Intrinsic fluorescence generation using exogenous fluorescent agents

Abstract

Methods, systems, and apparatus for determining glomerular filtration rate (GFR) by acquiring a measurement dataset. Furthermore, this disclosure includes: acquiring a measurement dataset comprising multiple measurement entries acquired before and after administration of an exogenous fluorescent agent; generating an intrinsic fluorescence (IF) signal, the IF signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent within a diffuse reflective medium; determining whether the IF signal includes a portion of early fluorescence data; after determining this portion of the early fluorescence data, identifying an operable IF signal range by filtering the IF signal associated with the early fluorescence data; determining a GFR value in the patient based on the rate of change of the operable IF signal; and providing the GFR value.

Description

Technical Field

[0001] This disclosure generally relates to operable intrinsic fluorescence signals, including modulation based on early fluorescence data. Background Technology

[0002] Monitoring biological parameters in critically ill or injured patients is important. Organ function can be impaired due to organ damage, aging, underlying diseases, and others. Assessing organ function allows for the identification of organ damage and / or organ failure. Attached Figure Description

[0003] Details of one or more aspects of the subject matter described in this disclosure are set forth in the accompanying drawings and the following description. However, the drawings illustrate only some typical aspects of this disclosure and should therefore not be considered as limiting the scope of this disclosure. Other features, aspects, and advantages will become apparent from the description, drawings, and claims.

[0004] In order to describe the ways in which the foregoing enumerations and other advantages and features of this disclosure can be obtained, a more specific description of the principles briefly described above will be presented by referring to specific examples of this disclosure illustrated in the accompanying drawings. It should be understood that these figures depict only exemplary examples of this disclosure and should therefore not be considered as limiting the scope of this disclosure; the principles herein are described and explained with additional specificity and detail using the accompanying drawings, in which: Figure 1 This is a schematic diagram of a single-light source monitoring device in one aspect; Figure 2 The illustration shows irradiation from a light source and an exogenous fluorescent agent, as well as detection performed by a first detector and a second detector; Figure 3 The illustration shows illumination from another light source and detection performed by a first detector and a second detector; Figure 4 This is a schematic diagram of a multi-source monitoring system in one aspect; Figure 5 An example of a sensor head with one or more sources and two detectors is illustrated. Figure 6 yes Figure 5 An exploded view of the inner housing of the sensor head shown; Figure 7 It is a summary of the absorption, transmission, and emission spectra of various devices, materials, and compounds associated with non-invasive monitoring of exogenous fluorescent agents in the light wavelength range of approximately 430 nm to approximately 650 nm. Figure 8 These are representative intrinsic fluorescence signal measurements (IF) obtained before and after the administration of exogenous fluorescent agents, detected by a renal monitoring device. agent(a graph of curves); Figure 9 The diagram illustrates a flowchart corresponding to a method for determining glomerular filtration rate (GFR) using exogenous fluorescent agents. Detailed Implementation

[0005] The various examples of this disclosure are discussed in detail below. While specific implementations are discussed, it should be understood that this is for illustrative purposes only. Those skilled in the art will recognize that other components and configurations can be used without departing from the spirit and scope of this disclosure. Therefore, the following description and figures are illustrative and should not be construed as limiting. Numerous specific details are described to provide a thorough understanding of this disclosure. However, in some cases, well-known or conventional details have not been described to avoid obscurity. A reference to an example or an example in this disclosure may be a reference to the same example or any example; and such a reference implies at least one of the examples.

[0006] The reference to "an example" or "a single example" means that a particular feature, structure, or characteristic described in connection with that example is included in at least one example of this disclosure. The phrase "in an example" appearing throughout the specification does not necessarily refer to the same example in all instances, nor is it a separate or alternative example mutually exclusive with other examples. Furthermore, the description may depict various features that can be shown through some examples but not through others.

[0007] The terms used in this specification generally have their ordinary meaning in the field, in the context of this disclosure, and in the specific context in which each term is used. Alternative language and synonyms may be used for any one or more of the terms discussed herein, and should not be given any special meaning regardless of whether the term is elaborated or discussed herein. In some cases, synonyms for certain terms are provided. The listing of one or more synonyms does not preclude the use of other synonyms. Examples used anywhere in this specification (including examples of any terms discussed herein) are merely illustrative and are not intended to further limit the scope and meaning of this disclosure or any of the example terms. Similarly, this disclosure is not limited to the individual examples given in this specification.

[0008] This disclosure is not intended to limit the scope of the invention. Examples of instruments, apparatus, methods, and related results based on this disclosure are provided below. It should be noted that the use of headings or subheadings in the examples may be for convenience of the reader and should in no way limit the scope of the disclosure. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of conflict, this document (including the definitions) shall prevail.

[0009] Additional features and advantages of this disclosure will be set forth in the following description, and will be apparent in part from the description, or may be learned by practice of the principles set forth herein. The features and advantages of this disclosure can be realized and obtained by means of the instruments and combinations specifically pointed out in the appended claims. These and other features of this disclosure will become more fully apparent from the following description and the appended claims, or may be learned by practice of the principles set forth herein. Furthermore, unless specifically required, the order of one or more of the steps may be as described or may be rearranged.

[0010] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” or any other variation thereof are intended to cover non-exclusive inclusion. For example, a process, product, article, or apparatus that includes a list of elements is not necessarily limited to those elements, but may include other elements not expressly listed or inherent to the process, article, or apparatus. Furthermore, unless expressly stated to the contrary, “or” means inclusive or, rather than exclusive, or. For example, any of the following conditions satisfy either A or B: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); and both A and B are true (or exist).

[0011] As used herein, the term "substantially" is defined as substantially conforming to a specific size, shape, or other word modified by "substantially," such that the part does not need to be precise. For example, "substantially cylindrical" means that the object resembles a cylinder but may have one or more deviations from a true cylinder.

[0012] The term "coupled" is defined as a connection, whether direct or indirect through an intermediary component, and is not necessarily limited to a physical connection. A connection can permanently or releasably link objects together. The term "including" means "including but not limited to"; it specifically refers to members in an open-ended sense of inclusion or description of a combination, group, series, etc.

[0013] The phrase "diffuse medium" refers to any material through which light propagates, including multiple parts, particles, or molecules that can scatter, reflect, and / or absorb light as it propagates. The distribution of these multiple parts, particles, and / or molecules can be uniform or non-uniform and can vary over time.

[0014] This disclosure provides a non-invasive monitoring of biological parameters indicative of organ function in a patient based on intrinsic fluorescence (IF) signals. The disclosure utilizes unique filtering of the IF signal to determine whether the IF signal includes a portion of early fluorescence data, and, having determined this portion of early fluorescence data, identifies an operable range of IF signals by filtering the IF signal associated with the early fluorescence data. The IF signal is based on the use of an appropriate indicator administered to the patient. In one example, administration may be by injection. In another example, administration may be by ingestion. In one example, organ function is intestinal barrier function, wherein intestinal barrier function in the patient is assessed based on the IF signal. In at least one example, organ function is renal function. This disclosure improves the accuracy of calculating renal function in a patient based on IF signals.

[0015] Suitable indicator substances for the methods and apparatus described herein are disclosed in U.S. Patent Nos. 8,155,000, 8,664,392, 8,697,033, 8,703,100, 8,722,685, 8,778,309, 9,005,581, 9,283,288, 9,376,399, RE47,413, RE47,255, 10,137,207, 10,525,149, and 11,590,244, the entire contents of which are incorporated herein by reference for all purposes. In some aspects, the indicator substance is eliminated from the patient's body by glomerular filtration. In some aspects, the indicator substance is eliminated from the patient's body by glomerular filtration only. In some aspects, the indicator substance is a GFR agent.

[0016] Systems, apparatus, methods, computer-readable media, and circuits for monitoring biological parameters indicating organ function using exogenous fluorescent agents in a patient are disclosed. According to at least one example, the method includes: obtaining a measurement dataset comprising multiple measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an intrinsic fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent within a diffuse reflective medium; determining whether the IF signal includes a portion of early fluorescence data; after determining this portion of the early fluorescence data, identifying an operable IF signal range by filtering the IF signal associated with the early fluorescence data; determining a biological parameter value in the patient based on the rate of change of the operable IF signal; and providing the biological parameter value. For example, the system acquires a measurement dataset including multiple measurement entries obtained before and after administration of an exogenous fluorescent agent; generates an intrinsic fluorescence (IF) signal, which represents the detected fluorescence intensity emitted from the exogenous fluorescent agent within a diffuse reflective medium; determines whether the IF signal includes a portion of early fluorescence data; after determining this portion of the early fluorescence data, identifies the range of operable IF signals by filtering the IF signals associated with the early fluorescence data; determines the biological parameter values ​​in the patient based on the rate of change of the operable IF signals; and provides the biological parameter values.

