also includes a VCC input which is operably coupled to the controller 110, a pulse width adjustment circuit 310, a pulse frequency or pulse rate adjustment circuit 312, an output circuit 314, and capacitors 316 and 318. As is known in the art, the timer IC 302 includes a VCC pin, a GND pin, a OUTPUT pin, a RESET pin, a DISCHARGE pin, a THRESHOLD pin, and a CONTROL pin.

(21) The capacitor 316 is coupled between the CONTROL pin and circuit ground. The GND pin is coupled to circuit ground. The capacitor 318 is coupled between the THRESHOLD pin and ground. The VCC input is coupled to the VCC pin. The pulse rate adjustment circuit 312 includes the variable resistor 306 coupled in series with a resistor 320, and is coupled between the VCC input and the DISCHARGE pin. The pulse width adjustment circuit 310 includes two series-coupled resistors 322 coupled in parallel to the adjustable resistor 304, all of which are series connected to another resistor 324. The variable resistor 304 has a variable output coupled to the junction of the series-coupled resistors 322. The pulse width adjustment circuit 310 is coupled between the DISCHARGE pin and the THRESHOLD pin.

(22) The output circuit 314 includes a PNP transistor 326, diodes 328, 330, a transformer 332, and the variable resistor 308. The OUTPUT pin is coupled to the base on the PNP transistor 326 via a resistor 328. The diode 328 is connected in reverse bias from the collector of the PNP transistor 326 to ground, and the diode 330 is connected in forward bias collector to the emitter of the PNP transistor 326. The emitter of the PNP transistor 326 is coupled to the VCC input. The primary winding of the transformer 332 is coupled between the collector of the PNP transistor 326 and circuit ground. The secondary winding of the transformer is coupled across the fixed terminals of the variable resistor 308. The circuit output terminals 314a, 314b are coupled, respectively, to a fixed terminal and the variable resistance terminal of the variable resistor 308. The circuit output terminals 314a, 314b in this example are coupled to a signal electrode 104a and a ground electrode 104b of the one or more electrodes.

(23) The stimulation circuit 300 is configured to generate pulse signals at the output, which propagates to the electrodes 104a, 104b. The variable resistor 304 may be adjusted to a desired pulse width. The variable resistor 306 may be adjusted to a desired pulse rate, and the variable resistor 308 may be adjusted to a desired pulse amplitude. In one embodiment, this circuit 300 may be used in conjunction with ultrasound and other techniques to identify a proper mix of pulse parameters (width, rate, amplitude) that corresponds to the muscles and nerves desired to be stimulated. In some embodiments, the variable resistors 304, 306 and 308 may not be necessary if a uniformly advantageous mix of pulse rate, amplitude and pulse width is employed over a broad spectrum of patients. In other embodiments, one or more variable resistors 304, 306 and 308 are operably coupled to be controlled by control signals of the controller 110, to enable real-time adjustment to the pulse parameters during normal operation. For example, different pulse widths, amplitudes and/or frequencies may be employed depending on the measured IOP values. In such a case, the controller 110 would generate control signals based on the IOP values for one or more of the variable resistors 304, 306, 308.

(24) The pulse signal or other signal may be selected such the electrode acts to reverse the flow of sodium into the eye, or such that the electrode hyperpolarizes the non-pigmented epithelium of the ciliary body.

(25) The pulse signal, which may be replaced by other stimulus signal, may suitably be a periodic pulse signal or a pulse signal having a series of burst pulses with various parameters, such as those disclosed in U.S. patent application Ser. No. 13/941,153, filed Jul. 12, 2013, which is incorporated herein by reference. Alternatively, the stimulation signal may incorporate methods disclosed in the published PCT application serial no. PCT/US2012/061687, filed Oct. 24, 2012, and which is incorporated herein by reference.

(26) In some embodiments, however, the controller 110 only provides control signals that selectively cause voltage to be available at the VCC input. To this end, the VCC input may suitably be coupled to the power source 114 via a switch (e.g. a transistor), not shown, that is controlled by the control signal from the controller 110. Thus, the controller 110 can cause the power source 114 to be selectively coupled to, or decoupled from, the VCC input of the stimulation circuit 300 to selectively operate, or not operate, based on whether the IOP values exceed one or more thresholds, as discussed above.

