Patent Publication Number: US-2021186429-A1

Title: On-demand intraocular physiological sensor with trabecular bypass flow

Description:
PRIORITY CLAIM 
     This application claims priority to U.S. Provisional Patent Application No. 62/951,687 filed on Dec. 20, 2019, entitled “ON-DEMAND INTRAOCULAR PHYSIOLOGICAL SENSOR WITH TRABECULAR BYPASS FLOW,” the entire contents of which are incorporated by reference herein and relied upon. 
    
    
     BACKGROUND 
     Field 
     The field of the invention generally relates to implantable physiological sensors with flow capabilities for trabecular meshwork bypass. In particular, embodiments of the invention generally relate to implantable intraocular sensors for measuring physiological characteristics such as intraocular pressure and/or glucose concentration, while simultaneously providing for trabecular bypass flow to reduce intraocular pressure in the anterior chamber of the eye. 
     Description of the Related Art 
     Some diseases, including glaucoma and diabetes, can be more effectively treated if they are diagnosed early and/or monitored effectively. Glaucoma, for example, is a leading cause of blindness. This disease damages the optic nerve in the eye due to elevated intraocular pressure, which can lead to complete vision loss if untreated. The risk of blindness can be reduced, however, if the elevated intraocular pressure is detected early and is appropriately managed. Similarly, diabetes is a serious condition which can be more effectively treated with early-stage detection of elevated blood glucose concentration and appropriate management. Appropriate management of either of these conditions can be improved using enhanced monitoring. 
     Accordingly, diagnostic physiological sensors have been developed for implantation within the human body in order to monitor physiological characteristics such as intraocular pressure and glucose concentration. Such implantable sensors may be used to effectively diagnose and treat certain physiological conditions. 
     SUMMARY 
     In light of the disclosure herein, and without limiting the scope of the invention in any way, in a first aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, an intraocular physiological sensor implant includes a physiological sensor and a fluid pathway including a fluid inlet and a fluid outlet. The physiological sensor includes a sensing layer, a coil layer, and an integrated circuit layer. 
     In a second aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the physiological sensor comprises a pressure sensor at the sensing layer. 
     In a third aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the pressure sensor comprises a capacitive pressure sensor. 
     In a fourth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the capacitive pressure sensor comprises a flexible diaphragm electrode spaced apart from a counter electrode. 
     In a fifth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the coil layer includes a looped coil, configured to communicate with an external reader. 
     In a sixth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the physiological sensor communicates physiological readings to the external reader, responsive to the external reader being held proximate to an eye of a patient. 
     In a seventh aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the fluid inlet is configured to reside in an anterior chamber of an eye, and wherein the fluid outlet is configured to reside in Schlemm&#39;s canal of the eye, such that aqueous humor flows from the anterior chamber to Schlemm&#39;s canal via the fluid pathway. 
     In an eighth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the sensing layer is hermetically sealed to the coil layer, and wherein the coil layer is hermetically sealed to the integrated circuit layer. 
     In a ninth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the intraocular physiological sensor implant further includes an anchor that is either coupled to a housing or integrally formed with the housing. 
     In a tenth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the anchor is configured to pierce a trabecular meshwork of an eye, such that the intraocular physiological sensor is retained in an anterior chamber of the eye, adjacent to the trabecular meshwork. 
     In an eleventh aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the anchor further includes a plurality of physical standoffs. 
     In a twelfth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the physiological sensor comprises a glucose sensor. 
     In a thirteenth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, an intraocular physiological sensor implant includes a physiological sensor, configured to sense a pressure and a housing. The physiological sensor includes a sensing layer, a coil layer, and an integrated circuit layer. The physiological sensor is configured to communicate pressure readings to an external reader, responsive to the external reader being held proximate to an eye of a patient. 
     In a fourteenth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the physiological sensor comprises a capacitive pressure sensor. 
     In a fifteenth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the capacitive pressure sensor comprises a flexible diaphragm electrode spaced apart from a counter electrode. 
     In a sixteenth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the coil layer includes a looped coil, configured to communicate with the external reader. 
     In a seventeenth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the sensing layer is hermetically sealed to the coil layer, and wherein the coil layer is hermetically sealed to the integrated circuit layer. 
     In an eighteenth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the intraocular physiological sensor implant further includes an anchor, wherein the anchor is either coupled to the housing or integrally formed with the housing. 
     In a nineteenth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the anchor is configured to pierce a trabecular meshwork of an eye, such that the intraocular physiological sensor is retained in an anterior chamber of the eye, adjacent to the trabecular meshwork. 
     In a twentieth aspect of the present disclosure, which may be combined with any other aspect listed herein unless specified otherwise, the anchor further includes a plurality of physical standoffs. 
     Additional features and advantages of the disclosed devices, systems, and methods are described in, and will be apparent from, the following Detailed Description and the Figures. The features and advantages described herein are not all-inclusive and, in particular, many additional features and advantages will be apparent to one of ordinary skill in the art in view of the figures and description. Also, any particular embodiment does not necessarily have to have all of the advantages listed herein. Moreover, it should be noted that the language used in the specification has been selected for readability and instructional purposes, and not to limit the scope of the inventive subject matter. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Various embodiments and features of devices, systems, and methods will be described with reference to the following drawings. The drawings, associated descriptions, and specific implementations are provided to illustrate embodiments of the invention and not to limit the scope of the disclosure. 
         FIGS. 1A-B  illustrate front and back perspective views of an intraocular physiological sensor implant. 
         FIGS. 1C-D  illustrate perspective and cross-sectional views of an anchor to be implemented with an intraocular physiological sensor implant. 
