WO2013059656A2

WO2013059656A2 - Methods and apparatus for detecting accommodative triggers

Info

Publication number: WO2013059656A2
Application number: PCT/US2012/061115
Authority: WO
Inventors: Amitava Gupta; Jean-Noel Fehr; Roland Michaely; Pier Paolo MONTICONE; Thomas MUEHLEMANN; Michael Morris; Urban Schnell
Original assignee: Elenza, Inc.
Priority date: 2011-10-20
Filing date: 2012-10-19
Publication date: 2013-04-25
Also published as: WO2013059656A3; WO2013059663A3; WO2013059663A2

Abstract

An intraocular implant includes a sensor that, when implanted the eye, detects a physiological change (e.g., change in pupil diameter) associated with an accommodative trigger and emits a signal representing the detected change. A processor coupled to the implant senses and interprets the signal based on one or more thresholds representing the patient's pupillary response to changes in object distance and/or ambient light level. If the processor determines that the signal represents an accommodative trigger, it actuates an electro-active optical element, such as a pixelated liquid-crystal cell, to change the eye's effective optical power and/or depth of field.

Description

METHODS AND APPARATUS FOR DETECTING ACCOMMODATIVE

TRIGGERS

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[00011 This application claims the benefit of U.S. Provisional Application No. 61 /549,280, which was filed on October 20, 201 1 , and is incorporated herein by reference in its entirety.

10002 ) This application also claims the benefit of U.S. Provisional Application No.

61 /556,536, which was on filed November 7, 201 1 , and is incorporated herein by reference in its entirety.

|0003] This application is also related to PCT Application (Attorney Docket No.

1 001 1 8-0303), which is entitled "Patient Screening Factors for Accommodative Implantable

Ophthalmic Devices," filed on even date, and is incorporated herein by reference in its entirety.

BACKGROUND

[0004] Accommodation is the process by which an eye focuses an image of an object less than six feet away. An accommodative response (a physiological response) occurs in response to an "accommodative stimulus," which is the intent of the subject to view a near object. Natural accommodative responses (i.e., those that occur naturally in vivo) include, but are not limited to, ciliary muscle contraction, zonule movement, alteration of lens shape, iris sphincter contraction, pupil constriction, and binocular convergence. The accommodative response (also known as the accommodative loop) includes at least three involuntary ocular responses: (1 ) ciliary muscle contraction, (2) iris sphincter contraction (pupil constriction increases depth of focus), and (3) convergence (looking inward enables binocular fusion at the object plane for maximum binocular summation and best stereoscopic vision). Together, these involuntary ocular responses are known as the "near triad," and accommodation and convergence are known as the "pupil near response." Ciliary muscle contraction is related to accommodation per se: the changing optical power of the lens. Pupil constriction and convergence relate to pseudo-accommodation; they do not affect the optical power of the lens, but they nevertheless enhance near-object focusing.

10005] In a healthy eye, the accommodative response follows the perception of an accommodative impulse (e.g., with a time delay in the range of about 0.1 - 1 .5 sec). The accommodative amplitude of the natural lens decreases with age, leading to a degradation or complete loss in the ability to focus on near objects. The loss of ability to focus on near objects is called presbyopia. In a presbyopic eye, the accommodative impulse may be followed by a sub-optimal or absent accommodative response. This degradation or loss of the

accommodative response makes it difficult or impossible to focus on near objects.

[0006] The natural lens can be replaced or supplemented with an artificial lens to enhance near vision. For example, many presbyopes use reading glasses or bifocals to view near objects. But reading glasses and bifocals are inconvenient because they do not provide any

accommodation; rather, the user accommodates by putting the glasses on. Static intraocular lenses do not provide accommodation either. A dynamic intraocular lens or other implantable ophthalmic device may be designed to provide an artificial accommodative response that mimics the eye's natural accommodative response. Such a device preferably includes one or more sensors that detect accommodative stimuli, and modulates a dynamic optical element, such as a lens or shutter, to change the eye's effective focal length or depth of field as disclosed in U.S. Patent No. 7,926,940 to Blum et al., which is incorporated herein by reference in its entirety.

SUMMARY

[0007] Embodiments of the present technology include implantable devices and

corresponding methods for actuating devices implanted in a human or animal body (e.g., in the eye). An exemplary device includes a sensor, a memory, and a processor. The sensor provides a signal representative of a physiological parameter. The memory stores (i) at least one initialization parameter associated with the physiological parameter under at least one of sustained conditions and transient conditions and (ii) at least one threshold parameter representative of a change in the physiological parameter. And the processor, which is communicatively coupled to the sensor and to the memory, actuates at least one component of the device based on the signal, the at least one initialization parameter, and the at least one threshold parameter. An exemplary device may also include an antenna to receive the initialization parameter and the threshold parameter.

In some examples, the implantable device is an implantable ophthalmic device, and

[0008] the sensor comprises at least one of a photosensor, an ion sensor, and an intraocular pressure sensor. In these examples, the processor is configured to determine a presence of the accommodative stimulus based on the signal, the initialization parameter, and the threshold parameter. For instance, the physiological parameter can be a pupil size, the initialization parameter can represent the pupil size under sustained and/or transient viewing conditions, and the threshold parameter can represent a change in pupil size associated with the

accommodative stimulus.

[0009] In further examples, the sensor may comprise a first photosensor configured to provide a first measurement indicative of an ambient light level and a second photosensor configured to provide a second measurement indicative of light transmitted through the pupil. Such a sensor may be termed "a pupil constriction sensor."

[0010] An exemplary processor may be configured to sample the signal from the sensor at a rate of about 1 Hz to about 12 Hz. It may also be configured to remove noise from the signal using a causal filter, such as a slew filter.

[0011] In some embodiments, the processor is configured to determine the presence of the accommodative stimulus based on: (i) a first comparison of a first pupil size measurement and the initialization parameter; and (ii) a second comparison of a difference between the change in pupil size and the threshold parameter. The first comparison may include determining if the first pupil size measurement is higher or lower than a threshold pupil size associated with viewing an object under a low light level, a high light level, a near object distance, and/or a far object distance. And the second comparison includes determining if the change in pupil size is higher or lower than a threshold pupil size for viewing an object under a low light level, a high light level, a near object distance, and/or a far object distance.

[0012] Such an exemplary implantable ophthalmic device may also include an electro-active optical element to provide a change at least one of the eye's effective optical power and the eye's effective depth of field in response to detection of the accommodative stimulus. The processor can be further configured to actuate the electro-active optical element within about 3.0 seconds of receiving the signal from the sensor. The electro-active optical element may be configured to provide: (i) an increase in the eye's effective optical power and/or the eye's effective depth of field in response to an indication that the change in pupil size exceeds a first threshold parameter; and/or (ii) a decrease in the eye's effective optical power and/or the eye's effective depth of field in response to an indication that the change in pupil size is smaller than a second threshold parameter that is greater than the first threshold parameter. Such an exemplary device may also include a static optical element with a fixed optical power in optical communication with the electro-active optical element, the static optical element.

[0013J In another embodiment, the sensor may include an intraocular pressure sensor that senses intraocular pressure (physiological parameter) and/or changes in intraocular pressure. The processor in such a device may be configured to actuate a shunt, a valve, and/or a pump in response to changes in intraocular pressure or a given intraocular pressure reading from the sensor. Alternatively, or in addition, the processor may be configured to actuate delivery of a drug based on the signal, the initialization parameter, and the threshold parameter.

[0014] The initialization parameter and/or the threshold parameter may be based on a pre-operative measurement and/or a post-operative measurement of the patient's pupil response to a change in ambient light level and/or object distance. They may be determined based on a measurement of pupil size under sustained viewing of an object at a fixed distance under a constant light level. They may also be determined based on a measurement of pupil size made while the subject views an object at a variable distance under a constant ambient light level. And they may be determined based on a measurement of pupil size made while the subject views an object at a constant distance under a variable ambient light level.

