Endogenous fluorescence generation using exogenous fluorescent agents

Abstract

The present disclosure provides a method, system, and apparatus for determining glomerular filtration rate (GFR) by acquiring a measurement dataset. The method of the present disclosure includes the steps of: acquiring a measurement dataset including a plurality of measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in a diffuse reflection medium; determining whether the IF signal includes a portion of early fluorescence data; determining a range of usable IF signals by filtering the IF signals associated with the early fluorescence data if the IF signal is determined to include a portion of early fluorescence data; determining a patient's GFR value based on the rate of change of the usable IF signal; and providing a GFR value.

Description

[Technical Field]

[0001] This disclosure generally relates to usable endogenous fluorescence signals, including adjustments based on early fluorescence data. [Background technology]

[0002] Monitoring biological parameters is crucial in patients with serious illnesses or injuries. Organ function can decline due to organ injury, aging, underlying diseases, and other factors. Assessment of organ function allows for the determination of organ injury or organ failure. [Overview of the project] [Means for solving the problem]

[0003] This disclosure provides non-invasive monitoring of biological parameters indicating a patient's organ function based on endogenous fluorescence (IF) signals. [Brief explanation of the drawing]

[0004] Details of one or more aspects of the subject matter described herein are given in the accompanying drawings and the following description. However, the accompanying drawings are merely illustrations of some typical aspects of the disclosure and should not be considered to limit the scope of the disclosure. Other features, aspects, and advantages of the disclosure will become apparent from this specification, the drawings, and the claims.

[0005] To illustrate how the above and other advantages and features of this disclosure are obtained, the principles of this disclosure, as briefly described above, will be described in more detail with reference to specific embodiments illustrated in the accompanying drawings. The principles of this disclosure will be described more specifically and in detail with reference to the accompanying drawings, understanding that the accompanying drawings are merely illustrative of exemplary embodiments of this disclosure and should not be considered as limiting the scope of this disclosure.

[0006] [Figure 1] Figure 1 is a schematic diagram of a single-light source type monitoring device in one embodiment. [Figure 2] Figure 2 shows the light emission from the light source and exogenous fluorescent agent, as well as the light detection by the first and second photodetectors. [Figure 3] Figure 3 shows the emission of light from another light source, as well as the detection of light by the first and second photodetectors. [Figure 4] Figure 4 is a schematic diagram of a multi-light source type monitoring system in one embodiment. [Figure 5] Figure 5 shows an embodiment of a sensor head equipped with one or more light sources and two detectors. [Figure 6] Figure 6 is an exploded view of the internal housing of the sensor head shown in Figure 5. [Figure 7] Figure 7 is a graph summarizing the absorbance, transmittance, and emission spectra of various devices, materials, and compounds related to the non-invasive monitoring of exogenous fluorescent agents in vivo, for optical wavelengths ranging from approximately 430 nm to approximately 650 nm. [Figure 8] Figure 8 is a graph showing typical endogenous fluorescence signal measurements (IFagent) detected by a renal monitoring device before and after administration of an exogenous fluorescent agent. [Figure 9] Figure 9 shows a flowchart corresponding to the method for measuring glomerular filtration rate (GFR) using an exogenous fluorescent agent. [Modes for carrying out the invention]

[0007] Various embodiments of this disclosure are described in detail below. While specific embodiments are described, 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 descriptions and drawings are illustrative and should not be construed as limiting. Various specific details are provided to provide a full understanding of this disclosure. However, in certain embodiments, details of the well-known or prior art are omitted to avoid obscuring the description of this disclosure. Any reference in this disclosure to one embodiment or any embodiment refers to the same embodiment or any embodiment, and such reference means at least one embodiment.

[0008] References to “one embodiment” or “a certain embodiment” mean that a particular function, structure, or feature described in relation to that embodiment is included in at least one embodiment of this disclosure. The phrase “in one embodiment” appearing in various parts of this specification does not necessarily refer to the same embodiment, nor are different embodiments mutually exclusive. Furthermore, some embodiments describe various features not shown in other embodiments.

[0009] The terms used herein generally have their common meanings in the art within the context of this disclosure and in the specific context in which each term is used. Any one or more terms described herein may be replaced by alternative expressions or synonyms, and no particular emphasis should be placed on whether or not such terms are described in detail herein. In some cases, synonyms are provided for specific terms. The enumeration of one or more synonyms does not preclude the use of other synonyms. Examples anywhere in this specification (including examples of terms described herein) are illustrative only and are not intended to further limit the scope of this disclosure or the meaning of any exemplary term. Similarly, this disclosure is not limited to the various embodiments described herein.

[0010] Without any intention to limit the scope of this disclosure, examples of apparatus, devices, methods, and related results from the embodiments of this disclosure are given below. Note that headings and subheadings may be used in the embodiments for the convenience of the reader, but these do not limit the scope of this disclosure. Unless otherwise defined, technical and scientific terms used herein have the meanings generally understood by those skilled in the art to which this disclosure pertains. In the event of any inconsistency, including definitions, this specification shall prevail.

[0011] Further features and advantages of this disclosure will be detailed in the following description, some of which will be obvious from the following description or will be understood through the practice of the principles disclosed herein. These features and advantages can be realized and obtained by means or combinations thereof specifically specified in the appended claims. These and other features of this disclosure will be more fully apparent from the following description and the appended claims or will be understood through the practice of the principles described herein. Furthermore, unless otherwise specified, the order of one or more steps may be as described or modified as appropriate.

[0012] As used herein, the terms “contains” or “has” or other variations thereof are intended to be non-exclusive. For example, a process (method), product, article, or apparatus containing the enumerated components is not necessarily limited to those components alone, and may include components not expressly listed, or other components specific to those products, articles, or apparatus. Furthermore, unless expressly stated otherwise, the term “or” means inclusive “or” and not exclusive “or.” For example, condition A “or” B satisfies one of the following: 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).

[0013] As used herein, the term “substantially” is defined as essentially conforming to a particular dimension, shape, or other modifier, and therefore the modifier does not need to be exact. For example, “substantially cylindrical” means that the object is similar to a cylinder, but may have one or more deviations from a true cylinder.

[0014] The term “joined” means being joined, whether directly or indirectly through intervening components, and is not necessarily limited to physical joining. Joints may be permanently or detachably joined. The term “includes” means “includes, but not necessarily limited to.” This specifically indicates open-ended inclusion or membership in such combinations, groups, series, etc.

[0015] The term "diffuse reflective medium" refers to any material through which light propagates, including multiple parts, particles, or molecules that can scatter, reflect, and / or absorb light during its propagation. The distribution of these multiple parts, particles, and / or molecules may be uniform or non-uniform and may change over time.

[0016] This disclosure provides non-invasive monitoring of biological parameters indicating a patient's organ function based on endogenous fluorescence (IF) signals. The disclosure uses proprietary filtering of the IF signal to determine whether the IF signal contains a portion of early fluorescence data, and if it is determined that the IF signal contains a portion of early fluorescence data, it filters the IF signal associated with the early fluorescence data to determine the usable IF signal range. The IF signal is based on the use of an appropriate indicator substance administered to the patient. In one embodiment, administration to the patient can be done by injection. In another embodiment, administration to the patient can be done by oral ingestion. In one embodiment, the organ function is intestinal barrier function, and the patient's intestinal barrier function is assessed based on the IF signal. In at least one embodiment, the organ function is renal function. This disclosure improves the accuracy of calculating a patient's renal function based on the IF signal.

[0017] Suitable indicator substances for use in the methods and apparatus of this disclosure are disclosed in U.S. Patents 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 entirety of the above U.S. patent disclosures is incorporated herein by reference for any purpose. In some embodiments, the indicator substance is removed from the patient's body by glomerular filtration. In some embodiments, the indicator substance is removed from the patient's body solely by glomerular filtration. In some embodiments, the indicator substance is a GFR agent.

[0018] Furthermore, the Disclosure also discloses systems, apparatus, methods, computer-readable media, and circuits for monitoring biological parameters indicating organ function in a patient using an exogenous fluorescent agent. In at least one embodiment, the method of the Disclosure includes the steps of: obtaining a measurement dataset including a plurality of measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in a diffuse reflectance medium; determining whether the IF signal includes a portion of early fluorescence data; determining an available IF signal range by filtering the IF signal associated with the early fluorescence data if the IF signal is determined to include a portion of early fluorescence data; determining a patient's biological parameter value based on the rate of change of the available IF signal; and providing the determined biological parameter value. For example, the system of this disclosure acquires a measurement dataset including multiple measurement entries obtained before and after administration of an exogenous fluorescent agent, generates an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in a diffuse reflectance medium, determines whether the IF signal includes a portion of early fluorescence data, and if it is determined that the IF signal includes a portion of early fluorescence data, specially determines the usable IF signal range by filtering the IF signal associated with the early fluorescence data, determines the patient's biological parameter values ​​based on the rate of change of the usable IF signal, and provides the determined biological parameter values.

[0019] In another embodiment, the present disclosure provides a system for determining a patient's biological parameters, such as glomerular filtration rate (GFR), using an exogenous fluorescent agent. The system of the present disclosure comprises storage (e.g., memory configured to store data such as provisional content data and one or more images) and one or more processors (e.g., implemented in a circuit) connected to the memory and configured to execute instructions, the processors together with various components (e.g., network interface, display, output device, etc.) to cause the system to perform the steps of: acquiring a measurement dataset including multiple measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in a diffuse reflection medium; determining whether the IF signal includes a portion of early fluorescence data; determining an available IF signal range by filtering the IF signal associated with the early fluorescence data if it is determined that the IF signal includes a portion of early fluorescence data; determining a patient's biological parameter value based on the rate of change of the available IF signal; and providing the determined biological parameter value.