(27) It will be appreciated that the stimulation circuit 300 is provided by way of example only, and that other circuits that can provide pulse signals (with or without variable pulse width, pulse frequency and pulse amplitude) may be employed. Such other embodiments of the stimulation circuit 300 preferably generate signals using first and ground electrodes 104a, 104b as shown in FIG. 3. For example, it will be appreciated that a single integrated circuit may be employed as both the microcontroller 110 and stimulation circuit 112. In some embodiments, the microcontroller 110 provides the stimulation signal pulse train, which is then merely amplified by the stimulation circuit 112.

(28) Referring again to FIG. 1, the one or more electrodes 104 are operably coupled to receive the stimulation signals from the stimulation circuit 112, and further configured to apply the signals to eye-related tissue. In at least some embodiments, the electrodes 104 are disposed inside the eye and are positioned to modulate the flow of sodium into the eye. In one embodiment, the electrodes 104 are disposed to modulate the release of sodium by the ciliary body into the anterior chamber of the eye. To this end, at least one electrode 104 may be disposed around a nerve proximate to the eye. The nerve, for example, may be the optic nerve, trigeminal nerve, the oculomotor nerve or a branch thereof.

(29) For example, FIG. 4 shows an exemplary embodiment of the electrodes 104 arranged in the form of a probe coupling 401 including a cuff 410 which may be disposed around nerves in or near the eye. The cuff 410 is in the form of a hollow sleeve which allows the cuff 410 to be arranged around the nerve. Disposed around at least portion of the circumference of the cuff 410 are the electrodes 104, which in this embodiment include two signal electrodes 104a and a ground electrode 104b. The electrodes 104 are configured to be electrically coupled to the nerve around which the cuff 410 is disposed. The electrodes 104a, 104b are disposed at different axial positions on the cuff 410.

(30) As shown in FIG. 5, the cuff 410 of the coupling 401 may be arranged about the oculomotor nerve 402. The cuff 410 may alternatively be disposed about a branch extending from the oculomotor nerve 402. In another case, the electrode 104 may comprise a penetrating electrode that penetrates into the nerve 402, and may be coupled to another type of probe coupling. In any event, the electrode 104 stimulates said nerve 402 to modulate activity in the ciliary body 404.

(31) FIG. 6 shows another embodiment in which the cuff 410 is disposed about the optic nerve 412 such that the electrode 104 stimulates the optic nerve 412.

(32) In another embodiment, the electrode is disposed in or around the ciliary body of the eye (shown in FIGS. 5 and 6). For example, FIG. 7 illustrates an embodiment of a probe coupling 402 wherein the signal electrode 104a is a ring electrode on a contact lens 414. The contact lens 414 is disposed on the eyeball in a conventional manner, such that the electrode 104a is adjacent to the ciliary body 404. The ground electrode 104b in this case is an HK loop electrode. The electrodes 104a, 104b may in such a position hyperpolarize the non-pigmented epithelium of the ciliary body. The embodiment of FIG. 7 may not have the same level of efficacy of as the embodiment of FIGS. 4 and 5. However, the embodiment of FIG. 7 is non-invasive, and does not require surgery.

(33) In yet other embodiments, the electrode 104 is a ring electrode 104 disposed around the circumference of the eye acting on the ciliary or other nerves and/or drainage tissues. In at least some embodiments, the electrode 104 modulates activity in the ciliary ganglion. Preferably, regardless of where the electrode(s) 104 are coupled, they operate, when subjected to the pulse signal, to stimulate a nerve to modulate activity in the ciliary body. To this end, the electrode is disposed in or around the ciliary body. The electrode modulates the release of sodium by the ciliary body into the anterior chamber of the eye, which is one way to modulate aqueous humor production. Alternatively, or in addition, some embodiments of direct nerve stimulation may modulate nerve activity in the ciliary ganglion, drainage tissues, scleral spur or iris to modulate IOP.

