Patent ID: 12186076

The details of one or more examples of this disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of this disclosure will be apparent from the description and drawings, and from the claims.

DETAILED DESCRIPTION

A medical device may include an optical sensor, processing circuitry, an antenna, and a power source. The optical sensor may include one or more light sources and one or more optical beacons. For example, the one or more light source may include a plurality of light emitting diodes (LEDs) that are configured to emit radiation (e.g., light) having a selected wavelength range. The one or more optical beacons may include a reference optical beacon and a test (e.g., active) optical beacon. Both optical beacons include a fluorophore configured to interact with a substance present in a sample fluid to which the optical sensor is exposed. Additionally, the test optical beacon includes a reagent substrate. In some examples, an analyte in the sample fluid may react with the reagent substrate to modulate a concentration of the substance in a region proximate the test optical beacon and affect the fluorescence of the fluorophore. As used herein, the region proximate the optical beacon may include a region in which a substance is able to chemically interact with the fluorophore within a duration of time of the fluorescence decay of the fluorophore. Each optical beacon may include a photodetector configured to detect at least an intensity and duration of the fluorescence decay of the respective fluorophores. When exposed to the radiation emitted from the one or more light source, the fluorescence of the test optical beacon may be indicative of a concentration of the analyte. The reference optical beacon may be used to adjust for an ambient concentration of the substance. The respective fluorescence of the reference optical beacon and the test optical beacon may be used to generate a respective signals, which are received and processed by the processing circuitry to determine the concentration of the analyte.

The described medical devices and technique may include several advantages over other analyte detection systems and techniques. For example, the described medical devices and system may enable analyte detection without reference electrodes as used electrochemical sensors. Eliminating the need for a reference electrode may simplify device design. Additionally, or alternatively, the described medical devices and techniques may increase device longevity compared to other sensors, such as electrochemical sensors. For example, the described medical devices and techniques may utilize sensor chemistries that have a longer working life relative to electrochemical electrodes.

FIG.1Ais a conceptual drawing illustrating an example medical system10in conjunction with a patient12according to various examples described in this disclosure. The systems, devices, and methods described in this disclosure may include examples configurations of an optical sensor102located on and/or within medical device100. For purposes of this description, knowledge of cardiovascular anatomy and functionality is presumed, and details are omitted except to the extent necessary or desirable to explain the context of the techniques of this disclosure. System10includes medical device100having optical sensor102, implanted at or near the site of a heart18of a patient12and an optional external computing device24.

Medical device100may be in wireless communication with at least one of external device24and other devices not pictured inFIG.1. In some examples, medical device100is implanted outside of a thoracic cavity of patient12(e.g., subcutaneously in the pectoral location illustrated inFIG.1). Medical device100may be positioned near the sternum near or just below the level of the heart of patient12, e.g., at least partially within the cardiac silhouette. In some examples, medical device100includes a plurality of electrodes48, and is configured to sense a cardiac electrogram (EGM) via the plurality of electrodes. In some examples, medical device100takes the form of the LINQ™ ICM, or another ICM similar to, e.g., a version or modification of, the LINQ™ ICM. Therefore, in some embodiments, medical device100may serve as a combination sensor device suitable for monitoring and/or facilitating treatment of multiple conditions. For example, in embodiments such as the LINQ™ embodiments described, the medical device100may serve as a combination of a glucose sensor and/an ECG or cardiac monitoring device that may be uniquely suited for monitoring patient comorbidities. Although described primarily in the context of examples in which medical device100is an ICM, in various examples, medical device100may represent a cardiac monitor, a defibrillator, a cardiac resynchronization pacer/defibrillator, a pacemaker, an implantable pressure sensor, a neurostimulator, or any other implantable or external medical device that may, for example, have appropriate access to an analyte.

External device24may be a computing device with a user interface, such as a display viewable by the user and an interface for providing input to external device24(i.e., a user input mechanism). In some examples, external device24may be a notebook computer, tablet computer, workstation, one or more servers, smartphone, smartwatch, smart injection pen (such as, for example the InPen™ device available from Companion Medical, Inc. and Medtronic MiniMed, Inc.), insulin pump (such as for example, any one of the MiniMed™ 630G System, MiniMed™ 670G System, or MiniMed™ 770G System available from Medtronic MiniMed, Inc.), personal digital assistant, or another computing device that may run an application that enables the computing device to interact with medical device100. External device24is configured to communicate with medical device100and, optionally, another computing device (not illustrated inFIG.1), via wireless communication. External device24, for example, may communicate via near-field communication technologies (e.g., inductive coupling, NFC or other communication technologies operable at ranges less than 10-20 cm) and far-field communication technologies (e.g., RF telemetry according to the 802.11 or Bluetooth® specification sets (including but not limited to BLE), or other communication technologies operable at ranges greater than near-field communication technologies).

External device24may be used to configure operational parameters for medical device100. External device24may be used to retrieve data from medical device100. The retrieved data may include values of physiological parameters measured by medical device100, indications of episodes of arrhythmia or other maladies detected by medical device100, and physiological signals recorded by medical device100. For example, external device24may retrieve analyte concentrations recorded by medical device100, e.g., due to medical device100determining that a change in analyte concentration exceeded a predetermined magnitude, or that predetermined maximum or minimum analyte concentration threshold was exceeded, during the segment, or in response to a request to record the segment from patient12or another user. Additionally, or alternatively, external device24may retrieve analyte concentrations, cardiac EGM segments recorded by medical device100, e.g., due to medical device100determining that an episode of arrhythmia or another malady occurred during the segment, or in response to a request to record the segment from patient12or another user. In some examples, one or more remote computing devices may interact with medical device100in a manner similar to external device24, e.g., to program medical device100and/or retrieve data from medical device100, via a network such as a cloud computing network suitable for storing and processing data for the benefit of patients and/or health care providers, such as, for example, the CareLink™ Diabetes therapy management system available from Medtronic MiniMed, Inc.

In various examples, medical device100may include one or more additional sensor circuits configured to sense a particular physiological or neurological parameter associated with patient12, or may include a plurality of sensor circuits, which may be located at various and/or different positions relative to patient12and/or relative to each other, and may be configured to sense one or more physiological parameters associated with patient12.

For example, medical device100may include a sensor operable to sense a body temperature of patient12in a location of the medical device100, or at the location of the patient where a temperature sensor coupled by a lead to medical device100is located. In another example, medical device100may include a sensor configured to sense motion, such as steps taken by patient12and/or a position or a change of posture of patient12. In various examples, medical device100may include a sensor that is configured to detect breaths taken by patient12. In various examples, medical device100may include a sensor configured to detect heartbeats of patient12. In various examples, medical device100may include a sensor that is configured to measure systemic blood pressure of patient12.

In some examples, one or more of the sensors of medical device100may be implanted within patient12, that is, implanted below at least the skin level of the patient. In some examples, one or more of the sensors of medical device100may be located externally to patient12, for example as part of a cuff or as a wearable device, such as a device imbedded in clothing that is worn by patient12. In various examples, medical device100may be configured to sense one or more physiological parameters associated with patient12, and to transmit data corresponding to the sensed physiological parameter or parameters to external device24, as represented by the lightning bolt22coupling medical device100to external device24.

Transmission of data from medical device100to external device24in various examples may be performed via wireless transmission, using for example any of the formats for wireless communication described above. In various examples, medical device100may communicate wirelessly to an external device (e.g., an instrument or instruments) other than or in addition to external device24, such as a transceiver or an access point that provides a wireless communication link between medical device100and a network. Examples of communication techniques used by any of the devices described herein may include radiofrequency (RF) telemetry, which may be an RF link established via Bluetooth®, BLE, Wi-Fi, or medical implant communication service (MICS).

In some examples, system10may include more or fewer components than depicted inFIG.1. For example, in some examples, system10may include multiple additional implantable medical devices (IMDs), such as implantable pacemaker devices or other IMDs, implanted within patient12. In these examples, medical device100may function as a hub device for the other IMDs. For example, the additional IMDs may be configured to communicate with the medical device100, which would then communicate to the external device24, such as a user's smartphone, via a low-energy telemetry protocol.

FIG.1Bis a conceptual diagram illustrating a schematic and conceptual diagram of medical device100including optical sensor102. In addition to the above described functionality, medical device100is configured to optically measure a concentration of one or more analytes in a sample fluid101of a biological system, such as a concentration of glucose of a human patient. Although described as detecting a concentration of glucose, in other examples, medical device100may be configured to measure of concentration of other analytes such as, for example, one or more of sodium, chloride, potassium, bicarbonate/carbon dioxide, blood urea nitrogen, creatinine, glucose, brain natriuretic peptide, C-reactive protein, troponin I, lactate, pH, or L-dopa. Sample fluid101may include, but is not limited to, one or more of blood, interstitial fluid, saliva, urine, spinal fluid, peritoneal fluid, or other bodily fluids.

