Multi-analyte sensing tissue-integrating sensors
Inventors
BALACONIS, Mary K. • Nichols, Scott • GUIDRY, Sierra • Zhang, Yu • SCHWELLER, Ryan • Gamsey, Soya • CLARY, Jacob William • PRADHAN, Sulolit • Wisniewski, Natalie
Assignees
Publication Number
US-11903702-B2
Publication Date
2024-02-20
Expiration Date
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Abstract
Some embodiments described herein relate to a sensor that includes a first a first polymer-luminescent sensing compound configured to produce a first luminescent signal in the presence of a first analyte and a second polymer-luminescent sensing compound configured to produce a second luminescent signal in the presence of a second analyte. The second luminescent signal can have a luminescent lifetime that is at least 1.1 times greater than a luminescent lifetime of the first luminescent signal. Such temporally differences in signal can be used to deconvolute the first luminescent signal from the second luminescent signal even when, for example, the first luminescent signal and the second luminescent signal have the same or a similar emission spectrum.
Core Innovation
Some embodiments described herein relate to a sensor that includes a first polymer-luminescent sensing compound configured to produce a first luminescent signal in the presence of a first analyte and a second polymer-luminescent sensing compound configured to produce a second luminescent signal in the presence of a second analyte. The second luminescent signal can have a luminescent lifetime that is at least 1.1 times greater than a luminescent lifetime of the first luminescent signal, and such temporal differences in signal can be used to deconvolute the first luminescent signal from the second luminescent signal even when the first luminescent signal and the second luminescent signal have the same or a similar emission spectrum.
A need exists for implantable sensors capable of detecting more than one analyte because it is difficult or impossible to detect more than one analyte using existing sensors and a particular challenge exists in deconvoluting signals associated with the different analytes detected by a sensor. Additionally, a polymer scaffold suitable for one luminescent sensing compound may not be suitable for a luminescent sensing compound configured to detect another analyte, and embodiments relate to combinations of luminescent sensing compounds and polymers particularly well suited to improve luminescent sensing compound performance and suitable for use as part of a multi-analyte sensing sensor.
The disclosure describes that polymer-dye formulations can alter a luminescent sensing compound's intensity and/or lifetime and that by selecting dye-polymer combinations the emission duration of a luminescent sensing compound can be tuned to be more easily detected and to improve the ability to deconvolute signals associated with multiple analyte-sensing luminescent sensing compounds. Embodiments include sensors formed with multiple dye-polymer portions (including single-dye formulations with different polymer portions) such that luminescent signals emitted from different portions have different temporal signatures that can be deconvoluted by a reader.
Claims Coverage
This patent includes six identified independent claims; the inventive features focus on polymer-luminescent sensing compounds/dye formulations that produce overlapping spectral signals distinguishable by differing luminescent lifetimes, and on a method of formulating such compounds.
Polymer-luminescent sensing compounds with overlapping spectra and differing lifetimes
A first polymer-luminescent sensing compound including a first polymer and a dye configured to produce a first luminescent signal in the presence of a first analyte, and a second polymer-luminescent sensing compound including a second polymer and the dye configured to produce a second luminescent signal in the presence of a second analyte, wherein a spectrum of the second luminescent signal overlaps a spectrum of the first luminescent signal and the second luminescent signal has a longer luminescent lifetime than the first luminescent signal.
Fluorescent dye in different polymer matrices to distinguish analytes by lifetime
A first polymer-luminescent compound including a first polymer and a fluorescent dye configured to emit light in an emission spectrum in response to being excited with light having an excitation frequency and produce a first luminescent signal in the presence of a first analyte; and a second polymer-luminescent compound including a second polymer and the fluorescent dye configured to produce a second luminescent signal in the presence of a second analyte, wherein a spectrum of the second luminescent signal overlaps a spectrum of the first luminescent signal and the second luminescent signal has a longer luminescent lifetime than the first luminescent signal.