[0015] Yet another embodiment includes an implantable ophthalmic device with two photosensors: a first photosensor to provide a first signal representative of a pupil size and a second photosensor to provide a second signal representative of an ambient light level. The first signal has a sampling frequency of about 1 Hz to about 12 Hz. This exemplary device also includes a memory to store (i) at least one initialization parameter associated with at least one of a pupil size under a sustained viewing condition and a pupil size under a transient viewing condition and (ii) at least one threshold parameter representative of a change in pupil size associated with an accommodative stimulus. A processor, communicatively coupled to the sensor and to the memory, filters the first signal so as to produce a filtered signal. The processor also determines a presence of the accommodative stimulus based on at least four sample of the filtered signal, the second signal, the at least one initialization parameter, and the at least one threshold parameter. And an electro-active element, communicatively coupled to the processor, provides an accommodative response in response to detection of the

accommodative stimulus within about 3.0 seconds of the processor filtering the first signal.

[0016] The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent by reference to the following drawings and the detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosed technology and together with the description serve to explain principles of the disclosed technology.

[0018] FIGS. 1A and I B are schematic diagrams of an implantable ophthalmic device that detects an accommodative stimulus based on one or more thresholds determined from pre- and/or post-operative pupil size measurements.

[0019] FIG. 2 is plot of pupil size data under various viewing conditions for a typical subject. The data were obtained in a clinical study comprising nine separate experiments involving variation of object distance and ambient illumination level, the two major environmental stimuli that control pupil size. The data were obtained under both sustained (static) and transient viewing conditions, with both stimuli either being held constant or varying in a square wave pattern, shown in the figure.

[0020] FIG. 3 shows close-up plots of the horizontal pupil diameter versus time

measurements in FIG. 2 with mean pupil diameters indicated by horizontal lines. The filtered data has been fitted with mean diameters, where σ is standard deviation in data on pupillary diameter of a single subject and Φ is the mean diameter measured under a certain set of environmental stimuli, including ambient illumination and object distance. 10021 ] FIG. 4 is a plot of mean horizontal pupil diameter for sustained viewing of a far object (upper plot), a near object (lower plot) at a low light level, and a threshold value for determining whether the object is near or far (dashed line); distributions of the pupil diameters are plotted at right on a vertically oriented axis

[0022] FIG. 5 is a plot of horizontal pupil diameter for transient viewing of an object that alternates between near and far distances at a low light level (upper plot) and a high light level (lower plot ) as well as threshold values (dashed lines) for transient viewing; distributions of the pupil diameters are plotted at right on a vertically oriented axis.

[0023] FIG. 6 is a flowchart that illustrates a process for detecting accommodative triggers using the implantable ophthalmic device of FIGS. 1A and I B.

[0024| FIG. 7 is a plot of pupil diameter as a function of ambient illumination for different accommodative stimuli.

[0025] FIG. 8A is a plot of a raw signal representing pupil diameter versus time and a filtered signal based on the raw signal.

[0026] FIG. 8B is a plot of a filtered version of the signal(s) shown in FIG. 4A along with plots of the dynamic thresholds used to filter the signal(s) shown in FIG. 4A.

[0027] FIG. 9 is a plot of a signal representing pupil size versus time before and after slew rate filtering.

[0028] FIG. 10 is a plot of horizontal pupil diameter versus time (left axis) and change in pupil diameter versus time (right axis) for a typical subject.

[0029] FIG. 1 1 illustrates pupillary size change profiles upon change of object distance for a typical subject.

[0030] FIG. 12 illustrates pupillary size change profiles upon change in ambient light level for a typical subject.

DETAILED DESCRIPTION

[0031] Presently preferred embodiments of the disclosure are illustrated in the drawings. An effort has been made to use the same or like reference numbers to refer to the same or like parts. [0032] Disclosed herein is an implant, such as an intraocular implant, that comprises a set of design modules implemented in hardware and a segment of instructions and data implemented in hardware, firmware, and/or software in an electronic signal processor, The processor receives raw signals from one or more sensors of a physiological response and performs causal data filtering on the signals. It then performs computation of specific statistical metrics from the sampled data so that these may be compared with reference values stored in look up tables either permanently in electrically erasable programmable read-only memory (EEPROM) units or in random access memory (RAM) within the processor. Exemplary statistical metrics include initialization and threshold parameters. These metrics may be measured

post-operatively on individual patients who have received the implants and transferred into the processor wirelessly. This enables accurate triggering of an electronically actuated function such as increasing optical power of a dynamic intraocular lens (IOL) optic, changing the depth of focus of the eye by adjusting the transmissive properties of an intraocular aperture, opening of a shunt, valve, or micropump to increase aqueous outflow, or delivering a specified dosage of a drug in the intraocular cavity (e.g., from a reservoir or cavity).

[0033] In this disclosure, accommodative stimulus is defined as one of the environmental stimulus that initiates an accommodative physiological response. An accommodative stimulus may be provided by bringing an object close to the eyes of a subject, and asking the subject to view the near object. The response to an environmental stimulus is a called a physiological response that can be identified and measured by suitably designed and located sensors. Signals from the sensors then travel to a signal processor that filters the raw signals, analyzes the signals in terms of their magnitude and time profiles, and compares them to stored data in the memory. If the signals conform to a particular type of an environmental stimulus based on this analysis, the processor may trigger an electronically actuated function in the implanted device. In an intraocular lens implant, the environmental stimulus being monitored is the

accommodative stimulus, while the physiological response that may be monitored may be a change in pupil size, an increase in Ca⁺⁺ ion concentration due to interaction of g proteins with the cell surfaces of smooth muscles comprising the iris sphincter muscle, and/or an increase in intraocular pressure. Intraocular implanted pressure sensors monitor the rate of outflow of aqueous humor from the eye (environmental stimulus) by measuring intraocular pressure, which generally increases when the outflow is impeded in any manner (physiological response). The implanted sensor may then trigger the opening of a valve or a shunt, actuation of a micropump, or release of a specified dosage of medication in the eye.

[0034] Pupillary Response and Accommodation, Cognitive Tasks, and Ambient Light

[0035] Pupil constriction correlates with accommodative stimuli. It also correlates with other phenomena, including changes in the ambient light level, cognitive processes and behavioral activities (task-induced changes), blinking (momentary constriction flowed by a return to the resting value), application of drugs, and age. For instance, in a healthy human, the pupil constricts when the ambient light level increases for an eye fixed on an object at a constant distance. In addition, the pupil diameter fluctuates under constant viewing conditions (e.g., viewing a near object in dim light). Thus, relying on pupillary constriction as the sole indicator of an accommodative stimulus may generate false positive accommodation signals.

[0036] Accommodative stimuli can be detected more reliably by measuring a patient's physiological response to environmental stimuli as a function of time, filtering the resulting measurement signal, and comparing the filtered signal to one or more threshold values based on pre- and/or post-operative measurements of the patient's pupillary response. One or more sensors may measure suitable physiological responses and/or physiological parameters (e.g., pupil diameter, ion concentration, or intraocular pressure). A processor electronically filters signals representing these physiological responses to remove unwanted variations, or noise that may be caused by blinking, loss of fixation, aging, and other environmental factors unrelated to accommodation (e.g., change in ambient illumination). The processor compares the filtered signal to one or more thresholds demarcating signal values that correspond to the presence and/or absence of an accommodative stimulus. The processor computes one or more statistical metrics from the filtered data sequence in real time shown in equations (1) and (2) (below) and uses these metrics to determine whether or not an accommodative stimulus is present; if so, it may actuate an electro-active optical element so as to provide an artificial accommodative response, e.g., an increase in the eye's effective optical power and/or depth of field.