(34) Referring again to FIG. 1, the IOP sensor 108 is a device configured to generate an electrical signal representative of a intraocular pressure. To this end, the IOP sensor 108 may suitably be disposed inside the eye. In another embodiment, the IOP sensor 108 is disposed outside the eye. For example, the IOP sensor 108 may be disposed inside a contact lens, which may suitably be the same contact lens 414 as that in which the electrode 104 is disposed.

(35) Using microcontroller technology, the electrical signal source 102 may be sufficiently small as to be mountable on a pair of eyeglass frames, not shown.

(36) Exemplary details regarding a first prototype of one of the embodiments described above is provided in the following Table 1

(37) TABLE-US-00001 TABLE 1 Technical Subcomponent Description Power 5VDC source Stimulator 32-162 Hz 0-42 V Electrode 0.5 cm pupil diameter 1.3 cm iris diameter 36 gauge silver wire

(38) Electric Field or tissue stimulation may have effect in addition to or independent of direct nerve stimulation. Accordingly, some embodiments can involve stimulation applied close to nerve and not in the nerve itself. The electrodes 104 may therefore stimulate tissue around circumference of eye, around drainage tissues of eye, around the scleral spur, or around ciliary ganglion or ciliary nerves.

(39) Preventions that can be incorporated into the design, such as adding limits to stimulation parameters are the first line of defense and help mitigate negative consequences if the device fails. As well as implementing preventative measures, it is important to be aware of the need for testing, especially of those aspects, such as mechanical lead failure which are difficult to implement preventative measures for. For these aspects, testing and statistical analysis are necessary to quantify the risk, and detection methods need to be made available to the user. Many of these extra tests and measures were not part of the teams original conception of the design. This dedicated analysis provides a structured method to focus on these what-if concerns, potentially increasing the marketability of the device, and preventing serious inconvenience and injury to the user. Much is still unknown about the effectiveness of the device as well as the risk associated with the surgical procedure. After initial surgeries are complete, it will be necessary to account for surgical complications and to make the procedure for the device as simple and safe as possible. There will surely be needed work in mitigation of the surgical risk.

(40) Design Verification Plans for Subcomponent

(41) As discussed above, the microcontroller 110 and stimulation circuit 112 are designed to perform the task of generating a square pulse waveform for electrical stimulation of nerves and muscles. One well established, but bulky device which currently performs this function is the Grass SD9 Square Pulse Stimulator [45]. The compact size, digital control and potential for closed-loop feedback would then push this prototype ahead of currently available muscle stimulators.

(42) The SD9 is rated with 10% accuracy on its stimulation parameters, so this will become the specification for the controlling components of the simulator prototype [45]. For effective therapy, it is important that the stimulator be able to adjust the frequency and duty cycle of the waveform. It is also important that the parameters inputted to the microcontroller result in an accurate output of a waveform with matching characteristics.

(43) Programmed versus measured frequencies and duty cycles can be recorded by inputting a waveform of the specified parameters (swept across the range of interest, 0-500 Hz and 0-100% duty cycle) and then measuring the real waveforms characteristics using an oscilloscope. This will satisfy the design specification for adjustable therapeutic effects.

(44) The SD9 for the prototype is a large, moderately heavy device at 24.1 cm×13.3 cm×14 cm and 1.6 kg [45]. The actual device is smaller and lighter than this model, satisfying the design specification for portability. The weight will be measured by placing the circuit, microcontroller, and electrodes on the scale and measuring in triplicate. The dimensions of the device will be measured using calipers and measured in three dimensions and in triplicate.

(45) Again the SD9 will set the baseline of 10% fidelity for the microcontroller. Since the amplitude of the waveform is not currently controlled digitally (but by an analog potentiometer) it is difficult to determine what the current amplitude is accurately without using an external measuring device, such as a multimeter.