Medical device100includes optical sensor assembly102(e.g., optical sensor102), processing circuitry104, an antenna106, a power source108, and housing110. Medical device100may be insertable into a biological system. For example, medical device100may be transcutaneously insertable or implantable in interstitial fluid or a body cavity of a human patient. In other examples, a first portion of medical device100may be inserted into the skin, e.g., exposed to or otherwise in fluidly coupled to an interstitial fluid of the patient, and a second portion of the medical device may be affixed to or worn by the patient, e.g., as a skin worn patch. In this way, medical device100may enable continuous or near continuous monitoring of one or more analyte concentrations in the biological system.

Optical sensor102includes light source112, reference optical beacon114, and test optical beacon116. Optical sensor102is configured to detect a fluorescence emitted by a fluorophore in response to exposure to an analyte, and produce a signal indicative of the concentration of the analyte.

Light source112includes one or more radiation sources configured to emit radiation having a selected wavelength range. For example, light source112may include one or more light emitting diodes (LEDs) or LASERs. In some examples, light source112may include two, three, four, five, or more LEDs arrange on an LED chip. Radiation emitted by light source112may include any suitable wavelength or range of wavelengths of radiation. In some examples, the radiation may include wavelengths in the visible range, e.g., within a range from about 380 nanometers (nm) to about 740 nm.

In some examples, light source112may emit radiation having a range of wavelengths selected based on an absorbance of a fluorophore of reference optical beacon114and/or test optical beacon116. For example, the absorbance of the fluorophore may be substantially within a range from about 480 nm to about 700 nm. As used herein, absorbance substantially within a particular wavelength range may include a percentage of absorption within the range relative to a total absorption spectrum that is greater than 90%, such as greater than 95% or greater than about 99%. In such examples, light source112may have an emission spectrum substantially within a range from about 480 nm to about 700 nm. As used herein, an emission spectrum substantially within a particular wavelength range may include a percentage of emission within the range relative to a total emission spectrum that is greater than 90%, such as greater than 95% or greater than about 99%. As another example, the fluorophore may have a maximum absorbance peak of less than about 600 nm, such as about 590 nm. In such examples, light source112may have a peak emission wavelength of about 590 nm.

In examples in which light source112includes one or more LEDs with an emission wavelength greater than about 580 nm, light source112may include one or more LEDs driven by less than about 100 milliamps and/or a voltage within a range from about 1.5 volts (V) to about 2.5 V, such as from about 1.9 V to about 2.2 V. By driving light source112in the milliamp range, with less than about 2.5 V, and/or with an emission wavelength greater than about 580 nm, light source112may include a less complex circuit compared to an LED configured to emit light having a wavelength less than about 580 nm.

The radiation may be incident on a respective fluorophore of reference optical beacon114and test optical beacon116. In response to the incident radiation, the respective fluorophore of reference optical beacon114and test optical beacon116may fluoresce. The respective fluorophores may include any suitable fluorophore. Example fluorophores include, but are not limited to, ruthenium-tris(4,7-diphenyl-1,10-phenanthroline) dichloride (Ru(dpp)), platinum(II) octaethylporphyrin (PtOEP), palladium(II) octaethylporphyrin (PdOEP), platinum(II)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorphenyl)-porphyrin (PtTFPP), palladium(II)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorphenyl)-porphyrin (PdTFPP), platinum(II) octaethylporphyrinketone (PtOEPK), palladium(II) octaethylporphyrinketone (PdOEPK), platinum(II) tetraphenyltetrabenzoporphyrin (PtTPTBP), palladium(II) tetraphenyltetrabenzoporphyrin (PtTPTBP), platinum(II) tetraphenyltetranaphthoporphyrin (PtPTPNP), or palladium(II) tetraphenyltetranaphthoporphyrin (PdPTPNP).

In some examples, a fluorophore may be selected to have a relatively higher light-emission efficiency, relatively higher brightness, and relatively longer emission time constant, compared to other fluorophores configured to interact with oxygen. In some examples, a fluorophore may be selected to fluoresce at a wavelength of about 580 nm or longer. In some examples, a fluorophore may be selected to have an emission wavelength within a range from about 600 nm to about 1100 nm and/or to match a peak sensitivity range for a silicon photodetector. In some examples, a fluorophore may be selected to be biocompatible and/or intrinsically stable for chronic use in vivo. The respective fluorophore of reference optical beacon114and test optical beacon116may have the same chemical composition or a different chemical composition.

The fluorophore may be configured to interact with a substance present in sample fluid101surrounding medical device100. In some examples, the respective fluorophore of reference optical beacon114and test optical beacon116may be positioned on an external surface of housing110of medical device100. In other examples, housing110may include one or more apertures fluidly coupling at least the respective fluorophore of reference optical beacon114and test optical beacon116to sample fluid101. In these ways, the respective fluorophore of reference optical beacon114and test optical beacon116may be in contact with sample fluid101.

In some examples, the fluorophore may interact with oxygen present in sample fluid101. For example, a fluorescence of the respective fluorophores may be quenched by oxygen. In other words, a higher concentration of oxygen proximate test optical beacon116may cause the fluorophore of test optical beacon116to emit a lesser intensity of fluorescence compared to the fluorescence of the fluorophore of a reference optical beacon114that is proximate to a relatively lower concentration of oxygen. In this way, the fluorescence of the fluorophore of reference optical beacon114and test optical beacon116may be used to determine a variation in a concentration of the substance proximate each respective fluorophore.

For example, reference optical beacon114may be used to adjust for an ambient concentration of a substance, such as oxygen, in sample fluid101, whereas test optical beacon116may include an additional chemistry configured to react with a selected analyte to change a concentration of the substance proximate to test optical beacon116. In some examples, in addition to the fluorophore, test optical beacon116includes a reagent substrate configured to react with a selected analyte to change a concentration of the substance proximate to test optical beacon116. The reagent substrate may include one or more enzymes, catalysts, antibodies, molecular imprinted polymers, aptamers, or other materials configured to react with an analyte to modulate a concentration of a selected substance.

In examples in which the analyte includes glucose, the reagent substrate may include glucose oxidase and catalase. For example, the glucose oxidase consumes oxygen (e.g., the substance) to oxidize glucose present in sample fluid101to yield gluconic acid and hydrogen peroxide (e.g., a bi-product). The catalase reduces the hydrogen peroxide to yield water and oxygen (e.g., the substance). By consuming the hydrogen peroxide, catalase may reduce or prevent inhibition of glucose oxidase by the hydrogen peroxide. By consuming oxygen via glucose oxidase and producing oxygen via catalase, the reagent substrate is configured to modulate a local oxygen concentration that is indicative of the concentration of glucose.

In some examples, reference optical beacon114and/or test optical beacon116may include limiting membrane and/or a selective ion transfer membrane disposed on the fluorophore and/or the reagent substrate. The membrane may be selectively permeable to the analyte. For example, the membrane may control a rate of diffusion of the analyte from sample fluid101to a reagent substrate of test optical beacon116. In this way, the membrane may control an extent of reaction or a rate of reaction of the analyte at a surface of the reagent substrate, e.g., by controlling a rate of exposure of the reagent substrate to the analyte. Additionally, or alternatively, the membrane may extend a linear range of a respective optical beacon, e.g., relative to a glucose concentration in the sample fluid101, by limiting a permeability of glucose. In other words, the membrane may prevent saturation of the reagent substrate (e.g., enzymes of the reagent substrate) over a greater range of glucose concentrations relative to an optical beacon without a reagent substrate. In this way, the chemistry of the fluorophore, reagent substrate, and/or membrane may be selected to be specific to the analyte, extend a linear range of the respective optical beacon, and/or increase a useable life of the respective optical beacon.