[0017] In another example, a system is provided for determining biological parameters (e.g., glomerular filtration rate (GFR)) in a patient using an exogenous fluorescent agent. The system includes: a storage device (e.g., a memory configured to store data such as virtual content data, one or more images, etc.); and one or more processors (e.g., implemented in a circuit system), coupled to the memory and configured to execute instructions, and combined with various components (e.g., a network interface, a display, an output device, etc.) to cause the system to: obtain a measurement dataset comprising multiple measurement entries obtained before and after administration of the exogenous fluorescent agent; generate an intrinsic fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent within a diffuse reflective medium; determine whether the IF signal includes a portion of early fluorescence data; after determining this portion of the early fluorescence data, identify an operable IF signal range by filtering the IF signal associated with the early fluorescence data; determine a biological parameter value (e.g., a glomerular filtration rate (GFR) value) in the patient based on the rate of change of the operable IF signal; and provide the biological parameter (e.g., GFR) value.

[0018] According to another example, a method for determining intestinal barrier function includes: obtaining a measurement dataset comprising multiple measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an intrinsic fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent within a diffuse reflective medium; determining whether the IF signal includes a portion of early fluorescence data; after determining this portion of the early fluorescence data, identifying an operable IF signal range by filtering the IF signal associated with the early fluorescence data; determining an intestinal barrier function value in the patient based on the rate of change of the operable IF signal; and providing the intestinal barrier function value.

[0019] In another example, the system described above for determining biological parameters determines intestinal barrier function by providing an intestinal barrier function value based on the rate of change of an operable IF signal.

[0020] Figure 1 This is a schematic diagram of a system 100 for administering an exogenous fluorescent agent 112 to a patient. A light source 108 emits light 106 into the patient 104. Light 106 can be described as excitation light or an excitation source. Light 106 can also be controlled to be at a single wavelength, multiple wavelengths varying over time, or multiple wavelengths emitted simultaneously. The exogenous fluorescent agent 112 generates fluorescence 102 in response to an excitation event, which includes: an excitation wavelength... Irradiation by light 106, occurrence of enzymatic reactions, changes in local potential, and any other known excitation events associated with exogenous fluorescent agents. Light source 108 can be configured to deliver an excitation wavelength ( ) to patient 104. λ ex The excitation wavelength of the light 106 is 106. Fluorescence 102 can be generated as described above. In at least one example, the excitation wavelength of the light 106 is (…). λ ex ) and the emission wavelength of fluorescence 102 ( λ em ) can be distinguished spectrally (i.e., ( λ ex )and( λ em () sufficiently different, such that the photodetector 110 can be configured to selectively detect only fluorescence 102 by including any known optical wavelength separation device, including optical filters).

[0021] Changes in fluorescence 102 can be analyzed to obtain information about organ function in patient 104. Two non-limiting examples of organ function, as described herein, could be either renal function and / or intestinal barrier function. In one example, the rate of decrease in fluorescence 102 could be proportional to the rate of clearance of exogenous fluorescent agent 112 by one or more organs of patient 104, thereby providing a biological parameter value. In another non-limiting example, the rate of decrease in fluorescence 102 could be proportional to the rate of clearance of exogenous fluorescent agent 112 by the kidneys of patient 104, thereby providing renal function measurements including renal decay time constant (RDTC) and / or glomerular filtration rate (GFR). Additionally, this disclosure allows for the calculation of permeability or leakage measurements when measuring intestinal function.

[0022] Figure 2 The illustration shows a light source 108 in the form of an excitation light-emitting diode (LED) 321 in the presence of an exogenous phosphor 112. The excitation LED 321 can emit light of one or more different excitation wavelengths. In one example, the excitation wavelength can be blue light. In other examples, the excitation wavelength can be both blue and green light. In other examples, the excitation wavelength can be selected based on a selected exogenous phosphor 112. The photodetector 110 can be in the form of a first photodetector 322 and a second photodetector 323. As shown, the first photodetector 322 can receive a first signal labeled SPM1, and the second photodetector 323 can receive a second signal labeled SPM2. In at least one example, the first photodetector 322 and the second photodetector 323 can be silicon photomultiplier tubes. While the photodetectors 322 and 323 can take many different forms, silicon photomultiplier tubes and / or photodiodes can provide the desired characteristics for performing measurements to achieve the accuracy expected in those measurements.

[0023] Additionally, filter 324 can be configured to filter out light before the second detector 323 receives it. Filter 324 can be configured to substantially or completely block the excitation light wavelength. Additionally, filter 324 can be configured to allow light emitted from the exogenous phosphor to pass through substantially unimpeded. In the example shown, the excitation light wavelength can be a blue wavelength, and filter 324 can be configured to allow green light to pass through. As a result, the first detector 322 is configured to measure the light received at both the excitation and emission wavelengths, and the second detector 323 is configured to detect only the light received at the emission wavelength. By combining alternating sequences of light at the excitation wavelength and light at the emission wavelength only, irradiating tissue 320 of patient 104, measurements from the first detector 322 and the second detector 323 can be analyzed, as described in U.S. Patent Nos. 10,548,521, 10,980,459, 10,952,656, 11,478,172, and 10,194,854, to measure the fluorescence of an exogenous fluorophore, and the fluorescence measurements are corrected by removing the effects of autofluorescence, excitation wavelength light leakage, and diffuse reflection of light according to the correction methods described therein. While the example shown includes only a single filter 324, additional filters may be configured in the example to filter the light before the first photodetector 322. In other examples, a single filter may be positioned before the first photodetector 322 instead of the second photodetector 323.

[0024] An excitation LED 321 (e.g., a blue LED) can emit light 325 directed towards the exogenous fluorescent agent 112. Additionally, the light emitted from the excitation LED 321 can travel through the patient 104, causing the patient's tissue 320 to act as diffuse light. This diffuse light can be referred to as a diffuse reflection (DR) signal. Furthermore, the light 325 striking the exogenous fluorescent agent 112 and the fluorescence emission (Flr) signal 334 travel to detectors 322 and 323. As shown, the first detector 322 receives a DR signal 333 labeled DRex1 and an Flr signal 332 labeled Flr1, and the second detector 323 receives a DR signal 335 labeled DRex2 and an Flr signal 334 labeled Flr2. Flr signals 332 and 334 include contributions from the exogenous fluorescent agent 112 and tissue autofluorescence. These measurements are used to derive the intrinsic fluorescence (IF) signal of the fluorescent agent alone, as described herein.

[0025] Figure 3The illustration shows a light source 108 in the form of another light-emitting diode (LED) 341. In one example, the other LED 341 may be a green LED. In other examples, the other LED 341 may be another type of LED that provides light with a wavelength different from that of the excitation LED 321. In one example, the other LED 341 may be operable to emit light with a wavelength substantially the same as that emitted from an exogenous agent. In other examples, a single LED capable of emitting light of various wavelengths may be implemented. The light emitted from the other LED 341 can travel through the patient 104, causing the patient's tissue 320 to act as diffuse light. The diffuse light may be referred to as a DR signal, as described herein. As shown, a first detector 322 receives a DR signal 342 labeled DRem1, and a second detector 323 receives a DR signal 344 labeled DRem2. Figure 2 In this context, a filter 324 can be implemented. This filter can be used with... Figure 2 The same applies to the previous example. Although the other LED 341 and the excitation LED 321 are indicated to be separate from each other, the other LED 341 and the excitation LED 321 can be coupled to each other. Although the example shown includes only a single filter 324, in this example, additional filters can be configured to filter the light before the first detector 322. In other examples, a single filter can be placed before the first detector 322 instead of the second detector 323.

[0026] Figure 4 This is an example schematic diagram of an organ monitoring system 200. The system may include a controller 212, which includes a processor 238 and a memory 242. The controller 212 may be coupled to one or more sensor heads 204. Each sensor head may include a first light source 218 and a second light source 220. The first light source 218 may be an excitation LED as indicated above. The second light source 220 may be another LED as indicated above. In other examples, the excitation LED may be the second light source 220, and the other LED may be the first light source 218. A first filter 246 and a second filter 244 are included, as shown. In other examples, only one of the first filter 246 and the second filter 244 may be implemented, such as for... Figure 2 and Figure 3As described, the sensor head 204 may optionally include one or more temperature sensors 228. The one or more temperature sensors 228 may collect data simultaneously with the first photodetector 222 and / or the second photodetector 224. The one or more temperature sensors 228 may be used to determine characteristics associated with the first photodetector 222 and / or the second photodetector 224. Additionally, the one or more temperature sensors 228 may be arranged to provide information about the patient 202. While the illustrated example includes a controller 212 separate from the sensor head 204, in other examples, the controller 212 and the sensor head 204 may be part of a single unit without being wired or wirelessly coupled.