[0020] In another embodiment, the present disclosure provides a method for determining intestinal barrier function. The method of the present disclosure includes the steps of: obtaining a measurement dataset including a plurality of measurement entries obtained before and after administration of an exogenous fluorescent agent; generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in a diffuse reflectance medium; determining whether the IF signal includes a portion of early fluorescence data; determining an available IF signal range by filtering the IF signal associated with the early fluorescence data if the IF signal is determined to include a portion of early fluorescence data; determining a patient's intestinal barrier function value based on the rate of change of the available IF signal; and providing the determined intestinal barrier function value.

[0021] In another embodiment, the system for determining the above-mentioned biological parameters determines the patient's intestinal wall barrier function value based on the rate of change of the available IF signal and provides the determined intestinal wall barrier function value.

[0022] Figure 1 is a schematic diagram of system 100 in which an exogenous fluorescent agent 112 is administered to patient 104. Light source 108 emits light 106 toward patient 104. Light 106 is also called excitation light or excitation light source. Light 106 can also be controlled to be a single wavelength, multiple wavelengths that change over time, or multiple wavelengths that are emitted simultaneously. The exogenous fluorescent agent 112 generates fluorescence 102 in response to excitation events. Excitation events include excitation wavelength (λ ex The excitation events include irradiation by light 106, the occurrence of an enzymatic reaction, a change in local potential, and any other known excitation events related to the exogenous fluorescent agent. The light source 108 has an excitation wavelength (λ ex The device is configured to deliver light 106 (λ) to patient 104. Fluorescence 102 is generated as described above. In at least one embodiment, the excitation wavelength (λ) of light 106 is configured to deliver light 106 to patient 104. ex ) and the emission wavelength (λ) of fluorescence 102 em ) are spectrally different. That is, (λ ex ) and (λ em Because the wavelengths are sufficiently different from each other, the photodetector 110 can selectively detect only the fluorescence 102 by equipping it with any known optical wavelength separator including an optical filter.

[0023] By analyzing changes in fluorescence 102, information regarding the organ function of patient 104 can be obtained. As described herein, two non-limiting examples of organ function are renal function and intestinal wall barrier function. In one embodiment, the decay rate of fluorescence 102 is proportional to the removal rate of the exogenous fluorescent agent 112 by one or more organs of patient 104, thereby providing biological parameter values. In another non-limiting example, the decay rate of fluorescence 102 is proportional to the removal rate of the exogenous fluorescent agent 112 by the kidneys of patient 104, thereby providing measurements of renal function, including the renal decay time constant (RDTC) and / or glomerular filtration rate (GFR). Furthermore, according to this disclosure, when measuring intestinal wall barrier function, measurements of intestinal wall permeability or leakage rate can be calculated.

[0024] Figure 2 shows a light source 108 in the form of an excitation light-emitting diode (LED) 321 in the presence of an exogenous fluorescent agent 112. The excitation LED 321 can emit light at one or more different excitation wavelengths. In one embodiment, the wavelength of the excitation light can be blue light. In another embodiment, the wavelength of the excitation light can be blue light and green light. In yet another embodiment, the wavelength of the excitation light can be selected based on a selected exogenous fluorescent agent 112. The photodetector 110 can take the form of a first photodetector 322 and a second photodetector 323. As shown, the first photodetector 322 can receive a first signal designated as SPM1, and the second photodetector 323 can receive a second signal designated as SPM2. In at least one embodiment, the first photodetector 322 and the second photodetector 323 can be silicon photomultiplier tubes. The first photodetector 322 and the second photodetector 323 can take various forms, but silicon photomultiplier tubes and / or photodiodes can provide the necessary characteristics to achieve the desired accuracy of the measurement.

[0025] Furthermore, a filter 324 is positioned in front of the light-receiving surface of the second photodetector 323, configured to filter the light received by the second photodetector 323. The filter 324 is configured to substantially or completely block the excitation light wavelength. In addition, the filter 324 is configured to allow light emitted from the exogenous fluorescent agent to pass through substantially unimpeded. In the illustrated embodiment, the excitation light wavelength can be a blue light wavelength, and the filter 324 is configured to allow green light to pass through. As a result, the first photodetector 322 is configured to receive and detect both the excitation wavelength light and the emission wavelength light, while the second photodetector 323 is configured to receive and detect only the emission wavelength light. By combining this with alternating emission of only the excitation wavelength light and only the emission wavelength light to the tissue 320 of patient 104, the measurements from the first photodetector 322 and the second photodetector 323 can be analyzed as described in U.S. Patents 10,548,521, 10,980,459, 10,952,656, 11,478,172, and 10,194,854. The fluorescence measurements can then be corrected by measuring the fluorescence of the exogenous fluorescent agent and removing the effects of autofluorescence, leakage of excitation wavelength light, and diffuse reflection of light. In the illustrated embodiment, only a single filter 324 is shown, but an additional filter for filtering light may be placed in front of the light-receiving surface of the first photodetector 322. In another embodiment, the single filter may be placed in front of the light-receiving surface of the first photodetector 322, rather than the second photodetector 323.

[0026] Excitation LED 321 (e.g., a blue LED) can emit light 325 toward the exogenous fluorescent agent 112. Furthermore, the light 325 emitted from the excitation LED 321 propagates through the tissue 320 of the patient 104, as the tissue 320 of the patient 104 functions to diffuse the light. This diffused light is referred to as a diffuse reflectance (DR) signal. Further, the light 325 emitted to the exogenous fluorescent agent 112 and the fluorescence emission (Flr) signal 334 generated by the exogenous fluorescent agent 112 propagate to the first photodetector 322 and the second photodetector 323. As illustrated, the first photodetector 322 outputs DR ex1 receives the DR signal 333 labeled with the reference sign, and the Flr signal 332 labeled with the reference sign Flr1. On the other hand, the second photodetector 323 outputs DR ex2 receives the DR signal 335 labeled with the reference sign, and the Flr signal 334 labeled with the reference sign Flr2. The Flr signal 332 and the Flr signal 334 include contributions from the exogenous fluorescent agent 112 and tissue autofluorescence. These measurements are used to derive an intrinsic fluorescence (IF) signal attributable only to the fluorescent agent, as described herein.

[0027] Figure 3 shows a scenario using the light source 108 in the form of another light emitting diode (LED) 341. In one embodiment, the other LED 341 may be a green LED. In another embodiment, the other LED 341 may be another type of LED that provides light of a different wavelength from the excitation LED 321. In one embodiment, the other LED 341 can operate to emit light of a wavelength substantially the same as the light emitted from the exogenous fluorescent agent. In another embodiment, a single LED capable of emitting light of various wavelengths can be used. The light emitted from the other LED 341 propagates through the tissue 320 of the patient 104, as the tissue 320 of the patient 104 functions to diffuse the light. This diffused light is referred to as a DR signal, as described above. As illustrated, the first photodetector 322 outputs DR eml receives the DR signal 342 labeled with the reference sign, and the second photodetector 323 outputs DR em2The DR signal 344, which is denoted by the symbol, is received. As in the case of Figure 2, a filter 324 can be used. This filter can be the same as the one in Figure 2. Another LED 341 and excitation LED 321 are shown separately from each other, but another LED 341 and excitation LED 321 may be coupled to each other. In the illustrated embodiment, only a single filter 324 is shown, but an additional filter for filtering light may be placed in front of the light-receiving surface of the first photodetector 322. In another embodiment, the single filter may be placed in front of the light-receiving surface of the first photodetector 322, rather than the second photodetector 323.

[0028] Figure 4 is an illustrative schematic diagram of the organ monitoring system 200. The organ monitoring system 200 comprises a controller 212 including a processor 238 and memory 242, and one or more sensor heads 204 connected to the controller 212. Each sensor head 204 includes a first light source 218, a second light source 220, a first photodetector 222, and a second photodetector 224. The first light source 218 may be an excitation LED as described above. The second light source 220 may be another LED as described above. In another embodiment, the excitation LED may be the second light source 220, and the other LED may be the first light source 218. As shown, each sensor head 204 includes a first optical filter 246 and a second optical filter 244. In another embodiment, only one of the first optical filter 246 and the second optical filter 244 may be used, as described with respect to Figures 2 and 3. The sensor head 204 may optionally include one or more temperature sensors 228. One or more temperature sensors 228 can collect data simultaneously with the first photodetector 222 and / or the second photodetector 224 when they are collecting data. One or more temperature sensors 228 can be used to determine characteristics related to the first photodetector 22 and / or the second photodetector 224. Furthermore, one or more temperature sensors 228 can be configured to provide information about the patient 202. In the illustrated embodiment, the controller 212 is shown separately from the sensor head 204, but in another embodiment, the controller 212 and the sensor head 204 may be configured as a single unit rather than being connected by wire or wireless.

[0029] The first light source 218 and the second light source 220 are configured to emit light toward the patient 202. The light emitted toward the patient 202 is diffused within the patient's body, with some of the light being received by the first photodetector 222 and some of the light being received by the second photodetector 224. The data acquired by the first photodetector 222 and / or the second photodetector 224 is transmitted to the controller 212. The data received by the controller 212 is stored in memory 242 or another storage device that the controller can electronically communicate with.

[0030] The processor 238 is operable to execute instructions in accordance with one or more methods of the present disclosure. The processor 238 is also operable to calculate biological parameter values. In one embodiment, the biological parameter values ​​may be glomerular filtration rate (GFR) and / or renal decay time constant (RDTC). In another embodiment, the biological parameter values ​​may be parameters representing intestinal wall permeability and / or leakage rate.

[0031] In various embodiments, the first light source 218 and the second light source 220 can be any light sources configured to deliver light of an excitation wavelength or light of an emission wavelength. Generally, the first light source 218 emits light toward the exogenous fluorescent agent with sufficient intensity to reach the exogenous fluorescent agent through the tissue of the patient 202 and to induce emission of the emission wavelength by the exogenous fluorescent agent. Generally, the first light source 218 emits light toward the exogenous fluorescent agent with sufficient intensity to reach the exogenous fluorescent agent even after it has been scattered and absorbed through the tissue of the patient 202 and to induce fluorescence of the emission wavelength by the exogenous fluorescent agent even after it has been scattered and / or absorbed. The intensity of the light emitted from the first light source 218 is subject to an upper limit to prevent adverse effects such as tissue burns, tissue tanning, cell damage, and / or photobleaching of the exogenous fluorescent agent and / or endogenous chromophores ("autofluorescence") in the skin.