Reference optical beacon114and test optical beacon116each include a respective photoreceptor in line-of-sight with the respective fluorophore. The respective photodetector of reference optical beacon114and test optical beacon116are configured to detect a respective intensity of the respective fluorescence of the fluorophore for each of reference optical beacon114and test optical beacon116. Although described as including two photodetectors, in some examples, optical sensor102may include a single photodetector, each of reference optical beacon114and test optical beacon116being disposed on a portion of the single photodetector. The respective photodetectors may include any suitable photodetector. In some examples, the photodetectors may include flip-chip photodetectors. The respective photodetectors may be selected to detect a wavelength or a range of wavelengths of radiation emitted by the respective fluorophore of reference optical beacon114and test optical beacon116. For example, in response to radiation emitted from light source112incident on the fluorophore, the fluorophore may have an emission spectrum substantially within a range from about 700 nm to about 820 nm, and/or a maximum emission peak of about 760 nm. In such examples, the photodetector may be configured to detect radiation within a range from about 380 nm to about 1100 nm, such as within a range from about 700 nm to about 820 nm, and/or with a peak detection sensitivity of within a range from about 700 nm to about 820 nm. In some examples, the peak detection sensitivity may be an intrinsic property of the photodetector, e.g., based on materials of construction and/or physical configuration. In some examples, the detection range or peak detection sensitivity of the photodetector may be modulated by, for example, one or more filters, such as a bandpass filter, a light absorbing gel or film, or other discrete filter between a fluorophore and a respective photodetector. Filtering may, for example, enable a photodetector to detect a fluorescence of a fluorophore, while substantially not detecting light emitted by a light source.

The respective photodetectors may transmit a signal indicative of the respective intensity to processing circuitry104. Processing circuitry104may include various types of hardware, including, but not limited to, microprocessors, controllers, digital signal processors (DSPs), application specific integrated circuits (ASICs), field-programmable gate arrays (FPGAs), or equivalent discrete or integrated logic circuitry, as well as combinations of such components. The term “processing circuitry” may generally refer to any of the foregoing logic circuitry, alone or in combination with other logic circuitry, or any other equivalent circuitry. In some examples, processing circuitry104may represent and/or include additional components. Processing circuitry104represents hardware that can be configured to implement firmware and/or software that sets forth one or more of the algorithms described herein. For example, processing circuitry104may be configured to implement functionality, process instructions, or both for execution of processing instructions stored within one or more storage components188, such as signal identification module196and/or signal analysis module198.

One or more storage components188may be configured to store information within medical device100. One or more storage components188, in some examples, include a computer-readable storage medium or computer-readable storage device. In some examples, one or more storage components188include a temporary memory, meaning that a primary purpose of one or more storage components188is not long-term storage. One or more storage components188, in some examples, include a volatile memory, meaning that one or more storage components188does not maintain stored contents when power is not provided to one or more storage components188. Examples of volatile memories include random access memories (RAM), dynamic random-access memories (DRAM), static random-access memories (SRAM), and other forms of volatile memories known in the art. In some examples, one or more storage components188are used to store program instructions for execution by processing circuitry104. One or more storage components188, in some examples, are used by software or applications running on processing circuitry104to temporarily store information during program execution.

In some examples, one or more storage components188may be configured for longer-term storage of information. In some examples, one or more storage components188may include non-volatile storage elements. Examples of such non-volatile storage elements include flash memories, or forms of electrically programmable memories (EPROM) or electrically erasable and programmable memories (EEPROM).

Processing circuitry104, e.g., signal identification module196, may be configured to identify a respective signal corresponding to a respective optical beacon. For example, signal identification module196may include a multiplexer configured to select between inputs from reference optical beacon114and test optical beacon116. In some examples, input selection maybe based on a timing of light emitted by light source112. For example, in response to a first light pulse emitted from light source112, processing circuitry104, e.g., signal identification module196, may select an input from reference optical beacon114that is then output to processing circuitry104and/or signal analysis module198for processing. In response to a second light pulse emitted from light source112that is separated in time from the first light pulse, processing circuitry104, e.g., signal identification module196, may select an input from test optical beacon116that is then output to processing circuitry104and/or signal analysis module198for processing. In some examples, a duration between the first light pulse and the second light pulse may be greater than 1 millisecond, greater than 10 milliseconds, greater than 100 milliseconds, greater than one second, or more. For example, the duration between the first light pulse and the second light pulse may be based on a duration of fluorescence of the respective fluorophore in response to the first light pulse.

Processing circuitry104, e.g., via signal analysis module198, may be configured to process the identified signal to determine a concentration of an analyte. In some examples, signal analysis module198may be coupled to one or more capacitors configured to receive from a respective photodetector of reference optical beacon114or test optical beacon116a respective amount of electrical energy indicative of a fluorescence emission from a respective fluorophore. Processing circuitry104, e.g., signal analysis module198, may determine a difference between a first amount of electrical energy associated with a fluorescent decay of the fluorophore of reference optical beacon114and a second amount of electrical energy associated with a fluorescent decay of the fluorophore of test optical beacon116. The fluorescent decay of the respective fluorophores may include substantially all fluorescence emitted by the respective fluorophore in response to incident light emitted by light source112, such as at least 80%, at least 90%, at least 95%, or at least 99% of a total fluorescent decay of the respective fluorophore. By using a capacitor to store electrical energy from the respective photodetectors in response to the fluorescent decay of the respective fluorophore, the amount electrical energy may more accurately represent the fluorescent decay compared to other methods, such as time dependent sampling of the fluorescence of the respective fluorophore. Additionally, or alternatively, using a capacitor to store electrical energy indicative of the fluorescent decay may simplify circuitry design relative to other methods, such as time dependent sampling of the fluorescence of the respective fluorophore.

Each of signal identification module196and signal analysis module198may be implemented in various ways. For example, one or more of signal identification module196and signal analysis module198may be implemented as an application or a part of an application executed by processing circuitry104. In some examples, one or more of signal identification module196and signal analysis module198may be implemented as part of a hardware unit of medical device100(e.g., as circuitry). In some examples, one or more of signal identification module196and signal analysis module198may be implemented remotely on external device24, for example, as part of an application executed by one or more processors of external device24or as a hardware unit of external device24. Functions performed by one or more of signal identification module196and signal analysis module198are explained below with reference to the example flow diagram illustrated inFIG.8.

Processing circuitry104may be configured to communicate, via antenna106, with one or more external devices24. For example, medical device100may include communications circuitry190operatively coupled to processing circuitry104. Communications circuitry may be configured to send and receive signals to enable communication with an external device24via antenna106. Communications circuitry190may include a communications interface, such as a radio frequency transmitter and/or receiver, cellular transmitter and/or receiver, a Bluetooth® interface card, or any other type of device that can send information or send and receive information. In some examples, the communications interface of communications circuitry190may be configured to send and/or receive data via antenna106. In some examples, medical device100uses communications circuitry190to wirelessly transmit (e.g., a one-way communication) data to external device24. In some examples, external devices24may include, but is not limited to, a radio frequency identification reader, a mobile device, such as a cell phone or tablet, or a computing device operatively coupled to an electronic medical records database or remote server system. In this way, antenna106may be operatively coupled to the processing circuitry and configured to transmit data representative of the concentration of the analyte to external device24.

Medical device100includes antenna106operatively coupled to processing circuitry104to enable medical device100to communicate to an external device24, e.g., while operating completely within a biological system. In some examples, processing circuitry104may cause communication circuitry190to transmit, via antenna106, data indicative of a determined concentration of an analyte, such as processed data, unprocessed signals from optical sensor184, or both. In some examples, external device24may continuously or periodically interrogate or poll communications circuitry190via antenna106to cause processing circuitry104to receive, identify, or process signals from optical sensor184. By receiving, identifying, or processing signals from optical sensor184only when interrogated or polled by external device24, processing circuitry may conserve power or processing resources.

Medical device includes power source108to enable medical device100to operate completely within the biological system. Power source108may be operatively coupled to optical sensor102(e.g., light source112), processing circuitry104, storage components188, and/or communication circuitry190. In some examples, power source108may be operatively coupled to optical sensor102to one or more LEDs of light source112. Power source108may include any suitable power source, such as, for example, primary cell, a secondary cell, a solid state battery, a lithium ion battery, a lithium ion micro battery, a fuel cell, or combinations thereof.

By using power source108to power the components of medical device100and antenna106to communicate with one or more external devices24, medical device100may be configured to enable chronic, continuous, and/or substantially continuous monitoring of the analyte concentration in the biological system.

Medical device100includes housing110that is configured to protect components of medical device100from the environment of the biological system. Housing110may be formed to separate at least a portion of one or more of optical sensor102, processing circuitry104, an antenna106, and/or a power source108from the environment surrounding medical device100. In some examples, housing110may include one or more biocompatible materials coating or encasing the components of medical device100. One or more components of medical device100, such as portions of optical sensor102or power source108may be disposed outside housing110, such as, for example, affixed to an external surface of housing110or defining an external surface of medical device100. As one example, antenna106may be affixed to an external surface of housing110to improve transmission properties of antenna106. Housing110may include any suitable shape, such as rectilinear or curvilinear. In some examples, housing110may be shaped to facilitate insertion of medical device100into a body cavity of a human patient. For example, housing110may include a cylindrical shape to be loaded into an insertion tool or include rounded corners and edges to reduce irritation to the patient.