[0027] The first light source 218 and the second light source 220 can be configured to emit light into the patient 202. The light can diffuse within the patient, and a portion of the light is received at the first photodetector 222, and / or a portion of the light is received at the second photodetector 224. Data acquired by the first photodetector 222 and / or the second photodetector 224 can be transmitted to the controller 212. The data can be stored in the memory 242 or another storage device in which the controller communicates electronically.

[0028] Processor 238 may be operable to execute one or more instructions according to the methods described herein. Processor 238 may be operable to calculate biological parameter values. In one example, the biological parameter value may be one or more of GFR and / or RDTC. In other examples, the biological parameter value may be a parameter describing intestinal wall permeability and / or leakage.

[0029] In each aspect, the first light source 218 and the second light source 220 can be any light source configured to deliver light at both the excitation and emission wavelengths. Typically, the first light source 218 delivers light with an intensity sufficient to penetrate the patient's tissue 202 to reach the exogenous fluorophore, thereby ensuring that the remaining intensity is sufficient to induce fluorescence at the emission wavelength by the exogenous fluorophore. However, the intensity of the light delivered by the first light source 218 is limited to an upper limit to prevent adverse effects such as tissue burns, tissue tanning, cell damage, and / or photobleaching of the exogenous fluorophore and / or endogenous chromophores (“autofluorescence”) in the skin.

[0030] Similarly, the second light source 220 is configured to deliver light of an emission wavelength sufficient to utilize the energy of the exogenous fluorophore that propagates through the first region of the patient and exits from the second and third regions, such that the remaining intensity is sufficient to be detected by the first photodetector 222 and the second photodetector 224, respectively. Like the first light source 218, the intensity of the light produced by the second light source 220 is limited to an upper limit to prevent adverse effects such as tissue burns, tissue tanning, cell damage, and / or photobleaching of exogenous fluorophores and / or endogenous chromophores (“autofluorescence”) in the skin.

[0031] In all aspects, the first light source 218 and the second light source 220 can be any light source suitable for use with a fluorescence medical imaging system and apparatus. Non-limiting examples of suitable light sources include: LEDs, diode lasers, pulsed lasers, continuous-wave lasers, xenon arc lamps or mercury vapor lamps with excitation filters, lasers, and supercontinuum light sources. In one aspect, the first light source 218 and / or the second light source 220 can produce light with a narrow spectral bandwidth suitable for monitoring the concentration of exogenous phosphors using the methods described herein. In another aspect, the first light source 218 and the second light source 220 can produce light with a relatively wide spectral bandwidth.

[0032] In one aspect, the selection of the intensity of light generated by the first light source 218 and the second light source 220 by system 200 may be influenced by any one or more of at least several factors, including but not limited to the maximum permissible exposure (MPE) of skin to a laser beam according to applicable regulatory standards (such as ANSI Standard Z136.1). In another aspect, the light intensity for system 200 may be selected to reduce the likelihood of photobleaching of exogenous fluorescent sources and / or other chromophores within the patient 202 tissue, including but not limited to: collagen, keratin, elastin, hemoglobin in erythrocytes, and / or melanin in melanocytes. In yet another aspect, the light intensity for system 200 may be selected to extract detectable fluorescence signals from exogenous fluorescent sources within the patient 202 tissue and from the first photodetector 222 and / or the second photodetector. In another aspect, the light intensity of system 200 can be selected to provide appropriately high light energy while reducing power consumption, suppressing heating / overheating of the first light source 218 and the second light source 220, and / or reducing the time the patient's skin is exposed to light from the first photodetector 222 and / or the second photodetector.

[0033] In various aspects, the intensity of the first light source 218 and the second light source 220 can be modulated to compensate for any one or more of at least several factors, including but not limited to: individual differences in chromophore concentration within the patient 202, such as variations in skin pigmentation. In various other aspects, the detection gain of the photodetector can be modulated to similarly compensate for variations in individual differences in skin properties. In one aspect, variations in skin pigmentation may exist between two different individual patients 202 or between two different locations on the same patient 202. In one aspect, light modulation can compensate for variations in the optical path taken by light through the tissue of the patient 202. The optical path may vary due to any one or more of at least several factors, including but not limited to: variations in the separation distance between the light source and the photodetector of the system 200; variations in the firmness of the sensor head 204 attached to the skin of the patient 202; variations in the light output of the light source due to exposure to environmental factors such as heat and moisture; variations in the sensitivity of the photodetector due to exposure to environmental factors such as heat and moisture; modulation of the duration of light source irradiation; and any other relevant operating parameters.

[0034] In various aspects, the first light source 218 and the second light source 220 can be configured to modulate the intensity of light produced as needed according to any one or more of the factors described above herein. In one aspect, if the first light source 218 and the second light source 220 are devices configured to continuously vary the output energy density as needed (e.g., LED light sources), the intensity of the light can be electronically modulated using methods including, but not limited to, modulating the potential, current, and / or power supplied to the first light source 218 and / or the second light source 220. In another aspect, the intensity of the light can be modulated using optical methods, including but not limited to: partially or completely blocking light leaving the first light source 218 and the second light source 220 using optical devices including but not limited to apertures, shutters, and / or one or more filters; and diverting the path of light leaving the first light source 218 and the second light source 220 away from a first region of the patient using optical devices including but not limited to lenses, mirrors, and / or prisms.

[0035] In various aspects, the intensity of the light produced by the first light source 218 and the second light source 220 can be modulated by controlling the laser energy density, which is defined herein as the rate of energy within the produced beam. In one aspect, the laser energy density may be limited to a range defined by safety standards, including but not limited to ANSI standards for exposure to laser energy, such as ANSI Z136.1.

[0036] In each aspect, the pulse width of the light produced by the first light source 218 and the second light source 220 can be independently selected as a duration ranging from about 0.0001 seconds to about 0.5 seconds.

[0037] Figure 5 An example of a sensor head having one or more light sources and two or more photodetectors is illustrated. As shown, a single opening 531 formed in the sensor head 510 allows light from a first light source 218 and a second light source 220 to pass through. The sensor head 510 also includes a first detector 530 and a second detector 532. A corresponding opening 531 may be formed in the sensor head 510 to allow light to reach the first detector 530 and / or the second detector 532. The second detector 532 is separated from the one or more light sources 218, 220 by a distance 534. The sensor head 510 may also include a clamp receiver 520, which is designed to be coupled to one or more components (not shown).

[0038] Figure 6 yes Figure 5 An exploded view of the inner housing 660 of the sensor head 510 shown. Figure 6 This is an isometric view of the sensor head 604a with the upper housing and various electrical components removed, exposing the inner housing 660. The inner housing 660 is housed within the housing. The inner housing 660 includes a sensor holder having a first detection recess 652, a second detection recess 650, and a light source recess 654 formed therethrough. A first photodetector 622 is mounted within the first detection recess 652, and a second photodetector 624 is mounted within the second detection recess 650. First and second light sources 618 / 620 are mounted within the light source recess 654. In one aspect, the first detection recess 652, the second detection recess 650, and the light source recess 654 of the sensor holder are optically isolated from each other to ensure that light from the light sources 618 / 620 does not reach the photodetectors 622 / 624 without being coupled through the patient's skin. The separation between the two detection recesses 652 / 650 ensures that the detected fluorescence signal from the exogenous fluorescent agent is distinguishable from the unfiltered excitation light, as described in detail above.

[0039] In one aspect, optically transparent windows 640, 642, and 644 are respectively coupled within the first detection opening, the second detection opening, and the light source opening to seal the openings, while also providing an optically transparent channel between the tissue and the interior of the sensor head 604a. Additionally, diffusers 630 and 632 are coupled above the optically transparent windows 640, 642, and 644, respectively. Diffusers 630 and 632 are configured to spatially homogenize the light delivered to the tissue by the light source 618 / 620 and to spatially homogenize the light detected by the photodetectors 622 / 624. In one aspect, an absorption filter 602a is coupled to the diffuser 630. In one aspect, an optically transparent adhesive is used to couple the absorption filter 602a to the diffuser 630.