         FIGS. 2A-B  illustrate an intraocular physiological sensor implant implanted into the trabecular meshwork of an eye. 
         FIG. 3  illustrates a measurement network communicating with an intraocular physiological sensor implant. 
         FIG. 4  illustrates a layer-by-layer perspective view of a microelectromechanical system (MEMS) to be implemented with an intraocular physiological sensor implant. 
         FIG. 5  illustrates a layer-by-layer cross-sectional view of a pressure sensor to be implemented with an intraocular physiological sensor implant. 
         FIG. 6  illustrates a layer-by-layer perspective cross-sectional view of a coil layer configuration. 
         FIG. 7  illustrates a planar view of a coil layer, prior to attachment of an integrated circuit. 
         FIG. 8  illustrates a planar view of an integrated circuit. 
         FIGS. 9A-B  illustrate layer-by-layer perspective and cross-sectional views of a MEMS system. 
         FIGS. 10A-B  illustrate layer-by-layer cross-sectional views of alternate pressure sensors. 
     
    
    
     DETAILED DESCRIPTION 
     There is a need to effectively monitor intraocular pressure within a patient&#39;s eye in order to detect or monitor the progression of glaucoma. Intraocular pressure can be measured non-invasively using, for example, a tonometer. While tonometers have the advantage of being non-invasive, they have the disadvantages of generally being expensive, non-portable, specialized equipment that requires skilled operation. Accordingly, as a practical matter, it is difficult to use a tonometer to effectively monitor intraocular pressure in a patient&#39;s eye with a time resolution greater than one measurement every few days or weeks during doctor visits. However, since intraocular pressure can vary significantly over relatively short periods of time, such relatively sparse intraocular pressure measurements may not provide a complete or accurate picture of the patient&#39;s risk for, or progression of, glaucoma. It would therefore be advantageous to be able to measure intraocular pressure more often or even continuously. Additionally, measurement of direct hydrostatic pressure inside the eye, such as within the anterior chamber of the eye, provides more accurate pressure readings than typical tonometry measurements, which are affected by the mechanical properties of the eye. Furthermore, it would be advantageous to measure intraocular pressure while simultaneously treating the underlying causes associated with glaucoma, for example. Namely, an implantable intraocular pressure sensor that also provides for aqueous humor drainage to Schlemm&#39;s canal may simultaneously monitor intraocular pressure while providing safe reduction of intraocular pressure via trabecular meshwork bypass. 
       FIGS. 1A and 1B  illustrate front and back perspective views of an intraocular physiological sensor implant  100 . The intraocular physiological sensor implant  100 , referred to herein as sensor implant  100 , further includes a pressure sensor  102  with a sensing port  104 . While the mechanics of pressure sensor  102  are described in greater detail herein, it should be appreciated that pressure sensor  102  generally communicates with its external environment, such as the anterior chamber of the eye, via sensing port  104 . For example, aqueous humor in the anterior chamber of the eye is in contact with sensing port  104 ; pressure sensor  102  measures the intraocular pressure within the anterior chamber of the eye via fluidic contact with sensing port  104 . 
     Sensor implant  100  further includes protective housing  106 . Protective housing  106  surrounds at least a portion of pressure sensor  102 , while simultaneously exposing at least a portion of sensing port  104  to the external environment. In some embodiments, housing  106  has contoured surfaces, such as edges that are rounded, filleted, or chamfered, to ensure more smooth contact surfaces with the eye. The selected materials for the housing  106  can be at least partially transmissive and transparent to radio frequency (RF) electromagnetic radiation. Housing  106  may be formed of any biocompatible material such as ceramic or glass. It should be appreciated, however, that other materials may be implemented. In an embodiment, housing  108  is made from a durable and RF transparent material such as ceramic, glass, sapphire, or other material. In the case of ceramic, housing may be micro-molded and/or machined with yttria-stabilized zirconia, zirconia toughened alumina, or other durable ceramics including, but not limited to other zirconia and alumina ceramics. Housing  106  can be further polished smooth to prevent inadvertent damage to surrounding tissue. 
     In an embodiment, a thin-film coating may be applied to the housing  108 , pressure sensor  102 , and/or sensor implant  100 . The thin film can be, for example, titanium dioxide. The thin-film coating may be applied using atomic layer deposition (ALD) techniques. For example, the pressure senor  102  can be alternately exposed to different gaseous precursor species. Each of the separate precursor species can react with the surface of the housing pressure sensor  102  in a self-limiting manner such that the reaction terminates once all the reactive sites on the surface have been filled. The reaction of each precursor species can deposit a monolayer of atoms on the surface of the pressure sensor  102 . By sequentially exposing the pressure sensor  102  to different precursor species, a perfect crystalline structure can be built up layer by layer. The thin-film ALD coating may be a conformal layer of pinhole-free, crystalline titanium dioxide (TiO 2 ). Other ALD coatings may be applied in a similar manner, including, but not limited to aluminum oxide (Al 2 O 3 ), silicon dioxide (SiO 2 ), silicon nitride (Si 3 N 4 ), halfnium dioxide (HfO 2 ). Additionally, by using appropriate precursor species in appropriate orders, multilayer ALD coatings consisting of two or more of the above materials, or additional materials, may be applied to the surface of pressure sensor  102 . Such multilayer coatings may consist of a single layer each of two or more materials, or a multitude of layers such that each material is present as several distinct layers within the entire layer stack up. All of these coating options may be applied to the housing  108 , pressure sensor  102 , and/or sensor implant  100 . An ALD coating such as this can provide several benefits. It can act as an additional hermetic seal to help prevent aqueous humor from penetrating or interacting with the housing  106  and pressure sensor  102 . The ALD coating can help prevent aqueous humor from interacting with metals from the metallic seal and dissolving them or reacting with them to produce corrosion, as well as prevent metals in the hermetic seal from leaching into solution. In addition, the ALD coating can protect the housing  106  and/or pressure sensor  102  from dissolution in the aqueous humor over time if the materials used to make the housing and/or pressure sensor  102  are in any way water-soluble. Namely, an ALD coating over the pressure sensor  102  and housing  106  could dramatically reduce the rate of dissolution or even prevent dissolution altogether, thereby helping to avoid the need for periodic re-calibration of the pressure sensor  102 . The ALD coating itself can be applied in a low-stress manner, so its presence does not significantly affect the mechanical performance of the pressure sensor  102 . 