Housing110may be any suitable dimensions. In some examples, a height of housing110may be between approximately 1 millimeter (mm) and approximately 8 mm, such as approximately 4 mm. In some examples, a width of housing110may be between approximately 5 mm and approximately 15 mm, such as approximately 7 mm. In some examples, a length of the housing182may be between approximately 20 mm and approximately 60 mm, such as approximately 45 mm. In some examples, the components of medical device100may be layered or stacked inside housing110to reduce the size of medical device100compared to a device in which the components are not layered or stacked.

In some examples, the components of medical device100may be arranged to facilitate operation of the components.FIG.2is a conceptual diagram illustrating a perspective view of an example medical device200including an optical sensor202. Medical device200may be the same or substantially similar to medical device100discussed above in reference toFIG.1. For example, medical device200may include optical sensor202including light source212, reference optical beacon214, and test optical beacon216?, processing circuitry204, antenna206, power source208, and housing210, which may be the same or substantially similar to the similarly numbered features discussed above in reference to medical device100illustrated inFIGS.1A and1B.

As illustrated inFIG.2, antenna206is disposed on an exterior surface211of housing210. In some examples, antenna206may include a substrate layer and a metalized layer formed on the substrate layer. The substrate layer may include, for example, biocompatible polymer, such as polyamide or polyimide, silica glass, silicon, sapphire, or the like. The metalized layer may include, for example, aluminum, copper, silver, or other conductive metals. Antenna206may include other materials, such as, for example, ceramics or other dielectrics (e.g., as in dielectric resonator antennas). In some examples, antenna206, e.g., a metalized layer or the like, may be formed directly on exterior surface211of housing210.

Regardless of the material, antenna206may include an opaque or substantially opaque material. For example, an opaque (e.g., or substantially opaque) material may block transmission of at least a portion of radiation of a selected wavelength, such as, between about 75% and about 100% of visible light.

In examples in which antenna206includes an opaque material, components of optical sensor202may be arranged relative to portions of antenna206to reduce or prevent optical interference between components. For example, as illustrated inFIG.2, light source212is positioned on an outer perimeter of antenna206, whereas reference optical beacon214and test optical beacons216are positioned within an aperture defined by antenna206. In this way, antenna206may define an optical boundary of opaque material that reduces or prevents transmission of light from light source directly to a respective photodetector of reference optical beacon214and test optical beacons216. Rather, light emitted from light source212must travel through an environment external to medical device200. In this way, the emitted light may be incident only on the fluorophore of reference optical beacon214and the fluorophore and/or reactive substrate of test optical beacon216. Hence, the optical signal generated by the respective photodetector of reference optical beacon214and test optical beacon216is produced substantially only by fluorescence of the respective fluorophores. Being produced substantially only by fluorescence of the respective fluorophores may exclude ambient radiation, fluorescence emitted by adjacent fluorophores, or light transmitted from light source212through components (e.g., a substrate) of medical device200to the respective photodetectors.

Although not illustrated inFIG.2, in some examples, reference optical beacon214and test optical beacon216may be disposed on opposing portions of antenna206. Disposing reference optical beacon214and test optical beacon216on opposing portions of antenna206may reduce or prevent fluorescence emitted by a respective fluorophore of reference optical beacon214and test optical beacon216from being detected by the respective photodetector of the other of reference optical beacon214and test optical beacon216.

Additionally, or alternatively, medical device200may include optional optical masks218A and218B (collectively, optical mask218). Optical mask218may be configured to reduce or prevent transmission of radiation out of or into a substrate of medical device200. For example, as discussed above in reference toFIG.1, a substrate of medical device200may include one or more transparent (e.g., or semi-transparent) materials, such as glass or sapphire. Portions of optical sensor202, such as light source212and/or respective photodetectors of reference optical beacon214and test optical beacon216may be disposed within (e.g., under) the transparent material, relative to the environment surrounding medical device200.

Light emitted from light source112may travel through the transparent material into the environment surrounding medical device200. In some examples, at least a portion of the light may be incident on the transparent material at an angle that causes reflection or total internal reflection of the portion of light. Additionally, or alternatively, in examples in which medical device200is implanted in a patient, the tissue or biological material surrounding medical device200may cause diffuse scattering of the light. At least a portion of the scattered light may be incident on the transparent material at an angle causing total internal reflection of the portion of scattered light. Optical mask218may be disposed on an interior surface and/or an exterior surface of the transparent material to reduce or prevent reflection and/or total internal reflection of the light. In this way, optical mask218may reduce or prevent stray light from being transmitted through the transparent substrate to respective photodetectors of reference optical beacon114and test optical beacon116.

The optional optical mask218may include a material configured to substantially absorb radiation emitted by light source212. In some examples, optical mask218may include titanium nitride, columnar titanium nitride, titanium, or another material suitable to absorb selected wavelengths of radiation that may be emitted by light source212.

FIG.3is a conceptual diagram illustrating a partial cross-sectional side view of an example medical device300including an optical sensor302. Medical device300may be the same or substantially similar to medical device100and/or medical device200discussed above in reference toFIGS.1and2. For example, optical sensor302may include light sources312A and312B (collectively, light sources312), reference optical beacon314, test optical beacon316, and antenna306, and may be optatively coupled to processing circuitry and a power source (not illustrated), and may be encased in housing310, which may be the same or substantially similar to the similarly numbered features discussed above in reference to medical device100and/or medical device200illustrated inFIGS.1A,1B, and2.

Optical sensor302may include any suitable arrangement of light sources312, reference optical beacon314, and test optical beacon316. As illustrated inFIG.3, medical device300includes a substrate layer320defining surfaces321and322. In some examples, substrate layer320may include sapphire, a sapphire wafer, silica glass, a glass wafer, silicon, a biocompatible polymer, polyamide, polyimide, a liquid crystal polymer, or a dielectric material. In some examples, surfaces321and/or322are substantially planar. In other examples, surfaces321and/or322may define surface features, such as ridges, valleys, or apertures, corresponding to features such as at least a portion of light sources312, reference optical beacon314, and test optical beacon316, electrical traces, through vias, light blocking regions, or the like. Surface features on or in surfaces321and/or322may be formed by any suitable means, such as, for example, machining, laser etching, chemical etching, or semiconductor manufacturing techniques such as front-end-of-line (FEOL) processes. In this way, substrate layer320may be formed to support additional layers, facilitate manufacture of the medical device300, or both.

An optical mask318may be disposed on at least a portion of surface322or, in some examples, a portion of surface321. As discussed above in reference toFIG.2, optical mask318is configured to reduce or prevent transmission of radiation out of or into substrate layer320of medical device200. For example, optical mask318may absorb radiation, such as light ray319, incident on optical mask318.

An interconnect layer324may be disposed on surface326of optical mask318. Interconnect layer324is configured to electrically couple light sources312, reference optical beacon314, and test optical beacon316to processing circuitry and/or a power source of medical device300. For example, light sources312, reference optical beacon314, and test optical beacon316may be electrically coupled to interconnect layer324by respective electrical traces313A,313B,315, and317.

Interconnect layer324may include an electrically conductive material, such as, for example, aluminum, cadmium, chromium, copper, gold, nickel, platinum, titanium, indium nitride, indium phosphide, zinc oxide, alloys thereof, or the like. In some examples, surface322may be metallized by, for example, chemical vapor deposition, physical vapor deposition, thermal spraying, cold spraying, or the like, to form interconnect layer324. In some examples, interconnect layer324may form a plurality of electrical traces, e.g., formed using semiconductor manufacturing techniques such as back-end-of-line (BEOL) processes. A respective electrical trace or the plurality of electrical traces may electrically couple one or more components of medical device300.

Although illustrated as embedded or partially embedded in optical mask318and interconnect layer324, in some examples, one or more portions of light sources312, reference optical beacon314, and test optical beacon316may be formed on a portion of optical mask318and/or interconnect layer324. For example, light sources312may be positioned on and electrically coupled to a surface of optical mask318and/or interconnect layer324, where optical mask318and interconnect layer324may define an aperture optically coupling light sources312to substrate320. Each of reference optical beacon314and test optical beacon316may be similarly positioned on a surface of optical mask318and/or interconnect layer324.