[0040] Figure 7 This is Figure 1210, which summarizes the absorption, transmission, and emission spectra of various devices, materials, and compounds associated with non-invasive monitoring of exogenous and in vivo fluorescent agents, defined in the wavelength range of approximately 430 nm to approximately 650 nm. Through illustrative examples, Figure 7 It is a summary of one aspect ( HbO 2) and ( Hb The absorption spectrum of LED 1211 and the absorption (1214) and emission spectra of exogenous fluorescent agent relmapirazin (also known as MB-102) (1215) are plotted. The emission spectra of blue LED light source 1211 and green LED light source 1212 are also shown superimposed on the graph. Figure 7 Above other spectra. In this respect, the system may include a blue LED as a first light source 218, and the excitation wavelength of the system may be an isoabsorbance wavelength of approximately 450 nm. Figure 7 As shown, the Hb absorption spectrum is strongly tilted at the isoabsorbance wavelength from approximately 420 nm to approximately 450 nm, which indicates that ( HbO 2)(1217) and ( Hb (1216) The relative absorbance at the isoabsorbance wavelength of approximately 450 nm is sensitive to small changes in the excitation wavelength. However, at wavelengths exceeding approximately 500 nm, ( HbO 2) / ( Hb The spectrum is more gently tilted, and a wider bandwidth light source, including but not limited to LEDs with a bandpass filter 1213, can be sufficient to serve as the first light source.

[0041] In another aspect, the excitation wavelength can be selected to enhance the contrast in absorbance between the chromophore within the patient tissue and the exogenous fluorescent agent. This can be achieved through non-limiting examples, such as... Figure 7 As shown, at the isoabsorbance wavelength of 452 nm, the absorbance ratio of remimapyrazine is ( HbO 2) and ( Hb The absorbance of remimapyrazine is more than three times higher. Without being limited to any particular theory, a higher proportion of light irradiating patient tissue at a wavelength of approximately 450 nm will be compared to (…). HbO 2) and ( Hb This absorption enhances the absorption efficiency of remimapyrazine and reduces the intensity of light at the excitation wavelength required to elicit a detectable fluorescence signal.

[0042] In various aspects, the wavelength of the second absorbance can also be selected as the emission wavelength of the system. By way of non-limiting example, Figure 7 The emission spectrum of a remimapyrazine exogenous contrast agent (1215) characterized by an emission peak at approximately 550 nm is shown. In this non-limiting example, an isoabsorbance wavelength of 570 nm can be selected as the emission wavelength to be detected by a first detector and a second detector. In various other aspects, the emission wavelength of the system can be selected to fall within a spectral range characterized by the relatively low absorbance of the chromophore within the patient's tissue 202. Without being limited to any particular theory, the low absorbance of the chromophore at the selected emission wavelength can reduce the loss of light emitted by the exogenous fluorescent agent and enhance the efficiency of fluorescence detection.

[0043] Figure 8 These are representative intrinsic fluorescence signal measurements obtained before and after the administration of exogenous fluorescent agents, detected by a renal monitoring device. IF agent The curve of 1250. Figure 8 This is a graph showing fluorescence measurements obtained from the patient over a period of approximately 15 hours following the administration of an exogenous fluorophore (such as remimapyrazine) after a baseline period of approximately 1 hour (1252). The pre-administration / baseline period (1252) is characterized by relatively low and stable fluorescence levels, possibly due to the absence of the exogenous fluorophore in the patient's blood. After administration of the exogenous fluorophore at 1253, fluorescence measurements show a sharp rise to a peak concentration of 1255, followed by a relatively smooth exponential decline back to background fluorescence levels as the kidneys clear the exogenous fluorophore from the patient's blood. Without being limited to any particular theory, it is assumed that the administered exogenous fluorophore, after an exponential decrease in concentration over a certain period of time, may homogenize. Following administration of an exogenous fluorophore (such as remimapyrazine), the exogenous fluorophore undergoes an equilibrium period of diffusion from the bloodstream to the remaining extracellular tissues of the patient. Once the exogenous fluorophore has diffused into the patient's extracellular tissues and reached quasi-steady-state conditions, post-equilibrium is achieved, and the fluorescence signal can be characterized as a single exponential decay. Without being limited to any particular theory, it is assumed that the pre-equilibrium region of the measurement dataset is characterized as the time region of the IF dataset.

[0044] like Figure 8As shown, the post-application period includes a mixing and distributing portion 1254 and a renal clearance-dominant portion 1256. The area where the mixing and distributing portion 1254 contacts and / or overlaps with the renal clearance-dominant portion 1256 can be defined as the beginning of the region dominated by the single exponential decay 1257. To calculate the region dominated by the single exponential decay 1257, the following methods and apparatus can be implemented in this system.

[0045] Figure 9 A flowchart corresponding to example method 700 is illustrated. Although example method 700 depicts a specific sequence of operations, this sequence can be changed without departing from the scope of this disclosure. For example, some of the depicted operations can be performed in parallel, or in different sequences that do not substantially affect the functionality of method 700. In other examples, different components of the example apparatus or system implementing method 700 can perform their functions substantially at the same time or in a specific sequence.

[0046] Based on some examples, such as Figure 9 As depicted, method 700 includes obtaining a measurement dataset at box 702, the measurement dataset comprising multiple measurement entries obtained before and after the application of an exogenous fluorescent agent. For example, Figure 4 The system and / or device shown can acquire a measurement dataset including multiple measurement entries obtained before and after administration of an exogenous fluorescent agent. For example, the system and / or device can be used to collect data from one or more sensor heads using one or more light sources and one or more detectors. Data collection can be managed by a controller and / or processor. In at least one example, the controller and / or processor can locally store the data for processing. In another example, the data can be sent to a secure remote computer for processing. The system and / or device can be configured such that one or more sensor heads are close to or in contact with the patient whose data is being measured. The system and / or device can operate for a predetermined period of time prior to administration. An example of data collection and processing to provide results of renal function values ​​can be found in… Figure 8 The diagram in the middle is shown.

[0047] In at least one example, each of the plurality of measurement entries includes at least two measurements, one of which is a fluorescence emission (Flr) signal, and the second of which is detected by a filter detector in a region adjacent to the diffuse medium during illumination by light of an excitation wavelength on the diffuse medium. In other examples, the filter detector may be positioned such that a filter is placed in front of the photodetector to optically filter the light based on a physical filter. In other examples, the light may be filtered by processing data from the photodetector.

[0048] In another example, each of the plurality of measurement entries includes at least one measurement result of an Flr signal detected by a filter detector at the diffuse medium during illumination of the diffuse medium by excitation wavelength light, wherein generating the IF signal includes transforming the at least one measurement result according to a transformation relation comprising a mathematical equation that converts the Flr signal into an IF signal. In yet another example, each of the plurality of measurement entries includes at least one measurement signal detected by a filter detector at the diffuse medium during illumination of the diffuse medium by light with a wavelength similar to or equal to that of the exogenous phosphor.

[0049] According to some examples, the method includes generating an intrinsic fluorescence (IF) signal at box 704 representing the detected fluorescence intensity emitted from an exogenous fluorophore within a diffuse medium. For example, Figure 4 The processor of the system shown can generate an IF signal representing the detected fluorescence intensity emitted from an exogenous fluorophore within a diffuse reflective medium. In at least one example, the diffuse reflective medium is one or more portions of the patient under discussion having the properties associated with diffuse reflective media described herein. In at least one example, the generation of the IF signal involves generating the IF signal directly from measurement data. Figure 4 In some configurations of the system and / or device, the IF signal can be measured directly. In other configurations, the system and / or device can perform calculations. In other examples presented herein, the IF signal can be generated through additional calculations. In other examples, generating the IF signal involves combining at least two measurements according to a transformation relation that includes a mathematical equation that converts a fluorescence emission (Flr) signal into an IF signal. Further examples of methods for generating IF signals are described in U.S. Patent Nos. 10,548,521, 10,980,459, 10,952,656, 11,478,172, 10,194,854, and 11,602,570.

[0050] According to some examples, the method includes determining at box 706 whether the IF signal includes a portion of earlier fluorescence data. For example, Figure 4 The processor of the system shown can determine whether the IF signal includes a portion of earlier fluorescence data. This can be considered as targeting... Figure 8 An example of a method for determining kidney function values. In at least one example, the method is... Figure 9Box 706 in the figure includes determining the falling segment of the IF signal. In other examples, when determining the falling segment of the IF signal, the method may identify a predetermined fitting window. A predetermined fitting window refers to a predetermined time window such that the window has a time length set to a predetermined length. The predetermined time window may allow the predetermined time window to adjust over time. In other examples, the predetermined time window has a fixed amount of time, but the window itself can move within the data. In one aspect, when determining biological parameter values ​​of a patient's renal function, the method may further include performing a single exponential curve fitting of the IF signal according to the following formula: IF fit =C0+C1 e -t / RDTC , where IF fit This represents the fitting of a portion of IF, where C0 and C1 are curve fitting constants, t is time, and RDTC is a time parameter. Additionally, the method can calculate multiple RDTC values ​​across at least two segments within a predetermined minimum fitting window. In this example, RDTC is a parameter that can vary over time. Furthermore, the method can compare multiple RDTC values ​​from these at least two segments until all of the multiple RDTC values ​​correspond to positive values.