[0032] Similarly, the second light source 220 emits light toward the exogenous fluorescent agent at an intensity that maintains sufficient residual intensity for detection by the first photodetector 222 and the second photodetector 224, respectively, when the light of the emission wavelength emitted from the exogenous fluorescent agent is scattered and absorbed through the first region of the patient and then emitted from the second and third regions. As with the first light source 218, the intensity of the light emitted from the second light source 220 is subject to an upper limit to prevent adverse effects such as tissue burns, tissue tanning, cell damage, and / or photobleaching of the exogenous fluorescent agent and / or endogenous chromophores ("autofluorescence") in the skin.

[0033] In various embodiments, the first light source 218 and the second light source 220 can be any light source suitable for use in 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 (ultra-broadband light sources). In one embodiment, the first light source 218 and / or the second light source 220 can generate light with a narrow spectral bandwidth suitable for monitoring the concentration of an exogenous fluorescent agent using the method of the present disclosure. In another embodiment, the first light source 218 and the second light source 220 can generate light with a relatively wide spectral bandwidth.

[0034] In one embodiment, the selection of the light intensity generated by the first light source 218 and the second light source 220 of the organ monitoring system 200 is influenced by at least one of several factors, including, but is not limited to, the maximum permissible exposure (MPE) to skin exposure to a laser beam based on applicable regulatory standards such as ANSI standard Z136.1. In another embodiment, the light intensity of the system 200 is selected to reduce the possibility of photobleaching of exogenous fluorescent sources and / or other chromophores (but not limited to collagen, keratin, elastin, hemoglobin in red blood cells, and / or melanin in melanocytes) in the tissues of the patient 202. In yet another embodiment, the light intensity of the system 200 is selected to cause the exogenous fluorescent sources in the tissues of the patient 202 to emit a fluorescence signal detectable by the first photodetector 222 and / or the second photodetector. In yet another embodiment, the light intensity of the system 200 is selected to provide appropriate 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 exposure time of the patient's skin to light emitted from the first photodetector 222 and / or the second photodetector.

[0035] In various embodiments, the light intensities of the first light source 218 and the second light source 220 can be adjusted to compensate for at least one of several factors (but not limited to, for example, variations in skin pigmentation or individual differences in the concentration of chromophores in the patient 202's body). In various other embodiments, the detection gain of the photodetector can be adjusted to compensate for variations in individual differences in skin characteristics. In one embodiment, variations in skin pigmentation may occur between two patients 202 or between two different locations in the same patient 202. In one embodiment, adjustment of the light intensity can compensate for variations due to the path of light through the patient 202's tissue. The path of light through the tissue of patient 202 may vary due to at least a few factors, but not limited to, one or more of the following: variations in the distance between the light source and the photodetector of the system 200, variations in the secure attachment of the sensor head 204 to the skin of patient 202, variations in the light output of the light source due to exposure of the light source to environmental elements such as heat and humidity, variations in the sensitivity of the photodetector due to exposure of the photodetector to environmental elements such as heat and humidity, adjustment of the light source's emission time, and any other relevant operating parameters.

[0036] In various embodiments, the first light source 218 and the second light source 220 may be configured to adjust the intensity of the generated light as needed, according to one or more of the elements described herein. In one embodiment, if the first light source 218 and the second light source 220 are devices configured to continuously change their output fluence as needed, such as LED light sources, the light intensity can be adjusted electronically, for example, by adjusting the potential, current, and / or power supplied to the first light source 218 and / or the second light source 220, but is not limited thereto. In another embodiment, the light intensity can be adjusted using optical methods, including, but not limited to, using optical devices (such as irises, shutters, and / or one or more filters) to partially or completely shield the light emitted from the first light source 218 and the second light source 220, or using optical devices (such as lenses, mirrors, and / or prisms) to divert the path of the light emitted from the first light source 218 and the second light source 220 away from a first area of ​​the patient.

[0037] In various embodiments, the intensity of light generated by the first light source 218 and the second light source 220 can be controlled by controlling the laser fluence, which is defined herein as the ratio of energy in the generated light beam. In one embodiment, the laser fluence can be limited to a range defined by safety standards such as ANSI standards for exposure to laser energy, such as ANSI Z136.1, but is not limited thereto.

[0038] In various embodiments, the pulse widths of the light generated by the first light source 218 and the second light source 220 can be independently selected from each other so that the duration is in the range of approximately 0.0001 seconds to approximately 0.5 seconds.

[0039] Figure 5 shows an embodiment of a sensor head comprising one or more light sources and two or more photodetectors. As shown, the sensor head 510 has a single aperture 531 formed to allow light emitted from a first light source 218 and a second light source 220 to pass through. The sensor head 510 also comprises a first photodetector 530 and a second photodetector 532. The sensor head 510 has each aperture 531 formed corresponding to each detector to allow light to reach the first photodetector 530 and / or the second photodetector 532. The second photodetector 532 is spaced 534 apart from one or more light sources 218, 220. The sensor head 510 further comprises a clip receiver 520 designed to be coupled to one or more components not shown.

[0040] Figure 6 is an exploded view of the internal housing 660 of the sensor head 510 shown in Figure 5. Figure 6 is an isometric view of the sensor head 604a with the upper housing and various electrical components removed to expose the internal housing 660. The internal housing 660 is housed within the housing. The internal housing 660 houses a sensor mount having a first detection well 652, a second detection well 650, and a light source well 654. Each well is formed through the sensor mount. The first photodetector 622 is located in the first detection well 652, and the second photodetector 624 is located in the second detection well 650. The first light source 618 and the second light source 620 are located in the light source well 654. In one embodiment, the first detection well 652, the second detection well 650, and the light source well 654 of the sensor mount are optically separated from each other so that light emitted from the first light source 618 and the second light source 620 does not reach the photodetector 622 / 624 without passing through the patient's skin and bonding. Furthermore, the separation between the first detection well 652 and the second detection well 650 makes it possible to distinguish the detection fluorescence signal emitted from the exogenous fluorescent agent from the unfiltered excitation light, as described above.

[0041] In one embodiment, light-transmitting windows 640, 642, and 644 are positioned at the openings of the first detection well 652, the second detection well 650, and the light source well 654, respectively, sealing each opening and providing a light-transmitting conduit between the patient's tissue and the inside of the sensor head 604a. Furthermore, diffusers 630 and 632 are positioned on the light-transmitting windows 640, 642, and 644, respectively. The diffusers 630 and 632 are provided to spatially homogenize the light emitted from the first light source 618 and the second light source 620 toward the patient's tissue, and to spatially homogenize the light detected by the first photodetector 622 and the second photodetector 624. In one embodiment, an absorption filter 602a is coupled to the diffuser 630. In one embodiment, a light-transmitting adhesive is used to bond the absorption filter 602a to the diffuser 630.

[0042] Figure 7 is a graph 1210 summarizing the absorbance, transmittance, and emission spectra of various devices, materials, and compounds related to the non-invasive monitoring of exogenous fluorescent agents in vivo, for optical wavelengths ranging from approximately 430 nm to approximately 650 nm. For example, Figure 7 is a graph summarizing the absorption spectra (1214) and emission spectra (1215) of oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb), as well as the frequency spectrum absorption spectrum (1214) and emission spectrum (1215) of relmapyrazine (also known as MB-102), an exogenous fluorescent agent. The emission spectra of blue LED light sources 1211 and green LED light sources 1212 are also shown superimposed on the other spectra in Figure 7. In this embodiment, the first light source 218 of the system can be a blue LED, and the excitation wavelength of the system can be an isoabsorptural wavelength of approximately 450 nm. As shown in Figure 7, the absorption spectrum of reduced hemoglobin (Hb) shows a steep slope in the isoabsorbent wavelength range from approximately 420 nm to approximately 450 nm. This indicates that the relative absorbance of oxyhemoglobin (HbO2) (1217) and the relative absorbance of reduced hemoglobin (Hb) (1216) at the isoabsorbent wavelength of approximately 450 nm are sensitive to small changes in excitation wavelength. However, at wavelengths above approximately 500 nm, the slope of the oxyhemoglobin (HbO2) spectrum / reduced hemoglobin (Hb) spectrum becomes gentler, and a broadband light source (but not limited to, an LED with a bandpass filter 1213) is sufficient for use as the primary light source.

[0043] In another embodiment, the excitation wavelength can be selected to enhance the absorbance contrast between the exogenous fluorescent agent and the chromophore in the patient's tissue. As a non-limiting example, as shown in Figure 7, at an isoabsorbent wavelength of 452 nm, the absorbance of relmapyrazine is more than three times higher than that of oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb). Although not limited to a specific theory, a higher proportion of the light emitted into the patient's tissue at a wavelength of approximately 450 nm is absorbed by relmapyrazine than by oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb), thus improving the absorption efficiency of relmapyrazine and thereby reducing the intensity of light at the excitation wavelength required to excite a detectable fluorescent signal.

[0044] In various embodiments, a second isosbestic wavelength can also be selected as the emission wavelength of this system. As a non-limiting example, Figure 7 shows the emission spectrum of a relmapyrazine exogenous fluorescent agent (1215) characterized by an emission peak at a wavelength of approximately 550 nm. In this non-limiting example, an isosbestic wavelength of 570 nm can be selected as the emission wavelength detected by the first and second photodetectors. In various other embodiments, the emission wavelength of this system can be selected to fall within a spectral range characterized by the relatively low absorbance of the chromophore in the tissue of patient 202. Although not limited to any particular theory, the low absorbance of the chromophore at the selected emission wavelength reduces the loss of light emitted from the exogenous fluorescent agent, thereby improving the efficiency of fluorescence detection.