In some examples, medical device300may include one or more optical barriers330extending at least partially through substrate layer320. For example, optical barrier330may extend through at least a portion of substrate layer320. Optical barriers330may extend through only a portion of substrate layer320to enable substrate layer320to define a hermetic seal between an interior and exterior of medical device300. Optical barrier330may be substantially the same as or similar to optical mask318, except that optical barrier330may extend into substrate layer320. For example, optical barrier330may include a material configured to absorb at least a portion of radiation transmitted through substrate layer320. In some examples, radiation, such as light ray331, may be incident on an interface between fluorophore324and substrate layer320at an angle that results in total internal reflection of the radiation. By orienting optical barrier330between components of optical sensor302, optical barrier may substantially reduce or prevent light ray331from reaching photodetector364of test optical beacon316. In this way, one or more optical barriers330may be disposed between reference optical beacon314and test optical beacon316to reduce or prevent fluorescence emitted from either reference optical beacon314and test optical beacon316from reaching the other of reference optical beacon314and test optical beacon316.

In operation, when light is emitted from light source312A, e.g., by LEDs311A, the light, e.g., light ray332, may travel through a portion of substrate layer320and may be incident on test optical beacon316. When light is emitted from light source312B, e.g., by LEDs311B, the light may travel through a portion of substrate layer320and may be incident on test optical beacon314.

Reference optical beacon314includes a fluorophore342and a photodetector344. At least a portion of radiation emitted by light source312B is incident on fluorophore342. Fluorophore342absorbs at least a portion of the radiation, and emits a fluorescence343that is incident on photodetector344. Fluorophore342is exposed to the environment surrounding medical device300. In some examples, as discussed above, the fluorescence343of fluorophore342in response to incident radiation is associated with a concentration of substance present in the environment surrounding medical device300. For example, fluorescence343may be quenched, e.g., reduced, proportional to a concentration of oxygen proximate fluorophore342.

Test optical beacon316includes a reagent substrate360, a fluorophore362, and a photodetector364. At least a portion of radiation, e.g., light ray332, emitted by light source312A is incident on fluorophore362. Fluorophore362absorbs at least a portion of the incident radiation, and emits a fluorescence363that is incident on photodetector364. Fluorophore362is exposed to reagent substrate360. Reagent substrate360, and in some examples at least a portion of fluorophore362, is exposed to the environment surrounding medical device300. Although illustrated as distinct layers, in some examples, reagent substrate360and fluorophore362may define a single layer, such as a layer composing a homogeneous mixture, heterogeneous mixture, or composite of reagent substrate360and fluorophore362.

As discussed above in reference toFIG.1, reagent substrate360may be configured to react with an analyte present in the proximate environment to modulate the concentration of the substance that interacts with fluorophore362. In some examples, reagent substrate360includes an immobilization substrate configured to immobilize a reagent. As discussed above, the reagent may include at least one enzyme, catalyst, or other material configured to react with the analyte to yield the substance. In examples in which the analyte include glucose and the substance includes oxygen, the reagent may include an oxidase enzyme, such as glucose oxidase. In some examples, the reagent may be immobilized on an immobilization substrate by, for example, physical entrapment (e.g., a respective reagent physically unable to pass through pores of the immobilization substrate), chemical bonding (e.g., ionic bonding, covalent bonding, van der Waals forces, and the like), or combinations thereof. In some examples, the immobilization substrate may include a polymer, such as polylysine, aminosilane, epoxysilane, or nitrocellulose, or a substrate having a three-dimensional lattice structure, such as a hydrogel, an organogel, or a xerogel. In some examples, the immobilization substrate may include a ligand configured to chemically bond to at least a portion of a respective reagent. For example, the immobilization substrate including glutaraldehyde may immobilize glucose oxidase. A respective immobilization substrate including primary amine conjugation enniatin may immobilize (used for sodium Na+ detection) can be immobilized to the working electrode through. In some examples, the immobilization substrate may include, but is not limited to, glutaraldehyde, thiol based conjugation compounds (e.g., 16-mercaptohexadecanoic acid (MHDA), diethyldithiocarbamic acid (DSH), dithiobissuccinimidylundecanoate (DSU), purine conjugation compounds, streptavidin-biotin conjugation compounds, a primary amine and a vinyl pyridine polymer, lysine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) coupling, agarose based gel and polymer mixtures, silane crosslinker, (hydroxyethyl)methacrylate, and poly(ethylene glycol) diacrylate polymer. In some examples, the immobilization substrate may be transparent or semi-transparent to enable radiation, e.g., light rays332B, to reach fluorophore362. By immobilizing a reagent, the immobilization substrate may reduce loss of the reagent to the sample fluid.

In examples in which reagent substrate360includes at least one enzyme, the at least one enzyme may be selected based on the analyte to be detected. For example, the at least one enzyme may be selected from the group consisting of glucose oxidase, lactate oxidase, catalase, or mixtures thereof. In some examples, the at least one enzyme may be selected to react with a selected analyte and provide a reaction pathway to enable detection of the concentration of the selected analyte. For example, fluorescence343may be quenched, e.g., reduced, proportional to a concentration of oxygen proximate fluorophore342. In examples in which reagent substrate360includes glucose oxidase (e.g., notatin), glucose oxidase may oxidize glucose in the sample fluid to produce D-glucono-δ-lactone and hydrogen peroxide. The hydrogen peroxide may be reduced by catalase to produce oxygen. This modulation in the oxygen concentration may be indicative of the glucose concentration in the sample fluid. In examples in which reagent substrate360includes lactate oxidase, lactate oxidase may oxidize lactic acid in the sample fluid to produce pyruvate and hydrogen peroxide. The hydrogen peroxide may be reduced by catalase to produce oxygen. This modulation in the oxygen concentration may be indicative of the lactic acid concentration in the sample fluid.

In some examples, reference optical beacon314and/or test optical beacon316may include one or more permeable membranes370. Membrane370may be permeable to at least the analyte and, in some examples, configured to block interfering cellular bodies or molecules from binding or adhering to a respective constituents of reference optical beacon314and/or test optical beacon316. For example, a glucose membrane may block large cellular bodies or molecules, such as red blood cells, white blood cells, acetaminophen, ascorbic acid, and the like. Membrane370may include, for example, one or more limiting membranes, one or more selective ion transfer membranes, one or more ionophore membranes, or combinations thereof. Limiting membranes may include, but are not limited to, polyurethane polyurea block copolymer including a mixture of materials, such as, e.g., hexamethylene, diisocyanate, aminopropyl-terminated siloxane polymer, and polyethylene glycol, or a vinyl pyridine-styrene copolymer mixed with epoxy groups and coated with polyethylene glycol. Selective ion transfer membranes may include a porous material having a net positive (or negative) charge to enabling permeation of ions having a like charge through the selective ion transfer membrane, while reducing permeation of ion having an opposite charge. Selective ion transfer membranes may include, but are not limited to, amino methylated polystyrene salicylaldehyde, dibenzo-18-crown-6, cezomycin, enniatin, gramicidin A, lasalocid, macrolides, monensin, narasin, nigericin, nigericin sodium salt, nonactin, polyimide/lycra blend, salinomycin, valinomycin, or mixtures thereof. Ionophore membranes may include a plurality of ionophores dispersed in an ionophore matrix material, where the plurality of ionophores may be selected to be preferentially permeable to a selected ion or group of ions. The ionophores may include, but are not limited to, crown ethers, cryptands, calixarenesm, phenols, amino methylated polystyrene salicylaldehyde, beauvericin, calcimycine, cezomycin, carbonyl cyanide m-chlorophenyl hydrazone, dibenzo-18-crown-6, enniatin, gramicidin A, ionomycin, lasalocid, macrolides, monensin, nigericin, nigericin sodium salt, narasin, nonactin, polyimide/lycra blend, salinomycin, tetronasin, valinomycin, potassium ionophore III (BME 44) or mixtures thereof. Ionophore matrix material may include, but is not limited to, polyvinylchloride, silicone, fluorosilicone, polyurethane, glutaraldehyde, UV curable polymers like PVA-SbQ, PVA hydrogels, pHEMA-HAA crosslinking, and agarose gel. In this way, the optical beacons may be configured to react with a selected analyte or a derivative thereof to produce a response signal to the presence of the selected analyte.

In some examples, one or more regions of membrane370may include a light absorbent material. For example, membrane370may include, in addition to the one or more above described limiting membranes, light absorptive material, a pigment, or a dye configured to at least partially absorb radiation incident on membrane370. In some examples, the light absorbing region of membrane370may include a portion of membrane370disposed between optical beacons314and316. In this way, membrane370may be configured to reduce transmission of radiation between fluorophores342and362. Additionally, or alternatively, the light absorbing region of membrane370may include the entire volume or at least a total surface area of membrane370. In this way, membrane370may substantially block ambient light incident on optical beacons314and316.