[0037] An Implantable Ophthalmic Device for Detecting Accommodative Triggers

[0038] FIGS. 1 A and I B illustrate an implantable ophthalmic device 100 that may be implanted in a human or other animal eye to compensate for the loss of or degradation in accommodative response due to presbyopia and/or other ophthalmic conditions. It includes a first sensor 1 10 and a second sensor 120 that measure a patient's physiological response (change in pupil diameter) to environmental stimuli (object distance and ambient light level) as a function of time. Together, sensors 1 10 and 120 form a pupil constriction sensor. The device 100 also includes a processor 130 that electronically filters the resulting measurement signal, performs computation on the filtered signal to generate statistical metrics and compares the filtered signal to one or more threshold values stored in a memory 140 to detect an accommodative trigger. These threshold values may be updated via an antenna 150, such as an inductive coil, that is coupled to the processor 130. This antenna 1 50 enables the device 100 to remain sterile while being reprogrammed before surgery, or intra-operatively, or remotely, after implantation.

[0039] The first sensor 1 10 has an annular active area with an inner diameter of about 0.9-1.2 mm, an outer diameter of about 1 .1—1 .3 mm, and a fill factor (ratio of active area to exposed sensor area) of about 100%. (By comparison, the pupil diameter 10 of a healthy adult human ranges from about 2.0-7.0 mm depending on ambient light levels, range of regard, and other factors.) The second sensor 120 includes a left active area 122 and a right active area 124 disposed along a diameter 1 12 of the first sensor 1 10. A gap of about 250-600 μιτι extends between the outer diameter of the first sensor 1 10 and the inner edges of the left and right active areas 122, 124, which may be up to several millimeters long (e.g., 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, or any length between any two of these values) and about 30-300 μπι wide. Those of skill in the art will readily appreciate that other sensor shapes and sizes fall within the scope of the present disclosure.

[0040] When the implantable ophthalmic device 100 is implanted properly, the first sensor 1 10 is concentric with and completely within the diameter 1 0 of the pupil and the active areas 122, 124 of the second sensor 120 are symmetric about the center of pupil. The first sensor 1 10 is typically positioned closer to the center of the pupil than the second sensor 120, but in general, the terms "first" and "second" are used to merely as a naming convention rather than to define any particular position, characteristic, or orientation. For example, the first sensor 1 10 may be implanted at a distance of about 0.45-0.55 mm from the center of the pupil, and the second sensor 120 may be implanted at a distance of about 0.80-1 .25 mm from the center of the pupil. [0041] In operation, the first sensor 1 10 and second sensor 120 detect the brightness, or illuminance, of incident light 12 as shown in FIG. 1 B. As understood by those of skill in the art, the illuminance is the total luminous flux per unit area (usually expressed in lux or lumens/m²). The illuminance in lux can be converted to irradiance, or power per unit area (usually expressed in W/m²), with knowledge of a wavelength-dependent conversion factor representing the eye's luminosity function. The first and second sensors 1 10, 120 detect irradiance over a given active area (i.e., power) and produce first and second photocurrents Ii, I₂, respectively, whose amplitudes are proportional to the illuminance of the incident light 12. In preferred embodiments, the first and second sensors 1 10, 120 have similar responsivities (quantum efficiencies), sensitivities, and dynamic ranges.

[0042] Changes in the pupil diameter 10 affect the amplitudes of the photocurrents generated by first and second sensors 1 10, 120 as follows. The outer diameter of the first sensor 1 10 is smaller than the minimum pupil diameter 10, so the entire active area of the first sensor 1 10 is always illuminated (provided that the eyelid is open). As a result, the amplitude of the photocurrent Ij emitted by the first sensor 1 10 varies with the ambient light level, but not the pupil diameter 10. Conversely, the pupil occludes or obscures portions of the active areas 122, 124 as it opens and closes in response to changes in ambient light levels and/or accommodative stimuli, which causes the amplitude of the photocurrent I₂ emitted by the second sensor 120 to vary with both the ambient light level and the pupil diameter 10.

[0043] Because the first and second sensors 1 10, 120 are positioned at different distances from the center of the pupil, the differential between the photocurrents Ii, I₂ generated by the first and second sensors 1 10, 120 can be used to determine the degree of pupil constriction. For example, when the first sensor 1 10 is positioned closer to the center of the pupil than the second sensor 120, the second sensor 120 is eclipsed by the constricting iris before or to a greater degree than the first sensor 1 10. When the pupil is dilated, both sensors 1 10, 120 may be exposed to ambient light. When the pupil is partially constricted, the second sensor 120 may be eclipsed by the iris, while the first sensor 1 10 remains exposed. When the pupil is further constricted, both photosensors may be eclipsed by the iris, but the second sensor 120 may be eclipsed to a greater degree than the first sensor 1 10. As the sensor 1 10 becomes more eclipsed, the amount of light detected at the corresponding ocular position decreases. [00441 The processor 130 uses the measurements of ambient light level and pupil diameter represented by the first and second photocurrents U, ½ from the first and second sensors 1 10, 120 to determine whether or not an accommodative stimulus is present. The processor 130 determines whether or not the pupil diameter has changed based on a ratio of the digitized photocurrents as described in greater detail in WO 2012/037019 to Schnell et al. , which is incorporated herein by reference in its entirety. These photocurrents may be digitized by an analog-to-digital converter (which could be part of the processor 1 30 or one or more separate components) at a rate of about 1 Hz to about 60 Hz (e.g., 3, Hz, 4 Hz, 12 Hz, or 15 Hz). The processor 1 30 filters the measurement signal to remove high-frequency (e.g., > 2-10 Hz) noise caused by blinking and/or medium-frequency (e.g., 0.5-2.0 Hz) noise caused by temporary loss of fixation as described below. The processor 1 30 may also filter out or otherwise compensate low-frequency drifts caused by fatigue, etc.

[0045] The processor 1 30 compares the filtered measurement signal to one or more thresholds representing accommodative triggers under transient and/or sustained viewing conditions. For instance, the processor 130 may compare a first pupil diameter measurement to an initialization threshold stored in the memory 140. Like the initialization parameter, these threshold parameters are based on pre- and/or post-operative measurements of the patient's pupillary response. If this first measurement exceeds this initialization threshold, the processor 1 30 may determine that the patient is subject to an accommodative stimulus. In response to this determination, the processor 130 may compare a number (e.g., 2-36) of successive pupil size measurements to one or more transition thresholds stored in the memory 1 40 and based on pre- and/or post-operative measurements of the patient's pupillary response. These transition thresholds represent the patient's pupil size (and/or change in pupil size) at low light levels, high light levels, near object distances, and/or far object distances. If the processor 1 30 determines that a predetermined number (or an average or median value) of these

measurements exceeds one or more of the transition thresholds, it concludes that an accommodative trigger is present.

[0046] Furthermore, the processor may compute the rate of change in the pupil diameter in order to obtain time profiles of change in pupillary diameter that can be compared with reference profiles for that particular subject measured ex-vivo post-operatively, and stored in the memory of the processor. This type of signal processing provides a high level of discrimination from changes in pupillary diameter caused by other environmental stimuli.

[0047] If the processor 130 senses an accommodative trigger, it actuates a dynamic electro-active element 140 (e.g., a liquid crystal cell or lens with a variable focal length) that changes the eye's effective optical power, focal length, depth of field, or any combination thereof. The electro-active element 140 may be pixelated or otherwise segmented (e.g., into annular pixels or segments) to provide a continuous or nearly continuous range of diameters and/or levels transmission in response to commands from the processor 130. For instance, the electro-active element 140 may provide a variable diameter aperture that closes and opens to increase the effective optical power and/or depth of field of the eye as described in U.S. Patent No. 7,926,940 to Blum et al. , which is incorporated herein by reference in its entirety.

[0048] As understood by those of skill in the art, the processor 130 and its functions may be implemented as any suitable combination of hardware and software (computer- implementable instructions stored in a nontransitory memory, e.g., memory 140). For instance, it may be implemented as one or more application-specific integrated circuits (ASICs) as described in PCT/US201 1/040896 to Fehr et al., which is incorporated herein by reference in its entirety. The processor 130 may be sized to fit inside an electronics module within the intraocular implant. For instance, the processor 130 may occupy a volume of less than 0.5 mm³ (e.g., less than 0.2 mm³, and with a length of less than 1 .0 mm in the longest dimension).