     Sensor implant  100  further includes anchor  108 . Anchor  108  includes at least a flow inlet  110 , a flow outlet  112 , and a standoff  114 . Generally, anchor  108  is affixed to housing  106  and includes a penetrating tip, which is designed to penetrate ocular tissue, such as the sclera, the trabecular meshwork, and the like, and a barb or other retention feature so as to remain anchored in the tissue after having been inserted. In some embodiments, anchor  108  can be drug eluting anchors, similar to the one illustrated in FIG. 18 of U.S. Patent Publication 2015/0342875 (see accompanying appendix), filed May 28, 2015, and entitled “IMPLANTS WITH CONTROLLED DRUG DELIVERY FEATURES AND METHODS OF USING SAME,” the entire contents of which are hereby incorporated by reference herein. Anchor  108  is typically constructed from a hard and durable material, such as titanium. Anchor  108  is attached to housing  106  by brazing, solder attachment, laser welding, physical attachment, such as press-fit, or other related attachment methods. In an embodiment, the housing  106  and anchor  108  are a single monolithic component constructed of ceramic or some other non-metal, such that the anchor  108  is integrally formed with the housing  106 . In an embodiment, the housing  106  and/or anchor  108  are constructed of metal in a frame structure or other configuration that limits the amount of material used with housing  106 , to ensure that housing  106  is at least partially transmissive and transparent to radio frequency (RF) electromagnetic radiation. 
     Generally, housing  106  is configured to at least partially surround pressure sensor  102 , such that anchor  108  may be coupled to housing  106 . It should be appreciated, however, that in alternate embodiments housing  106  is not needed. Namely, for example, in an alternate embodiment anchor  108  is coupled directly to pressure sensor  102  (including its layers), such as via a clip, brace, or other related features. In another alternate embodiment, anchor  108  is glued or welded directly to one or more layers of pressure sensor  102 . In these embodiments, where the housing  106  is not included, each of the layers of pressure sensor  102  are hermetically attached to one another. 
     Anchor  108  may generally be characterized as a drainage stent. Namely, anchor  108  includes flow inlet  110  and flow outlet  112 . Thus, anchor  108  enhances outflow of aqueous humor from the eye, similar to the anchor illustrated in FIG. 18 of U.S. Pat. No. 9,554,940 (see accompanying appendix), filed Mar. 14, 2013, and entitled “SYSTEM AND METHOD FOR DELIVERING MULTIPLE OCULAR IMPLANTS,” the entire contents of which are hereby incorporated by reference herein. 
     Specifically, anchor  108  may include flow inlet  110 , flow outlet  112 , and a fluid passageway connecting flow inlet  110  to flow outlet  112 . While one flow inlet  110  and one flow outlet  112  are illustrated by  FIG. 1B , it should be appreciated that additional inlets and outlets are contemplated in various embodiments. For example, opposing inlet and outlets may be disposed on the back side of sensor implant  100  (and thus not shown by  FIG. 1B ). In an embodiment, sensor implant includes at least two flow inlets  110  and at least two flow outlets  112 , connected by at least one branched fluid passageway. 
     In an embodiment, once the anchor  108  is inserted through the trabecular meshwork and affixed, the flow inlet  110  resides in the anterior chamber of the eye and the flow outlet  112  resides in Schlemm&#39;s canal, such that the anchor  108  conducts fluid from the anterior chamber to Schlemm&#39;s canal via the fluid passageway. 
     In an embodiment in which the anchor  108  is a drug eluting anchor, it serves at least two functions: (1) securing the housing  106  (and entire sensor implant  100 ) to the ocular tissue; and (2) providing to the eye a slow-release drug elution into the anterior chamber to assist with any ocular medical condition requiring continuous medication, such as improving aqueous outflow and treating glaucoma. One such stand-alone drug eluting anchor is described in U.S. Patent Publication No. 2015/0342875, entitled “IMPLANTS WITH CONTROLLED DRUG DELIVERY FEATURES AND METHODS OF USING SAME,” which is incorporated by reference herein. Although only discussed as a stand-alone drug eluting implant in U.S. Patent Pub. No. 2015/0342875, it should be appreciated that the anchor portion of the drug eluting implant could serve the additional purpose of securing to ocular tissue the intraocular sensor  100  discussed herein or any other desirable ocular implant intended to remain static within the anterior chamber (or any other anatomical portion) of the eye. 