[0051] In at least one example used to determine renal function values, when determining whether the IF signal includes a portion of early fluorescence data, the method can identify the time at which the initial GFR occurs (t). GFRprel Preliminary GFR value at ) prel In one example, determine GFR prel This includes calculating the renal decay time constant (RDTC) through the following steps: based on determining the IF signal at t GFRprel When the preceding segment exceeds a quality threshold, an initial estimate is performed on the single exponential curve fitting of the IF signal across at least the sequential or overlapping portions of the IF signal. The method may also include determining the start time t. start The start time indicates the time during the evaluation of t. GFRprel Prior to and during the determined IF signal descent phase, the starting point of the fitting interval for the single exponential curve fitting is determined, which is the starting time t. start Multiply the first constant by the exponent of the Euler number and add the second constant (t) toeq The sum of the calculated values ​​of ); the fitting interval is set to a single exponential curve fit. In one example, once at t GFRprel GFR determined at the location prel , then determine t start , and t start It is t GFRprel Subtract time t interpol This time is using GFR prel Determined by linear interpolation between the following two: having associated time t lowLow GFR boundary (GFR low ) and / or with associated time t high High GFR boundary (GFR high ).

[0052] In another example, this method can determine the start time (t). start The start time represents a point in time prior to the single exponential curve fitting of the operable IF signal range and during the determined IF signal descent phase. In at least one example, the method sets the start point (t) of the single exponential curve fitting of the operable IF signal range. eq ), where t eq =t start +t toeq ,and = × - prel / + Where A, B, and C are constants. This method can also be based on determining the IF... fit When should the single exponential curve fit of the equation exceed the quality threshold to set t? eq The quality threshold can be a fixed value based on previous measurements. In other examples, the quality threshold is a set value. In at least one example, the method can determine the peak of the IF signal using a recursive filter. The recursive filter can be a variety of different filters. Additionally, the method can exclude data from the fit within a predetermined time period after the peak of the IF signal. The amount of data excluded from the fit can be a predetermined fixed time period. In at least one example, the fixed time period can be between ten minutes and ten hours. In other examples, the fixed time period can be between twenty minutes and five hours. In other examples, the fixed time period can be between twenty minutes and one and a half hours. In other examples, the amount of data excluded can be determined using a variable time period to determine when the data stabilizes, thereby increasing the speed of the remainder of the process.

[0053] Furthermore, this method is effective in determining GFR. prelThe estimated value of the single exponential curve fit during the determined IF signal descent phase can be determined, and the setting of the starting point for the single exponential curve fit in the measurement dataset (which occurs during or after the initial estimation of the single exponential curve fit for the measurement dataset) includes performing a reverse-look component filter. In this process, recursive or variable methods can be implemented to improve the accuracy of the overall results. A reverse-look component filter can be implemented to exclude parts of the dataset in a reverse-look manner. That is, data initially to be excluded from the calculation can be included after it has been determined to be above a threshold. For example, if the excluded data is stable, it can be included, thereby reducing the total time in the process. However, if the data does not maintain the same quality as the current data or data previously recorded for that dataset, the dataset is still excluded.

[0054] Based on some examples, the method includes Figure 9 At the location depicted in box 708, after determining a portion of the early fluorescence data, the range of operable IF signals is identified by filtering the IF signals associated with the early fluorescence data. For example, Figure 4 The processor of the illustrated system can identify a range of operable IF signals by filtering the IF signal associated with the early fluorescence data after determining a portion of the early fluorescence data. In at least one example, filtering the IF signal associated with the early fluorescence data includes omitting a portion of the early fluorescence data when generating the IF signal. In other examples, filtering the IF signal can make calculations necessary to modify the IF signal to more accurately represent the operable IF signal. In at least one example, filtering the IF signal associated with the early fluorescence data includes omitting a portion of the early fluorescence data when identifying the IF signal, such that this portion of the early fluorescence data is included in the IF signal and subsequently excluded from the operable IF signal.

[0055] Based on some examples, the method includes Figure 9 The 710 points depicted were used to determine the biological parameter values ​​in the patient based on the rate of change of an operable IF signal. For example, Figure 4 The processor of the system shown can determine the value of a patient's biological parameters based on the rate of change of an operable IF signal. In one example, the biological parameter is the glomerular filtration rate (GFR). In another example, the biological parameter is intestinal barrier function.

[0056] In at least one example, the method determines the GFR based on the rate of change of the operable IF signal after the start of a single exponential curve fitting of the operable IF signal. An example of single exponential curve fitting is explained herein. In another example, a method for determining GFR is disclosed in U.S. Patent No. 11,602,570. In at least one example, determining the GFR value includes calculating the renal decay time constant (RDTC) by performing a single exponential curve fitting of the operable IF signal across at least a sequential portion of the operable IF curve. A continuous portion of the operable IF curve refers to portions that are temporally adjacent or overlapping. In one example, single exponential curve fitting of the operable IF signal includes performing a logarithmic transformation on the operable IF signal and subsequently fitting a linear function to the logarithmically transformed operable IF signal.

[0057] This method can also determine the GFR value from the operable IF signal (t) identified in box 706. eq The method begins at the starting point of the single exponential curve fitting of the operable IF signal. Furthermore, when determining the GFR, this method can be based on the rate of change of the operable IF signal after the start of the single exponential curve fitting of the operable IF signal.

[0058] According to some examples, the method includes providing a biological parameter value at box 712. For example, Figure 4 The processor of the system shown can provide biological parameter values. In at least one example, the biological parameter value is one of GFR and / or intestinal barrier function. In at least one example, providing the biological parameter value includes displaying the biological parameter value on a display screen. In another example, providing the biological parameter value includes transmitting the biological parameter value to a remote device. In other examples, the method may include transmitting the biological parameter value to a remote device and also displaying the biological parameter value on a local display screen. The local display screen may include, for example... Figure 4 On the device shown. The local display screen can be connected to... Figure 4 The system 200 is included together with the controller 212.

[0059] The illustrative aspects of this disclosure include: Aspect 1. A method for determining glomerular filtration rate (GFR) in a patient using an exogenous fluorescent agent, the method comprising: obtaining a measurement dataset including multiple measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an intrinsic fluorescence (IF) signal representing the detected fluorescence intensity emitted from an exogenous fluorescent agent within a diffuse reflective medium; determining whether the IF signal includes a portion of early fluorescence data; after determining this portion of the early fluorescence data, identifying an operable IF signal range by filtering the IF signal associated with the early fluorescence data; determining a GFR value in the patient based on the rate of change across the operable IF signal range; and providing the GFR value.

[0060] Aspect 2. The method according to aspect 1, wherein determining whether the IF signal includes early fluorescence data includes determining the falling segment of the IF signal.

[0061] Aspect 3. The method according to aspect 2, wherein determining whether the IF signal includes early fluorescence data includes: determining the portion occurring at the initial GFR time (t GFRprel Preliminary GFR value at ) prel ), among which, GFR is determined prel This includes calculating the renal decay time constant (RDTC) through the following steps: based on determining the IF signal at t GFRprel When the preceding segment exceeds the quality threshold, an initial estimate is performed on the single exponential curve fit of the IF signal for at least the sequential or overlapping portions of the IF signal.

[0062] Aspect 4. The method according to aspect 3 further includes: determining the start time t. start The start time indicates the time during the evaluation of t. GFRprel Prior to and during the determined falling segment of the IF signal, the starting point of the fitting interval for the single exponential curve fitting of the operable IF signal is determined, which is the starting time t. start Multiply the first constant by the exponent of the Euler number and add the second constant (t) toeq The sum of the calculated values ​​of ) ; set the fitting interval to a single exponential curve fitting of the operable IF signal.

[0063] Aspect 5. According to the method described in aspect 4, wherein, once in t GFRprel The location determined GFR prel , then determine t start , and t start It is t GFRprel Subtract time t interpol This time is using GFR prel Determined by linear interpolation between the following two: having associated time t low Low GFR boundary (GFR low ) and / or with associated time t high High GFR boundary (GFR high ).