J0049] The processor 130, sensors 1 10 and 120, memory 140, and/or antenna 150 may be powered by a rechargeable battery or other power supply for powering the processor 130 and the electro-active element 140 as described in PCT/US201 1/050533 to Fehr et al, which is also incorporated herein by reference in its entirety. This power supply may be recharged inductively via the antenna 150 and/or by shining light on the sensors 1 10 and/or 120. The device 100 may also be designed and/or operated so as to reduce electrical power consumption and/or leakage current.

[0050] The implantable ophthalmic device 100 may also include one or more lens elements that provide static optical power (e.g., 1-30 Diopters) in addition to the dynamic effective optical power and/or depth of field provided by the dynamic aperture 102. In cases where the implantable ophthalmic device is an intraocular lens (IOL), the IOL may have at least one static optical power provided by a curved surface and/or a graded index profile. For example, the IOL may include spherical optical element and/or an aspheric optical element as described in PCT/US201 1/038597 to Blum et ciL, which is incorporated herein by reference in its entirety. Alternatively, the implantable ophthalmic device may be an intraocular optic (IOO), which has little to no optical power, but also includes a dynamic aperture that provides an increased depth of field. In some illustrative devices with dynamic apertures, opening and closing the aperture serves to provide a continuous range of focus between the fixed or static corrective powers of the ophthalmic lens.

[0051 j Inventive sensor systems can be embedded in or affixed to an IOL, IOO, corneal inlay, corneal onlay, or other implantable ophthalmic device. Implantable ophthalmic devices, such as the device 100 of FIG. 1 , may be inserted or implanted in the anterior chamber or posterior chamber of the eye, into the capsular sac, or the stroma of the cornea (similar to a corneal inlay), or into the epithelial layer of the cornea (similar to a corneal onlay), or within any anatomical structure of the eye. When implanted, the first and second sensors 1 10, 120 are positioned on substantially the same coronal plane. For example, when the sensors are integral with an IOL, the sensors can be positioned on the plane of the IOL.

[0052] The device 100 may be calibrated for an individual patient. Pupil size and constriction response vary among individuals and may even vary between eyes of the same individual. The device 100 may be calibrated by one or more of: raising or lowering one or more initialization thresholds; raising or lowering one or more transition thresholds; altering the position of one or more sensors; modifying the accommodative trigger function; changing the electro-active optical element's response (e.g., the minimum and/or maximum aperture sizes or minimum and/or maximum focal lengths); and/or modifying the sensitivity of the system (e.g., the pupil constriction lower limit and/or the ambient light upper limit).

[0053] Identifying Accommodative Triggers Based on Pupil Size Measurements

[0054] As described above, changes in pupil size are one type of physiological response to accommodative triggers. Clinical studies show that changes in pupil size are nearly universal across a variety of viewing conditions, including for individuals with and without intraocular lenses and before and after cataract surgery. More specifically, the study results show that the pupillary response to an accommodative stimulus of 2.5 Diopters (corresponding to an object presented to the subject at 40 cm from the eye) is nearly universal (it occurs in > 99.4% of test subjects). In fact, only 2 out of 350 subjects experienced pupillary changes that could not be measured experimentally. However, the study results show that the change in pupil size over time (the magnitude and time profile of the pupillary dynamics) varies by almost an order of magnitude across the study population.

TABLE 1 : Viewing Conditions (Experiment Nos.) in the Clinical Study

Exp. No. Viewing Condition Object Distance Ambient Light Level Comments

1 Calibration Set detection threshold

(grey level)

2 Calibration Model eye (pupil size

= 8 mm), converts pixels to mm

3 Sustained viewing Far Low >6 meters; 75 lux

4 Sustained viewing Near Low 40 cm (corresponding to 2.5 D of accommodative stimulus)

5 Transient viewing Varying Low (constant) Every 15 seconds

6 Transient viewing Varying High (constant) 15 sec; 1500 lux

7 Transient viewing Far (constant) Varying 15 sec

8 Transient viewing Near (Constant) Varying 15 sec

9 Transient viewing Intermediate varying 73 cm (corresponding

(constant) to 1.33 D of

accommodative stimulus)

[0055] FIG. 2 is a plot of pupil size data for a typical subject viewing an object under the viewing conditions listed in TABLE 1. The data have been filtered to remove noise, including blinks. FIG. 2 shows that the subject's horizontal pupil diameter remains relatively constant under a given sustained viewing condition. For instance, when viewing a near object at a low light level (Exp. No. 3), the first subject's horizontal pupil diameter shrinks from about 4 mm to about 3.5 mm over about 300 seconds. FIG. 2 also shows that the subject's minimum horizontal pupil diameter under Exp. No. 3 is greater than his maximum horizontal pupil diameter under Exp. No. 4. As a result, it is possible to detect an accommodative trigger by measuring only ambient light level and the patient's pupil size. Similarly, the patient's pupil size varies repeatably (e.g., with a smaller standard deviation) under transient viewing conditions (Exp. Nos. 7 -9).

[0056] The study results also show that the noise, or undesired variance in pupil diameter, varies greatly from subject to subject. Noise in the data comes from several sources, including high-frequency noise from blinks and experimental artifacts, medium-frequency noise from oscillatory pupillary dynamics characteristics of hippus, and low-frequency noise from loss of attention (and hence fixation on the target) and fatigue. This large variation in noise coupled with the large variation in pupil size change leads to a signal-to-noise ratio (SNR) that varies dramatically from subject to subject. FIG. 3 shows a typical set of pupil data acquired on a single subject. Fortunately, the noise power spectrum can be used to filter raw signals from pupil constriction sensors as described below.

|0057] The study data suggest that control of the operation of an implanted ophthalmic device should be based on patient-specific data, e.g., pupil responses as a function of object distance and ambient illumination level for the individual receiving the implant. Other patient-specific data suitable for controlling actuation of an implantable ophthalmic device may include excyclorotation of the eye or Ca⁺⁺ ion expression that bind to the G protein on the cellular surface of the smooth muscles comprising the pupil or the ciliary body. Temporal profiles of intraocular pressure changes can also be used control actuation of an implantable ophthalmic device.

[0058] The study data also suggest using different thresholds for identifying when to provide an artificial accommodative response and when to stop providing the artificial accommodative response— in other words, introducing hysteresis for turning the electro-active optical implant on and off. This hysteresis compensates for uncertainty or noise in the plot correlating object distance (or its inverse, accommodative stimulus) with pupillary size. For example, the processor may be programmed to activate or deactivate the electro-active optical element at a value of object distance for which the threshold pupillary size is not precisely fixed. In that case, the device may go into an uncontrolled oscillatory response if the object distance happens to approximately coincide with the trigger point set (threshold). This behavior can be avoided by separating the trigger points (initialization parameters and threshold parameters) in both directions, e.g., by setting the ON threshold at one object distance (for example, 67 cm), while setting the OFF threshold at a different object distance (for example, 100 cm). The gap between W

these two object distances should exceed the variability in the stimulus response curve, and may be made patient specific.

[0059] The study results also suggest that the photosensors and the processor should be able to reliably detect a change in pupillary diameter for an incremental change in the stimulus (e.g., the intensity of ambient illumination or the object distance). For example, if the photosensors and the processor can resolve changes in pupil size to within 10 microns, then the pupil size must change by at least 15 microns in response to the stimuli to achieve a signal-to-noise ratio of 1.5 or more. The magnitude of pupillary response upon application of the two stimuli may be determined clinically to determine whether it is feasible to use the response to trigger an electro-active optic; if proven feasible, the response magnitude can be used to determine the maximum number of incremental changes in stimuli magnitude over which the device operates effectively.