     Standoff  114  is a physical protrusion disposed between flow inlet  110  and flow outlet  112 . For example, as illustrated by  FIG. 1B , standoff  114  may be disposed on either side of anchor  108 . When sensor implant  100  is implanted into the trabecular meshwork of the eye (as described in greater detail below), there is a concern that the sensor implant  100  may have the potential to limit the outflow of aqueous humor, such as through the “conventional” outflow pathway comprising the trabecular meshwork and Schlemm&#39;s canal. For example, when implanted, the sensor implant  100  could collapse Schlemm&#39;s canal. Standoff  114  thus is configured to provide a pressure relief at the surface of engagement between a face of anchor  108  and the trabecular meshwork. By reducing pressure at the surface of engagement, the likelihood of collapsing Schlemm&#39;s canal is substantially reduced. More generally, standoff  114  ensures that aqueous humor may exit the anterior chamber via the physiological outflow pathways even when the sensor implant  100  is positioned against the trabecular meshwork. 
     In a different embodiment, as illustrated by  FIG. 1C , standoff  114  is disposed in a central portion of anchor  108 , thus providing a pressure relief to either side of standoff  114  (as described in greater detail above). As previously noted, anchor  108  may include at least two flow inlets  110  and at least two flow outlets  112 . This embodiment is illustrated by  FIG. 1D . Namely, two flow inlets  110  are disposed in the anterior chamber, whereas two flow outlets  112  are disposed within Schlemm&#39;s canal. The two flow inlets  110  and two flow outlets  112  are connected by an angled fluid passageway. 
     In some embodiments, standoff  114  and/or anchor  108  can be made out of or include a porous material, such as fritted glass, porous plastic such as polypropylene, polyethylene, porous bonded polymer fibers such as polyethylene, polyester, or other materials that are preferably hydrophilic and can be formed into an open-cell porous structure. Such porous materials provide a plurality of fluid handling capillary or pseudo-capillary structures that enable fluid transfer through the bulk structure of the material itself. For example, anchor  108  could be made of a frit (sintered) material, such as titanium; by being porous, the entire anchor  108  could act as a drainage flow path from the anterior chamber to Schlemm&#39;s canal. In an embodiment only a portion of anchor  108 , such as a distal portion that transits Schlemm&#39;s canal, is porous, whereas the remainder of anchor  108  includes a fluid pathway (as previously described). In an embodiment, standoff  114  can be formed directly onto anchor  108  or housing  106 . 
     As illustrated by  FIG. 1A , the entire sensor implant  100  including anchor  108  is approximately 1.9 mm in length, 0.7 mm in width, and 0.5 mm in height. It should be appreciated, however, that smaller and/or larger dimensions are contemplated. 
       FIGS. 2A and 2B  illustrate sensor implant  100 , implanted into the trabecular meshwork (TM) of an eye. Sensor implant  100  is implanted in an ab interno injectable surgery. For example, once a surgeon has positioned the sensor implant  100  at the desired location within the patient&#39;s eye, he or she exerts a force directed toward the trabecular meshwork or, alternatively, a force is exerted by a specialized inserter device or other surgical tool. This causes the anchor  108  to extend into ocular tissue, so as to hold the housing  106  and entire sensor implant  108  in place. In an embodiment, particular materials of the housing  106  may be configured to “match” the patient&#39;s iris. For example, housing  106  may be colored by incorporation of dye, or non dye-including processing techniques such as hot-isostatic pressing (HIPping) or thin film coating such as ALD coating to be more aesthetically camouflaged when implanted. This in turn limits the external visibility of the sensor implant  100 . In some embodiments, the sensor implant  100  can be provided with documentation that instructs a surgeon to position the sensor implant  100  at the superior portion of the patient&#39;s eye. This position can take advantage of the fact that the upper eyelid typically extends further than the lower eyelid and is therefore able to more effectively hide the sensor implant  100 . 
     While sensor implant  100  is generally described with respect to implantation into the trabecular meshwork (TM) of the eye, in various embodiments, it should be appreciated that the sensors disclosed herein, such as sensor implant  100 , could be implanted and positioned in alternate locations within the eye. For example, sensor implant  100  could be implanted into the vitreous cavity, onto or around the retina, onto the intraocular lens, into the iridocorneal angle, and the like. Alternate location implantation can be performed with limited, if any, design changes to the sensor implant  100  disclosed herein. Thus, in certain embodiments, sensor implant  100  is location agnostic. 
       FIG. 3  illustrates a measurement network  116 , configured for communicating with sensor implant  100 . Namely, as previously noted, sensor implant  100  may be implanted into the eye using a specialized inserter device  118 . In an embodiment, the specialized inserter device is a pre-loaded, single-use, device. Once implanted, sensor implant  100  communicates with a reader  120  in an on-demand fashion. 
     For example, the patient may hold the reader  120 , such as a wand or other hand-held device, up to his or her eye; once the reader  120 , which includes an inductive coil, is in close enough proximity to the sensor implant  100  (e.g., 5 to 10 mm), the reader  120  inductively powers the sensor implant  100  and wirelessly communicates with the sensor implant  100  to receive a digital readout of the measured capacitance of the pressure sensor  102 , which correlates to absolute intraocular pressure. The measured capacitance is converted to a pressure measurement by using a calibration that can be stored on the reader  120  (or accessed remotely, such as via a server). Sensor  100  communicates in an on-demand fashion, in that it only sends a measured capacitance reading when the reader  120  is in close enough proximity; likewise, sensor  100  communicates the instantaneous measured capacitance reading at a particular point in time. 
     In an embodiment, reader  120  includes audible and/or visual cues to notify the patient as to when the reader  120  is wirelessly communicating with the sensor implant  100 . For example, reader  120  can include a speaker that beeps or alarms once the reader  120  has communicated with sensor implant  100 . Likewise, for example, reader  120  can include lights, such as red and green lights; in this example, reader  120  displays a red light until it has communicated with sensor  100 , at which time it displays a green light. It should be appreciated that other audible and/or visual techniques similar to those discussed above are contemplated herein. 