[0064] Aspect 6. The method according to aspect 3 further includes: determining a start time (t start The start time represents the point in time prior to the single exponential curve fitting of the operable IF signal and during the defined falling segment of the IF signal; it sets the starting point (t) for the single exponential curve fitting of the operable IF signal range. eq ); where t eq =t start +ttoeq ,and , where A, B and C are constants.

[0065] Aspect 7. The method according to Aspect 3, wherein determining the falling segment of the IF signal comprises: identifying a predetermined fitting window; and performing a single exponential curve fitting of the IF signal according to the following formula: IF fit =C0+C1 e -t / RDTC , where IF fit This represents the fitting of a portion of IF, where C0 and C1 are curve fitting constants, t is time, and RDTC is a time parameter; calculates the RDTC values ​​in at least two segments of a predetermined fitting window; compares the RDTC values ​​from these at least two segments until all RDTC values ​​correspond to positive values.

[0066] Aspect 8. The method according to aspect 7 further includes: determining a start time (t start The start time represents the point in time prior to the single exponential curve fitting of the operable IF signal and during the determined falling segment of the IF signal; setting the starting point (t) for the single exponential curve fitting of the operable IF signal. eq ); where t eq =t start +t toeq ,and , where A, B and C are constants.

[0067] Aspect 9. The method according to aspect 8, wherein, based on determining according to IF fit When should the single exponential curve fit of the equation exceed the quality threshold to set t? eq .

[0068] Aspect 10. The method according to aspect 8, wherein, once in t GFRprel The location determined GFR prel , then determine t start , and t start It is t GFRprel Subtract time (t) interpol (This time is using GFR) prel Determined by linear interpolation between the following two: having associated time t low Low GFR boundary (GFR low ) and / or with associated time t high High GFR boundary (GFR high ).

[0069] Aspect 11. The method according to aspect 3, wherein determining whether the IF signal includes a portion of the early fluorescence data further includes performing a reverse look-through component filter.

[0070] Aspect 12. The method according to any one of Aspects 1 to 11, wherein determining the GFR value comprises calculating the renal decay time constant (RDTC) by performing a single exponential curve fitting of the operable IF signal across at least a sequential or overlapping portion of the operable IF signal.

[0071] Aspect 13. The method according to aspect 12, wherein the single exponential curve fitting of the operable IF signal includes performing a logarithmic transformation on the operable IF signal and subsequently fitting a linear function to the logarithmically transformed operable IF signal.

[0072] Aspect 14. The method according to aspect 12, wherein, at the starting point (t) of the single exponential curve fitting of the operable IF signal eq The GFR value is determined starting at ().

[0073] Aspect 15. The method according to aspect 12, wherein the GFR value is determined based on the rate of change of the operable IF signal after the start of a single exponential curve fitting of the operable IF signal.

[0074] Aspect 16. The method according to any one of Aspects 1 to 15, wherein providing the GFR value includes displaying the GFR value on a display screen.

[0075] Aspect 17. The method according to any one of Aspects 1 to 16, wherein providing the GFR value includes transmitting the GFR value to a remote device.

[0076] Aspect 18. The method according to any one of Aspects 1 to 17, wherein generating the IF signal comprises generating the IF signal directly from the measurement data.

[0077] Aspect 19. The method according to any one of Aspects 1 to 18, wherein filtering the IF signal associated with the early fluorescence data includes omitting a portion of the early fluorescence data when generating the IF signal.

[0078] Aspect 20. The method according to any one of aspects 1 to 19, wherein each of the plurality of measurement entries includes at least two measurement results, one of which is a fluorescence emission (Flr) signal, and the second of which is a diffuse reflection signal detected by a filter detector in a region adjacent to the diffuse reflection medium during irradiation of the diffuse reflection medium with excitation wavelength light; wherein generating the IF signal includes combining the at least two measurement results according to a transformation relation comprising a mathematical equation that converts the Flr signal into an IF signal.

[0079] Aspect 21. The method according to any one of aspects 1 to 20, wherein each of the plurality of measurement entries includes at least one measurement result of a fluorescence emission (Flr) signal detected by a filter detector at the diffuse medium during irradiation of the diffuse medium by an excitation wavelength light, wherein generating the IF signal includes transforming the at least one measurement result according to a transformation relation comprising a mathematical equation that converts the Flr signal into an IF signal.

[0080] Aspect 22. The method according to aspect 21, wherein the excitation wavelength light includes the wavelength of the exogenous fluorescent agent.

[0081] Aspect 23. A method for determining biological parameters in a patient using an exogenous fluorescent agent, the method comprising: obtaining a measurement dataset including multiple measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an intrinsic fluorescence (IF) signal, the IF signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent within a diffuse reflective medium; determining whether the IF signal includes a portion of early fluorescence data; after determining this portion of the early fluorescence data, identifying an operable IF signal range by filtering the IF signal associated with the early fluorescence data; determining a biological parameter value in the patient based on the rate of change of the operable IF signal; and providing the biological parameter value.

[0082] Aspect 24. A method for determining glomerular filtration rate (GFR) in a patient using an exogenous fluorescent agent, the method comprising: obtaining a measurement dataset including multiple measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an intrinsic fluorescence (IF) signal representing the detected fluorescence intensity emitted from an exogenous fluorescent agent within a diffuse reflective medium; determining whether the IF signal includes a portion of early fluorescence data; after determining this portion of the early fluorescence data, identifying an operable IF signal range by filtering the IF signal associated with the early fluorescence data; determining a GFR value in the patient based on the rate of change across the operable IF signal range; and providing the GFR value.

[0083] Aspect 25. The method according to aspect 24, wherein determining whether the IF signal includes early fluorescence data includes determining the falling segment of the IF signal.

[0084] Aspect 26. The method according to aspect 25, wherein determining whether the IF signal includes the portion of early fluorescence data comprises: determining the portion occurring at the initial GFR time (t GFRprel Preliminary GFR value at ) prel ), among which, GFR is determined prel This includes calculating the renal decay time constant (RDTC) through the following steps: based on determining the IF signal at t GFRprelWhen the preceding segment exceeds the quality threshold, an initial estimate is performed on the single exponential curve fit of the IF signal for at least the sequential or overlapping portions of the IF signal.

[0085] Aspect 27. The method according to aspect 26 further includes: determining a start time t. start The start time indicates the time during the evaluation of t. GFRprel Prior to and during the determined falling segment of the IF signal, the starting point of the fitting interval for the single exponential curve fitting of the operable IF signal is determined, which is the starting time t. start Multiply the first constant by the exponent of the Euler number and add the second constant (t) toeq The sum of the calculated values ​​of ) ; set the fitting interval to a single exponential curve fitting of the operable IF signal.

[0086] Aspect 28. The method according to aspect 27, wherein, once in t GFRprel The location determined GFR prel , then determine t start , and t start It is t GFRprel Subtract time t interpol This time is using GFR prel Determined by linear interpolation between the following two: having associated time t low Low GFR boundary (GFR low ) and / or with associated time t high High GFR boundary (GFR high ).

[0087] Aspect 29. The method according to aspect 26 further includes: determining a start time (t start The start time represents the point in time prior to the single exponential curve fitting of the operable IF signal and during the defined falling segment of the IF signal; it sets the starting point (t) for the single exponential curve fitting of the operable IF signal range. eq ); where t eq =t start +t toeq ,and , where A, B and C are constants.

[0088] Aspect 30. The method according to aspect 26, wherein determining the falling segment of the IF signal comprises: identifying a predetermined fitting window; and performing a single exponential curve fitting of the IF signal according to the following formula: IF fit =C0+C1 e -t / RDTC , where IF fitThis represents the fitting of a portion of IF, where C0 and C1 are curve fitting constants, t is time, and RDTC is a time parameter; calculates the RDTC values ​​in at least two segments of a predetermined fitting window; compares the RDTC values ​​from these at least two segments until all RDTC values ​​correspond to positive values.

[0089] Aspect 31. The method according to aspect 30 further includes: determining a start time (t start The start time represents the point in time prior to the single exponential curve fitting of the operable IF signal and during the determined falling segment of the IF signal; setting the starting point (t) for the single exponential curve fitting of the operable IF signal. eq ); where t eq =t start +t toeq ,and , where A, B and C are constants.

[0090] Aspect 32. The method according to aspect 31, wherein, based on determining according to IF fit When should the single exponential curve fit of the equation exceed the quality threshold to set t? eq .

[0091] Aspect 33. The method according to aspect 31, wherein, once in t GFRprel The location determined GFR prel , then determine t start , and t start It is t GFRprel Subtract time (t) interpol (This time is using GFR) prel Determined by linear interpolation between the following two: having associated time t low Low GFR boundary (GFR low ) and / or with associated time t high High GFR boundary (GFR high ).