(46) A prototype that was tested is composed of a few major subcomponents. The actual stimulation will be done using an Arduino Uno microcontroller which can manipulate the frequency, pulse width, and amplitude of the stimulation, as well as the total duration. The microcontroller will be controlled using a GUI built from Processing. There were a number of electrodes used to perform the actual stimulation including contact electrodes, HK loop electrodes, DTL fibre electrodes, and cuff electrodes. Rabbits were the animal that stimulation will be tested on and after the first round of surgeries, the optimal parameters of stimulation will be found and used to create the second prototype. This solution is an innovative approach to treating glaucoma by targeting the underlying mechanisms which regulate intraocular pressure using electrical stimulation. The final device incorporates known principles of nerve and muscle stimulation but involves new design in terms of parameters tailored to the intended areas of the eye. Further sophistication has been added by a GUI for controlling parameters which operates through the microcontroller. The microprocessor is also capable of simultaneously recording signal. By avoiding the side effects and need for repeated surgery associated with current treatments, this option aims to provide effective glaucoma relief for those who may have been ineligible for conventional treatment. By targeting the electrical activity directly this therapy also has potential to improve patient outcomes.

(47) Fortunately the Arduino can read voltages, and can be leveraged to act as a multimeter and report the current amplitude to the user, or for use in a control loop. This process is, however subject to error and variation, so the requirements stated will demonstrate whether the device has the appropriate level of accuracy.

(48) The first step into verifying the microcontroller's ability to accurately report voltage is to feed in a known voltage from a function generator and compare the measurements taken using a multimeter to those reported by the Arduinos code. Expected versus measured voltages can then be plotted for the voltage range we are interested in, and a measure of error can be calculated.

(49) The next step was to apply the same procedure with voltages generated by the Arduino. It is possible that in the process of generating waveforms, some error could be introduced to the Arduino's measurements. An input-output curve again can be plotted and the error can be quantified. This is necessary to fulfill the design specification for accurate reporting of stimulation parameters.

(50) The device must deliver the desired range of therapeutic waveforms to ensure the patient is receiving the proper treatment and the patients eyes are not being damaged as per the design specifications. The results we want to achieve are less than 10 mA, 0-15 V.sub.pp, and average of pulses <100 mV [9] [11].

(51) The procedure for finding these parameters will be using an oscilloscope to measure the output of the circuit across a load and use the oscilloscope functions to find the waveform average and the pulse voltage. An ammeter can be used to find the current.

(52) The operational amplifiers railing level needs to be taken into account to ensure the amplifier performs as desired in the needed ranges. The datasheet by Texas Instruments shows with a ±15V input the expected output is ±14V [46].

(53) It is necessary to make sure that the electrodes are not inhibiting the electrical stimulation of the desired tissues to fulfill our design specification for electrical conductivity. This test both ensures that the parameters that are expected to be delivered are actually delivered, as well as controls the productions of electrodes and allows standardization to occur.

(54) A multimeter will be connected to a positive and ground wire which will be connected to either side of the electrode. The resistance value will then be recorded in triplicate. The average and standard deviation of the resistance will be recorded and the resistances from different electrodes will be compared using t-tests.

(55) We have the design specification for cytotoxity. The agar diffusion test is important for determining if the materials used in our device will cause damage to the cells that they are exposed to. The agar diffusion test uses an agar petri dish with cells and the material being tested placed in the dish. The cells are left to incubate for 24 hours. The petri dish is then studied under a microscope to determine the diameter around the material that the cells do not grow in. The larger the diameter, the greater the toxicity of the material [47] [48].

(56) Localization of stimuli is important to ensure that only the desired tissues are being stimulated so no damage is caused to surrounding tissue. It is also necessary to prevent patient discomfort.

(57) Our goal for determining localization of stimulation is through observations during the rabbit surgeries. If the rabbits head or facial muscles twitch or jerk during stimulation and at no other time, then the electrodes are not localizing the current to the anatomy of the eye we are targeting. Another observation we can make is if there are jumps in the heart rate or spO2 levels. This means that the stimulation is traveling to the heart and lungs causing stimulation in those areas. These are also signs that the electrodes are not localizing the stimulation to the anatomy of the eye. In the future a mathematical model of the charge distribution through stimulation may be helpful in characterizing the anatomical structures that are being affected. These models can use the material properties and shapes of the electrodes as well as those of the eye and surrounding tissue to some extent to determine the flow of charge over time during different stimulation parameters.