     In an embodiment, on-demand communication advantageously reduces any power and/or memory requirements within sensor implant  100 . Thus, the overall size of sensor implant  100  is drastically reduced as compared to an implant with autonomous functionality including battery power and/or memory for storing measurement data. 
     Reader  120  may further include a built-in high-accuracy atmospheric pressure sensor, to measure the ambient environmental pressure at the time of the sensor-reading; this measured pressure can be used in combination with measurements from the sensor implant  100  in order to determine intraocular pressure (IOP), which is defined as the gauge pressure of absolute pressure inside the eye minus local atmospheric pressure. Reader  120  further includes memory, for storing intraocular pressure readings provided by sensor implant  100 . In an embodiment, reader  120  has the form factor similar to an eye dropper, providing a degree of familiarity to the patient and facilitating correct positioning of the inductive coil during readings. In an embodiment, reader  120  has the form factor similar to a pair of standard eyeglasses, providing a means for the patient to reliably and repeatably position the reader in relation to their eye and the implant location. 
     Measurement network  116  may further include a number of additional “downstream” devices and/or systems to handle, display, distribute, and manage patient data, as illustrated in  FIG. 3 . 
     For example, reader  120  may transfer received intraocular pressure readings to another external device such as a cellular device  122  or a base station  124 . For example, cellular device  122  may run a mobile app that bridges communication between reader  120  and external servers  126 . Additionally or alternatively, cellular device  122  may bridge communication between reader  120  and other external devices such as wrist-worn storage devices or smartwatches, which may, likewise, be communicating with reader  120 . In various embodiments, the reader  120  communicates with the wrist-worn storage device (or cellular device  122 ) via Bluetooth, WiFi, Zigbee, or other related wireless communication. It should be appreciated that other external devices, such as bracelets, any other wearable electronic device, cell phones, tablets, e-readers, laptops, and the like are contemplated for communicating with the reader  120 . 
     Cellular device  122  may provide visual information, such as intraocular pressure readings and historical data, to the patient. Base station  124  may, additionally or alternatively, provide similar hardware functionalities as those provided by cellular device  122 . 
     External servers  126  may process and store patient data, such as data wirelessly received from cellular device  122 . External servers  126  may further deliver data to portal applications in an on-demand fashion. For example, physician portal  128  provides physicians with an intuitive interface to view patients&#39; intraocular pressure readings, setup alerts, send messages directly to patients and cellular devices  122 , and remotely adjust the functionality of sensor implant  100  and/or reader  120 . Similarly, for example, patient portal  130  provides patients with simple intraocular pressure measurement tracking information and messages, such as those received from the physician. 
     Turning now to the specifics of sensor implant  100 ,  FIGS. 4 and 5  illustrate a layer-by-layer perspective and cross-sectional views of a microelectromechanical system (MEMS), also referred to as pressure sensor  102 , to be implemented with sensor implant  100 . 
     Generally speaking, pressure sensor  102  includes three distinct systems: (1) a pressure sensor (along with a reference sensor) that outputs a capacitive signal, (2) an application-specific integrated circuit (ASIC) that converts the capacitive signals to digital representations and communicates with reader  120  by modulating an inductive coil, and (3) an inductive coil that enables the ASIC to receive wireless power from reader  120  and communicate wirelessly with the reader  120 . With that in mind, the MEMS device or pressure sensor  102  includes three layers, a pressure sensor layer  132 , a coil layer  134 , and an integrated circuit layer  136 . As illustrated, pressure sensor layer  132  further includes sensing port  104  (as previously discussed). 
     For example,  FIG. 5  illustrates a cross-sectional view of pressure sensor layer  132 . Pressure sensor layer  132  generally includes a capacitive pressure sensor fabricated from silicon. The pressure sensor design is essentially a typical parallel plate capacitive pressure sensor in which a flexible membrane electrode  138  is moved closer to a pressure sensor counter electrode  140  when pressure increases, thereby increasing the capacitance of the overall structure. 
     Both the flexible membrane electrode  138  and pressure sensor counter electrode  140  are made from conductive silicon. In other embodiments the counter electrode is made from a different conductive material, such as gold, platinum, aluminum, or other similar metal. The pressure sensor counter electrode  140  is positioned atop a silicon oxide layer  142  approximately 0.5 to 4 μm thick. The flexible membrane electrode  138  is made from a layer that is thicker in some areas such that it extends down and is positioned atop the same silicon oxide layer  142 . A gap  144  of about 0.1 to 1 μm separates the two electrodes and an annular gap surrounds the entire pressure sensor counter electrode  140 , such that the two electrodes are isolated. Above the flexible membrane electrode  138  there is another silicon oxide layer  142  approximately 0.5 to 4 μm thick that separates the flexible membrane electrode  138  from a bulk silicon layer  146  above, which provides structure to the pressure sensor  102 . In some embodiments, bulk silicon layer  146  is not present. At a portion of the pressure sensor  102  is sensing port  104  in which this bulk silicon layer  146  is removed, and optionally the approximately 0.5 to 4 μm thick silicon oxide layer  142  is also removed, such that the flexible membrane electrode  138  is free-standing and can deflect in response to external pressure. For example, the membrane can deflect responsive to intraocular pressure within the anterior chamber. 
