Near-IR glucose sensors
Inventors
Gamsey, Soya • BERNAT, Viachaslau • KUTYAVIN, Alex • CLARY, Jacob William • PRADHAN, Sulolit
Assignees
Publication Number
US-10717751-B2
Publication Date
2020-07-21
Expiration Date
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Abstract
The present disclosure provides polymerizable luminescent dyes useful for incorporation into polymers. The dyes and the polymers can be used in sensing and imaging applications, for example, to provide accurate and optionally long term measurements of glucose in vivo. The present disclosure also provides sensors including the polymers described herein. The sensors can be implanted into a tissue of a subject and used for long-term or short-term continuous and semi-continuous collection of data of various biochemical analytes, optionally without the use of implantable hardware of any type and/or enzymatic and electrochemical detection methods.
Core Innovation
The disclosure provides polymerizable luminescent dyes useful for incorporation into polymers, and polymers including covalently attached residues of the dyes, which are useful in sensing and imaging applications to provide accurate and optionally long term measurements of glucose in vivo. The disclosure also provides sensors including the polymers described herein that can be implanted into a tissue of a subject and used for long-term or short-term continuous and semi-continuous collection of data of various biochemical analytes, optionally without the use of implantable hardware of any type and/or enzymatic and electrochemical detection methods.
The technical background describes a need for a better long-term, minimally invasive glucose-monitoring system because current methods are expensive, cumbersome, time consuming, and do not provide accurate, real-time blood glucose concentration information. Monitoring non-invasively through the skin requires dyes with excitation and emission wavelengths in the optical window of the skin (approximately 550 to 1100 nm) to minimize light scattering and absorbance and to achieve a high signal-to-noise ratio, and current dyes require excitation with light which is largely absorbed by the skin and underlying tissue; additionally, presently available sensors are made of rigid materials that differ from tissue mechanical properties, are bulky, and induce biological events that culminate in formation of a fibrous capsule.
A central inventive aspect is a set of compounds of Formulae I-IIIH and related structures that include one or more near-infrared (NIR) dye moieties and one or more polymerizable moieties, polymers comprising residues of such compounds (including luminescent biocompatible hydrogels), and luminescent sensors that incorporate the polymers. The sensors can be tissue-integrating or include a tissue-integrating scaffold, produce a detectable signal in the presence of the analyte, and can be formed in various shapes and sizes for in vivo or in vitro detection of analytes such as glucose.
Claims Coverage
Four inventive features are identified corresponding to the independent claims: a compound of Formula I, a polymer comprising residues of the compound, a sensor comprising the polymer, and a method of measuring blood glucose using the sensor.
Compound of Formula I
A compound of Formula I (or an isomer, tautomer, or salt thereof) that includes one or more NIR dye moieties and one or more polymerizable moieties, wherein the dotted lines denote a bond or absence of a bond and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, L1, L2, and L3 are as defined in the specification.
Polymer comprising residues of the compound
A polymer comprising one or more residues of a compound of Formulae I-IIIH, wherein the polymers can be luminescent biocompatible hydrogels and include covalently attached residues of the polymerizable luminescent dyes.
Sensor comprising the polymer
A sensor for detecting an analyte comprising a polymer that includes one or more residues of a compound of Formulae I-IIIH, the sensor optionally being tissue-integrating and producing a detectable signal in the presence of the analyte when placed or implanted into tissue.
Method of measuring blood glucose using implanted sensor
A method comprising implanting a sensor that comprises a polymer including residues of the compound into subcutaneous tissue of a mammalian subject; measuring at least one wavelength of light in the glucose-concentration-dependent luminescent signal from the sensor with a detector to produce a detected luminescent signal; and processing the detected luminescent signal to produce a glucose concentration.
The independent claims cover (1) compounds of Formula I-IIIH that couple NIR dye moieties with polymerizable moieties, (2) polymers comprising residues of those compounds (including luminescent hydrogels), (3) sensors incorporating such polymers for analyte detection, and (4) a method of measuring blood glucose by implanting and optically interrogating such a sensor.
Stated Advantages
Excitation and emission wavelengths in the optical window of the skin (approximately 550 nm to 1100 nm) allowing detection of analytes deep within a tissue or an organ.
High signal-to-noise ratio.
Large Stokes shifts and emission.
Photostability, e.g., the dyes and/or polymers do not undergo rapid photobleaching.
Sensors generate stable signal over long periods of time (examples given include greater than a week up to greater than 6 months).
Sensors that are placed or implanted and integrate into the subject's tissue (e.g., through tissue and/or capillary in-growth) and accurately assess analyte concentration for long periods of time.
Devices can be implanted through syringe injection or trocar injection, do not include sensor electronics in the body, and can have small dimensions for increased patient comfort.
Documented Applications
Sensing and imaging applications, for example to provide accurate and optionally long term measurements of glucose in vivo.
Sensors implanted into tissue of a subject for long-term or short-term continuous and semi-continuous collection of data of various biochemical analytes, optionally without implantable hardware and/or enzymatic and electrochemical detection methods.
Luminescent sensors in forms such as powder, fabric (e.g., bandage), needle, rod, disk, or other suitable forms for in vitro or in vivo analyte detection.
Tissue-integrating sensors or sensors that include a tissue-integrating scaffold to provide detection of analytes when implanted into tissue.
Multi-analyte sensing where glucose is one of two or more analytes detected by the polymer scaffold (e.g., detection of oxygen, reactive oxygen species, glucose, lactate, pyruvate, cortisol, creatinine, urea, ions, hormones, pH, cytokines, insulin, small molecule drugs, and the like) as explicitly listed.
A method of measuring blood glucose concentration in a mammalian subject by implanting the sensor in subcutaneous tissue and optically measuring a glucose-concentration-dependent luminescent signal.
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