[0045] Figure 8 shows representative endogenous fluorescence signal (IF) measurements detected by a renal monitoring device before and after administration of an exogenous fluorescent agent. agentGraph 1250 shows the results. Figure 8 is a graph showing fluorescence measurements obtained from patients over approximately 15 hours after administration of an exogenous fluorescent agent such as relmapyrazine, following a baseline period of approximately 1 hour 1252. The pre-administration / baseline period 1252 is characterized by relatively low, stable fluorescence levels, presumably due to the absence of the exogenous fluorescent agent in the patient's blood. After administration of the exogenous fluorescent agent 1253, fluorescence measurements rise sharply to peak concentration 1255, and then decrease relatively smoothly and exponentially to background fluorescence levels as the kidneys remove the exogenous fluorescent agent from the patient's blood. While not limited to any particular theory, it is thought that the administered exogenous fluorescent agent is well mixed after a period of exponential decrease in concentration. After administration of an exogenous fluorescent agent such as relmapyrazine, the exogenous fluorescent agent undergoes an equilibrium period during which it diffuses from the bloodstream into the patient's extracellular tissues. When the diffusion of the exogenous fluorescent agent into the patient's extracellular tissue reaches a quasi-steady state condition, equilibrium is achieved, and the fluorescence signal is characterized as a single exponential decay. While not limited to any particular theory, we tentatively assume that the pre-equilibrium region of the measurement dataset is characterized as the time domain of the IF dataset.

[0046] As shown in Figure 8, the post-administration period includes a mixed and dispersed portion 1254 and a renal clearance-dominant portion 1256. The region where the mixed and dispersed portion 1254 and the renal clearance-dominant portion 1256 contact and / or overlap can be defined as the start of the region dominated by a single exponential decay 1257. To calculate the region dominated by a single exponential decay 1257, the system can use the following methods and apparatus.

[0047] Figure 9 shows a flowchart corresponding to an exemplary method 700. While the exemplary method 700 shows a specific order of steps, this order can be changed without departing from the scope of the disclosure. For example, some of the steps shown may be performed in parallel or in a different order, to the extent that it does not substantially affect the functionality of the method 700. In another embodiment, various components of an apparatus or system implementing the method 700 may perform the functionality of the method 700 substantially simultaneously or in a specific order.

[0048] According to several embodiments, as shown in Figure 9, the method 700 includes a step 702 of acquiring a measurement dataset containing multiple measurement entries obtained before and after the administration of an exogenous fluorescent agent. For example, the system and / or apparatus shown in Figure 4 can acquire a measurement dataset containing multiple measurement entries obtained before and after the administration of an exogenous fluorescent agent. For example, the system and / or apparatus can collect data using one or more sensor heads equipped with 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 embodiment, the controller and / or processor can store the data locally and perform processing. In another embodiment, the data can be transmitted to a secure remote computer and processed on the remote computer. The system and / or apparatus can be positioned so that one or more sensor heads are in close proximity to or in contact with the patient whose data is being measured. The system and / or apparatus can be operated for a predetermined period of time before the administration of an exogenous fluorescent agent. Figure 8 shows one embodiment of data collection and data processing results for providing renal function values.

[0049] In at least one embodiment, each of the multiple measurement entries includes at least two measurements, one of which is a fluorescence emission (Flr) signal and the other is a diffuse reflection signal detected by a filtered photodetector in a region adjacent to the diffuse reflection medium during irradiation of the diffuse reflection medium with excitation wavelength light. In another embodiment, the filtered photodetector may be one in which a filter is placed in front of the light-receiving surface of the photodetector to optically filter the light based on a physical filter. In yet another embodiment, the light can be filtered by processing the data obtained by the photodetector.

[0050] In another embodiment, each of the multiple measurement entries includes at least one measurement of the Flr signal detected in the diffuse reflective medium by a filtered photodetector while the diffuse reflective medium is irradiated with excitation wavelength light, and the generation of the IF signal includes transforming at least one measurement according to a transformation relation that includes a mathematical equation that transforms the Flr signal into an IF signal. In yet another embodiment, each of the multiple measurement entries includes at least one measurement signal detected in the diffuse reflective medium by a filtered photodetector while the diffuse reflective medium is irradiated with light of a wavelength similar to or equal to the wavelength of the exogenous fluorescent agent.

[0051] According to several embodiments, the method includes step 704 of generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from an exogenous fluorescent agent in a diffuse reflecting medium. For example, the processor of the system shown in Figure 4 can generate an IF signal representing the detected fluorescence intensity emitted from an exogenous fluorescent agent in a diffuse reflecting medium. In at least one embodiment, the diffuse reflecting medium is one or more sites of a patient having the properties described herein in relation to the diffuse reflecting medium. In at least one embodiment, the generation of the IF signal includes generating the IF signal directly from measurement data. In some configurations of the system and / or apparatus shown in Figure 4, it is possible to directly measure the IF signal. In other configurations, the system and / or apparatus can perform calculations. In other embodiments described herein, the generation of the IF signal can be performed by additional calculations. In yet another embodiment, the generation of the IF signal includes 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 embodiments of methods for generating IF signals are described in U.S. Patents 10,548,521, 10,980,459, 10,952,656, 11,478,172, 10,194,854, and 11,602,570.

[0052] According to several embodiments, the method includes a step 706 of determining whether the IF signal contains a portion of early fluorescence data. For example, the processor of the system shown in Figure 4 can determine whether the IF signal contains a portion of early fluorescence data. This can be seen in relation to Figure 8 as one embodiment for determining renal function values. In at least one embodiment, step 706 of the method shown in Figure 9 includes determining an interval in which the IF signal decreases. In another embodiment, when determining an interval in which the IF signal decreases, the method may determine a predetermined fitting window. A predetermined fitting window refers to a predetermined time window having a time length set to a predetermined length. The predetermined time window may be configured to be adjusted over time. In another embodiment, the predetermined time window has a fixed time length, but the window itself can be moved within the data. In one embodiment, when determining biological parameter values ​​related to a patient's renal function, the method may further include a step of performing a single exponential curve fitting on the IF signal according to the following formula. IF fit =C0+C1*e -t / RDTC In the above formula, IF fit The ∫ represents the fitting to the IF portion, C0 and C1 represent curve fitting constants, t represents time, and RDTC represents the time parameter. Furthermore, this method can calculate multiple RDTC values ​​in at least two intervals within a given minimum fitting window. In this embodiment, RDTC is a parameter that can change over time. Furthermore, this method can compare multiple RDTC values ​​obtained in at least two intervals until all of the multiple RDTC values ​​correspond to positive values.

[0053] In at least one embodiment for determining renal function values, the method determines whether the IF signal contains a portion of early fluorescence data, using the provisional GFR time (tGFR). prel ) The provisional GFR value (GFR) that results from this prel This includes the step of determining the GFR. prelThe step to determine tGFR prel The method includes the step of calculating the renal decay time constant (RDTC) by performing an initial estimate of a single exponential curve fitting of the IF signal over at least a continuous or overlapping portion of the IF signal, based on the determination of the point in time when the previous interval of the IF signal exceeded a property threshold. The method also includes the step of calculating the renal decay time constant (RDTC) by performing an initial estimate of a single exponential curve fitting of the IF signal over at least a continuous or overlapping portion of the IF signal. prel The starting point t represents the point in time before the evaluation and within the interval in which it was determined that the IF signal would decrease. start The steps to determine the starting point t start And, the second constant (t) is obtained by multiplying the first constant by Euler's number. toeq The steps include determining the start point of a fitting interval for single exponential curve fitting of the available IF signal, which is the sum of the values ​​up to the exponent obtained by adding ) and setting this fitting interval as the interval for single exponential curve fitting of the available IF signal. In one embodiment, t start tGFR prel GFR prel It was decided after it was decided, star tGFR prel Therefore, GFR prel Using time t low Low GFR boundary (GFR) related to low ) and / or time t high High GFR boundary (GFR) related to high Time t is determined by linear interpolation between ) interpol This is the result after subtracting [amount].

[0054] In yet another embodiment, the method uses a starting point (t) that represents a point in time prior to the single exponential curve fitting of the available IF signal range and within the interval in which it is determined that the available IF signal decreases. start ) can be determined. In at least one embodiment, the method can determine the start time (t) of the single exponential curve fitting of the available IF signal. eq Set ). Here, t eq =t start +t toeq and t toeq =A × e -GFRprel / B+C, where A, B, and C are constants. Furthermore, this method is IF fit Based on the determination of when the single exponential curve fitting based on the equation exceeds the property threshold, t eq It is also possible to set the property threshold. The property threshold can be a fixed value based on prior measurements. In another embodiment, the property threshold is a set value. In at least one embodiment, the method can use a recursive filter to determine the peak of the IF signal. The recursive filter may be a variety of filters. Furthermore, the method can exclude data from fitting for a predetermined period after the peak of the IF signal. The amount of data excluded from fitting may be a fixed amount for the predetermined period. In at least one embodiment, the fixed period may be in the range of 10 minutes to 10 hours. In another embodiment, the fixed period may be in the range of 20 minutes to 5 hours. In yet another embodiment, the fixed period may be in the range of 20 minutes to 1.5 hours. In another embodiment, the amount of data excluded may use a variable period to determine when the data stabilizes, thereby improving the speed of the rest of the process.

[0055] Furthermore, this method uses GFR prelWhen determining the IF signal, an estimate of the single exponential curve fitting can be determined in the interval where the IF signal is determined to decrease. Setting the start time of the single exponential curve fitting in the measured dataset, or the start time of the single exponential curve fitting in the measured dataset that occurs thereafter, involves performing reverse-looking component filtering. In this process, recursive or variable methods can be used to improve the accuracy of the overall result. Reverse-looking component filtering can be used to exclude parts of the dataset in a reverse-looking manner. That is, if data that is initially excluded from the calculation is determined to exceed a threshold, that data can be included. For example, if the data to be excluded is stable, that data can be included, thereby reducing the overall time required for the process. However, if the data to be excluded does not have the same properties as the current data or data recorded before that dataset, that dataset should remain excluded.