     Through-silicon vias  148  are provided to connect the flexible membrane electrode  138  and the pressure sensor counter electrode  140 . For example, through-silicon vias  148  transit a bottom silicon oxide layer and make electrical contact with each electrode from the underside. In a preferred embodiment, the vias  148  are made from conductive silicon. In other embodiments, the vias  148  may be made from metal. The vias  148  may be solid conductor or, alternatively, predominately open vias with the conductor only on the sidewall of the via. Other structures, such as annular conductor vias, are likewise contemplated in various embodiments. Generally, each of the vias  148  is isolated from the surrounding silicon by an insulator such as silicon oxide, silicon nitride, or another electrically-insulated material such as a polymer. In an embodiment, the bulk silicon layers that are present below and above conductive silicon oxide layers  142  may be instead a different material such as glass or ceramic, or a different material on each side. 
     In an embodiment, pressure sensor  102  further includes a reference sensor, including a reference sensor counter electrode  150 , disposed adjacent to the pressure sensor counter electrode  140 . The structure of the reference sensor is similar to that described above with respect to flexible membrane electrode  138  and pressure sensor counter electrode  140 , except that the sensing port  104  is not present. Thus, the bulk silicon layer  146  above the reference sensor prevents the flexible membrane electrode  138  in that location, i.e., the portion of flexible membrane electrode  138  that is opposed from reference sensor counter electrode  150 , from appreciably responding to pressure changes within the anterior chamber. In this embodiment, a third through-silicon via  148  is used to connect to the reference sensor counter electrode  150 . The membrane electrode  138  of the reference sensor is shared with the membrane electrode  138  of the pressure sensor and therefore can share the same via  148  for signal routing when the pressure sensor and reference sensor are measured sequentially. In an alternative embodiment, the membrane electrode  138  is not shared between the pressure sensor and reference sensor, but rather there are two isolated membrane electrodes, one for each sensor. In this embodiment, there is a fourth via required to connect to the second isolated membrane electrode. The capacitive signal generated by the reference sensor counter electrode  150  can be used to filter out effects unrelated to changes in pressure, such as intrinsic stresses, mechanical stresses, temperature changes, and the like, thereby improving the accuracy of the system as a whole. Signal from the reference sensor can be used directly, such as via a direct analogue subtraction of its capacitance from the capacitance of pressure sensor counter electrode  140  and flexible membrane  138  within the ASIC&#39;s operation or a digital subtraction of the same, or indirectly by reading its value substantially concurrently with reading the capacitance of pressure sensor counter electrode  140  and flexible membrane  138  and using both measurements during downstream data processing/calibration. In the preferred embodiment, the reference sensor counter electrode  150  has the same dimensions as the pressure sensor counter electrode  140 , but can also be of different size and shape and still provide similar utility. 
     For example, as implemented, pressure sensor layer  132 , when combined with the rest of the system of the sensor implant  100 , is capable of measuring intraocular pressure from about 0 mmHg to about 50 mmHg of gauge pressure within the eye with about ±0.5 mmHg resolution. In some embodiments, the gap  144  underneath the membrane electrode  138  is sealed under vacuum, and the pressure sensor layer  132  responds over the range of approximately 500 to 1000 mmHg absolute pressure with about an essentially infinite resolution as the output is a variable analogue capacitance signal. The atmospheric pressure can be measured independently outside the body (via a built-in high-accuracy atmospheric pressure sensor disposed within reader  120 ) and subtracted from the absolute pressure measured by the pressure sensor  102  to yield the intraocular pressure. In some embodiments, the capacitance varies in an approximately linear fashion relative to the intraocular pressure. In some embodiments, the capacitance may increase approximately linearly from approximately 1 picofarads (pF) to approximately 4 pF over the range of absolute pressure from 500 to 1000 mmHg. In other embodiments the absolute pressure range is smaller or larger or the sensitivity of the sensor is more or less. In some embodiments, the capacitance varies in a non-linear fashion relative to intraocular pressure. 
       FIGS. 6 and 7  illustrate a layer-by-layer perspective cross-sectional and planar views of a coil layer  134  for pressure sensor  102 . Namely, coil layer  134  is contiguous with pressure sensor layer  132  and is adjacent to the via-containing side of pressure sensor layer  132 . The coil layer  134  is constructed of silicon and has an integrated inductive coil  152 . Alternatively, the coil layer  134  could be of glass, sapphire, or ceramic. In an embodiment, pressure sensor layer  132  is hermetically attached to the coil layer  134  using a silicon fusion bond. In other embodiments, the hermetic attachment is made with a silicon-silicon oxide fusion bond, an anodic bond, metal fusion bond such as Au—Au, or eutectic bond such as Si—Au, In—Au, Sn—Au, or the like. 
     In an embodiment, integrated inductive coil  152  is a copper coil. In other embodiments, integrated inductive coil  152  is gold, silver, or any other conductive material such as other metals or conductive silicon. Generally, copper is preferred due to its high electrical conductivity, which improves the quality-factor of the coil  152 . The cross-sectional dimensions of each turn of the conductor of the coil  152  are approximately 2-10 μm wide by 5-25 μm tall. Between each turn of the coil is an insulator, such as silicon dioxide or glass, that is about 1-4 um wide. The insulator also separates the coil  152  from the bulk silicon. There are approximately 10 to 35 windings of the coil  152  in a planar configuration (as illustrated by  FIG. 7 ). It should be appreciated that the dimensions provided herein relate to one example embodiment of coil  152 ; other dimensions of the coil, including its cross-section and the total number of windings, are contemplated. 
     As an alternative to a coil and inductive coupling as described herein, several other alternative wireless transfer technologies are likewise contemplated such as, but not limited to, capacitive coupling, electric-field coupling, and ultrasound. These technologies would substitute the coil (e.g., coil  152 ) for a conductive plate, an antenna, or a piezoelectric material, respectively. The external reader would also be designed to provide the corresponding powering signal. For capacitive coupling, electric-field, and inductive coupling, the external reader includes an AC signal that is driven into a plate, antenna, or coil, to generate appropriate signal to power the implant. For ultrasonic, the external reader includes a transducer that transmits ultrasonic signals, which would excite the piezoelectric material and consequently generate power for the implant. 