Polymer alters temporal characteristics of fluorescent dye
A first polymer-luminescent compound including a first polymer and a fluorescent dye configured to emit light in an emission spectrum in response to being excited with light and a second polymer-luminescent compound including a second polymer and the fluorescent dye, wherein at least one of the first polymer or the second polymer is configured to alter temporal characteristics of the fluorescent dye such that the second luminescent signal has a longer lifetime than the first luminescent signal.
Common spectral signature with differing lifetimes
A first polymer-luminescent sensing compound configured to produce a first luminescent signal in the presence of a first analyte and a second polymer-luminescent sensing compound configured to produce a second luminescent signal in the presence of a second analyte, wherein the first luminescent signal and the second luminescent signal have a common spectral signature and the second luminescent signal has a longer luminescent lifetime than the first luminescent signal.
Oxygen-sensitive dye used for oxygen and other analytes via lifetime differences
A first polymer-luminescent sensing compound including an oxygen-sensitive dye configured to produce a first luminescent signal in the presence of oxygen and a second polymer-luminescent sensing compound including the oxygen-sensitive dye configured to produce a second luminescent signal in the presence of an analyte selected from glucose, lactate, alcohol, ascorbate, histamine, cholesterol, and pyruvate, wherein a spectrum of the second luminescent signal overlaps a spectrum of the first luminescent signal and the second luminescent signal has a longer luminescent lifetime than the first luminescent signal.
Formulation method to produce polymer-luminescent compounds with differing lifetimes
Formulating a first polymer-luminescent sensing compound by polymerizing a fluorescent dye with at least one of a first monomer, a first crosslinker, or a first polymer such that the first polymer-luminescent sensing compound produces a first luminescent signal in the presence of a first analyte, and formulating a second polymer-luminescent sensing compound by polymerizing the fluorescent dye with at least one of a second monomer, a second crosslinker, or a second polymer such that the second polymer-luminescent sensing compound produces a second luminescent signal in the presence of a second analyte, the second luminescent signal having a longer luminescent lifetime than the first luminescent signal.
The independent claims cover sensors and formulation methods in which the same or similar spectral emission signals from dye-containing polymeric sensing compounds are rendered distinguishable by engineering different luminescent lifetimes via selection or variation of polymers, monomers, or crosslinkers, and apply this approach to oxygen and other analytes and to layered or multiplexed sensor architectures.
Stated Advantages
Enables deconvolution of multiple analyte signals based on temporal differences even when emission spectra overlap.
Permits tuning of luminescent intensity and lifetime through polymer-dye formulation to improve sensing performance.
Reduces the risk that a more intense dye will wash out a less intense dye by adjusting dye-polymer formulations to produce comparable intensities and differing temporal signatures.
Facilitates multi-analyte sensing (e.g., 2-plex, 4-plex, 9-plex) using combinations of dyes and polymers with distinguishable temporal and/or spectral characteristics.
Documented Applications
Implantable tissue-integrating sensors for monitoring analyte levels in the body of a human or animal patient or subject, including subcutaneous implantation and optical readout from the skin surface.
Multi-analyte sensors for measuring oxygen and other analytes such as glucose, lactate, and pyruvate, including a 2-plex glucose and O2 sensor.
4-plex sensors configured to measure O2, glucose (using glucose oxidase), lactate (using lactate oxidase), and pyruvate (using pyruvate oxidase).
9-plex sensor designs using multiple O2-sensitive porphyrin dyes and multiple polymers to multiplex detection of analytes such as alcohol, bilirubin, lactate, ascorbate, cholesterol, glucose, histamine, and pyruvate.
Use with an external optical detector/reader placed on the skin that illuminates the sensor and detects emission light for temporal deconvolution and analyte quantification.
Layered and dual-sensor configurations such as lactate/O2 layered sensors and oxygen/oxygen sensor pairs with passive coatings and reference layers.
Incorporation of dye-containing particles into host polymers to form particle-based sensing elements for inclusion in sensors.
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