[0056] According to several embodiments, the method includes a step 708 in which, when determining the portion of early fluorescence data, the method determines the usable IF signal range by filtering the IF signal associated with the early fluorescence data. For example, the processor of the system shown in Figure 4 can determine the usable IF signal range by filtering the IF signal associated with the early fluorescence data when determining the portion of early fluorescence data. In at least one embodiment, filtering the IF signal associated with the early fluorescence data includes excluding the portion of the early fluorescence data from the generation of the IF signal. In another embodiment, the filtering of the IF signal may be configured to perform calculations that modify the IF signal to more accurately represent the usable IF signal. In at least one embodiment, filtering the IF signal associated with the early fluorescence data includes omitting the portion of the early fluorescence data from the determination of the IF signal, thereby excluding the portion of the early fluorescence data included in the IF signal from the usable IF signal.

[0057] According to several embodiments, the method includes a step 710 in which the patient's biological parameter values ​​are determined based on the rate of change of the available IF signal. For example, the processor of the system shown in Figure 4 can determine the patient's biological parameter values ​​based on the rate of change of the available IF signal. In one embodiment, the biological parameter value is glomerular filtration rate (GFR). In another embodiment, the biological parameter value is intestinal wall barrier function.

[0058] In at least one embodiment, the method includes the step of determining the GFR based on the rate of change of the available IF signal after commencing single exponential curve fitting of the available IF signal. One embodiment of single exponential curve fitting has been described herein. In another embodiment, a method for determining the GFR is disclosed in U.S. Patent No. 11,602,570. In at least one embodiment, the step of determining the GFR value includes calculating the renal decay time constant (RDTC) by performing single exponential curve fitting of the available IF signal over at least a continuous portion of the available IF curve. A continuous portion of the available IF curve refers to portions that are adjacent or overlapping in time. In one embodiment, single exponential curve fitting of the available IF signal includes logarithmically transforming the available IF signal and then fitting a linear function to the logarithmically transformed available IF signal.

[0059] Furthermore, in this method, the GFR value is determined by the available IF signal (t) determined in step 706. eq The process begins from the start of the single exponential curve fitting to the available IF signal. Furthermore, in this method, the GFR is determined based on the rate of change of the available IF signal after the start of the single exponential curve fitting to the available IF signal.

[0060] According to several embodiments, the method includes a step 712 of providing biological parameter values. For example, the processor of the system shown in Figure 4 can provide biological parameter values. In at least one embodiment, the biological parameter values ​​are GFR and / or intestinal wall barrier function. In at least one embodiment, providing biological parameter values ​​includes displaying the biological parameter values ​​on a display screen. In another embodiment, providing biological parameter values ​​includes transmitting the biological parameter values ​​to a remote device. In yet another embodiment, the method includes transmitting the biological parameter values ​​to a remote device and displaying the biological parameter values ​​on a local display screen. The local display screen can be incorporated into the device as shown in Figure 4. The local display screen can be incorporated into the controller 212 of the system 200 shown in Figure 4.

[0061] Exemplary embodiments of this disclosure include the following:

[0062] (Aspect 1) A method for determining a patient's glomerular filtration rate (GFR) using an exogenous fluorescent agent, The steps include obtaining a measurement dataset containing multiple measurement entries obtained before and after administration of an exogenous fluorescent agent, The steps include generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in the diffuse reflection medium, The steps include determining whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data, If it is determined that the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, the steps include determining the usable range of the endogenous fluorescence (IF) signal by filtering the endogenous fluorescence (IF) signal related to the early fluorescence data, The steps include determining the patient's glomerular filtration rate (GFR) value based on the rate of change of the available endogenous fluorescence (IF) signal, A method comprising the step of providing the glomerular filtration rate (GFR) value.

[0063] (Aspect 2) The method according to embodiment 1, A method comprising the step of determining whether the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, wherein the step of determining the interval over which the endogenous fluorescence (IF) signal decreases.

[0064] (Aspect 3) The method according to embodiment 2, The step of determining whether the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data is: Provisional GFR time (tGFR) prl ) The provisional GFR value (GFR) that results from this prl This includes the step of determining, A method for determining the provisional GFR value, comprising the step of calculating the renal decay time constant (RDTC) by performing an initial estimate of a single exponential curve fitting of the endogenous fluorescence (IF) signal over at least a continuous or overlapping portion of the endogenous fluorescence (IF) signal, based on a determination of the time at which the previous interval of the endogenous fluorescence (IF) signal of the provisional GFR time exceeded a property threshold.

[0065] (Aspect 4) The method according to embodiment 3, The aforementioned provisional GFR time (tGFR) prl The starting point (t) is the point in time before the evaluation of the endogenous fluorescence (IF) signal, and represents the point in time within the interval in which it was determined that the endogenous fluorescence (IF) signal decreases. start ) and the step of determining The starting point (t start ) and the second constant (t) obtained by multiplying the first constant by Euler's number. toeq The steps include determining the starting point of the fitting interval for single-exponential curve fitting of the available endogenous fluorescence (IF) signal, which is the sum of the values ​​up to the exponent obtained by adding ) A method further comprising the step of setting the fitting interval as an interval for single exponential curve fitting of the usable endogenous fluorescence (IF) signal.

[0066] (Appendix 5) The method according to aspect 4, The starting point (t start ) is the provisional GFR time (tGFR prl ) with the aforementioned provisional GFR value (GFR prl ) was decided after the decision was made, The starting point (t start ) is the provisional GFR time (tGFR prl ) Using GFRprel, time t low Low GFR boundary (GFR) related to low ) and / or time t high High GFR boundary (GFR) related to high Time (t) is determined by linear interpolation between ) interpol A method that subtracts ).

[0067] (Aspect 6) The method according to embodiment 3, The starting point (t) represents a point in time prior to the single exponential curve fitting of the available endogenous fluorescence (IF) signal, and within the interval in which the available endogenous fluorescence (IF) signal is determined to decrease. start ) and the step of determining The start time (t) for fitting a single exponential curve of the available endogenous fluorescence (IF) signal. eq ) and further include the step of setting, t eq =t start +t toeq And, t toeq =A × e -GFRprel / B It is +C, A, B, and C are constants, method.

[0068] (Aspect 7) The method according to embodiment 3, The step of determining the interval in which the endogenous fluorescence (IF) signal decreases is: The steps include determining a predetermined fitting window, The steps include: performing a single exponential curve fitting of the endogenous fluorescence (IF) signal according to the following formula; IF fit =C0+C1*e -t / RDTC (In the above formula, IF fit (where represents the fitting to the IF portion, C0 and C1 represent the curve fitting constants, t represents time, and RDTC represents the time parameter.) The steps include: calculating the RDTC value in at least two intervals within the predetermined fitting window; A method comprising the step of comparing the RDTC values ​​obtained in at least two intervals until all of the RDTC values ​​correspond to positive values.

[0069] (Pattern 8) The method according to aspect 7, The starting point (t) represents a point in time prior to the single exponential curve fitting of the available endogenous fluorescence (IF) signal, and within the interval in which the available endogenous fluorescence (IF) signal is determined to decrease. start ) and the step of determining The start time (t) for fitting a single exponential curve of the available endogenous fluorescence (IF) signal. eq ) and further include the step of setting, t eq =t start +t toeq And, t toeq =A × e -GFRprel / B It is +C, A, B, and C are constants, method.

[0070] (Aspect 9) The method according to aspect 8, The starting point (t eq The setting of ) is IF fit A method in which single exponential curve fitting based on an equation is performed based on a determination of when a property threshold is exceeded.

[0071] (Aspect 10) The method according to aspect 8, The starting point (t start ) is the provisional GFR time (tGFR prl ) with the aforementioned provisional GFR value (GFR prl ) was decided after the decision was made, The starting point (t start ) is the provisional GFR time (tGFR prl ) Using GFRprel, time t low Low GFR boundary (GFR) related to low ) and / or time t high High GFR boundary (GFR) related to high Time (t) is determined by linear interpolation between ) interpol A method that subtracts ).

[0072] (Aspect 11) The method according to embodiment 3, The method further comprises the step of performing reverse-looking component filtering, wherein the step of determining whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data.

[0073] (Aspect 12) A method according to any of embodiments 1 to 11, The step of determining the glomerular filtration rate (GFR) is as follows: A method comprising the step of calculating a renal decay time constant (RDTC) by performing a single exponential curve fitting of the available endogenous fluorescence (IF) signals in portions in which the available endogenous fluorescence (IF) signals are at least continuous or overlapping.

[0074] (Aspect 13) The method according to embodiment 12, A method for fitting a single exponential curve of the available endogenous fluorescence (IF) signal, comprising logarithmically transforming the available endogenous fluorescence (IF) signal and then fitting a linear function to the logarithmically transformed available endogenous fluorescence (IF) signal.

[0075] (Aspect 14) The method according to aspect 12, wherein the step of determining the glomerular filtration rate (GFR) value starts from the start time (t eq ) of single exponential curve fitting to the available intrinsic fluorescence (IF) signal.

[0076] (Aspect 15) The method according to aspect 12, wherein the step of determining the glomerular filtration rate (GFR) value is performed based on the rate of change of the available intrinsic fluorescence (IF) signal after the start of single exponential curve fitting to the available intrinsic fluorescence (IF) signal.

[0077] (Aspect 16) The method according to any one of aspects 1 to 15, wherein the step of providing the glomerular filtration rate (GFR) value comprises the step of displaying the glomerular filtration rate (GFR) value on a display screen.

[0078] (Aspect 17) The method according to any one of aspects 1 to 16, wherein the step of providing the glomerular filtration rate (GFR) value comprises the step of transmitting the glomerular filtration rate (GFR) value to a remote device.

[0079] (Aspect 18) The method according to any one of aspects 1 to 17, wherein the step of generating the intrinsic fluorescence (IF) signal comprises the step of directly generating the intrinsic fluorescence (IF) signal from the measurement dataset.