Antenna306may be disposed on surface321of substrate layer320. In some examples, antenna306may define an optical boundary of opaque material that reduces or prevents transmission of light between fluorophores342and362and/or between fluorophore342and photodetector364and/or between fluorophore362and photodetector344. Antenna may include any suitable material, such as, for example, titanium. or a titanium foil.

Electrode layer307may be disposed on antenna306. Electrode layer307may define a conductive surface of medical device300that is configured to detect electrical signals within a human patient, such as, for example, ECG signals. Electrode layer307may include any suitable material, such as, for example, titanium nitride.

FIG.4is a graph400illustrating an example absorption and emission spectra of an optical sensor. The example absorption and emission spectrum may indicative of the absorption and emission of one or more of the fluorophores described above in reference toFIGS.1through3. As illustrated inFIG.4, the absorption and emission spectrums are plotted as wavelength versus normalized intensity. The wavelength is limited to a range between 400 nanometers (nm) and 800 nm. In some examples, at least a portion of the absorption and/or emission spectra may lie outside of the illustrated range.

Solid line402illustrates the example absorption of a fluorophore, which may include a peak absorption at or near 590 nm. Given a peak absorption at or near 590 nm, a light source may be selected to emit radiation at or near 590 nm. In this way, matching or at least coordinating the fluorophore absorption spectrum and light source emission spectrum may reduce a duration of emission by the light source to achieve a selected absorption (and/or associated fluorescence emission) and/or an energy consumption by the light source to achieve the selected absorption (and/or associated fluorescence emission).

Dashed line404illustrates an example fluorescence emission by the fluorophore, which may include a peak emissivity at or near 760 nm. Given a peak emissivity at or near 760 nm, the photodetector of an optical beacon may be selected to detect radiation at or near 760 nm with greater sensitivity relative to wavelengths that are significantly shorter or longer, e.g., less than 700 nm (such as less than 400 nm or less than 600 nm) or greater than 800 nm (such as greater than 900 nm or greater than 1000 nm). In this way, matching or at least coordinating the detection sensitivity of a photodetector to the peak emissivity of the fluorophore may improve detection accuracy, and thereby improve an accuracy of the determination of an analyte concentration.

FIG.5is a graph500illustrating time-domain filtering of an example fluorescence decay of an optical sensor, such as the example optical sensors describe above in reference toFIGS.1-3. In some examples, a light source may be pulsed for a duration from T0to T1, illustrated as pulse502. The duration of pulse502may be within a range from about 1 millisecond (ms) to about 10 ms. In some examples, the duration of pulse502may be shorter than 1 ms or greater than 10 ms, such as greater than about 100 ms or greater than 1 second. In some examples, the pulse duration may be selected to result in a fluorescence of a fluorophore sufficient for detection by a photodetector. In some examples, the pulse duration may be selected to reduce power consumption by a light source.

The fluorescence decay504of reference optical beacon may include a duration from about T1to TREF. The fluorescence decay506of test optical beacon may include a duration from about T1to TTEST. In some examples, the intensity of both fluorescence decay504and fluorescence decay506over the respective duration may be stored, for example, by respective capacitors as discussed above. In this way, the stored electrical energy may be indicative of an integral of the respective fluorescence decay for the respective duration. The difference between the integrals of fluorescence decay504and fluorescence decay506may be indicative of a difference in a substance proximate reference optical beacon and test optical beacon, respectively. The difference may be indicative of an absolute difference or, in other examples, a ratio of fluorescence decay504and fluorescence decay506or other mathematical association between fluorescence decay504and fluorescence decay506that is indicative of the concentration of the analyte proximate each respective optical beacon. Hence, when the concentration of the substance proximal the respective optical beacon is associated (e.g., proportional) to the concentration of an analyte, the difference between the electrical energy stored in respective capacitors may be used to determine the concentration of the analyte.

Although described as including a single pulse502, in other examples, two pulses may be used. For example, a first pulse may be used to generate fluorescence decay504, and a second light pulse may be used to generate fluorescence decay506. Additionally, or alternatively, the stored electrical energy may be sampled at discrete time intervals during an integration period to determine a light emission decay time constant. For example, the light emission decay time constant may be based on a rate of change of the stored electrical energy. The light emission decay time constant may be indicative of photo-bleaching of a fluorophore. In some examples, the light emission decay time constant may be used to mitigate the effect of photo-bleaching over time that would attenuate the overall signal amplitude.

The above described medical devices and optical sensors may be formed using any suitable technique.FIG.6is a flow diagram illustrating an example technique of forming an optical sensor. Although the technique illustrated inFIG.6will be described with respect to medical device300as illustrated inFIG.3, in some examples, the technique may be used to form other medical devices, including, but not limited to, medical devices100and200illustrated inFIGS.1and2.

The technique illustrated inFIG.6includes forming substrate layer320defining surface322(602). In some examples, forming substrate layer320may include forming surface features in substrate layer320, such as, for example, optical barriers330, by, for example, machining, laser etching, or chemical etching. In some examples, forming substrate layer320may include forming a plurality of regions each associated with substrate layer of a respective medical device.

The technique illustrated inFIG.6also includes depositing optical mask318on at least a portion of surface322to define surface326opposite surface322(604). Depositing optical mask318may include metallizing surface322by, for example, sputtering, chemical vapor deposition, physical vapor deposition, sputtering, thermal spraying, cold spraying, or the like. In some examples, depositing optical masking318may include sputtering columnar titanium oxide directly onto surface322(e.g., nominal thickness within a range from about 250 nm to about 500 nm), and optionally dry etching optical mask318to pattern surface326. In some examples, depositing optical mask318may include polishing at least a portion of surface326or etching at least a portion of optical mask318.

In some examples, the technique ofFIG.6may include depositing interconnect layer324on surface326(606). In some examples, depositing interconnect layer324may include metallizing surface326by, for example, chemical vapor deposition, physical vapor deposition, sputtering, thermal spraying, cold spraying, or the like. In some examples, depositing interconnect layer324may include polishing or etching at least a portion of interconnect layer324.

The technique illustrated inFIG.6also includes positioning light sources312, reference electrode314, and test optical beacon316on interconnect layer324(608). For example, as discussed above forming optical mask318and/or interconnect layer324may include forming apertures, which may be sized to receive one or more components of optical sensor102.

Optionally, the technique may include forming antenna306and/or electrode layer307on substrate layer320. In some examples, forming antenna306and/or electrode layer307may include metallizing surface321by, for example, chemical vapor deposition, physical vapor deposition, sputtering, thermal spraying, cold spraying, or the like. Additionally, the technique may optionally include etching at least a portion of antenna306and/or electrode layer307.

After positioning light sources312and photodetectors344and364, the technique may include forming fluorophores342and362on surface321of substrate layer320(610). Forming fluorophores342and362may include, for example, spray coating, spin coating, slot coating, or dip coating.

After forming fluorophore362, the technique may include forming reagent substrate360on fluorophore362(610). Forming reagent substrate360may include, for example, spray coating, spin coating, slot coating, or dip coating. In examples in which fluorophore362and reagent substrate360include a single layer, the technique may include forming fluorophore362with reagent substrate360.

In some examples, forming an optical sensor, as illustrated inFIG.6, may be performed as part of a technique of forming a medical device.

FIG.7is a flow diagram illustrating an example technique of forming a medical device including an optical sensor, processing circuitry, an antenna, and a power source. Although the technique illustrated inFIG.7will be described with respect to medical device100illustratedFIG.1, in some examples, the technique illustrated inFIG.7may be used to form other medical devices, including, but not limited to, medical devices200and300illustrated inFIGS.2and3.

The technique illustrated inFIG.7includes forming optical sensor302(702). Prior to forming optical sensor302, subsequent to forming optical sensor302, or together with forming optical sensor302, the technique includes forming circuitry on substrate layer320(704). In some examples, forming circuitry on substrate layer320may include forming a conductive circuit pattern on or in interconnect layer324. In some examples, forming circuitry may include positioning a plurality of integrated chips on substrate layer320and/or interconnect layer324. In some examples, each of the plurality of integrated chips may be positioned at correspond die locations on substrate layer320. In some examples, a plurality of consecutive layers of a plurality of integrated chips may be positioned on substrate layer320. For example, each consecutive layer of the plurality of consecutive layers may include one or more of processing circuitry104, storage components188, and communicant circuitry190. Forming medical device300using consecutive layers may reduce a surface area of medical device300to facilitate implanting medical device300and/or improve patient comfort. In some examples, the circuitry may include individual circuit layouts (which are the same or substantially similar) for each respective die location (i.e., each respective medical device300of a plurality of medical devices). The circuitry for each die location includes electrically conductive traces, contact pads, and features designed for compatibility with the multilayer component stack to be mounted to the die location. Forming a plurality of medical devices may reduce manufacturing cost and/or time.