(58) It is also necessary to find a non-invasive method to measure IOP reliably and accurately as per the design specification for accuracy of IOP measurement. This cited reference states that researchers used the tono-pen and received measurements with an accuracy of 0:6 mmHg [49]. Accordingly such may be employed as the IOP sensor 108.

(59) The time to successfully initiate stimulation for experienced and inexperienced users will be recorded. This may also develop into a user test that can be taken for certification after a brief training session. A user survey of satisfaction on a scale of 1-10 will also be distributed to determine if the user feels the controls are acceptably easy to use.

(60) The goal of this project is to use electrical stimulation to reduce IOP to treat glaucoma [30]. During the testing on 29 Oct. 2013, this was done measuring IOP changes before and after using simulation as well as using ultrasound to measure flow rates and view anatomical changes within the eye. The procedure consisted of first taking baseline IOP measurement before stimulation in triplicate. The stimulation parameter was then programmed in and applied to the appropriate anatomy. Finally, the IOP was measured in triplicate after stimulation and the change in the mean IOP before and after was calculated. This analysis is performed at a variety of stimulation parameters to determine the optimal input parameters.

(61) The ultrasound measurements determine the effectiveness of IOP measurements in a few ways. One way is in allowing one to view the ciliary body real-time during stimulation. It is critical in initial exploratory testing to determine if the stimulation of various parts of the anatomy are affecting the muscles and flow as is hypothesized. Ultrasound offers a unique way to visualize these changes. Ultrasound also allows the measurement of flow within the eye. It can certainly measure the arterial and venous flow and it may measure the aqueous flow if sensitive enough. Ultrasound will be used before and after stimulation of the ciliary body and before, during, and after oculomotor nerve stimulation. Changes in flow and the anatomy will be recorded and analyzed statistically and qualitatively. While the key measurement is IOP, tonography or other methods may be used to measure drainage, and fluorophotometric methods may be used to measure aqueous production.

(62) The heart rate and oxygen saturation (SpO2) measurements will determine the acute distress of the animal during the procedure. A correlation of the various aspects of the procedure to the time points of the plotted heart rate and SpO2 will determine if some parts of the procedure are more stressful for the animal than others. This data will be most useful when the anesthesia is switched from propofol to isoflurane, as isoflurane is a more consistent form of anesthesia. The procedure will be optimized to minimize stress to the animal by maintaining an elevated spO2 and keeping the heart rate within an acceptable range (140 to 170 bpm).

(63) Design Verification Subcomponent Testing Results

(64) Table 3 shows that although the basic function has been established, some desired specifications were not achieved. Implementing an additional DC blocking capacitor will help improve the performance to achieve the specifications. The results seen in FIGS. 19, 20, 21, 22 and Table 2 show the current prototype meets specifications for adjustable therapeutic effects. The failure of some of the higher

(65) TABLE-US-00002 TABLE 2 Table with error of Arduino outputs Error Met Specs? Frequency Fidelity Prediction matches R.sup.2 for regression = Yes (to programmed measured with 0.961 value) R.sup.2 >.9 Duty Cycle Range Max error <10% 0%-100% Duty Yes for full duty cycle Cycle <4% error range Duty Cycle Prediction matches R.sup.2 for regression = Yes Fidelity measured with 0.999 R.sup.2 >0.9

(66) TABLE-US-00003 TABLE 3 Table for the delivery of the desired range of therapeutic waveforms Specified Measured Met Specs? Current (100 kΩ load) <10 mA 0.570 ± 0.007 mA Yes Voltage (100 kΩ load) 0-15 Vpp  11.2 ± 0.03 Vpp No Biphasic waveform <100 mVavg 581 mVavg No

(67) TABLE-US-00004 TABLE 4 Arduino frequency range. Specified Measured Met Specs? Frequency Range 0-500 Hz, 0-170 Hz with No (Partial Suc- Max <10% Error. 250, cess) error <10% for 500 Hz <10% full frequency