[0080] (Aspect 19) The method according to any one of aspects 1 to 18, wherein the filtering of the intrinsic fluorescence (IF) signal related to the early fluorescence data A method comprising excluding the portion of the early fluorescence data from the generation of the endogenous fluorescence (IF) signal.

[0081] (Aspect 20) A method according to any of embodiments 1 to 19, Each of the aforementioned measurement entries includes at least two measurements, One of the at least two measurements is a fluorescence emission (Flr) signal, and the other is a diffuse reflection signal detected by a filtered photodetector in a region adjacent to the diffuse reflection medium during irradiation of the diffuse reflection medium with excitation wavelength light. A method comprising the step of generating the intrinsic fluorescence (IF) signal, wherein the step of combining the at least two measurements according to a transformation relation that includes a mathematical equation for converting the fluorescence emission (Flr) signal to the intrinsic fluorescence (IF) signal.

[0082] (Aspect 21) A method according to any one of embodiments 1 to 20, Each of the plurality of measurement entries includes at least one measurement of the fluorescence emission (Flr) signal detected in the diffuse reflective medium by a filtered photodetector while the diffuse reflective medium is illuminated with excitation wavelength light, A method comprising the step of generating the intrinsic fluorescence (IF) signal, wherein the step of transforming the at least one measurement is performed according to a transformation relation which includes a mathematical equation that transforms the fluorescence emission (Flr) signal into the intrinsic fluorescence (IF) signal.

[0083] (Aspect 22) The method according to embodiment 21, A method wherein the excitation wavelength light includes the wavelength of the exogenous fluorescent agent.

[0084] (Aspect 23) A method for determining a patient's biological parameters using an exogenous fluorescent agent, The steps include obtaining a measurement dataset containing multiple measurement entries obtained before and after administration of an exogenous fluorescent agent, The steps include generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in the diffuse reflection medium, The steps include determining whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data, If it is determined that the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, the steps include determining the usable range of the endogenous fluorescence (IF) signal by filtering the endogenous fluorescence (IF) signal related to the early fluorescence data, The steps include determining the patient's biological parameter values ​​based on the rate of change of the available endogenous fluorescence (IF) signal, A method comprising the step of providing the aforementioned biological parameter values.

[0085] (Aspect 24) A method for determining a patient's glomerular filtration rate (GFR) using an exogenous fluorescent agent, The steps include obtaining a measurement dataset containing multiple measurement entries obtained before and after administration of an exogenous fluorescent agent, The steps include generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in the diffuse reflection medium, The steps include determining whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data, If it is determined that the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, the steps include determining the usable range of the endogenous fluorescence (IF) signal by filtering the endogenous fluorescence (IF) signal related to the early fluorescence data, The steps include determining the patient's glomerular filtration rate (GFR) value based on the rate of change of the available endogenous fluorescence (IF) signal, A method comprising the step of providing the glomerular filtration rate (GFR) value.

[0086] (Aspect 25) The method according to aspect 24, A method comprising the step of determining whether the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, wherein the step of determining the interval over which the endogenous fluorescence (IF) signal decreases.

[0087] (Aspect 26) The method according to aspect 25, The step of determining whether the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data is: Provisional GFR time (tGFR) prl ) The provisional GFR value (GFR) that results from this prl This includes the step of determining, A method for determining the provisional GFR value, comprising the step of calculating the renal decay time constant (RDTC) by performing an initial estimate of a single exponential curve fitting of the endogenous fluorescence (IF) signal over at least a continuous or overlapping portion of the endogenous fluorescence (IF) signal, based on a determination of the time at which the previous interval of the endogenous fluorescence (IF) signal of the provisional GFR time exceeded a property threshold.

[0088] (Aspect 27) A method of embodiment 26, The aforementioned provisional GFR time (tGFR) prl The starting point (t) is the point in time before the evaluation of the endogenous fluorescence (IF) signal, and represents the point in time within the interval in which it was determined that the endogenous fluorescence (IF) signal decreases. start ) and the step of determining The starting point (t start ) and the second constant (t) obtained by multiplying the first constant by Euler's number. toeq The steps include determining the starting point of the fitting interval for single-exponential curve fitting of the available endogenous fluorescence (IF) signal, which is the sum of the values ​​up to the exponent obtained by adding ) A method further comprising the step of setting the fitting interval as an interval for single exponential curve fitting of the usable endogenous fluorescence (IF) signal.

[0089] (Aspect 28) The method according to embodiment 27, the said start time point (t start ) is determined after the said provisional GFR value (GFR prl ) is determined at the said provisional GFR time (tGFR prl ), the said start time point (t start ) is the value obtained by subtracting, from the said provisional GFR time (tGFR prl ), the time (t low ) determined by linear interpolation between the low GFR boundary (GFR low ) associated with time t high and / or the high GFR boundary (GFR high ) associated with time t interpol using GFRprel, the method.

[0090] (Aspect 29) The method according to Aspect 26, further comprising the step of determining a start time point (t that represents a time point within the interval determined to have the usable intrinsic fluorescence (IF) signal decreasing and before single exponential curve fitting of the usable intrinsic fluorescence (IF) signal start ); and the step of setting the start time point (t for single exponential curve fitting of the usable intrinsic fluorescence (IF) signal eq ), t eq =t start +t toeq , t toeq =A×e -GFRprel / B +C, where A, B, and C are constants, the method.

[0091] (Aspect 30) The method according to Aspect 26, the said step of determining the interval in which the said intrinsic fluorescence (IF) signal decreases comprises the step of determining a predetermined fitting window; and the step of performing single exponential curve fitting of the said intrinsic fluorescence (IF) signal according to the following formula; IF fit =C0+C1*e-t / RDTC (In the above formula, IF fit (where represents the fitting to the IF portion, C0 and C1 represent the curve fitting constants, t represents time, and RDTC represents the time parameter.) The steps include: calculating the RDTC value in at least two intervals within the predetermined fitting window; A method comprising the step of comparing the RDTC values ​​obtained in at least two intervals until all of the RDTC values ​​correspond to positive values.

[0092] (Aspect 31) The method according to embodiment 30, The starting point (t) represents a point in time prior to the single exponential curve fitting of the available endogenous fluorescence (IF) signal, and within the interval in which the available endogenous fluorescence (IF) signal is determined to decrease. start ) and the step of determining The start time (t) for fitting a single exponential curve of the available endogenous fluorescence (IF) signal. eq ) and further include the step of setting, t eq =t start +t toeq And, t toeq =A × e -GFRprel / B It is +C, A, B, and C are constants, method.

[0093] (Aspect 32) The method according to embodiment 31, The starting point (t eq The setting of ) is IF fit A method in which single exponential curve fitting based on an equation is performed based on a determination of when a property threshold is exceeded.

[0094] (Aspect 33) The method according to embodiment 31, The starting point (t start ) is the provisional GFR time (tGFR prl) with the aforementioned provisional GFR value (GFR prl ) was decided after the decision was made, The starting point (t start ) is the provisional GFR time (tGFR prl ) Using GFRprel, time t low Low GFR boundary (GFR) related to low ) and / or time t high High GFR boundary (GFR) related to high Time (t) is determined by linear interpolation between ) interpol A method that subtracts ).

[0095] (Aspect 34) A method of embodiment 26, The method further comprises the step of performing reverse-looking component filtering, wherein the step of determining whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data.

[0096] (Aspect 35) A method according to any one of embodiments 24 to 34, The step of determining the glomerular filtration rate (GFR) is as follows: A method comprising the step of calculating a renal decay time constant (RDTC) by performing a single exponential curve fitting of the available endogenous fluorescence (IF) signals in portions in which the available endogenous fluorescence (IF) signals are at least continuous or overlapping.

[0097] (Aspect 36) The method according to aspect 35, A method for fitting a single exponential curve of the available endogenous fluorescence (IF) signal, comprising logarithmically transforming the available endogenous fluorescence (IF) signal and then fitting a linear function to the logarithmically transformed available endogenous fluorescence (IF) signal.

[0098] (Aspect 37) The method according to aspect 35, The step of determining the glomerular filtration rate (GFR) is as follows: The start time (t) of single exponential curve fitting for the available endogenous fluorescence (IF) signal. eq A method that starts from ).

[0099] (Aspect 38) The method according to aspect 35, The step of determining the glomerular filtration rate (GFR) is as follows: A method based on the rate of change of the available endogenous fluorescence (IF) signal after the start of single exponential curve fitting to the available endogenous fluorescence (IF) signal.

[0100] (Aspect 39) A method according to any of embodiments 24 to 38, The step of providing the glomerular filtration rate (GFR) value includes the step of displaying the glomerular filtration rate (GFR) value on a display screen.

[0101] (Approach 40) A method according to any of embodiments 24 to 39, A method comprising the step of providing the glomerular filtration rate (GFR) value, wherein the step of transmitting the glomerular filtration rate (GFR) value to a remote device.

[0102] (Aspect 41) A method according to any of embodiments 24 to 40, A method comprising the step of generating the endogenous fluorescence (IF) signal, wherein the step of directly generating the endogenous fluorescence (IF) signal from the measurement dataset.

[0103] (Aspect 42) A method according to any one of embodiments 24 to 41, The filtering of the endogenous fluorescence (IF) signal related to the early fluorescence data is performed as follows: A method comprising excluding the portion of the early fluorescence data from the generation of the endogenous fluorescence (IF) signal.

[0104] (Aspect 43) A method according to any of embodiments 24 to 42, Each of the aforementioned measurement entries includes at least two measurements, One of the at least two measurements is a fluorescence emission (Flr) signal, and the other is a diffuse reflection signal detected by a filtered photodetector in a region adjacent to the diffuse reflection medium during irradiation of the diffuse reflection medium with excitation wavelength light. A method comprising the step of generating the intrinsic fluorescence (IF) signal, wherein the step of combining the at least two measurements according to a transformation relation that includes a mathematical equation for converting the fluorescence emission (Flr) signal to the intrinsic fluorescence (IF) signal.