The technique ofFIG.7also includes forming a power source (e.g., power source108) (706). In some examples, forming power source108may include forming power source108on substrate layer320. In some examples, forming power source108may include operatively coupling power source108to the circuitry, such as optical sensor102, processing circuitry104, storage components188, or communicant circuitry190. In some examples, forming power source108on substrate layer320may include positioning a plurality of power sources on substrate layer320, the plurality of power sources corresponding to a respective die location or respective medical device.

The technique also includes forming housing310and antenna306(708). For example, substrate320, optical sensor302, power source108, and associated circuitry may be disposed at least partially within housing310. In some examples, antenna306may be formed on at least a portion of housing310, and operatively coupled to the circuitry of medical device300. In some examples, forming housing310may include forming a seal between one or more components of housing310and or components of medical device300, such as components of optical sensor302. The seal may be hermetic or non-hermetic. In examples in which the seal is hermetic, medical device100may have improved performance, improved device longevity, or both. In some examples, housing310may be attached to substrate layer320and/or other components of medical device300using an adhesive, epoxy, or other bond material. In this way, housing310may be configured to encapsulate components of medical device300. In some examples, housing310may be configured to dissipate heat produced by components of medical device300(e.g., at power source108). For example, housing310may include one or more baffles configured to improve heat transfer from power source108to an environment surrounding medical device100(e.g., sample fluid101). By placing the cap wafer on power source108, medical device100may reduce exposure of a patient to power source108.

FIG.8is a flow diagram illustrating an example technique of detecting a concentration of an analyte. Although the technique illustrated inFIG.8will be described with respect to medical device100illustrated inFIG.1, in some examples, the technique illustrated inFIG.8may use other medical devices or other optical sensors to detect a concentration of an analyte, including, but not limited to, medical devices200and300illustrated inFIGS.2and3.

The technique illustrated inFIG.8includes emitting, by a light source112of an optical sensor102, a selected wavelength or wavelength range of radiation (802). As discussed above, light source112may include one or more LEDs, and emitting the radiation may include emitting from the one or more LEDs one or more wavelengths of radiation within a range from about 500 nm to about 680 nm. In some examples, the radiation may have a wavelength of about 590 nm, which can allow for less complex circuitry relative to, for example, LEDs configured to emit light having a wavelength greater than 590 nm. In some examples, processing circuitry104may be configured to control a timing of light pulse emitted by light source112, such as a duration of pulse and/or a period of time between pulses.

The technique also includes detecting, by a photodetector (e.g., photodetector344) of optical sensor102, a first fluorescence emitted by a first fluorophore (e.g., fluorophore342) of reference optical beacon114of optical sensor102in response to absorption of the radiation emitted by light source112(804). As discussed above, the first fluorescence is based on a first concentration of a substance proximate reference optical beacon114. In some examples, the detecting may include storing, on a first capacitor, an electrical charge generated by the photodetector in response to the first fluorescence.

The technique also includes detecting, by a photodetector (e.g., photodetector364), a second fluorescence emitted by a second fluorophore (e.g., fluorophore362) of test optical beacon116of optical sensor102in response to absorption of the radiation emitted by light source112(806). As discussed above, the second fluorescence is based on a second concentration of the substance proximate test optical beacon116. In some examples, the detecting may include storing, on a second capacitor, a second electrical charge generated by the photodetector in response to the second fluorescence. Additionally, test optical beacon116includes a reagent substrate (e.g., reagent substrate360) that is configured to react with an analyte proximate the reagent substrate to produce the substance. Hence, the concentration of the substance proximate the second fluorophore is related to (e.g., proportional to) the concentration of the analyte.

Although described as including two photodetectors and, optionally, two capacitors, in some examples, optical sensor102may include a single photodetector and/or a single capacitor.

The technique also includes determining, processing circuitry104operatively coupled to optical sensor102, based on the first fluorescence and the second fluorescence, a concentration of the analyte (808). For example, determining the concentration of the analyte may include determining a difference between the first fluorescence and the second fluorescence.

In some examples, the technique may include receiving, by processing circuitry104from one or more photodetectors (e.g., photodetectors344and/or364), one or more signals indicative of a first intensity of the first fluorescence over a first duration of time and a second intensity of the second fluorescence over a second duration of time. In some examples, the first and second durations of time may be the same and/or overlap. For example, a single light pulse may be configured to be absorbed by both the first and second fluorophores. Alternatively, the first and second durations of time may be separate. The technique also may include determining, by processing circuitry104, a first integral of the first intensity over the first duration of time. The technique also may include determining, by processing circuitry104, a second integral of the second intensity over the second duration of time. As discussed above, determining the integrals of the first and second intensity may include storing, on at least one capacitor, the total electrical energy generated by the photodetector in response to the respective fluorescence. The technique also may include determining, by processing circuitry104, e.g., via signal analysis module198, a difference between the first integral and the second integral. For example, determining the difference between the first integral and the second integral may include determining, by processing circuitry104, e.g., via signal analysis module198, a difference between a first amount of energy stored on the capacitor and a second amount of energy stored on the capacitor. In some examples, the difference may be compared to predetermined values to determine a concentration of the analyte. For example, determining the analyte concentration may include, after determining a difference between the first integral and the second integral, comparing, by processing circuitry104, e.g., via signal analysis module198, the difference to predetermined differences associated with respective analyte concentration values. In some examples, the predetermined differences and respective analyte concentration values may be stored in, e.g., via signal analysis module198, one or more lookup tables. Additionally, or alternatively, determining the analyte concentration may include, after determining a difference between the first integral and the second integral, determining, by processing circuitry104, e.g., via signal analysis module198, the analyte concentration based on an algorithm.

In some examples, the technique may include alerting a user of the analyte concentration. For example, external device24may receive an indication of the analyte concentration from processing circuitry104, e.g., signal analysis module198. In examples in which external device24includes a user interface, the technique amy include causing the user interface to generate an alert representative of the concentration of the analyte. The alert may be any type of information understandable by a human or machine, such as a user or another entity.

In some examples, the technique illustrated inFIG.8may be performed while medical device100is disposed within a biological system, such as inserted within an interstitial fluid of a human patient. In some examples, the technique illustrated inFIG.8optionally includes transmitting, by antenna106operatively coupled to processing circuitry104, the determined concentration of the respective analyte to external device24. In some examples, external device24may be located outside of the biological system, such as outside of the interstitial fluid of a human patient.

The techniques described in this disclosure may be implemented, at least in part, in hardware, software, firmware or any combination thereof. For example, various aspects of the described techniques may be implemented within one or more processors, including one or more microprocessors, digital signal processors (DSPs), application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), or any other equivalent integrated or discrete logic circuitry, as well as any combinations of such components. The term “processor” or “processing circuitry” may generally refer to any of the foregoing logic circuitry, alone or in combination with other logic circuitry, or any other equivalent circuitry. A control unit including hardware may also perform one or more of the techniques of this disclosure.

Such hardware, software, and firmware may be implemented within the same device or within separate devices to support the various operations and functions described in this disclosure. In addition, any of the described units, modules or components may be implemented together or separately as discrete but interoperable logic devices. Depiction of different features as modules or units is intended to highlight different functional aspects and does not necessarily imply that such modules or units must be realized by separate hardware or software components. Rather, functionality associated with one or more modules or units may be performed by separate hardware or software components, or integrated within common or separate hardware or software components.

The techniques described in this disclosure may also be embodied or encoded in a computer-readable medium, such as a computer-readable storage medium, containing instructions. Instructions embedded or encoded in a computer-readable medium may cause a programmable processor, or other processor, to perform the method, e.g., when the instructions are executed. Computer-readable media may include non-transitory computer-readable storage media and transient communication media. Computer readable storage media, which is tangible and non-transitory, may include random access memory (RAM), read only memory (ROM), programmable read only memory (PROM), erasable programmable read only memory (EPROM), electronically erasable programmable read only memory (EEPROM), flash memory, a hard disk, a CD-ROM, a floppy disk, a cassette, magnetic media, optical media, or other computer-readable storage media. It should be understood that the term “computer-readable storage media” refers to physical storage media, and not signals, carrier waves, or other transient media.