[0092] Aspect 34. The method according to aspect 26, wherein determining whether the IF signal includes a portion of the early fluorescence data further includes performing a reverse look-through component filter.

[0093] Aspect 35. The method according to any one of Aspects 24 to 34, wherein determining the GFR value comprises calculating the renal decay time constant (RDTC) by performing a single exponential curve fitting of the operable IF signal across at least a sequential or overlapping portion of the operable IF signal.

[0094] Aspect 36. The method according to aspect 35, wherein the single exponential curve fitting of the operable IF signal includes performing a logarithmic transformation on the operable IF signal and subsequently fitting a linear function to the logarithmically transformed operable IF signal.

[0095] Aspect 37. The method according to aspect 35, wherein the GFR value is determined at the starting point (t) of the single exponential curve fitting of the operable IF signal. eq Start at ).

[0096] Aspect 38. The method according to aspect 35, wherein the GFR value is determined based on the rate of change of the operable IF signal after the start of a single exponential curve fitting of the operable IF signal.

[0097] Aspect 39. The method according to any one of Aspects 24 to 38, wherein providing the GFR value includes displaying the GFR value on a display screen.

[0098] Aspect 40. The method according to any one of aspects 24 to 39, wherein providing the GFR value includes transmitting the GFR value to a remote device.

[0099] Aspect 41. The method according to any one of Aspects 24 to 40, wherein generating the IF signal comprises generating the IF signal directly from the measurement data.

[0100] Aspect 42. The method according to any one of Aspects 24 to 41, wherein filtering the IF signal associated with the early fluorescence data includes omitting a portion of the early fluorescence data when generating the IF signal.

[0101] Aspect 43. The method according to any one of aspects 24 to 42, wherein each of the plurality of measurement entries includes at least two measurement results, one of which is a fluorescence emission (Flr) signal, and the second of which is a diffuse reflection signal detected by a filter detector in a region adjacent to the diffuse reflection medium during irradiation of the diffuse reflection medium with excitation wavelength light; wherein generating the IF signal includes combining the at least two measurement results according to a transformation relation comprising a mathematical equation that converts the Flr signal into an IF signal.

[0102] Aspect 44. The method according to any one of aspects 24 to 43, wherein each of the plurality of measurement entries includes at least one measurement of a fluorescence emission (Flr) signal detected by a filter detector at the diffuse medium during irradiation of the diffuse medium by an excitation wavelength light, wherein generating the IF signal includes transforming the at least one measurement according to a transformation relation comprising a mathematical equation that converts the Flr signal into an IF signal.

[0103] Aspect 45. The method according to aspect 44, wherein the excitation wavelength light includes the wavelength of the exogenous fluorescent agent.

[0104] Aspect 46. A method for determining biological parameters in a patient using an exogenous fluorescent agent, the method comprising: obtaining a measurement dataset including multiple measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an intrinsic fluorescence (IF) signal, the IF signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent within a diffuse reflective medium; determining whether the IF signal includes a portion of early fluorescence data; after determining this portion of the early fluorescence data, identifying an operable IF signal range by filtering the IF signal associated with the early fluorescence data; determining a biological parameter value in the patient based on the rate of change of the operable IF signal; and providing the biological parameter value.

[0105] Aspect 47. A system for determining glomerular filtration rate (GFR) in a patient using an exogenous fluorescent agent, the system comprising: at least one storage device including a memory configured to store instructions; a processor configured to execute the instructions and cause the processor to perform the following steps: obtaining a measurement dataset including multiple measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an intrinsic fluorescence (IF) signal representing the detected fluorescence intensity emitted from an exogenous fluorescent agent within a diffuse reflective medium; determining whether the IF signal includes a portion of early fluorescence data; after determining this portion of the early fluorescence data, identifying an operable IF signal range by filtering the IF signal associated with the early fluorescence data; determining a GFR value in the patient based on the rate of change across the operable IF signal range; and providing the GFR value.

[0106] Aspect 48. The system according to aspect 47, wherein determining whether the IF signal includes early fluorescence data includes determining the falling segment of the IF signal.

[0107] Aspect 49. The system according to aspect 48, wherein determining whether the IF signal includes the portion of early fluorescence data comprises: determining the portion occurring at the initial GFR time (t GFRprel Preliminary GFR value at ) prel ), among which, GFR is determined prel This includes calculating the renal decay time constant (RDTC) through the following steps: based on determining the IF signal at t GFRprel When the preceding segment exceeds the quality threshold, an initial estimate is performed on the single exponential curve fit of the IF signal for at least the sequential or overlapping portions of the IF signal.

[0108] Aspect 50. The system according to aspect 49, wherein the processor is configured to: determine the start time t start The start time indicates the time during the evaluation of t.GFRprel Prior to and during the determined falling segment of the IF signal, the starting point of the fitting interval for the single exponential curve fitting of the operable IF signal is determined, which is the starting time t. start Multiply the first constant by the exponent of the Euler number and add the second constant (t) toeq The sum of the calculated values ​​of ) ; set the fitting interval to a single exponential curve fitting of the operable IF signal.

[0109] Aspect 51. The system according to aspect 50, wherein, once in t GFRprel The location determined GFR prel , then determine t start , and t start It is t GFRprel Subtract time t interpol This time is using GFR prel Determined by linear interpolation between the following two: having associated time t low Low GFR boundary (GFR low ) and / or with associated time t high High GFR boundary (GFR high ).

[0110] Aspect 52. According to the system described in aspect 49, the processor is configured to: determine the start time (t start The start time represents the point in time prior to the single exponential curve fitting of the operable IF signal and during the defined falling segment of the IF signal; it sets the starting point (t) for the single exponential curve fitting of the operable IF signal range. eq ); where t eq =t start +t toeq ,and , where A, B and C are constants.

[0111] Aspect 53. The system according to aspect 49, wherein determining the falling segment of the IF signal comprises: identifying a predetermined fitting window; performing a single exponential curve fitting of the IF signal according to the following formula: IF fit =C0+C1 e -t / RDTC , where IF fit This represents the fitting of a portion of IF, where C0 and C1 are curve fitting constants, t is time, and RDTC is a time parameter; calculates the RDTC values ​​in at least two segments of a predetermined fitting window; compares the RDTC values ​​from at least two segments until all RDTC values ​​correspond to positive values.

[0112] Aspect 54. According to the system described in aspect 53, the processor is configured to: determine the start time (t startThe start time represents the point in time prior to the single exponential curve fitting of the operable IF signal and during the determined falling segment of the IF signal; setting the starting point (t) for the single exponential curve fitting of the operable IF signal. eq ); where t eq =t start +t toeq ,and , where A, B and C are constants.

[0113] Aspect 55. The system according to aspect 54, wherein, based on determining according to IF fit When should the single exponential curve fit of the equation exceed the quality threshold to set t? eq .

[0114] Aspect 56. The system according to aspect 54, wherein, once in t GFRprel The location determined GFR prel , then determine t start , and t start It is t GFRprel Subtract time t interpol This time is using GFR prel Determined by linear interpolation between the following two: having associated time t low Low GFR boundary (GFR low ) and / or with associated time t high High GFR boundary (GFR high ).

[0115] Aspect 57. The system according to aspect 49, wherein determining whether the IF signal includes a portion of early fluorescence data further includes performing a reverse look-through component filter.

[0116] Aspect 58. The system according to any one of Aspects 47 to 57, wherein determining the GFR value comprises calculating the renal decay time constant (RDTC) by performing a single exponential curve fitting of the operable IF signal across at least a sequential or overlapping portion of the operable IF signal.

[0117] Aspect 59. The system according to aspect 58, wherein the single exponential curve fitting of the operable IF signal includes performing a logarithmic transformation on the operable IF signal and subsequently fitting a linear function to the logarithmically transformed operable IF signal.

[0118] Aspect 60. The system according to aspect 58, wherein the GFR value is determined in the operable IF signal (t eq The fitting of the single exponential curve begins at the starting point.

[0119] Aspect 61. The system according to aspect 58, wherein the GFR value is determined based on the rate of change of the operable IF signal after the start of a single exponential curve fitting of the operable IF signal.

[0120] Aspect 62. The system according to any one of Aspects 47 to 61, wherein providing the GFR value includes displaying the GFR value on a display screen.

[0121] Aspect 63. The system according to any one of Aspects 47 to 62, wherein providing the GFR value includes transmitting the GFR value to a remote device.

[0122] Aspect 64. The system according to any one of Aspects 47 to 62, wherein generating the IF signal comprises generating the IF signal directly from the measurement data.