[0060] For example, consider a patient who exhibits a linear response to accommodative stimuli. If applying an accommodative stimulus of 3.0 D yields a total pupil response of 0.15 mm, and if it is desired to set the ON trigger at 1.5 D (corresponding to an object distance of about 67 cm) of stimulus, then up to 5 decrements can be set. Any lag or non-linearity in pupillary response may further reduce this number. In this case, the profile of change in pupillary diameter may be difficult to isolate, which may reduce the effectiveness of matching such a profile with a profile (or set of profiles) stored in the memory of the microcontroller or ASIC,

[0061] The time delay of the pupillary response (or more generally, its temporal profile) may be used to determine the number of data points that the processor can collect and analyze before determining whether to switch the electro-active optical element on or off. Since the patient experiences a time delay that is approximately equal to that of the natural

accommodative response, the time constants of the device's pupillary response and its triggering subsystem (data acquisition, data analysis, issuance of trigger signal, and implementation of the optical power change) should add to a value that is less than that of the natural accommodative response. For example, the processor's maximum time delay before issuing a trigger signal may be approximately 3 seconds (e.g., about 0-1 .5 seconds). [0062] Similarly, the sensors may collect data at a rate of about 1- 2 Hz (e.g., 2-6 Hz). This allows the sensors and the processor to collect and analyze four or more (e.g., six) data points for determining if a change in pupillary diameter is taking place in response to an

accommodative stimulus. These data may also be used to determine the accommodative stimulus's magnitude. Collecting data at a rate of 12 Hz enables detection of a physiological response that lasts about 0.33 seconds or more. Taking into account the response time of the photosensors and the processor, this yields a time constant for the physiological response that lasts about 0.44 seconds or longer. For instance, it may be in the range 0-1 .5 seconds. Clinical measurements of the pupillary response and the device's capability may be used to verify the device's feasibility for triggering an artificial accommodative response in a manner that meets the patient's neural and psychophysical needs.

[0063] The devices and techniques disclosed herein have wider applications than operational control of dynamic optics in intraocular lenses and other implantable ophthalmic devices. For example, they may be used to filter and/or isolate the signal from an intraocular pressure sensor like the one disclosed in U.S. Patent No. 8,246,569 to Meng et αί , which is incorporated herein by reference in its entirety. This filtered/isolated signal may be used as a reliable trigger for delivering medication from an implanted device and/or for operating a shunt that accelerates the outflow of aqueous humor through the Schlemms canal or the trabecular meshwork. They can also be used in devices that use an amplified external stimulus, such as a focused light beam or a laser beam, to enhance the SNR and to enable reliable generation of a trigger signal. For example, they can be used to generate a reliable trigger signal for actuating an intraocular drug delivery device (e.g., a shunt or micro-pump) like the one disclosed in U.S. Patent No. 7,879,019 to Santini et al, which is incorporated herein by reference in its entirety.

[0064[ Initialization and Threshold Parameters for Detecting Accommodative Triggers

[0065] An exemplary processor may use at least two types of input parameters to determine whether or not a physiological response represents an accommodative trigger: initialization parameters and threshold parameters. Threshold parameters refer to upper and/or lower bounds of pupil size variations for a specified object distance or accommodative stimulus and a specified level of ambient illumination that cause triggering to take place when the signal recorded in real time exceeds or falls below a threshold. Thresholds may depend on individual pupillary response to ambient illumination levels and object distance. Thresholds can be specified such that they are refined as the processor operates, moving further from the noisy signal (for example, pupil size at high light levels) and moving closer to the less noisy signal (for example signal at low light levels). Initialization parameters are actual pupil size data measured on an individual at a specific illumination level and object distance over a period of time. Both types of parameters may be stored in memory, e.g., in look-up tables.

[0066] These threshold parameters may be tailored to each patient— for instance, they may be based on pre- and/or post-operative measurements of the patient's pupillary response to accommodative stimuli. For instance, both initialization parameters and threshold parameters may be obtained on each patient prior to surgical implantation of the device, or both prior to and after implantation, in order to capture any change in the parameters due to the surgical procedure and the healing process that follows.

[0057] In practice, a caregiver may perform a specified set of dynamic pupil size measurements utilizing a pupillometer, in a diagnostic test that could include certain elements of the clinical study in this example. This diagnostic test would include pupil measurements preferably carried out without placing any monitoring instruments or constraints on the patient's head or in front of the eyes, as a function of ambient illumination level and object distance, measured when performing viewing tasks when there is no change in the stimuli, and also when one or the other stimulus is varied to create transients.

[0058] The study data described above exemplifies clinical measurement data suitable for programming the thresholds stored in the processor's memory. Such data can be obtained using a pupillometer, such as an infrared video pupillometer, to measure pupil metrics including but not limited to: mean pupil diameter, median pupil diameter, median absolute deviation (MAD) in pupil diameter for different combinations of near and far object distances and high and low light levels. These measurements are indicated here as median PNL, median PDL, median PNH, median PDH, MAD PNL, MAD PDL, MAD PNH and MAD PDH, in which P stands for pupil; D and N represent far and near object distances, respectively; and L and H represent low and high light levels, respectively. Other ranges may be specified for each of the stimuli, for example, and intermediate object distance may be specified when the corresponding accommodative stimulus is in the range of 1.0 D to 1 .5 D. [0067] This pupil data can be filtered to remove noise, and used to compute the initialization parameters and threshold parameters. These parameters include Δ = median PDL - median PNL, which represents the difference in median pupil size for different object distances at low light levels. Pupil size measured under steady state conditions may differ from those measured under transient stimuli, so it is beneficial to compute Δ from two sets of diagnostic tests: one in which the patient views an object at a fixed distance for a sustained period and one in which either the light level or the object distance is varied in a square wave mode. The parameters also include Ratio = (median PDL - median PNL)/ (median PDL + median PNL), again computing ratios from sustained viewing and transient viewing data separately. And the parameters also include Threshold - [(median PDL)(MAD PNL) + (median PNL)(MAD PDL)]/(mad PDL + mad PNL), again computing thresholds from steady state and transient data separately.

[0068] FIG. 3 is a plot of initialization data for one subject; it includes horizontal pupil diameter measurements taken under the viewing conditions for Exp. Nos. 3-6 as listed in TABLE 1 and shown in FIG. 2. The experimental data are plotted over median data values 0DLx, where x is the experiment number. For exemplary processors, initialization parameters are derived from pupil size measurements made under various combinations of low and high light levels, near (40 cm) and far (>6 m) object distances, and sustained and transient changes in the stimuli, including both illumination level and object distance. More specifically, the following eight parameters were calculated from the clinical data:

[0069] Four initialization parameters for use at low light levels (e.g., from Exp. Nos. 3, 4, 5, 7, and 8):

Mean pupil diameter at low light and distance target: 0DL

Pupil noise at low light and distance target: aDL

Mean pupil diameter at low light and near target: 0NL

Pupil noise at low light and near target: σΝΧ

[0070] Four initialization parameters for use at high light levels (e.g., from Exp. Nos. 6-8)

Mean pupil diameter at high light and distance target: 0DH

Pupil noise at low high and distance target: aDH

Mean pupil diameter at high light and near target: 0ΝΗ Pupil noise at high light and near target: σΝΗ

10071] Exp 3 is initialized by taking 20s out of Exp3 (0DL, aDL) and 20s out of Exp 4 (0NL, aNL). Exp 4 is initialized by taking 20s out of Exp3 (0DL, aDL), and 20s out of Exp 4 (0NL, aNL). Exp 5 is initialized by taking 10s out of Exp 5 (distant target)( 0DL, aDL), and 10s out of Exp 5 (near target) (0NL, aNL). Exp 6 is initialized by taking 10s out of Exp 6 (distant target) (0DH, aDH), and 10s out of Exp 6 (near target) (0ΝΗ, σΝΉ). The analysis is shown in Figure 4, based on the threshold obtained by comparing pupil sizes measured while the subject was viewing objects at far (>6 m) and near (40 cm) distances at low light level (100 lux), T_L3>4 (defined below in Eq. (1 )) in which T is threshold, L indicates low light level, and 3 and 4 refer to the experiments described above.

|0072] Similarly, suitable threshold parameters can be calculated from values of pupil sizes (e.g., mean and/or median values), taking into account noise, in such a way as to give more weight to cleaner data and less weight to noisier data. Thresholds may be calculated for both sustained and transient viewing tasks. For instance, the threshold parameter for sustained viewing a low light level may be defined as:

' L3 A ~

[0073] ^Σ01,1 + ^ΣΝ1.Α (J )

[0074] And thresholds for transient object distance viewing under low and high levels, respectively, may be defined as:

_T _ Φρΐ. ,5 ^σΜ. ,5 + ΦΜ. ,5 ^ΣΡ1.5

I L 5,5 ~

[0075] ^σ°'-^{5 σ}^·⁵ (2) r _ ΦθΗ ,5 ° Nil ,5 ⁺ ΦΝΗ .5 ° DH .5

'^{/ 5}·^{5 —} τ

[0076] ^σηΗ,5 + ^σΝΗ .5 (3)

[0077] The subscript numbers refer to the experiment numbers given in TABLE 1. For example, 0NH,5 is the pupil diameter measured at near distance and high light level in Exp. No. 5.