     There is topology on the adjoining surface of the sensor layer  132 , such that when it is hermetically bonded to the coil layer  134 , a cavity  154  is created adjacent to the turns of the coil  152 . This cavity  154  advantageously reduces parasitic capacitance and the formation eddy currents in the bulk silicon, both of which would otherwise reduce the wireless performance of the inductive coil  152 . Likewise, when the integrated circuit layer  136  is joined to the other side of the coil layer  134  (as is described below), a similar cavity  156  is also created adjacent to the turns of the coil  152 , due to the height of the metallic hermetic bond between the layers, which also affords the aforementioned benefits. 
     The side of the coil layer  134  not in contact with the pressure sensor layer  132  includes a number of metal pads (and metal traces that electrically connect the coil  152  to the metal pads), which are appropriately positioned and structured to make electrical connection to the integrated circuit layer  132 . For example, coil layer  134  includes a first coil pad  158  and a second coil pad  160 . Additionally, the through-silicon vias  148  from the pressure sensor layer  132  transit the coil layer  134  and are also connected to similar metal pads. For example, coil layer  134  includes a pressure sensor electrode pad  162  communicating with pressure sensor counter electrode  140 , a membrane sensor electrode pad  164  communicating with membrane electrode  138 , and a reference electrode pad  166  communicating with reference sensor counter electrode  150 , as illustrated by  FIGS. 5 and 7 . 
     In an embodiment, the through-silicon vias  148  are created after the coil layer  134  is joined to the sensor layer  132 , such that the through-silicon vias  148  are continuous through both of the pressure sensor layer  132  and the coil layer  134 . Alternatively, two distinct sets of vias could be created in each layer, and electrical connections could be made at the interface between the two layers. 
     The metal pads  162 ,  164 ,  166  on the coil layer  134  are positioned such that they make contact to similar metal pads on the integrated circuit layer  136  when these two layers are adjoined face-to-face. Coil layer  134  may further include a seal ring  168 , disposed around the entire perimeter of the coil layer  134 . Seal ring  168  forms a hermetic seal when the integrated circuit layer  136  is attached to the coil layer  134 . 
       FIG. 8  illustrates a planar view of integrated circuit layer  136 , which includes the ASIC. The ASIC itself includes several circuits, including a controller, voltage rectifier, transceiver, capacitance-to-digital converter, non-volatile and/or volatile memory, and the like. The ASIC is fabricated in silicon using complementary metal-oxide-semiconductor (CMOS) fabrication processes. Generally, the ASIC may have an uneven surface topology at the completion of standard CMOS processing. This topology may be on the order of approximately 1 μm, and therefore could interfere with hermetic bonding. Thus, the uneven top-side may be planarized, prior to hermetic bonding, such as by depositing a silicon dioxide layer and then polishing, to create a flat and smooth surface on the top-side. The oxide must be opened at the ASIC contact locations, and a number of metal pads  170  must be formed for connecting to the corresponding pads  160 ,  162 ,  164 ,  166  on the coil layer  134 . A metal seal ring  172  is also formed around the perimeter of the integrated circuit layer  136  to match the seal ring  168  on the coil layer  134 . 
     The bond between the coil layer  134  and the integrated circuit layer  136  accomplishes two things. First, it enables the electrical connections between the ASIC and the MEMS components so that the ASIC can measure the sensors and utilize the inductive coil  152  for wireless communication. It also provides for a hermetical seal ring at the perimeter of the part, which isolates the connections from the outside environment, thus preventing crosstalk/leakage and parasitic capacitances. In various embodiments, the bond is an Au—Au fusion bond, a thermo-compression bond, or an eutectic bond such as Si—Au, In—Au, Sn—Au, or other related bonds. In one embodiment a hermetic surface bond is created between coil layer  134  and circuit layer  136  instead of a hermetic seal ring. In this embodiment the bond is continuous across the entire surface, such as a silicon oxide to silicon oxide bond, and the electrical connection transit through the hermetic bond itself as opposed to being surrounded by a hermetic seal ring. 
       FIGS. 9A and 9B  illustrate layer-by-layer perspective cross-sectional and cross-sectional views of a pressure sensor  102  as previously described herein. In summary, the pressure sensor  102  includes the pressure sensor layer  132 , which is hermetically bonded to the coil layer  134 , which is hermetically bonded to the integrated circuit layer  136 . The hermetic bonds can be formed by various bonding methods such as fusion bonding, eutectic bonding, thermo-compression bonding, or related bonding techniques. Because each of the layers  132 ,  134 ,  136  are hermetically bonded or sealed with no exposed electrical connections, the entire pressure sensor  102  is hermetically sealed. Thus, housing  106  is not required to be hermetically sealed, as pressure sensor  102  is already protected via its own seals from the external environment. 
     In a preferred embodiment, the pressure sensor  102  is fabricated at a wafer level, in which the above-described structures are fabricated in batch fabrication in the full wafer format. Only at the completion of the processing are the individual pressure sensors  102  separated (into “dies” or “dice”). The separation may be accomplished using a dicing method, such as blade dicing, laser dicing, or stealth dicing. For example, fabrication at a wafer level helps to ensure part to part consistency and a much lower per-piece cost. However, it is theoretically possible to build the layers  132 ,  134 ,  136  separately and perform the hermetic bonding operations at a die-level. 