[0123] Aspect 65. The system according to any one of Aspects 47 to 64, wherein filtering the IF signal associated with the early fluorescence data includes omitting a portion of the early fluorescence data when generating the IF signal.

[0124] Aspect 66. The system according to any one of aspects 47 to 65, wherein each of the plurality of measurement entries includes at least two measurement results, one of which is a fluorescence emission (Flr) signal, and the second of which is a diffuse reflection signal detected by a filter detector in a region adjacent to the diffuse reflection medium during irradiation of the diffuse reflection medium with excitation wavelength light; wherein generating the IF signal includes combining the at least two measurement results according to a transformation relation comprising a mathematical equation that converts the Flr signal into an IF signal.

[0125] Aspect 67. The system according to any one of aspects 47 to 66, wherein each of the plurality of measurement entries includes at least one measurement of a fluorescence emission (Flr) signal detected by a filter detector at the diffuse medium during irradiation of the diffuse medium by an excited wavelength light, wherein generating the IF signal includes transforming the at least one measurement according to a transformation relation comprising a mathematical equation that converts the Flr signal into an IF signal.

[0126] Aspect 68. The system according to aspect 67, wherein the excitation wavelength light includes the wavelength of the exogenous fluorescent agent.

[0127] Aspect 69. A system for determining biological parameters in a patient using an exogenous fluorescent agent, the system comprising: at least one storage device including a memory configured to store instructions; a processor configured to execute the instructions and cause the processor to perform the following steps: obtaining a measurement dataset including multiple measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an intrinsic fluorescence (IF) signal representing the detected fluorescence intensity emitted from an exogenous fluorescent agent within a diffuse reflective medium; determining whether the IF signal includes a portion of early fluorescence data; after determining this portion of the early fluorescence data, identifying an operable IF signal range by filtering the IF signal associated with the early fluorescence data; determining a biological parameter value in the patient based on the rate of change of the operable IF signal; and providing the biological parameter value.

Claims

1. A method for determining glomerular filtration rate (GFR) in a patient using an exogenous fluorescent agent, the method comprising: A measurement dataset is obtained, which includes multiple measurement entries obtained before and after the application of the exogenous fluorescent agent; Generate intrinsic fluorescence (IF) signal, which represents the detected fluorescence intensity emitted from an exogenous fluorescent agent within a diffuse reflective medium; Determine whether the IF signal includes a portion of early fluorescence data; After determining the portion of the early fluorescence data, the range of operable IF signals is identified by filtering the IF signal associated with the early fluorescence data; The GFR value in the patient is determined based on the rate of change across the range of the operable IF signal. Provide the GFR value.

2. The method according to claim 1, wherein, Determining whether the IF signal includes the portion of the early fluorescence data includes determining the falling segment of the IF signal.

3. The method according to claim 2, wherein, Determining whether the IF signal includes the portion of the early fluorescence data includes: Determining the occurrence at the initial GFR time (t) GFRprel Preliminary GFR value at ) prel ), among which, GFR is determined prel This includes calculating the renal decay time constant (RDTC) through the following steps: based on determining the IF signal at t GFRprel When the preceding segment exceeds the quality threshold, an initial estimate is performed on the single exponential curve fitting of the IF signal across at least the sequential or overlapping portions of the IF signal.

4. The method according to claim 3, further comprising: Determine the start time t start The start time refers to the time during the evaluation t. GFRprel Previously and during the determined falling segment of the IF signal; Determine the start of the fitting interval for the single exponential curve fitting of the operable IF signal, wherein the fitting interval is the start time t. start Multiply the first constant by the exponent of the Euler number and add the second constant (t) toeq The sum of the calculated values ​​of ). The fitting interval is set to fit the single exponential curve of the operable IF signal.

5. The method according to claim 4, wherein, Once in t GFRprel The location determined GFR prel , then determine t start , and t start It is t GFRprel Subtract time t interpol The time t interpol Is using GFR prel Determined by linear interpolation between the following two: having associated time t low Low GFR boundary (GFR low ) and / or with associated time t high High GFR boundary (GFR high ).

6. The method according to claim 3, further comprising: Determine the start time (t) start The start time refers to a point in time before the single exponential curve fitting of the operable IF signal and during the determined falling segment of the IF signal; The starting point (t) of the single exponential curve fitting is set for the range of the operable IF signal. eq ); Among them, t eq =t start +t toeq ,and , where A, B and C are constants.

7. The method according to claim 3, wherein, Determining the falling segment of the IF signal includes: Identify the predefined fitting window; Perform a single-exponential curve fitting of the IF signal according to the following formula: IF fit = C0 + C1 e -t / RDTC , Where IF fit This represents the fitting of a portion of IF, where C0 and C1 are curve fitting constants, t is time, and RDTC is the time parameter; Calculate the RDTC values ​​in at least two segments of the predetermined fitting window; Compare the RDTC values ​​from the at least two segments until all RDTC values ​​correspond to positive values.

8. The method according to claim 7, further comprising: Determine the start time (t) start The start time refers to a point in time before the single exponential curve fitting of the operable IF signal and during the determined falling segment of the IF signal; Set the starting point (t) of the single exponential curve fitting of the operable IF signal. eq ); Among them, t eq =t start +t toeq ,and , where A, B and C are constants.

9. The method according to claim 8, wherein, Based on the determination according to the IF fit The equation's single-exponential curve fit is set to determine when t exceeds a quality threshold. eq .

10. The method according to claim 8, wherein, Once in t GFRprel The location determined GFR prel , then determine t start , and t start It is t GFRprel Subtract time (t) interpol The time mentioned is using GFR prel Determined by linear interpolation between the following two: having associated time t low Low GFR boundary (GFR low ) and / or with associated time t high High GFR boundary (GFR high ).

11. The method according to claim 3, wherein, Determining whether the IF signal includes the portion of the early fluorescence data also includes performing a reverse lookup component filter.

12. The method according to claim 1, wherein, Determining the GFR value involves calculating the renal decay time constant (RDTC) by performing a single exponential curve fitting of the operable IF signal across at least a sequential or overlapping portion of the operable IF signal.

13. The method according to claim 12, wherein, The single-exponential curve fitting of the operable IF signal includes performing a logarithmic transformation on the operable IF signal and then fitting a linear function to the logarithmically transformed operable IF signal.

14. The method according to claim 12, wherein, The GFR value is determined at the starting point (t) of the single exponential curve fitting of the operable IF signal. eq Start at ).

15. The method according to claim 12, wherein, The GFR value is determined based on the rate of change of the operable IF signal after the start of the single exponential curve fitting of the operable IF signal.

16. The method according to claim 1, wherein, Providing the GFR value includes displaying the GFR value on a display screen.

17. The method according to claim 1, wherein, Providing the GFR value includes transmitting the GFR value to a remote device.

18. The method according to claim 1, wherein, Generating the IF signal includes generating the IF signal directly from the measurement data.

19. The method according to claim 1, wherein, Filtering the IF signal associated with the early fluorescence data includes omitting a portion of the early fluorescence data when generating the IF signal.

20. The method according to claim 1, wherein, Each of the plurality of measurement entries includes at least two measurement results, one of which is a fluorescence emission (Flr) signal, and the second of which is a diffuse reflection signal detected by a filter detector in a region adjacent to the diffuse reflection medium during the period when the diffuse reflection medium is irradiated with excitation wavelength light; Generating the IF signal includes combining the at least two measurement results according to a transformation relationship comprising a mathematical equation that converts the Flr signal into the IF signal.

21. The method according to claim 1, wherein, Each of the plurality of measurement entries includes at least one measurement of a fluorescence emission (Flr) signal detected by a filter detector at the diffuse medium during the period when the diffuse medium is irradiated with excitation wavelength light; Generating the IF signal includes transforming the at least one measurement result according to a transformation relationship comprising a mathematical equation that converts the Flr signal into the IF signal.

22. The method according to claim 21, wherein, The excitation wavelength light includes the wavelength of the exogenous fluorescent agent.

23. A method for determining biological parameters in a patient using an exogenous fluorescent agent, the method comprising: A measurement dataset is obtained, which includes multiple measurement entries obtained before and after the application of the exogenous fluorescent agent; Generate intrinsic fluorescence (IF) signal, which represents the detected fluorescence intensity emitted from an exogenous fluorescent agent within a diffuse reflective medium; Determine whether the IF signal includes a portion of early fluorescence data; After determining the portion of the early fluorescence data, the range of operable IF signals is identified by filtering the IF signal associated with the early fluorescence data; The biological parameter values ​​in the patient's body are determined based on the rate of change of the operable IF signal; Provide the biological parameter values.

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