(68) TABLE-US-00005 TABLE 5 Pulse modes from Arduino. Specified Measured Met Specs? Several Pulse Pulse train, pulse Pulse train, pulse Yes Modes burst, and single burst, and single pulse modes pulse modes
frequencies to remain within 10% of the specified value seems to be an artifact of rounding error within the Arduino's delay function, but for the purposes of testing stimulation parameters, having specific low-error frequencies in the upper end of this range is good enough. Further work is being done to allow for more freedom in waveform shape creation including charge-balanced non-symmetric waveforms.

(69) TABLE-US-00006 TABLE 6 Amplitude reporting from Arduino. Specified Measured Met Specs? Amplitude Max error <10% error Yes, R.sup.2 = 0.9998 Re-porting <10% for 0- for 0-9.5 V

(70) The results for amplitude reporting are promising (Table 6), showing a near-perfect correlation between predicted and measured values allowing us to use the Arduino as a self-monitoring system. The Arduino is, however limited to voltages between 0V and +10V meaning division and or offset will have to be performed to measure a wider range of signals.

(71) Table 7 shows that an op-amp used in connection with the Arduino Uno microcontroller works well in the ranges required, and provides the desired gain.

(72) TABLE-US-00007 TABLE 7 Op-amp performance Specified Measured Met Specs? Gain (V.sub.in = 4.3 V.sub.pp 4.25 + 0.001 V.sub.pp Yes V.sub.Rail,upper V.sub.out> 13.997 + 0.001 V.sub.pp Yes V.sub.Rail,lower V.sub.out< −12.386 V.sub.avg Yes

(73) TABLE-US-00008 TABLE 8 This shows the device is well within the design specifications for size and weight. Cytotoxicity levels still need to be determined using Agar Diffusion tests (Direct Contact). Specified Measured Met Specs? Size 24.1 cm × 13.3 cm × 7.95 cm × 5.33 cm × Yes  14 cm  4 cm Weight 1.6 kg 56 g Yes

(74) TABLE-US-00009 TABLE 9 Table of resistances for electrodes [50]. Specified Measured Met Specs? HK Loop Electrode <5Ω 0.233 ± 0.058Ω Yes, p <0.0005 Cuff Electrode <5Ω 0.267 ± 0.058Ω Yes, p <0.0005 Corneal Electrode <5Ω  9.97 ± 4.97Ω No p = 0.887

(75) The resistance values for the HK Loop Electrode and the Cuff Electrode (on table 17) were well below our specifications. The Corneal Electrode was above our specifications. This electrode was bought online, so we may need to adjust our specifications for this electrode. This electrode has also had a bit of injury to it from the initial surgery. The fact that part of the foil has been removed may have caused the increased resistance that is seen in experimentation.

(76) Observations during animal surgeries showed that the stimulation was not localized to the desired tissues. The rabbits facial muscles twitched when stimulation was applied.

(77) The twitches of the rabbits facial muscles indicates that the electrodes did not adequately localize the stimulation to the desired areas. Further investigation needs to be carried out to determine whether the delocalization of stimulation was due to the rupture of gold foil or our corneal electrode.

(78) Baseline IOP: 11:17±0:753 Chi-Squared Analysis: Expected Variance (E)=0.6

(79) Observed Variance (O)=0.753 Chi-Squared value (x.sup.2)=0.0389

(80) TABLE-US-00010 TABLE 10 IOP Accuracy design spec. Specified Measured Met Specs? IOP accuracy Max variance Variance Yes, x.sup.2 value <10% for full fre- is less than quency range 0.10

(81) Based on the results of this statistical analysis, the IOP measurements taken are accurate enough based on what accuracy has been achieved in the literature. A chi-squared analysis shows the multitude of variance that occurs and based on the value being less than 0.1, there is less than 10% variance.

(82) The surgery time in one implementation was 2.5 hours.