The following examples include subject matter of the present disclosure.Example 1: A medical device comprising an optical sensor comprising a light source configured to emit radiation; a reference optical beacon comprising a first fluorophore configured to absorb at least a portion of the radiation emitted by the light source and emit, based on a first concentration of a substance proximate the reference optical beacon, a first fluorescence; a test optical beacon comprises a reagent substrate configured to react with an analyte proximate the reagent substrate to modulate a concentration of the substance; and a second fluorophore configured to absorb at least a portion of the radiation emitted by the light source and emit, based on a second concentration of the substance proximate the second fluorophore, a second fluorescence; and a photodetector configured to detect the first fluorescence and the second fluorescence; and processing circuitry operatively coupled to the optical sensor, wherein the processing circuitry is configured to: receive, from the optical sensor, one or more signals indicative of the first fluorescence and the second fluorescence; and determine, based on the one or more signals, a difference between the first fluorescence and the second fluorescence, wherein the difference is indicative of a concentration of the analyte.Example 2: The medical device of example 1, wherein the reagent substrate comprises at least one enzyme configured to react with the analyte to modulate a concentration of the substance.Example 3: The medical device of any of examples 1 and 2, wherein the substance comprises oxygen, wherein the analyte comprises glucose, and wherein the reagent substrate comprises: glucose oxidase, wherein the glucose oxidase is configured to convert the glucose into hydrogen peroxide; and catalase, wherein the catalase is configured to convert the hydrogen peroxide into oxygen.Example 4: The medical device of any of examples 1 through 3, wherein the difference between the first fluorescence and the second fluorescence comprises a difference between a first integral of a first intensity of the first fluorescence over a duration of time and a second integral of a second intensity of the second fluorescence over the duration of time.Example 5: The medical device of any of examples 1 through 4, wherein optical sensor further comprises an opaque material disposed between the reference optical beacon and the test optical beacon.Example 6: The medical device of example 5, wherein the opaque material comprises titanium nitride.Example 7: The medical device of any of examples 1 through 6, wherein the optical sensor further comprises a membrane configured to control diffusion of the analyte to the reagent substrate.Example 8: The medical device of example 7, wherein the membrane comprises a light absorptive material.Example 9: The medical device of any of examples 1 through 8, wherein the light source comprises one or more light emitting diodes configured to emit one or more wavelengths of radiation within a range from about 500 nm to about 680 nm.Example 10: The medical device of any of examples 1 through 9, wherein the first fluorophore and the second fluorophore comprise the same material.Example 11: The medical device of any of examples 1 through 10, wherein the first fluorophore and the second fluorophore comprises at least one of ruthenium-tris(4,7-diphenyl-1,10-phenanthroline) dichloride (Ru(dpp)), platinum(II) octaethylporphyrin (PtOEP), palladium(II) octaethylporphyrin (PdOEP), platinum(II)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorphenyl)-porphyrin (PtTFPP), palladium(II)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorphenyl)-porphyrin (PdTFPP), platinum(II) octaethylporphyrinketone (PtOEPK), palladium(II) octaethylporphyrinketone (PdOEPK), platinum(II) tetraphenyltetrabenzoporphyrin (PtTPTBP), palladium(II) tetraphenyltetrabenzoporphyrin (PtTPTBP), platinum(II) tetraphenyltetranaphthoporphyrin (PtPTPNP), or palladium(II) tetraphenyltetranaphthoporphyrin (PdPTPNP).Example 12: The medical device of any of examples 1 through 11, further comprising an antenna operatively coupled to the processing circuitry, wherein the antenna is configured to transmit data representative of the concentration of the analyte to an external device.Example 13: An optical sensor comprising: a light source configured to emit radiation; a reference optical beacon comprising a first fluorophore configured to absorb at least a portion of the radiation emitted by the light source and emit, based on a first concentration of a substance proximate the reference optical beacon, a first fluorescence; and a test optical beacon comprising a reagent substrate configured to react with an analyte proximate the reagent substrate to modulate a concentration of the substance; and a second fluorophore configured to absorb at least a portion of the radiation emitted by the light source and emit, based on a second concentration of the substance proximate the second fluorophore, a second fluorescence; and a photodetector configured to detect the first fluorescence and the second fluorescence, wherein the concentration of the analyte is related to a difference between the first fluorescence and the second fluorescence.Example 14: The optical sensor of example 13, wherein the reagent substrate comprises at least one enzyme configured to react with the analyte to modulate a concentration of the substance.Example 15: The optical sensor of any of examples 13 and 14, wherein the substance comprises oxygen, wherein the analyte comprises glucose, and wherein the reagent substrate comprises: glucose oxidase, wherein the glucose oxidase is configured to convert the glucose into hydrogen peroxide; and catalase, wherein the catalase is configured to convert the hydrogen peroxide into oxygen.Example 16: The optical sensor of any of examples 13 through 15, further comprising an opaque material disposed between the reference optical beacon and the test optical beacon.Example 17: The optical sensor of example 16, wherein the opaque material comprises titanium nitride.Example 18: The optical sensor of any of examples 13 through 17, wherein the optical sensor further comprises a membrane configured to control diffusion of the analyte to the reagent substrate.Example 19: The optical sensor of any of examples 13 through 18, wherein the membrane comprises a light absorptive material.Example 20: The optical sensor of any of examples 13 through 19, wherein the light source comprises one or more light emitting diodes configured to emit one or more wavelengths of radiation within a range from about 500 nm to about 680 nm.Example 21: The optical sensor of any of examples 13 through 20, wherein the first fluorophore and the second fluorophore comprise the same material.Example 22: The optical sensor of any of examples 13 through 21, wherein the first fluorophore and the second fluorophore comprises at least one of ruthenium-tris(4,7-diphenyl-1,10-phenanthroline) dichloride (Ru(dpp)), platinum(II) octaethylporphyrin (PtOEP), palladium(II) octaethylporphyrin (PdOEP), platinum(II)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorphenyl)-porphyrin (PtTFPP), palladium(II)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorphenyl)-porphyrin (PdTFPP), platinum(II) octaethylporphyrinketone (PtOEPK), palladium(II) octaethylporphyrinketone (PdOEPK), platinum(II) tetraphenyltetrabenzoporphyrin (PtTPTBP), palladium(II) tetraphenyltetrabenzoporphyrin (PtTPTBP), platinum(II) tetraphenyltetranaphthoporphyrin (PtPTPNP), or palladium(II) tetraphenyltetranaphthoporphyrin (PdPTPNP).Example 23: A method comprising: emitting, by a light source of an optical sensor, radiation; detecting, by a photodetector of the optical sensor, a first fluorescence emitted by a first fluorophore of a reference optical beacon of the optical sensor in response to absorption of the radiation emitted by the light source, wherein the first fluorescence is based on a first concentration of a substance proximate the reference optical beacon; detecting, by the photodetector, a second fluorescence emitted by a second fluorophore of a test optical beacon of the optical sensor in response to absorption of the radiation emitted by the light source, wherein the second fluorescence is based on a second concentration of the substance proximate the test optical beacon, wherein the test optical beacon comprises a reagent substrate configured to react with an analyte proximate the reagent substrate to modulate a concentration of the substance; and determining, by processing circuitry operatively coupled to the optical sensor, based on the first fluorescence and the second fluorescence, a concentration of the analyte.Example 24: The method of example 23, wherein the light source comprises one or more light emitting diodes, wherein emitting the radiation comprises emitting from the one or more light emitting diodes one or more wavelengths of radiation within a range from about 500 nm to about 680 nm.Example 25: The method of any of examples 23 and 24, wherein determining the concentration of the analyte comprises determining a difference between the first fluorescence and the second fluorescence.Example 26: The method of any of examples 23 through 25, wherein determining the concentration of the analyte comprises: receiving, by the processing circuitry from the photodetector, one or more signals indicative of a first intensity of the first fluorescence over a duration of time and a second intensity of the second fluorescence over the duration of time; determining, by the processing circuitry, a first integral of the first intensity over the duration of time; determining by the processing circuitry, a second integral of the second intensity over the duration of time; and determining by the processing circuitry, a difference between the first integral and the second integral.Example 27: The method of any of examples 23 through 26, wherein the method further comprises transmitting, by an antenna operatively coupled to the processing circuitry, the determined concentration of the analyte to an external device.Example 28: The method of any of examples 23 through 27, further includes emitting, by the light source, a first pulse of light, wherein the first fluorescence is emitted in response to the first pulse of light; and emitting, by the light source, a second pulse of light a selected duration of time after the first pulse of light, wherein the second fluorescence is emitted in response to the second pulse of light.

Various examples have been described. These and other examples are within the scope of the following claims.