[0105] (Aspect 44) A method according to any of embodiments 24 to 43, Each of the plurality of measurement entries includes at least one measurement of the fluorescence emission (Flr) signal detected in the diffuse reflective medium by a filtered photodetector while the diffuse reflective medium is illuminated with excitation wavelength light, A method comprising the step of generating the intrinsic fluorescence (IF) signal, wherein the step of transforming the at least one measurement is performed according to a transformation relation which includes a mathematical equation that transforms the fluorescence emission (Flr) signal into the intrinsic fluorescence (IF) signal.

[0106] (Aspect 45) The method according to aspect 44, A method wherein the excitation wavelength light includes the wavelength of the exogenous fluorescent agent.

[0107] (Aspect 46) A method for determining a patient's biological parameters using an exogenous fluorescent agent, The steps include obtaining a measurement dataset containing multiple measurement entries obtained before and after administration of an exogenous fluorescent agent, The steps include generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in the diffuse reflection medium, The steps include determining whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data, If it is determined that the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, the steps include determining the usable range of the endogenous fluorescence (IF) signal by filtering the endogenous fluorescence (IF) signal related to the early fluorescence data, The steps include determining the patient's biological parameter values ​​based on the rate of change of the available endogenous fluorescence (IF) signal, A method comprising the step of providing the aforementioned biological parameter values.

[0108] (Aspect 47) A system for determining a patient's glomerular filtration rate (GFR) using an exogenous fluorescent agent, A storage device including at least one memory configured to store instructions, A processor configured to execute the aforementioned instructions, comprising: The aforementioned instruction is, The steps include obtaining a measurement dataset containing multiple measurement entries obtained before and after administration of an exogenous fluorescent agent, The steps include generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in the diffuse reflection medium, The steps include determining whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data, If it is determined that the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, the steps include determining the usable range of the endogenous fluorescence (IF) signal by filtering the endogenous fluorescence (IF) signal related to the early fluorescence data, The steps include determining the patient's glomerular filtration rate (GFR) value based on the rate of change of the available endogenous fluorescence (IF) signal, A system comprising the step of providing the glomerular filtration rate (GFR) value.

[0109] (Aspect 48) The system described in aspect 47, The system includes the step of determining whether the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, wherein the step of determining the interval over which the endogenous fluorescence (IF) signal decreases.

[0110] (Aspect 49) The system described in aspect 48, The step of determining whether the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data is: Provisional GFR time (tGFR) prl ) The provisional GFR value (GFR) that results from this prl This includes the step of determining, The system comprises the step of determining the provisional GFR value, which includes the step of calculating the renal decay time constant (RDTC) by performing an initial estimate of a single exponential curve fitting of the endogenous fluorescence (IF) signal over at least a continuous or overlapping portion of the endogenous fluorescence (IF) signal, based on a determination of the time at which the previous interval of the endogenous fluorescence (IF) signal of the provisional GFR time exceeded a property threshold.

[0111] (Appearance 50) The system described in aspect 49, The aforementioned provisional GFR time (tGFR) prl The starting point (t) is the point in time before the evaluation of the endogenous fluorescence (IF) signal, and represents the point in time within the interval in which it was determined that the endogenous fluorescence (IF) signal decreases. start ) and the step of determining The starting point (t start ) and the second constant (t) obtained by multiplying the first constant by Euler's number. toeq The steps include determining the starting point of the fitting interval for single-exponential curve fitting of the available endogenous fluorescence (IF) signal, which is the sum of the values ​​up to the exponent obtained by adding ) A system further comprising the step of setting the fitting interval as an interval for single exponential curve fitting of the usable endogenous fluorescence (IF) signal.

[0112] (Aspect 51) The system described in aspect 50, The starting point (t start ) is the provisional GFR time (tGFR prl ) with the aforementioned provisional GFR value (GFR prl ) was decided after the decision was made, The starting point (t start ) is the provisional GFR time (tGFR prl ) Using GFRprel, time t low Low GFR boundary (GFR) related to low ) and / or time t high High GFR boundary (GFR) related to high Time (t) is determined by linear interpolation between ) interpol A system that subtracts ).

[0113] (Appearance 52) The system described in aspect 49, The starting point (t) represents a point in time prior to the single exponential curve fitting of the available endogenous fluorescence (IF) signal, and within the interval in which the available endogenous fluorescence (IF) signal is determined to decrease. start ) and the step of determining The start time (t) for fitting a single exponential curve of the available endogenous fluorescence (IF) signal. eq ) and further include the step of setting, t eq =t start +t toeq And, t toeq =A × e -GFRprel / B It is +C, A, B, and C are constants in this system.

[0114] (Aspect 53) The system described in aspect 49, The step of determining the interval in which the endogenous fluorescence (IF) signal decreases is: The steps include determining a predetermined fitting window, The steps include: performing a single exponential curve fitting of the endogenous fluorescence (IF) signal according to the following formula; IF fit =C0+C1*e -t / RDTC (In the above formula, IF fit (where represents the fitting to the IF portion, C0 and C1 represent the curve fitting constants, t represents time, and RDTC represents the time parameter.) The steps include: calculating the RDTC value in at least two intervals within the predetermined fitting window; A system comprising the step of comparing the RDTC values ​​obtained in at least two intervals until all of the RDTC values ​​correspond to positive values.

[0115] (Aspect 54) The system described in embodiment 53, The starting point (t) represents a point in time prior to the single exponential curve fitting of the available endogenous fluorescence (IF) signal, and within the interval in which the available endogenous fluorescence (IF) signal is determined to decrease. start ) and the step of determining The start time (t) for fitting a single exponential curve of the available endogenous fluorescence (IF) signal. eq ) and further include the step of setting, t eq =t start +t toeq And, t toeq =A × e -GFRprel / B It is +C, A, B, and C are constants in this system.

[0116] (Aspect 55) The system described in aspect 54, The starting point (t eq The setting of ) is IF fit A system in which single exponential curve fitting based on equations is performed based on a determination of when a property threshold is exceeded.

[0117] (Aspect 56) The system described in aspect 54, The starting point (tstart ) is the provisional GFR time (tGFR prl ) with the aforementioned provisional GFR value (GFR prl ) was decided after the decision was made, The starting point (t start ) is the provisional GFR time (tGFR prl ) Using GFRprel, time t low Low GFR boundary (GFR) related to low ) and / or time t high High GFR boundary (GFR) related to high Time (t) is determined by linear interpolation between ) interpol A system that subtracts ).

[0118] (Aspect 57) The system described in aspect 59, The system further comprises the step of performing reverse-looking component filtering, which determines whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data.

[0119] (Pattern 58) A system described in any of aspects 47 to 57, The step of determining the glomerular filtration rate (GFR) is as follows: A system comprising the step of calculating the renal decay time constant (RDTC) by performing a single exponential curve fitting of the available endogenous fluorescence (IF) signals in portions in which the available endogenous fluorescence (IF) signals are at least continuous or overlapping.

[0120] (Aspect 59) The system described in aspect 58, A system for fitting a single exponential curve of the available endogenous fluorescence (IF) signal includes logarithmically transforming the available endogenous fluorescence (IF) signal and then fitting a linear function to the logarithmically transformed available endogenous fluorescence (IF) signal.

[0121] (Appendix 60) The system described in aspect 58, The step of determining the glomerular filtration rate (GFR) is as follows: The start time (t) of single exponential curve fitting for the available endogenous fluorescence (IF) signal. eq A system that starts from ).

[0122] (Aspect 61) The system described in aspect 58, The step of determining the glomerular filtration rate (GFR) is as follows: A system based on the rate of change of the available endogenous fluorescence (IF) signal after the start of single exponential curve fitting to the available endogenous fluorescence (IF) signal.

[0123] (Aspect 62) A system according to any one of embodiments 47 to 61, The system includes the step of providing the glomerular filtration rate (GFR) value, which includes the step of displaying the glomerular filtration rate (GFR) value on a display screen.

[0124] (Aspect 63) A system according to any of embodiments 47 to 62, The step of providing the glomerular filtration rate (GFR) value includes the step of transmitting the glomerular filtration rate (GFR) value to a remote device.

[0125] (Personal aspect 64) A system according to any of embodiments 47 to 63, The system comprises the step of generating the endogenous fluorescence (IF) signal, which includes the step of directly generating the endogenous fluorescence (IF) signal from the measurement dataset.

[0126] (Patent 65) A system according to any of embodiments 47 to 64, The filtering of the endogenous fluorescence (IF) signal related to the early fluorescence data is performed as follows: A system comprising excluding the portion of the early fluorescence data from the generation of the endogenous fluorescence (IF) signal.

[0127] (Aspect 66) A system according to any of the embodiments 47 to 65, Each of the aforementioned measurement entries includes at least two measurements, One of the at least two measurements is a fluorescence emission (Flr) signal, and the other is a diffuse reflection signal detected by a filtered photodetector in a region adjacent to the diffuse reflection medium during irradiation of the diffuse reflection medium with excitation wavelength light. The system comprises a step of combining the at least two measurements according to a transformation relation which includes a mathematical equation that converts the fluorescence emission (Flr) signal into the endogenous fluorescence (IF) signal.

[0128] (Patent 67) A system according to any of embodiments 47 to 66, Each of the plurality of measurement entries includes at least one measurement of the fluorescence emission (Flr) signal detected in the diffuse reflective medium by a filtered photodetector while the diffuse reflective medium is illuminated with excitation wavelength light, The system comprises the step of generating the intrinsic fluorescence (IF) signal, which includes the step of transforming the at least one measurement according to a transformation relation that includes a mathematical equation for transforming the fluorescence emission (Flr) signal into the intrinsic fluorescence (IF) signal.

[0129] (Pattern 68) The system described in aspect 67, The excitation wavelength light includes the wavelength of the exogenous fluorescent agent in the system.