[0078] FIG. 4 is a plot of mean pupil diameter and an exemplary threshold parameter (Eq. ( 1 )) for sustained viewing for a typical subject. The mean pupil value is 0; the standard deviation is σ; ΔΕ3,4 = 0DL,3-0NL,4; and the signal-to-noise ratio is RatioL3,4 = AL3,4 / (oDL,3+ ffNL,4). The pupil diameter distributions are plotted against a vertical axis at right.

[0079] FIG. 5 is a plot of threshold values (dashed lines) given in Eqs. (2) and (3) derived from transient viewing data (also plotted) acquired in Exp. Nos. 5 and 6. The pupil diameter distributions are plotted against a vertical axis at right. In this case, the accommodative stimulus is changing (as shown in FIG. 3), while the level of illumination is kept constant for each measurement. The signal is much noisier in Exp. No. 5, obtained under low light conditions. The threshold accordingly comes much closer to the mean (or median) pupil size achieved under high light conditions when detecting transients in accommodative stimuli.

|0080] Process for Detecting Accommodative Triggers

[0081] FIG. 6 is a flowchart that illustrates a process 600 for detecting accommodative triggers based on initialization and threshold parameters. In step 602, the processor downsamples physiological parameter and/or physiological response data from one or more sensors (e.g., photosensors, intraocular pressure sensors, or ion concentration sensors). It performs an initial sanity check in step 604 to verify that the data are within expected ranges and that the sensor(s) is (are) operating properly. The processor interpolates (e.g., using a linear or cubic-spline interpolation) over unusable data in step 606.

[0082] FIG. 7 is a plot of pupil diameter as a function of ambient illumination over a range of accommodative stimuli. FIG. 7 also shows on (solid line) and off (dashed line) threshold parameters for triggering artificial accommodative responses. The processor may use the data shown in FIG. 7 to determine whether or not the pupil size measurement passes the sanity check in step 604. For instance, if the pupil diameter and illuminance are in region indicated as "Distant" or "Near," the processor may determine that the patient is viewing (or attempting to view) a distant object or a near object, respectively, and trigger the appropriate response (e.g., turning the electro-active optical element off or on). If the data is in a "No Change" region, which is present to provide hysteresis in the device's response to accommodative stimulus, the processor may determine that the electro-active optical element should remain in its current state, e.g., on or off. If the pupil diameter and illuminance are in a region indicated as "Invalid Data," the processor may discard the data as spurious and/or query the photosensor's functional status. And if the data are in an "Out of Light Range," the processor may determine that the patient's eyelid is closed or that the patient is viewing a very bright light.

[0083] In step 608, the processor filters the data, e.g., using a causal filter. A causal filter is one that operates on data as it is being received in real time. In other words, a causal filter cannot create a model (e.g., best fit) of the data based on data collected over a sustained period, then filter the entire body of the data going backwards. As the processor continues to operate, causal filters become more effective in isolating signal from noise. When deployed in the implant, this causal filter removes data affected by high-frequency (> 2-10 Hz) noise caused by blinks and other sources and medium-frequency (0.5-2 Hz) noise caused by temporary loss of fixation. Low-frequency drifts are corrected by modifying initialization values, since the processor has learning capability. Typically, the photosensors are sampled at about 1-12 Hz (e.g., 4 Hz). Increasing the frequency of data collection causes an increase in power consumption, while improving the accuracy of the operation of the algorithm and also reducing the delay of trigger signal issued by the algorithm. In this example, the delay is a maximum of 3 seconds after a signal indicating a change in object distance viewed by the subject is received. Examples of causal filtering techniques include slew-rate filtering, low-pass filtering, median filtering, and short-window median filtering.

[0084] FIGS. 8A and 8B illustrate data subjected to median-based causal filtering. FIG. 8A shows a raw signal that is provided as input to the processor from a pupil constriction sensor and filtered version of the same signal. The signal becomes highly noisy at 1 80 seconds as the patient presumably experiences fatigue induced hippus. FIG. 8B shows the effect of causal filtering the input signal of FIG. 8 A and the dynamic thresholds used for causal filtering.

[0085] FIG. 9 is a plot of pupil size data subjected to slew-rate filtering, which involves measuring pupil size at a number of different object distances (corresponding to

accommodative stimuli) as a function of ambient illumination levels. As understood by those of skill in the art, the slew rate of an electrical signal is a vector representing the signal's maximum rate of change. In slew rate filtering, if SRr equals the slew rate rise (mm/s), SRf equals the slew rate fall (mm/s) and Fs is the sample frequency (Hz), the slew rate filter can be expressed as follows for a digital signal x(n): if x(n+l ) > x(n) and if x(n+l ) > x(n)+ SRr/Fs, then x(n+l) = x(n)+ SRr/Fs; if x(n+l ) < x(n) - SRf/Fs, then x(n+ l ) = x(n) - SRf/Fs. The frequency ranges over which the processor applies the slew filter may be set or adjusted for each patient and the thresholds recomputed postoperatively. The revised data can then be reprogrammed into the algorithm remotely. This approach serves to filter out blinks when pupil size falls below a lower threshold, and pupil sizes outside a specified range of illumination level.

[0086] Referring again to FIG. 6, the processor compares the filtered sensor data to one or more initialization parameters stored in memory (step 610). For instance, the processor may compare the measured pupil diameter to a threshold pupil diameter stored in a look-up table; this stored data may be based on the measurements described above with respect to FIG. 3. If the measured pupil diameter is less than this threshold pupil diameter, the processor may determine that an accommodative trigger may be present.

10087] In response to the determination in step 610, the processor initiates a comparison of successive physiological response measurements to one or more threshold parameters stored in the memory (step 612). For instance, the processor may determine the change in pupil size from two successive pupil diameter measurements (e.g., sample 0 (step 614) and sample = sample + 1 (step 616)) and compare this change with an expected change in pupil diameter for a given ambient light level and object distance for a predetermined number of samples or sample pairs (e.g., until an "end" sample in step 616). Again, the processor computes threshold values (step 620) and performs a threshold sanity check (step 622) to eliminate spurious data and to ensure that the processor and sensor(s) are working properly.

[0088] The processor may take one of two approaches to model and code pupil data as a function of ambient illumination and object distance. In the first approach, shown in FIG. 6, the processor divides the entire range of ambient illumination (for example, from bright sunlight to start light, covering up to 10 decades of illumination levels) into a number of smaller ranges, e.g., three or more. In the second approach, the processor divides the entire range of pupil size into a number of smaller ranges, e.g., three or more. In each approach, the processor may define an upper range and a lower range in which the trigger remains inactivated and one or more intermediate ranges in which the trigger is operational.

[0089J If the data pass the sanity check in step 622, the processor determines whether the data show that the ambient illumination is in the higher or lower range of illumination levels stored in the memory (step 624). It separates low light level data (step 630) from high-light level data (step 640), then determines whether the data indicate a transient over the successive measurements (steps 632 and 642). if the data indicate a transient, the variables are re-initialized (steps 634 and 644) before the processor compares them to pupil diameter thresholds for the appropriate illumination level (steps 636 and 646); otherwise, the processor compares them to pupil diameter thresholds for the appropriate illumination level without re-initializing them (steps 636 and 646).