(83) TABLE-US-00011 TABLE 11 One sample t-test for IOP changes. N Mean StDev SE Mean 95% C.I. 3 7.667 1.528 0.882 (3.872, 11.461)

(84) TABLE-US-00012 TABLE 12 IOP change after stimulation Specified Measured Met Specs? IOP change after IOP change >0 ΔIOP Yes, 0 change is outside stimulation the 95% C.I.

(85) This study provides an initial result. In the first surgery there were many unknown variables that were accounted for which caused less than perfect results. The initial results indicated that the stimulation does seem to be changing the IOP by a statistically significant amount.

(86) Design Verification for Final Prototype

(87) The immunological response to the device in the eye is an important indicator in how much harm the electrode itself and the stimulation are causing to the surface of the cornea. This consideration will be accounted for by measuring the corneal thickness before and after stimulation using ultrasound. The corneal thickness is an indicator of inflammation of the eye before and after stimulation. Ultrasound measurement offers an extremely precise measurement method. The corneal thickness before and after stimulation will be measured in the stimulated eye and the other eye (control eye) to determine if there is a statistical difference in the corneal thickness due to the electrode and stimulation.

(88) The agar diffusion test is important for determining if the materials used in our device will cause damage to the cells that they are exposed to. The agar diffusion test uses an agar petri dish with cells and the material being tested placed in the dish. The cells are left to incubate for 24 hours. The petri dish is then studied under a microscope to determine the diameter around the material that the cells do not grow in. The larger the diameter, the greater the toxicity of the material [47].

(89) Measuring the waveforms entering the eye is necessary information to know so we are aware exactly what is being applied to the eye. This is done by using the Arduino as a multimeter.

(90) For the safety of the patient, it is critical to ensure the sterility of the electrodes before the procedure. Sterilization can be performed through gamma rays or EtOH, but the most convenient and prevalent method is autoclaving. The electrodes used in the procedure undergo autoclaving for two reasons. The first reason is to determine if the electrodes are mechanically sound enough to endure the harsh method of autoclaving. This will be determined by physical inspection of the electrodes as well as electrical characteristic testing. The second reason is to determine if the electrodes are sterilized by the autoclaving. This will be determined by a bacterial growth test by swabbing the electrodes after autoclaving and seeing if anything from them will grow.

(91) It is important to make sure that the device does not inhibit vision while wearing it, but it is also important to make sure that the stimulation does not cause immediate vision trouble or chronic vision trouble. To ensure that our device does not affect vision, a visual acuity test is performed before, during, and after device has been applied. The acuity test before the device will yield a base score. The tests during will tell us if the device is inhibiting vision due to the materials used or because of the stimulation. The test after will indicate that the stimulation does not have chronic effects. The test is performed by placing the chart 20 feet away from the patient and asking them to read the smallest line.

(92) The device is currently undergoing trials in the rabbit animal model to examine how well it reduces intraocular pressure. These experiments involve the following steps (but a more in depth procedure can be found by examining the surgical logs): Anesthetize the rabbit, establish a running IV drip of anesthesia Measure baseline levels of IOP before any treatment, then again with electrodes in place, but with no stimulation. Stimulation would then be administered through the arduino and circuit, controlled by a laptop. IOP is then triple sampled 5 seconds after the predetermined end of stimulation.

(93) Not only are we interested in the ability of the device to lower IOP in the rabbit, but also that the magnitude of therapy (the reduction in pressure) is adjustable to several levels. The severity of glaucoma will vary between patients and over time, therefore there is a customer need for the device to adapt therapy levels. This will be tested using an addition the above procedure wherein parameters of stimulation will be chosen at levels predicted to provide intermediate IOP changes. Statistical analysis will then be performed on the results that would confirm or deny that several levels of therapeutic effect are achievable.

(94) This product is intended for use in the reduction of intraocular pressure in patients with open-angle glaucoma, as well as other types of glaucoma and/or ocular hypertension (OHT) through the principles of Neuromuscular Electrical Nerve Stimulation (NMES) on the surface of the eye, ocular motor nerve, ciliary nerves and optic nerve [51] [52] [53].

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