       FIGS. 10A and 10B  illustrate layer-by-layer cross-sectional views of alternative pressure sensors  200  and  250 . For example,  FIG. 10A  illustrates pressure sensor  200  including combined sensor and coil layers  202 , which are attached to housing  204  via hermetic seal  206 . Combined sensor and coil layers  202  are similar to pressure sensor layer  132  and coil layer  134  described above. Pressure sensor  200  further includes integrated circuit layer  208 , which is attached to sensor and coil layers  202  via a non-hermetic connection  210 , such as a conductive adhesive bond. In this embodiment, though sensor layer and coil layer  202  are not hermetically bonded to integrated circuit layer  208 , the entire pressure sensor  200  is nonetheless hermetically sealed via housing  204  and hermetic seal  206 . 
     Similarly, for example,  FIG. 10B  illustrates a pressure sensor  250  including sensor layer  252 , which is attached to housing  254  via hermetic seal  256 . Pressure sensor  250  further includes coil layer  258  and integrated circuit layer  260 , each of which is attached to other layers via a non-hermetic connection  262 , such as a conductive adhesive bond. In this embodiment, though none of sensor layer  252 , coil layer  258 , and integrated circuit layer  260  are hermetically bonded, the entire pressure sensor  250  is nonetheless hermetically sealed via housing  254  and hermetic seal  256 . 
     While the embodiments of the sensor implant  100  described above relate to the measurement of intraocular pressure, it should be appreciated that some embodiments may additionally, or alternatively, measure glucose concentration in the aqueous humor. Specifically, there is a need to measure glucose concentration within the human body as a means to treat or prevent complications from diabetes. Glucose is typically measured from blood or urine sampling. Some implantable glucose sensors have been developed that measure glucose from interstitial fluids; however, the body may have a negative immunological response to such implants, which may degrade the performance of the sensor over time. The eye, especially the anterior chamber of the eye, is an immunologically-privileged site within the body. Thus, an intraocular sensor implant for measuring glucose within the eye can have advantages over other implantable sensors that are made to measure glucose in non-immunologically privileged parts of the body. In addition, although the glucose concentration within the aqueous humor may not be identical to blood glucose concentration, the two may be correlated such that a measurement of glucose concentration in the aqueous humor can be predictive of blood glucose concentration. 
     In an embodiment, the sensor implant  100  runs a current and measures an initial rate of decay of reactive buildup on a glucose sensor. The reactive buildup may be a buildup of glucose itself or another chemical species related to the measurement of glucose, such as hydrogen peroxide. From this measured initial rate of decay, the sensor implant  100  implements an algorithm to approximate glucose levels at the time at which all buildup would have decayed had the sensor run a current for a longer period of time. In this way, sensor  100  advantageously avoids unnecessary power consumption associated with burning off the entire reactive buildup. Sensor may additionally communicate detected glucose levels in an on-demand fashion with reader  120 , as previously described above. 
     It may be advantageous to measure both intraocular pressure and glucose concentration in the aqueous humor because the glucose concentration measurement can be used to diagnose and/or treat diabetes. Meanwhile, diabetes patients are also at higher risk of developing glaucoma. Thus, there may be a significant overlap of the patient population for whom intraocular pressure and glucose concentration measurements would be valuable. 
     Furthermore, in various embodiments, it should be appreciated that the sensors disclosed herein, such as sensor implant  100 , could be implanted and positioned in alternate locations within the human body. For example, sensor implant  100  could measure pressure of other organs, such as the brain or heart, or other locations, such as the thoracic cavity, intracranial space, exterior limbs, and the like. Likewise, sensor implant  100  could measure other values, such as glucose concentration, at these alternate locations. Alternate location implantation can be performed with limited, if any, design changes to the sensor implant  100  disclosed herein. Thus, in certain embodiments, sensor implant  100  is location agnostic. 
     Various embodiments of implantable physiological sensors, and associated methods, with a variety of features, have been described herein. Although not every embodiment has been illustrated with every feature, it should be understood that the features described herein can be freely combined with the various embodiments that are described and illustrated. The various physiological sensors described herein can also have any feature, characteristic, element, or the like that is disclosed in connection with the sensor devices described in the following U.S. patent documents, which are each hereby incorporated by reference in their entirety: U.S. Pat. Nos. 6,981,958; 7,678,065; 8,142,364; and U.S. Patent Publication No. 2010/0056979. In addition, the various physiological sensors described herein can be used in, for example, any manner or application that is described in the foregoing patent documents. 
     The various illustrative devices, logical blocks, modules, circuits, and algorithm steps described in connection with the embodiments disclosed herein can be implemented as, for example, electronic hardware, such as analog and/or digital circuitry, computer software, or combinations of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, circuits, and steps have been described above generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. The described functionality can be implemented in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the disclosure. 
     Some of the various illustrative logical blocks, modules, and circuits described in connection with the embodiments disclosed herein can be implemented or performed with a general purpose processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. 
     Embodiments have been described in connection with the accompanying drawings. However, it should be understood that the figures are not necessarily drawn to scale. Distances, angles, and other dimensions are merely illustrative and do not necessarily bear an exact relationship to actual dimensions and layout of the devices illustrated. In addition, the foregoing embodiments have been described at a level of detail to allow one of ordinary skill in the art to make and use the devices, systems, and methods described herein. A wide variety of variation is possible. Components, elements, and/or steps can be altered, added, removed, or rearranged. While certain embodiments have been explicitly described, other embodiments will become apparent to those of ordinary skill in the art based on this disclosure. The scope of certain inventions disclosed herein is indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.