[0090] Based on the results of these comparisons, the processor determines with the patient is focusing on (or trying to focus on) a near object (steps 638 and 648) or a far object (steps 639 and 649). These object-distance determinations are upsampled in step 652, then subjected to another sanity check in step 654. If the object-distance determination passes this sanity check, the processor may actuate the electro-active optical element to provide the optical power suitable for enabling the patient to view the desired object.

[0091] Transient Detection

[0092] In executing the process 600, the processor performs at least two functions: (1 ) it maintains the device's triggering status during sustained viewing by filtering out noise and discriminating between spurious transients; and (2) it recognizes a real transient within a specified short period of time, so that the electro-active optical power is triggered ON or OFF when the patient changes his/her object of regard. Transient detection may be carried out by using static thresholds, e.g., thresholds calculated from data obtained during sustained viewing tasks. The accuracy of capturing a change in object distance may also be improved when additional signal processing methods are applied, as shown in FIG. 10.

[0093] FIG. 10 is a plot of pupil diameter (left axis) and change in pupil diameter (right axis) that illustrates the presence of a transient. In this case, the sampling frequency is 6 Hz in order to detect and response to a transient within 3 seconds. This data is drawn from records of subject no 2080 in the clinical study undergoing Exp. No. 6. Here, the filtered data is shown in blue, and a reference pattern of a transient expected from application of an accommodative stimulus of 2.5 Diopters is imposed on the data using the time scale (grey sloped lines). The analysis is the convolution of these two plots (the data and the reference profile). A peak is obtained when one or more reference segments coincide with the actual data. The peak provides the time constant and occurrence time of the transient. The size of the peak (that may be compared with a threshold) indicates if^" the transient is due to the correct or desired environmental stimulus.

[0094] Thresholds may be used to analyze transient signals from the photosensors. These transient thresholds enable the processor to accurately recognize when a change in

accommodative stimulus is taking place, and hence issue an appropriate trigger. In FIG. 10, thresholds to detect transients arising out change in light level and object distance were calculated from the clinical data obtained from the transient experiments (Exp. Nos. 5-8).

[0095] FIGS. 1 1 and 12 include plots of pupillary response profiles upon changes in object distance and illuminance, respectively, for a single subject. These profiles may be used in a pattern recognition approach to transient detection. For instance, the processor may implement two modules: a first module to monitor sustained viewing situations and a second module designed to monitor occurrence of transients. The overall accuracy of the processor's accommodative trigger detection may depend on the weight placed on each of these two separate modules. For example, the static or sustained viewing conditions may be given more weight, with transient detection taking over when conservatively estimated thresholds are breached. A merit function may be constructed, expressing the processor's overall accuracy as a function of the weights placed on these two modules, and the processor's overall accuracy may be measured either in real time on a patient during a post-operative check up, or using results obtained in a diagnostic test performed on the patient during a post-operative check-up.

[0096J Computer Implementations

[0097] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0098] The above-described embodiments can be implemented in any of numerous ways. For example, the embodiments may be implemented using hardware, software or a combination thereof. When implemented in software, the software code can be executed on any suitable processor or collection of processors, whether provided in a single computer or distributed among multiple computers.

[0099] Further, it should be appreciated that a computer may be embodied in any of a number of forms, such as a rack-mounted computer, a desktop computer, a laptop computer, or a tablet computer. Additionally, a computer may be embedded in a device not generally regarded as a computer but with suitable processing capabilities, including a Personal Digital Assistant (PDA), a smart phone or any other suitable portable or fixed electronic device.

[0100] Also, a computer may have one or more input and output devices. These devices can be used, among other things, to present a user interface. Examples of output devices that can be used to provide a user interface include printers or display screens for visual presentation of output and speakers or other sound generating devices for audible presentation of output. Examples of input devices that can be used for a user interface include keyboards, and pointing devices, such as mice, touch pads, and digitizing tablets. As another example, a computer may receive input information through speech recognition or in other audible format.

[0101] Such computers may be interconnected by one or more networks in any suitable form, including a local area network or a wide area network, such as an enterprise network, and intelligent network (IN) or the Internet. Such networks may be based on any suitable technology and may operate according to any suitable protocol and may include wireless networks, wired networks or fiber optic networks. W

101021 The various methods or processes outlined herein may be coded as software that is executable on one or more processors that employ any one of a variety of operating systems or platforms. Additionally, such software may be written using any of a number of suitable programming languages and/or programming or scripting tools, and also may be compiled as executable machine language code or intermediate code that is executed on a framework or virtual machine.

[0103) In this respect, various inventive concepts may be embodied as a computer readable storage medium (or multiple computer readable storage media) (e.g., a computer memory, one or more floppy discs, compact discs, optical discs, magnetic tapes, flash memories, circuit configurations in Field Programmable Gate Arrays or other semiconductor devices, or other non-transitory medium or tangible computer storage medium) encoded with one or more programs that, when executed on one or more computers or other processors, perform methods that implement the various embodiments of the invention discussed above. The computer readable medium or media can be transportable, such that the program or programs stored thereon can be loaded onto one or more different computers or other processors to implement various aspects of the present invention as discussed above.

[0104] The terms "program" or "software" are used herein in a generic sense to refer to any type of computer code or set of computer-executable instructions that can be employed to program a computer or other processor to implement various aspects of embodiments as discussed above. Additionally, it should be appreciated that according to one aspect, one or more computer programs that when executed perform methods of the present invention need not reside on a single computer or processor, but may be distributed in a modular fashion amongst a number of different computers or processors to implement various aspects of the present invention.

[0105] Computer-executable instructions may be in many forms, such as program modules, executed by one or more computers or other devices. Generally, program modules include routines, programs, objects, components, data structures, etc. that perform particular tasks or implement particular abstract data types. Typically the functionality of the program modules may be combined or distributed as desired in various embodiments. [0106] Also, data structures may be stored in computer-readable media in any suitable form. For simplicity of illustration, data structures may be shown to have fields that are related through location in the data structure. Such relationships may likewise be achieved by assigning storage for the fields with locations in a computer-readable medium that convey relationship between the fields. However, any suitable mechanism may be used to establish a relationship between information in fields of a data structure, including through the use of pointers, tags or other mechanisms that establish relationship between data elements.

[0107] Also, various inventive concepts may be embodied as one or more methods, of which an example has been provided. The acts performed as part of the method may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.

[0108] Conclusion

[0109] The use of flowcharts is not meant to be limiting with respect to the order of operations performed. The herein described subject matter sometimes illustrates different components contained within, or connected with, different other components. It is to be understood that such depicted architectures are merely exemplary, and that in fact many other architectures can be implemented which achieve the same functionality. In a conceptual sense, any arrangement of components to achieve the same functionality is effectively "associated" such that the desired functionality is achieved. Hence, any two components herein combined to achieve a particular functionality can be seen as "associated with" each other such that the desired functionality is achieved, irrespective of architectures or intermediate components. Likewise, any two components so associated can also be viewed as being "operably connected", or "operably coupled", to each other to achieve the desired functionality, and any two components capable of being so associated can also be viewed as being "operably coupiable", to each other to achieve the desired functionality. Specific examples of operably couplable include but are not limited to physically mateable and/or physically interacting components and/or wirelessly interactable and/or wirelessly interacting components and/or logically interacting and/or logically interactable components. [0110] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity.

|0111J It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "includes but is not limited to," etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations.

10112) However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim recitation to inventions containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (e.g., "a" and/or "an" should typically be interpreted to mean "at least one" or "one or more"); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of "two recitations," without other modifiers, typically means at least two recitations, or two or more recitations).

[0113] Furthermore, in those instances where a convention analogous to "at least one of A, B, and C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to "at least one of A, B, or C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., "a system having at least one of A, B, or C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.).

[01 14] It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B."