[0130] (Patent 69) A system for determining a patient's biological parameters using exogenous fluorescent agents, A storage device including at least one memory configured to store instructions, A processor configured to execute the aforementioned instructions, comprising: The aforementioned instruction is, The steps include obtaining a measurement dataset containing multiple measurement entries obtained before and after administration of an exogenous fluorescent agent, The steps include generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in the diffuse reflection medium, The steps include determining whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data, If it is determined that the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, the steps include determining the usable range of the endogenous fluorescence (IF) signal by filtering the endogenous fluorescence (IF) signal related to the early fluorescence data, The steps include determining the patient's biological parameter values ​​based on the rate of change of the available endogenous fluorescence (IF) signal, A system comprising the step of providing the aforementioned biological parameter values.

Claims

1. A method for determining a patient's glomerular filtration rate (GFR) using an exogenous fluorescent agent, The steps include obtaining a measurement dataset containing multiple measurement entries obtained before and after administration of an exogenous fluorescent agent, The steps include generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in the diffuse reflection medium, The steps include determining whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data, If it is determined that the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, the steps include determining the usable range of the endogenous fluorescence (IF) signal by filtering the endogenous fluorescence (IF) signal related to the early fluorescence data, The steps include determining the patient's glomerular filtration rate (GFR) value based on the rate of change of the available endogenous fluorescence (IF) signal, A method comprising the step of providing the glomerular filtration rate (GFR) value.

2. The method according to claim 1, A method comprising the step of determining whether the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, wherein the step of determining the interval over which the endogenous fluorescence (IF) signal decreases.

3. The method according to claim 2, The step of determining whether the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data is: Provisional GFR time (tGFR) ｐｒｌ ) The provisional GFR value (GFR ｐｒｌ This includes the step of determining, A method comprising the step of determining the provisional GFR value, wherein the step of calculating the renal decay time constant (RDTC) is performed by making an initial estimate of a single exponential curve fitting of the endogenous fluorescence (IF) signal over at least a continuous or overlapping portion of the endogenous fluorescence (IF) signal, based on a determination of the time at which the previous interval of the endogenous fluorescence (IF) signal prior to the provisional GFR time exceeded a property threshold.

4. The method according to claim 3, The aforementioned provisional GFR time (tGFR ｐｒｌ The starting point (t) is the point in time before the evaluation of the endogenous fluorescence (IF) signal, and represents the point in time within the interval in which it was determined that the endogenous fluorescence (IF) signal decreases. ｓｔａｒｔ ) and The starting point (t ｓｔａｒｔ ) and the second constant (t) obtained by multiplying the first constant by Euler's number. ｔｏｅｑ The steps include determining the starting point of the fitting interval for single exponential curve fitting of the available endogenous fluorescence (IF) signal, which is the sum of the values ​​up to the exponent obtained by adding ) A method further comprising the step of setting the fitting interval as an interval for single exponential curve fitting of the usable endogenous fluorescence (IF) signal.

5. The method according to claim 4, the aforementioned start time point (t ｓｔａｒｔ ) is determined after the aforementioned provisional GFR time (tGFR ｐｒｌ ) is used to determine the aforementioned provisional GFR value (GFR ｐｒｌ ), The starting point (t ｓｔａｒｔ ) is the provisional GFR time (tGFR ｐｒｌ ) Using GFRprel, time t ｌｏｗ Low GFR boundary (GFR) related to ｌｏｗ ) and / or time t ｈｉｇｈ High GFR boundary (GFR) related to ｈｉｇｈ The time (t) is determined by linear interpolation between ) ｉｎｔｅｒｐｏｌ A method that subtracts ).

6. The method according to claim 3, The starting point (t) represents a point in time prior to the single exponential curve fitting of the available endogenous fluorescence (IF) signal, and within the interval in which the available endogenous fluorescence (IF) signal is determined to decrease. ｓｔａｒｔ ) and The start time (t) of fitting the single exponential curve of the available endogenous fluorescence (IF) signal. ｅｑ The steps include setting ) and further include, t ｅｑ = t ｓｔａｒｔ +t ｔｏｅｑ And, t ｔｏｅｑ = A × e －ＧＦＲｐｒｅｌ／Ｂ It is +C, A, B, and C are constants in this method.

7. The method according to claim 3, The step of determining the interval in which the endogenous fluorescence (IF) signal decreases is: The steps include determining a predetermined fitting window, The steps include: performing a single exponential curve fitting of the endogenous fluorescence (IF) signal according to the following formula; IF ｆｉｔ =C ０ +C １ *e －ｔ／ＲＤＴＣ (In the above formula, IF ｆｉｔ This represents the fitting to the IF part, C ０ and C １ (where represents the curve fitting constant, t represents time, and RDTC represents the time parameter) The steps include: calculating the RDTC value in at least two intervals within the predetermined fitting window; A method comprising the step of comparing the RDTC values ​​obtained in at least two intervals until all of the RDTC values ​​correspond to positive values.

8. The method according to claim 7, The starting point (t) represents a point in time prior to the single exponential curve fitting of the available endogenous fluorescence (IF) signal, and within the interval in which the available endogenous fluorescence (IF) signal is determined to decrease. ｓｔａｒｔ ) and The start time (t) of fitting the single exponential curve of the available endogenous fluorescence (IF) signal. ｅｑ The steps include setting ) and further include, t ｅｑ = t ｓｔａｒｔ +t ｔｏｅｑ And, t ｔｏｅｑ = A × e －ＧＦＲｐｒｅｌ／Ｂ It is +C, A, B, and C are constants in this method.

9. The method according to claim 8, The starting point (t ｅｑ The setting for ) is IF ｆｉｔ A method in which single exponential curve fitting based on an equation is performed based on a determination of when a property threshold is exceeded.

10. The method according to claim 8, The starting point (t ｓｔａｒｔ ) is the provisional GFR time (tGFR ｐｒｌ ) with the provisional GFR value (GFR ｐｒｌ ) was decided after the decision was made, The starting point (t ｓｔａｒｔ ) is the provisional GFR time (tGFR ｐｒｌ ) Using GFRprel, time t ｌｏｗ Low GFR boundary (GFR) related to ｌｏｗ ) and / or time t ｈｉｇｈ High GFR boundary (GFR) related to ｈｉｇｈ The time (t) is determined by linear interpolation between ) ｉｎｔｅｒｐｏｌ A method that subtracts ).

11. The method according to claim 3, The method further comprises the step of performing reverse-looking component filtering, wherein the step of determining whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data.

12. The method according to claim 1, The step of determining the glomerular filtration rate (GFR) value is: A method comprising the step of calculating the renal decay time constant (RDTC) by performing a single exponential curve fitting of the available endogenous fluorescence (IF) signals in portions in which the available endogenous fluorescence (IF) signals are continuous or overlapping.

13. The method according to claim 12, A method for fitting a single exponential curve of the available endogenous fluorescence (IF) signal, comprising logarithmically transforming the available endogenous fluorescence (IF) signal and then fitting a linear function to the logarithmically transformed available endogenous fluorescence (IF) signal.

14. The method according to claim 12, The step of determining the glomerular filtration rate (GFR) value is: The start time (t) of fitting a single exponential curve to the available endogenous fluorescence (IF) signal. ｅｑ A method that starts from ).

15. The method according to claim 12, The step of determining the glomerular filtration rate (GFR) value is: A method based on the rate of change of the available endogenous fluorescence (IF) signal after the start of single exponential curve fitting to the available endogenous fluorescence (IF) signal.

16. The method according to claim 1, The step of providing the glomerular filtration rate (GFR) value includes the step of displaying the glomerular filtration rate (GFR) value on a display screen.

17. The method according to claim 1, The step of providing the glomerular filtration rate (GFR) value includes the step of transmitting the glomerular filtration rate (GFR) value to a remote device.

18. The method according to claim 1, A method comprising the step of generating the endogenous fluorescence (IF) signal, the step of directly generating the endogenous fluorescence (IF) signal from the measurement dataset.

19. The method according to claim 1, The filtering of the endogenous fluorescence (IF) signal related to the early fluorescence data is performed as follows: A method comprising excluding the portion of the early fluorescence data from the generation of the endogenous fluorescence (IF) signal.

20. The method according to claim 1, Each of the aforementioned multiple measurement entries includes at least two measurement values, One of the at least two measurements is a fluorescence emission (Flr) signal, and the other is a diffuse reflection signal detected by a filtered photodetector in a region adjacent to the diffuse reflection medium during irradiation of the diffuse reflection medium with excitation wavelength light. A method comprising the step of generating the endogenous fluorescence (IF) signal, wherein the step of combining the at least two measurements according to a transformation relation that includes a mathematical equation for converting the fluorescence emission (Flr) signal to the endogenous fluorescence (IF) signal.

21. The method according to claim 1, Each of the plurality of measurement entries includes at least one measurement of the fluorescence emission (Flr) signal detected in the diffuse reflective medium by a filtered photodetector while the diffuse reflective medium is illuminated with excitation wavelength light, A method comprising the step of generating the endogenous fluorescence (IF) signal, wherein the step of transforming the at least one measurement is performed according to a transformation relation which includes a mathematical equation that transforms the fluorescence emission (Flr) signal into the endogenous fluorescence (IF) signal.

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

23. A method for determining a patient's biological parameters using an exogenous fluorescent agent, The steps include obtaining a measurement dataset containing multiple measurement entries obtained before and after administration of an exogenous fluorescent agent, The steps include generating an endogenous fluorescence (IF) signal representing the detected fluorescence intensity emitted from the exogenous fluorescent agent in the diffuse reflection medium, The steps include determining whether the endogenous fluorescence (IF) signal includes a portion of the early fluorescence data, If it is determined that the endogenous fluorescence (IF) signal includes the portion of the early fluorescence data, the steps include determining the usable range of the endogenous fluorescence (IF) signal by filtering the endogenous fluorescence (IF) signal related to the early fluorescence data, The steps include determining the patient's biological parameter values ​​based on the rate of change of the available endogenous fluorescence (IF) signal, A method comprising the step of providing the aforementioned biological parameter values.

Images