[0115] The foregoing description of illustrative embodiments has been presented for purposes of illustration and of description. It is not intended to be exhaustive or limiting with respect to the precise form disclosed, and modifications and variations are possible in light of the above teachings or may be acquired from practice of the disclosed embodiments. It is intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims

WHAT IS CLAIMED IS;

1 . An implantable device comprising:

a sensor to provide a signal representative of a physiological parameter;

a memory to store (i) at least one initialization parameter associated with the physiological parameter under at least one of sustained conditions and transient conditions and (ii) at least one threshold parameter representative of a change in the physiological parameter; and

a processor, communicatively coupled to the sensor and to the memory, to actuate at least one component of the device based on the signal, the at least one initialization parameter, and the at least one threshold parameter.

2. The implantable device of claim 1 wherein the device is an implantable ophthalmic device,

the sensor comprises at least one of a photosensor, an ion sensor, and an intraocular pressure sensor, and

the processor is configured to determine a presence of the accommodative stimulus based on the signal, the at least one initialization parameter, and the at least one threshold parameter.

3. The implantable device of claim 2 wherein the physiological parameter is a pupil size, the at least one initialization parameter represents at least one of a pupil size under sustained viewing conditions and a pupil size under transient viewing conditions, and

the at least one threshold parameter represents a change in pupil size associated with the accommodative stimulus.

4. The implantable device of claim 3 wherein the sensor comprises:

a first photosensor configured to provide a first measurement indicative of an ambient light level; and

a second photosensor configured to provide a second measurement indicative of light transmitted through the pupil.

5. The implantable device of claim 3 wherein the processor is configured to sample the signal from the sensor at a rate of about 1 Hz to about 12 Hz.

6. The implantable device of claim 3 wherein the processor is further configured to remove noise from the signal using a causal filter.

7. The implantable device of claim 6 wherein the causal filter comprises a slew filter.

8. The implantable device of claim 3 wherein the processor is configured to determine the presence of the accommodative stimulus based on:

(i) a first comparison of a first pupil size measurement and the at least one

initialization parameter; and

(ii) a second comparison of a difference between the change in pupil size and the at least one threshold parameter.

9. The implantable device of claim 3 further comprising:

an electro-active optical element to provide a change at least one of the eye's effective optical power and the eye's effective depth of field in response to detection of the

accommodative stimulus.

10. The implantable device of claim 9 wherein the processor is further configured to actuate the electro-active optical element within about 3.0 seconds of receiving the signal from the sensor.

1 1. The implantable device of claim 9 wherein the electro-active optical element is configured to provide:

(i) an increase in at least one of the eye's effective optical power and the eye's effective depth of field in response to an indication that the change in pupil size exceeds a first threshold parameter; and

(ii) a decrease in at least one of the eye's effective optical power and the eye's effective depth of field in response to an indication that the change in pupil size is smaller than a second threshold parameter, the second threshold parameter being greater than the first threshold parameter.

12. The implantable device of claim 9 further comprising:

a static optical element in optical communication with the electro-active optical element, the static optical element having a fixed optical power.

13. The implantable device of claim 1 wherein the sensor comprises an intraocular pressure sensor,

the physiological parameter includes intraocular pressure, and

the processor is configured to actuate at least one of a shunt, a valve, and a pump in response to a change in intraocular pressure.

14. The implantable device of claim 1 wherein the processor is configured to actuate delivery of a drug based on the signal, the at least one initialization parameter, and the at least one threshold parameter.

15. The implantable device of claim 1 further comprising:

an antenna to receive the at least one initialization parameter and the at least one threshold parameter.

16. A method of actuating a device implanted in a human, the method comprising:

storing, in a memory of the device, (i) at least one initialization parameter associated with a physiological parameter under at least one of sustained conditions and transient conditions and (ii) at least one threshold parameter representative of a change in the physiological parameter;

performing a first comparison of a first measurement of the physiological parameter and the at least one initialization parameter;

in response to the first comparison, determining a change in the physiological parameter based on a difference between the first measurement of the physiological parameter and a second measurement of the physiological parameter;

performing a second comparison of the difference and the at least one threshold parameter;

actuating the device implanted in the human based on the second comparison.

17. The method of claim 16 wherein the device is an implantable ophthalmic device, the physiological parameter is a pupil size,

the at least one initialization parameter represents at least one of a pupil size under sustained viewing conditions and a pupil size under transient viewing conditions

at least one threshold parameter represents a change in pupil size associated with an accommodative stimulus, and

actuating the device comprises actuating an electro-active optical element so as to provide an accommodative response.

18. The method of claim 17 further comprising:

identifying the presence of the accommodative stimulus based on the second comparison,

19. The method of claim 18 wherein the first comparison includes determining if the first pupil size measurement is higher or lower than a threshold pupil size associated with viewing an object under at least one of a low light level, a high light level, a near object distance, and a far object distance.

20. The method of claim 18 wherein the second comparison includes determining if the change in pupil size is higher or lower than a threshold pupil size for viewing an object under at least one of a low light level, a high light level, a near object distance, and a far object distance.

21. The method of claim 18 wherein actuating the electro-active optical element occurs within about 3.0 seconds of performing the first comparison.

22. The method of claim 18 wherein actuating the electro-active optical element includes at least one of:

(i) increasing at least one of the eye's effective optical power and the eye's

effective depth of field in response to an indication that the change in pupil size exceeds a first threshold parameter; and

(ii) decreasing at least one of the eye's effective optical power and the eye's

effective depth of field in response to an indication that the change in pupil size is smaller than a second threshold parameter, the second threshold parameter being greater than the first threshold parameter.

23. The method of claim 18 further comprising:

filtering a signal representing at least one of the first pupil size measurement, the second pupil size measurement, and the change in pupil size.

24. The method of claim 18 further comprising:

measuring the pupil size at a rate of about 1 Hz to about 12 Hz so as to provide the first pupil size measurement and the second pupil size measurement.

25. The method of claim 18 further comprising:

determining at least one of the at least one initialization parameter and the at least one threshold parameter based on at least one pre-operative measurement of the patient's pupil response to a change in at least one of an ambient light level and an object distance.

26. The method of claim 18 further comprising:

determining at least one of the at least one initialization parameter and the at least one threshold parameter based on at least one post-operative measurement of the patient's pupil response to a change in at least one of an ambient light level and an object distance; and

transmitting an updated initialization parameter.

27. The method of claim 18 further comprising:

determining at least one of the at least one initialization parameter and the at least one threshold parameter comparison based on at least one measurement of pupil size under sustained viewing of an object at a fixed distance under a constant light level.

28. The method of claim 18 further comprising:

determining at least one of the at least one initialization parameter and the at least one threshold parameter comparison based on at least one measurement of pupil size under viewing of an object at a variable distance under a constant ambient light level.

29. The method of claim 18 further comprising:

determining the at least one threshold parameter comparison based on at least one measurement of pupil size under viewing of an object at a constant distance under a variable ambient light level.

30. The method of claim 16 wherein the physiological parameter includes a change in intraocular pressure, and actuating the device includes actuating at least one of a shunt, a valve, and a pump in response to the change in intraocular pressure.

31 . The method of claim 16 wherein actuating the device includes releasing a drug into the patient's body.

32. An implantable ophthalmic device comprising:

a first photosensor to provide a first signal representative of a pupil size, the first signal have a sampling frequency of about 1 Hz to about 12 Hz;

a second photosensor to provide a second signal representative of an ambient light level;

a memory to store (i) at least one initialization parameter associated with at least one of a pupil size under a sustained viewing condition and a pupil size under a transient viewing condition and (ii) at least one threshold parameter representative of a change in pupil size associated with an accommodative stimulus; and

a processor, communicatively coupled to the sensor and to the memory, to filter the first signal so as to produce a filtered signal and to determine a presence of the accommodative stimulus based on at least four sample of the filtered signal, the second signal, the at least one initialization parameter, and the at least one threshold parameter; and

an electro-active element, communicatively coupled to the processor, to provide an accommodative response in response to detection of the accommodative stimulus within about 3.0 seconds of the processor filtering the first signal.